Original Research

Atrial fibrillation (AF) is the most common chronic cardiac rhythm disturbance and increases an individual’s risk of stroke 5-fold.¹ Anticoagulation therapy reduces the risk of stroke by > 60% in patients with AF.² The risk of AF increases with age, yet the perceived risk of fall in elderly patients taking warfarin reduces the use of this therapy.³

A single-institution study in 2000 revealed that 49% of veterans with AF were not receiving anticoagulation therapy. In 13% of cases, warfarin was withheld due to the perceived fall risk.⁴ Some studies of anticoagulation therapy for AF, in keeping with recommendations of the Medicare Health Care Quality Improvement Program National Stroke Project, have excluded patients who are deemed at high risk for falls.⁵ Although fall risk is being used in both research and clinical settings to determine the safety of prescribing warfarin for AF, how to determine such a patient’s fall risk has not been defined.

Although several rules for predicting falls in community dwellers have been published, none are routinely assessed during a patient’s hospital stay.⁶ Research shows the Morse Fall Scale (MFS) is a widely used, validated tool for assessing fall risk among hospitalized patients and indicates VA patients to be at high risk for falls.^7,8 All patients hospitalized at the John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas, receive a MFS score at admission. If the MFS score is predictive of the postdischarge risk of a veteran with AF falling, the score would assist in determining which patients can be safely discharged while taking anticoagulation therapy.

The present study is a retrospective chart review of all patients with AF discharged from the JLMMVH during 2006 and their subsequent risk of falls requiring acute medical care. Based on CDC data indicating the risk for nonfatal falls by persons aged > 65 years to be more than twice that of younger persons and the established fall risk ranges of the MFS, it was hypothesized that AF patients aged ≥ 65 years with a modified MFS score (MMS) ≥ 55 would be at a significantly greater risk of fall requiring acute medical care following hospital discharge than would those of the same age with lower scores.

Methods

This study was approved by the JLMMVH Institutional Review Board. The electronic medical records (EMRs) of all veterans with a diagnosis of AF discharged from the JLMMVH during 2006 were manually reviewed for study inclusion. The year 2006 was chosen in order to ensure adequate subject follow-up time.

Inclusion criteria consisted of discharge from an acute care unit and the patient’s most recent electrocardiogram (ECG) prior to the index discharge, showing AF or atrial flutter; or the most recent ECG prior to the index discharge, showing a fully paced rhythm consistent with an underlying rhythm of AF and documentation of previously diagnosed chronic AF for which a permanent pacemaker was placed.

Exclusion criteria consisted of discharge due to patient death; transient (persisting < 24 hours) AF associated with an acute medical illness or surgical procedure; index hospitalization representing transfer temporarily from another VAMC for the sole purpose of performing a procedure; hospitalization lasting < 24 hours (not coded as a hospital admission); mechanical heart valve; index admission for a neurosurgical procedure, hemorrhagic stroke, or bleeding esophageal/gastric varices; anticoagulation therapy recommended by the physician at the time of discharge but declined by the patient; incomplete or missing MFS score in the EMR; and lack of follow-up after the index discharge. Temporary transfers from outside facilities were excluded, due to anticipated difficulty in performing follow-up. Individuals for whom anticoagulation therapy was either inappropriate (eg, bleeding varices) or absolutely required (eg, mechanical heart valve) also were excluded.

Data Collection

Each EMR was reviewed, and the following data were abstracted: (1) patient age; (2) date of first hospital discharge during 2006; (3) final MFS score and subscores recorded during the index hospitalization; (4) date of the first fall requiring acute medical evaluation; (5) severe bleeding associated with the fall; (6) date of the subject’s death; and (7) date of the last recorded follow-up. The occurrence of a postdischarge fall and of fall-associated severe bleeding was determined by review of all hospitalizations, clinic visits, emergency department (ED) visits, outside records scanned into the EMR, and visiting nurse reports. The MFS score was converted to a MMS by subtracting points given for the presence of an IV line during the hospitalization, as such a fall risk would end at discharge.

Endpoints

The primary endpoint for the study was the occurrence of a fall following hospital discharge, resulting in evaluation of the subject in an outpatient clinic or ED within 24 hours. The primary comparison was between subjects aged ≥ 65 years with a MMS ≥ 55 and subjects aged ≥ 65 years with a MMS < 55.

A secondary endpoint was the occurrence of severe bleeding associated with a fall. Severe bleeding was defined as fatal bleeding; and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome; and/or bleeding causing a fall in hemoglobin level of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of whole blood or red blood cells.⁹

Statistical Analysis

An estimated analyzable sample size (df = 1, α = 0.05, and a critical value for χ2 of 3.841) of 180 subjects was based on CDC age-related fall rates, MFS-related fall rates, and published sensitivity and specificity values of the MFS.^7,10,11 An estimated exclusion rate of 25% to 30% based on published rates of AF-related hospital mortality; transient (persisting < 24 hours) AF; patients with AF declining recommended anticoagulation therapy; and hospital admissions lasting < 24 hours (coded as observations) yielded a total estimated study sample size of 240 to 257 subjects.

Life-table analysis (time until fall) was performed using the LIFETEST procedure (SAS Institute Inc.; Cary, NC). Subject death and end of follow-up in EMRs were treated as censored events. Comparison of survival curves was accomplished using the log-rank statistic. To generate a user-friendly predictive rule, intervals of 5-year age cutoff values (eg, aged 55, aged 60, aged 65 years) were used for survival comparisons. The MMS is calculated in multiples of 5, hence, all possible score cutoffs were considered in survival comparisons. The 2-sample t test was performed for comparison of mean age and MMS between groups and reported as mean ± SD. A P value < .05 was considered statistically significant. Statistical analysis was performed using SAS Enterprise Guide 5.1.

Results

A search of JCMMVH EMRs yielded 270 patients with a diagnosis of AF discharged from the hospital during 2006. Seventy-seven patients were excluded from analysis for the following reasons: dead at time of discharge, 28; transient (persisting < 24 hours) AF associated with an acute medical illness, 12; referred solely for a procedure, 19; mechanical heart valve, 2; patient declined to take anticoagulation therapy, 2; hemorrhagic stroke, 1; bleeding esophageal varices, 1; lacking MFS documentation, 10; and no postdischarge follow-up documented, 2. All subjects except 1 were male. Both the age and MMS of subjects represented non-normal distributions (Anderson-Darling statistic 1.8, P < .001; and 6.7, P < .005). The median subject age was 74 years; the median MMS was 25.

During the approximately 7-year follow-up period (follow-up range 2-2,545 days), 59 of the 193 subjects (31%) fell. No fall resulted in severe bleeding or death. The mean age of subjects who fell was 73.0 ± 10.3 years compared with 71.6 ± 10.5 years for nonfallers (P = .40). Likewise, the mean MMS for subjects who fell was 34.1 ± 22.3 compared with 30.3 ± 19.9 for nonfallers (P = .24). The mean time until first fall (mean survival) was 725 ± 642 days; whereas the mean length of follow-up for people who did not fall (including those censored due to death) was 1,050 ± 869 days. Subject age and MMS were positively correlated, though weakly (Pearson r = 0.36; Spearman r = 0.37).

Grouping subjects by MMS alone yielded significantly divergent survival curves only for cutoffs of MMS ≥ 40, ≥ 50, ≥ 55 (log-rank statistic P = .0061, P = .0002, and P < .0001, respectively). Figure 1 (red) shows the difference in survival for MMS ≥ 55 vs MMS < 55, where the mean time to fall was 701 ± 88 days for those with a MMS ≥ 55 compared with 1,628 ± 65 days for MMS < 55.

When age cutoff alone (using 5-year age intervals) was used to construct fall survival curves, only breakpoints of age ≥ 60, ≥ 75, and ≥ 80 years yielded significantly divergent curves (log-rank statistic P = .0215, P = .0264, and P = .011, respectively). Figure 1 (green) shows the difference in survival for subjects aged < 60 years vs aged ≥ 60 years.

The hypothesized combined cutoff of subjects aged ≥ 65 years and MMS ≥ 55 yielded divergent survival curves (log-rank statistic of P = .0011). However, survival curves based on a cutoff of subjects aged ≥ 60 years and ≥ 55 MMS yielded the most statistically significant separation (logrank statistic P < .0001) (Figure 2). Subjects aged < 60 years or with a MMS < 55 had a mean survival of 1,634 ± 65 days; whereas those aged ≥ 60 years and a MMS ≥ 55 had a mean survival of 668 ± 90 days.

A notable similarity of the survival curves for MMS ≥ 55 vs MMS < 55 compared with those based on a cutoff of subjects aged ≥ 60 years and ≥ 55 MMS is observed in comparing Figures 1 (red) and 2. The log-rank statistic chi-square values are 17.44 and 22.75, respectively, suggesting the separation of subjects by a combination of age and MMS yields a more robust divergence in outcomes than does separation by MMS alone.

Discussion

This retrospective chart review evaluated the utility of a MMS combined with age in predicting the risk of patients with AF experiencing serious falls following hospital discharge. When used alone, the MMS separates those at relatively low and high risk of subsequent falls requiring acute medical care. When combined with the factor of patient age, this separation improves and is most predictive for the group of AF patients aged ≥ 60 years with a MMS of ≥ 55. Half of this group had fallen 668 ± 90 days after discharge; whereas those aged < 60 years or with a MMS < 55 did not reach the point of 50% falling until 1,634 ± 65 days after discharge. Age alone allows a statistically significant differentiation of fall risk, but less so than does the MMS alone or the MMS combined with age.

Assessing fall risk can be as simple as asking whether a patient has fallen during the previous year or has a problem with balance or gait, or it can be as complex as an in-depth investigation of physical, cognitive, pharmacologic, environmental, and social factors.^12,13 Beyond the parameters of validity and discrimination power, a predictive tool must be easy to use. Within the VA hospital system, where the MFS is a part of every nursing intake assessment, a MMS can be obtained within seconds from the EMR. This, coupled with the patient’s age, allows the provider to immediately identify those patients with AF who are at high risk for serious falls following hospital discharge.

Strengths and Limitations

A major strength of the present study is the fact that the data accuracy was ensured by individual review of each subject’s EMR. Administrative coding was used only for the initial identification of potential subjects for inclusion. Although 28.5% of potential subjects were excluded from this analysis, > 50% of such exclusions were due to death as the reason for discharge and transient AF associated with an acute medical stressor. Other strengths include the length of follow-up (1,050 ± 869 days, excluding subject deaths) and the generalizability of the subject population. The major weakness of this study is the relatively small sample size and its retrospective methodology.

Summary

The validity of the MFS modified for the postdischarge setting was demonstrated as a readily available tool for identifying patients with AF at high risk of falls following a hospital stay. Such a tool should allow physicians to appropriately prescribe anticoagulation therapy for those patients with AF who are at a lower risk of falls.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Atrial fibrillation (AF) is the most common chronic cardiac rhythm disturbance and increases an individual’s risk of stroke 5-fold.¹ Anticoagulation therapy reduces the risk of stroke by > 60% in patients with AF.² The risk of AF increases with age, yet the perceived risk of fall in elderly patients taking warfarin reduces the use of this therapy.³

A single-institution study in 2000 revealed that 49% of veterans with AF were not receiving anticoagulation therapy. In 13% of cases, warfarin was withheld due to the perceived fall risk.⁴ Some studies of anticoagulation therapy for AF, in keeping with recommendations of the Medicare Health Care Quality Improvement Program National Stroke Project, have excluded patients who are deemed at high risk for falls.⁵ Although fall risk is being used in both research and clinical settings to determine the safety of prescribing warfarin for AF, how to determine such a patient’s fall risk has not been defined.

Although several rules for predicting falls in community dwellers have been published, none are routinely assessed during a patient’s hospital stay.⁶ Research shows the Morse Fall Scale (MFS) is a widely used, validated tool for assessing fall risk among hospitalized patients and indicates VA patients to be at high risk for falls.^7,8 All patients hospitalized at the John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas, receive a MFS score at admission. If the MFS score is predictive of the postdischarge risk of a veteran with AF falling, the score would assist in determining which patients can be safely discharged while taking anticoagulation therapy.

The present study is a retrospective chart review of all patients with AF discharged from the JLMMVH during 2006 and their subsequent risk of falls requiring acute medical care. Based on CDC data indicating the risk for nonfatal falls by persons aged > 65 years to be more than twice that of younger persons and the established fall risk ranges of the MFS, it was hypothesized that AF patients aged ≥ 65 years with a modified MFS score (MMS) ≥ 55 would be at a significantly greater risk of fall requiring acute medical care following hospital discharge than would those of the same age with lower scores.

Methods

This study was approved by the JLMMVH Institutional Review Board. The electronic medical records (EMRs) of all veterans with a diagnosis of AF discharged from the JLMMVH during 2006 were manually reviewed for study inclusion. The year 2006 was chosen in order to ensure adequate subject follow-up time.

Inclusion criteria consisted of discharge from an acute care unit and the patient’s most recent electrocardiogram (ECG) prior to the index discharge, showing AF or atrial flutter; or the most recent ECG prior to the index discharge, showing a fully paced rhythm consistent with an underlying rhythm of AF and documentation of previously diagnosed chronic AF for which a permanent pacemaker was placed.

Exclusion criteria consisted of discharge due to patient death; transient (persisting < 24 hours) AF associated with an acute medical illness or surgical procedure; index hospitalization representing transfer temporarily from another VAMC for the sole purpose of performing a procedure; hospitalization lasting < 24 hours (not coded as a hospital admission); mechanical heart valve; index admission for a neurosurgical procedure, hemorrhagic stroke, or bleeding esophageal/gastric varices; anticoagulation therapy recommended by the physician at the time of discharge but declined by the patient; incomplete or missing MFS score in the EMR; and lack of follow-up after the index discharge. Temporary transfers from outside facilities were excluded, due to anticipated difficulty in performing follow-up. Individuals for whom anticoagulation therapy was either inappropriate (eg, bleeding varices) or absolutely required (eg, mechanical heart valve) also were excluded.

Data Collection

Each EMR was reviewed, and the following data were abstracted: (1) patient age; (2) date of first hospital discharge during 2006; (3) final MFS score and subscores recorded during the index hospitalization; (4) date of the first fall requiring acute medical evaluation; (5) severe bleeding associated with the fall; (6) date of the subject’s death; and (7) date of the last recorded follow-up. The occurrence of a postdischarge fall and of fall-associated severe bleeding was determined by review of all hospitalizations, clinic visits, emergency department (ED) visits, outside records scanned into the EMR, and visiting nurse reports. The MFS score was converted to a MMS by subtracting points given for the presence of an IV line during the hospitalization, as such a fall risk would end at discharge.

Endpoints

The primary endpoint for the study was the occurrence of a fall following hospital discharge, resulting in evaluation of the subject in an outpatient clinic or ED within 24 hours. The primary comparison was between subjects aged ≥ 65 years with a MMS ≥ 55 and subjects aged ≥ 65 years with a MMS < 55.

A secondary endpoint was the occurrence of severe bleeding associated with a fall. Severe bleeding was defined as fatal bleeding; and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome; and/or bleeding causing a fall in hemoglobin level of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of whole blood or red blood cells.⁹

Statistical Analysis

An estimated analyzable sample size (df = 1, α = 0.05, and a critical value for χ2 of 3.841) of 180 subjects was based on CDC age-related fall rates, MFS-related fall rates, and published sensitivity and specificity values of the MFS.^7,10,11 An estimated exclusion rate of 25% to 30% based on published rates of AF-related hospital mortality; transient (persisting < 24 hours) AF; patients with AF declining recommended anticoagulation therapy; and hospital admissions lasting < 24 hours (coded as observations) yielded a total estimated study sample size of 240 to 257 subjects.

Life-table analysis (time until fall) was performed using the LIFETEST procedure (SAS Institute Inc.; Cary, NC). Subject death and end of follow-up in EMRs were treated as censored events. Comparison of survival curves was accomplished using the log-rank statistic. To generate a user-friendly predictive rule, intervals of 5-year age cutoff values (eg, aged 55, aged 60, aged 65 years) were used for survival comparisons. The MMS is calculated in multiples of 5, hence, all possible score cutoffs were considered in survival comparisons. The 2-sample t test was performed for comparison of mean age and MMS between groups and reported as mean ± SD. A P value < .05 was considered statistically significant. Statistical analysis was performed using SAS Enterprise Guide 5.1.

Results

A search of JCMMVH EMRs yielded 270 patients with a diagnosis of AF discharged from the hospital during 2006. Seventy-seven patients were excluded from analysis for the following reasons: dead at time of discharge, 28; transient (persisting < 24 hours) AF associated with an acute medical illness, 12; referred solely for a procedure, 19; mechanical heart valve, 2; patient declined to take anticoagulation therapy, 2; hemorrhagic stroke, 1; bleeding esophageal varices, 1; lacking MFS documentation, 10; and no postdischarge follow-up documented, 2. All subjects except 1 were male. Both the age and MMS of subjects represented non-normal distributions (Anderson-Darling statistic 1.8, P < .001; and 6.7, P < .005). The median subject age was 74 years; the median MMS was 25.

During the approximately 7-year follow-up period (follow-up range 2-2,545 days), 59 of the 193 subjects (31%) fell. No fall resulted in severe bleeding or death. The mean age of subjects who fell was 73.0 ± 10.3 years compared with 71.6 ± 10.5 years for nonfallers (P = .40). Likewise, the mean MMS for subjects who fell was 34.1 ± 22.3 compared with 30.3 ± 19.9 for nonfallers (P = .24). The mean time until first fall (mean survival) was 725 ± 642 days; whereas the mean length of follow-up for people who did not fall (including those censored due to death) was 1,050 ± 869 days. Subject age and MMS were positively correlated, though weakly (Pearson r = 0.36; Spearman r = 0.37).

Grouping subjects by MMS alone yielded significantly divergent survival curves only for cutoffs of MMS ≥ 40, ≥ 50, ≥ 55 (log-rank statistic P = .0061, P = .0002, and P < .0001, respectively). Figure 1 (red) shows the difference in survival for MMS ≥ 55 vs MMS < 55, where the mean time to fall was 701 ± 88 days for those with a MMS ≥ 55 compared with 1,628 ± 65 days for MMS < 55.

When age cutoff alone (using 5-year age intervals) was used to construct fall survival curves, only breakpoints of age ≥ 60, ≥ 75, and ≥ 80 years yielded significantly divergent curves (log-rank statistic P = .0215, P = .0264, and P = .011, respectively). Figure 1 (green) shows the difference in survival for subjects aged < 60 years vs aged ≥ 60 years.

The hypothesized combined cutoff of subjects aged ≥ 65 years and MMS ≥ 55 yielded divergent survival curves (log-rank statistic of P = .0011). However, survival curves based on a cutoff of subjects aged ≥ 60 years and ≥ 55 MMS yielded the most statistically significant separation (logrank statistic P < .0001) (Figure 2). Subjects aged < 60 years or with a MMS < 55 had a mean survival of 1,634 ± 65 days; whereas those aged ≥ 60 years and a MMS ≥ 55 had a mean survival of 668 ± 90 days.

A notable similarity of the survival curves for MMS ≥ 55 vs MMS < 55 compared with those based on a cutoff of subjects aged ≥ 60 years and ≥ 55 MMS is observed in comparing Figures 1 (red) and 2. The log-rank statistic chi-square values are 17.44 and 22.75, respectively, suggesting the separation of subjects by a combination of age and MMS yields a more robust divergence in outcomes than does separation by MMS alone.

Discussion

This retrospective chart review evaluated the utility of a MMS combined with age in predicting the risk of patients with AF experiencing serious falls following hospital discharge. When used alone, the MMS separates those at relatively low and high risk of subsequent falls requiring acute medical care. When combined with the factor of patient age, this separation improves and is most predictive for the group of AF patients aged ≥ 60 years with a MMS of ≥ 55. Half of this group had fallen 668 ± 90 days after discharge; whereas those aged < 60 years or with a MMS < 55 did not reach the point of 50% falling until 1,634 ± 65 days after discharge. Age alone allows a statistically significant differentiation of fall risk, but less so than does the MMS alone or the MMS combined with age.

Assessing fall risk can be as simple as asking whether a patient has fallen during the previous year or has a problem with balance or gait, or it can be as complex as an in-depth investigation of physical, cognitive, pharmacologic, environmental, and social factors.^12,13 Beyond the parameters of validity and discrimination power, a predictive tool must be easy to use. Within the VA hospital system, where the MFS is a part of every nursing intake assessment, a MMS can be obtained within seconds from the EMR. This, coupled with the patient’s age, allows the provider to immediately identify those patients with AF who are at high risk for serious falls following hospital discharge.

Strengths and Limitations

A major strength of the present study is the fact that the data accuracy was ensured by individual review of each subject’s EMR. Administrative coding was used only for the initial identification of potential subjects for inclusion. Although 28.5% of potential subjects were excluded from this analysis, > 50% of such exclusions were due to death as the reason for discharge and transient AF associated with an acute medical stressor. Other strengths include the length of follow-up (1,050 ± 869 days, excluding subject deaths) and the generalizability of the subject population. The major weakness of this study is the relatively small sample size and its retrospective methodology.

Summary

The validity of the MFS modified for the postdischarge setting was demonstrated as a readily available tool for identifying patients with AF at high risk of falls following a hospital stay. Such a tool should allow physicians to appropriately prescribe anticoagulation therapy for those patients with AF who are at a lower risk of falls.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Atrial fibrillation (AF) is the most common chronic cardiac rhythm disturbance and increases an individual’s risk of stroke 5-fold.¹ Anticoagulation therapy reduces the risk of stroke by > 60% in patients with AF.² The risk of AF increases with age, yet the perceived risk of fall in elderly patients taking warfarin reduces the use of this therapy.³

A single-institution study in 2000 revealed that 49% of veterans with AF were not receiving anticoagulation therapy. In 13% of cases, warfarin was withheld due to the perceived fall risk.⁴ Some studies of anticoagulation therapy for AF, in keeping with recommendations of the Medicare Health Care Quality Improvement Program National Stroke Project, have excluded patients who are deemed at high risk for falls.⁵ Although fall risk is being used in both research and clinical settings to determine the safety of prescribing warfarin for AF, how to determine such a patient’s fall risk has not been defined.

Although several rules for predicting falls in community dwellers have been published, none are routinely assessed during a patient’s hospital stay.⁶ Research shows the Morse Fall Scale (MFS) is a widely used, validated tool for assessing fall risk among hospitalized patients and indicates VA patients to be at high risk for falls.^7,8 All patients hospitalized at the John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas, receive a MFS score at admission. If the MFS score is predictive of the postdischarge risk of a veteran with AF falling, the score would assist in determining which patients can be safely discharged while taking anticoagulation therapy.

The present study is a retrospective chart review of all patients with AF discharged from the JLMMVH during 2006 and their subsequent risk of falls requiring acute medical care. Based on CDC data indicating the risk for nonfatal falls by persons aged > 65 years to be more than twice that of younger persons and the established fall risk ranges of the MFS, it was hypothesized that AF patients aged ≥ 65 years with a modified MFS score (MMS) ≥ 55 would be at a significantly greater risk of fall requiring acute medical care following hospital discharge than would those of the same age with lower scores.

Methods

This study was approved by the JLMMVH Institutional Review Board. The electronic medical records (EMRs) of all veterans with a diagnosis of AF discharged from the JLMMVH during 2006 were manually reviewed for study inclusion. The year 2006 was chosen in order to ensure adequate subject follow-up time.

Inclusion criteria consisted of discharge from an acute care unit and the patient’s most recent electrocardiogram (ECG) prior to the index discharge, showing AF or atrial flutter; or the most recent ECG prior to the index discharge, showing a fully paced rhythm consistent with an underlying rhythm of AF and documentation of previously diagnosed chronic AF for which a permanent pacemaker was placed.

Exclusion criteria consisted of discharge due to patient death; transient (persisting < 24 hours) AF associated with an acute medical illness or surgical procedure; index hospitalization representing transfer temporarily from another VAMC for the sole purpose of performing a procedure; hospitalization lasting < 24 hours (not coded as a hospital admission); mechanical heart valve; index admission for a neurosurgical procedure, hemorrhagic stroke, or bleeding esophageal/gastric varices; anticoagulation therapy recommended by the physician at the time of discharge but declined by the patient; incomplete or missing MFS score in the EMR; and lack of follow-up after the index discharge. Temporary transfers from outside facilities were excluded, due to anticipated difficulty in performing follow-up. Individuals for whom anticoagulation therapy was either inappropriate (eg, bleeding varices) or absolutely required (eg, mechanical heart valve) also were excluded.

Data Collection

Each EMR was reviewed, and the following data were abstracted: (1) patient age; (2) date of first hospital discharge during 2006; (3) final MFS score and subscores recorded during the index hospitalization; (4) date of the first fall requiring acute medical evaluation; (5) severe bleeding associated with the fall; (6) date of the subject’s death; and (7) date of the last recorded follow-up. The occurrence of a postdischarge fall and of fall-associated severe bleeding was determined by review of all hospitalizations, clinic visits, emergency department (ED) visits, outside records scanned into the EMR, and visiting nurse reports. The MFS score was converted to a MMS by subtracting points given for the presence of an IV line during the hospitalization, as such a fall risk would end at discharge.

Endpoints

The primary endpoint for the study was the occurrence of a fall following hospital discharge, resulting in evaluation of the subject in an outpatient clinic or ED within 24 hours. The primary comparison was between subjects aged ≥ 65 years with a MMS ≥ 55 and subjects aged ≥ 65 years with a MMS < 55.

A secondary endpoint was the occurrence of severe bleeding associated with a fall. Severe bleeding was defined as fatal bleeding; and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome; and/or bleeding causing a fall in hemoglobin level of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of whole blood or red blood cells.⁹

Statistical Analysis

An estimated analyzable sample size (df = 1, α = 0.05, and a critical value for χ2 of 3.841) of 180 subjects was based on CDC age-related fall rates, MFS-related fall rates, and published sensitivity and specificity values of the MFS.^7,10,11 An estimated exclusion rate of 25% to 30% based on published rates of AF-related hospital mortality; transient (persisting < 24 hours) AF; patients with AF declining recommended anticoagulation therapy; and hospital admissions lasting < 24 hours (coded as observations) yielded a total estimated study sample size of 240 to 257 subjects.

Life-table analysis (time until fall) was performed using the LIFETEST procedure (SAS Institute Inc.; Cary, NC). Subject death and end of follow-up in EMRs were treated as censored events. Comparison of survival curves was accomplished using the log-rank statistic. To generate a user-friendly predictive rule, intervals of 5-year age cutoff values (eg, aged 55, aged 60, aged 65 years) were used for survival comparisons. The MMS is calculated in multiples of 5, hence, all possible score cutoffs were considered in survival comparisons. The 2-sample t test was performed for comparison of mean age and MMS between groups and reported as mean ± SD. A P value < .05 was considered statistically significant. Statistical analysis was performed using SAS Enterprise Guide 5.1.

Results

A search of JCMMVH EMRs yielded 270 patients with a diagnosis of AF discharged from the hospital during 2006. Seventy-seven patients were excluded from analysis for the following reasons: dead at time of discharge, 28; transient (persisting < 24 hours) AF associated with an acute medical illness, 12; referred solely for a procedure, 19; mechanical heart valve, 2; patient declined to take anticoagulation therapy, 2; hemorrhagic stroke, 1; bleeding esophageal varices, 1; lacking MFS documentation, 10; and no postdischarge follow-up documented, 2. All subjects except 1 were male. Both the age and MMS of subjects represented non-normal distributions (Anderson-Darling statistic 1.8, P < .001; and 6.7, P < .005). The median subject age was 74 years; the median MMS was 25.

During the approximately 7-year follow-up period (follow-up range 2-2,545 days), 59 of the 193 subjects (31%) fell. No fall resulted in severe bleeding or death. The mean age of subjects who fell was 73.0 ± 10.3 years compared with 71.6 ± 10.5 years for nonfallers (P = .40). Likewise, the mean MMS for subjects who fell was 34.1 ± 22.3 compared with 30.3 ± 19.9 for nonfallers (P = .24). The mean time until first fall (mean survival) was 725 ± 642 days; whereas the mean length of follow-up for people who did not fall (including those censored due to death) was 1,050 ± 869 days. Subject age and MMS were positively correlated, though weakly (Pearson r = 0.36; Spearman r = 0.37).

Grouping subjects by MMS alone yielded significantly divergent survival curves only for cutoffs of MMS ≥ 40, ≥ 50, ≥ 55 (log-rank statistic P = .0061, P = .0002, and P < .0001, respectively). Figure 1 (red) shows the difference in survival for MMS ≥ 55 vs MMS < 55, where the mean time to fall was 701 ± 88 days for those with a MMS ≥ 55 compared with 1,628 ± 65 days for MMS < 55.

When age cutoff alone (using 5-year age intervals) was used to construct fall survival curves, only breakpoints of age ≥ 60, ≥ 75, and ≥ 80 years yielded significantly divergent curves (log-rank statistic P = .0215, P = .0264, and P = .011, respectively). Figure 1 (green) shows the difference in survival for subjects aged < 60 years vs aged ≥ 60 years.

The hypothesized combined cutoff of subjects aged ≥ 65 years and MMS ≥ 55 yielded divergent survival curves (log-rank statistic of P = .0011). However, survival curves based on a cutoff of subjects aged ≥ 60 years and ≥ 55 MMS yielded the most statistically significant separation (logrank statistic P < .0001) (Figure 2). Subjects aged < 60 years or with a MMS < 55 had a mean survival of 1,634 ± 65 days; whereas those aged ≥ 60 years and a MMS ≥ 55 had a mean survival of 668 ± 90 days.

A notable similarity of the survival curves for MMS ≥ 55 vs MMS < 55 compared with those based on a cutoff of subjects aged ≥ 60 years and ≥ 55 MMS is observed in comparing Figures 1 (red) and 2. The log-rank statistic chi-square values are 17.44 and 22.75, respectively, suggesting the separation of subjects by a combination of age and MMS yields a more robust divergence in outcomes than does separation by MMS alone.

Discussion

This retrospective chart review evaluated the utility of a MMS combined with age in predicting the risk of patients with AF experiencing serious falls following hospital discharge. When used alone, the MMS separates those at relatively low and high risk of subsequent falls requiring acute medical care. When combined with the factor of patient age, this separation improves and is most predictive for the group of AF patients aged ≥ 60 years with a MMS of ≥ 55. Half of this group had fallen 668 ± 90 days after discharge; whereas those aged < 60 years or with a MMS < 55 did not reach the point of 50% falling until 1,634 ± 65 days after discharge. Age alone allows a statistically significant differentiation of fall risk, but less so than does the MMS alone or the MMS combined with age.

Assessing fall risk can be as simple as asking whether a patient has fallen during the previous year or has a problem with balance or gait, or it can be as complex as an in-depth investigation of physical, cognitive, pharmacologic, environmental, and social factors.^12,13 Beyond the parameters of validity and discrimination power, a predictive tool must be easy to use. Within the VA hospital system, where the MFS is a part of every nursing intake assessment, a MMS can be obtained within seconds from the EMR. This, coupled with the patient’s age, allows the provider to immediately identify those patients with AF who are at high risk for serious falls following hospital discharge.

Strengths and Limitations

A major strength of the present study is the fact that the data accuracy was ensured by individual review of each subject’s EMR. Administrative coding was used only for the initial identification of potential subjects for inclusion. Although 28.5% of potential subjects were excluded from this analysis, > 50% of such exclusions were due to death as the reason for discharge and transient AF associated with an acute medical stressor. Other strengths include the length of follow-up (1,050 ± 869 days, excluding subject deaths) and the generalizability of the subject population. The major weakness of this study is the relatively small sample size and its retrospective methodology.

Summary

The validity of the MFS modified for the postdischarge setting was demonstrated as a readily available tool for identifying patients with AF at high risk of falls following a hospital stay. Such a tool should allow physicians to appropriately prescribe anticoagulation therapy for those patients with AF who are at a lower risk of falls.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Osteoarthritis (OA) is one of the most common diseases affecting the general population and is characterized by progressive, noninflammatory degenerative changes primarily involving the hips, knees, spine, hands, and feet. Among veterans the incidence and prevalence of OA is considerably higher than the incidence found in the general population. A study examining active-duty service members between 1999 and 2008 reported a 19-fold higher incidence in service members aged > 40 years compared with those aged < 20 years.1 In addition, women and African American service members seem to have a higher incidence of OA compared with other populations. Overall, the economic burden of OA is estimated to approach or exceed $60 billion annually and will continue to increase due to longer life expectancies in veterans.^2,3 Much of this burden relates to a lack of disease-modifying treatment and inadequacy of analgesic therapy.

Patterns of Osteoarthritis

The strongest risk factor associated with OA is age. Osteoarthritis is the most common cause of pain and disability in the elderly population.⁴ A heritable component seems to be associated with primary OA as shown by family risk studies.⁵ Estrogenic effects seem to protect younger women, whereas postmenopausal women are at greater risk after age 50 years. Previous joint trauma and activities have a large impact on the risk of developing OA later, particularly those activities and occupations requiring high-impact joint loading, such as those often seen in veterans. Other modifiable risk factors include smoking and obesity. The risk for knee OA has been found to increase 30-fold in patients with a body mass index > 30.⁶

Several OA disease patterns exist. The disorder can be characterized as primary or secondary. Primary OA classically presents in the aging male or postmenopausal female involving the apophyseal joints of the lumbar and cervical spine; base of the thumb (first carpometacarpal,[CMC] joint); proximal or distal interphalangeal joints (PIPs and DIPs) of the hand, knee, or hip; or the first metatarsophalangeal joint. The disease may be localized to 1 joint (localized OA) or involve multiple joints (generalized OA). The disease is more common in men aged < 45 years and more common in women aged > 45 years. In either sex, progression with age is a prominent feature.

Rarely, patients may present with inflammatory arthritis in a distribution typical of OA that is not associated with psoriasis or another disease. This form is known as inflammatory or erosive OA. A minority of cases present with rapidly progressive hip or knee degeneration, the cause of which is unknown. Osteoarthritis involving the metacarpophalangeal joints (MCPs), wrists, elbows, shoulders, or ankles is much less common. Patients with radiographic evidence of OA at these sites should be evaluated for a cause of secondary OA.

Patients often develop secondary OA in the setting of inflammatory arthritis, crystal-induced arthritis, and other systemic diseases. Causes of secondary OA should be considered when OA manifests in an atypical joint. Common causes of secondary OA are outlined in Table 1. A careful history may undercover a prior diagnosis of gout, calcium pyrophosphate deposition disease, or infectious arthritis in the affected joint. An important metabolic cause of secondary OA is hemochromatosis, which can lead to osteophytic change primarily in the second and third MCPs. Patients with diabetes mellitus-associated neuropathy may develop destructive changes in the foot (Charcot joint).

Symptoms and Examination

Osteoarthritis encompasses a wide spectrum of common conditions with similar pathophysiology. Most of these conditions share similar historic features, including pain during or after use and stiffness after prolonged periods of inactivity. Other common symptoms include swelling, joint locking or “cracking,” instability, and joint fatigue. Patients may perceive OA discomfort in different ways. Whereas one patient with knee OA may describe a sharp, gnawing pain, another may experience painless swelling and instability. Although OA is mainly considered a localized disease, patients may present with multiple areas of pain, suggesting a more generalized pattern. Patients with OA may have short periods of morning stiffness and “gelling,” but prolonged stiffness suggests the presence of inflammatory arthritis.

Examination of the osteoarthritic joint is performed with thorough palpation and range of motion testing. Evidence of joint swelling may be present near the joint line with pain on palpation. Palpable crepitus is commonly noted with restricted range of motion, usually inducing pain at the maximal range. Osteophytes or chondrophytes at the joint line may be tender and are commonly mistaken for joint swelling. In the hands, bony hypertrophy of the PIP and DIP joints may be noted (Bouchard’s and Heberden’s nodes, respectively). Pain at the base of the thumb is a common complaint in patients with OA of the CMC joint.

Most cases of OA can be diagnosed by taking a history and a physical examination without further investigation; however, plain radiographs are frequently obtained to confirm the diagnosis. Joint inflammation, when present, is usually mild. Occasionally, patients may present with evidence of warmth, effusion, and severe pain with restriction of motion. Patients with these symptoms should undergo prompt arthrocentesis to rule out infection, crystal-associated arthritis, hemarthrosis, or other inflammatory causes.

Radiographic Features

Plain radiographs are extremely helpful in denoting the extent of OA in a particular joint. Radiographic features of OA include narrowing of the joint space, osteophyte formation, and subchondral bone abnormalities. Narrowing of the joint space and alignment abnormalities occur due to loss of articular cartilage. Changes in the subchondral bone include sclerosis and cystic lesions. Erosive changes, ankylosis, and calcification of the articular cartilage are typically absent.

In the hands, a particular pattern is noted involving the PIP and DIP joints with characteristic sparing of the MCPs (Figure 1A). The first CMC joint is also commonly involved, with bony osteophyte formation and joint space loss. In the knee and hip, loss of joint space with subchondral bone cyst and osteophyte formation is common (Figure 1B).

The cervical and/or lumbar spine may reveal spondylosis, disc space narrowing, and osteophytes. More than 50% of people aged > 65 years have radiologic evidence of OA. However, radiographic evidence of OA is at least twice as common as symptomatic OA, warranting careful consideration when contemplating treatment.⁷

Pathogenesis

Normal articular cartilage is a complex tissue composed of extracellular matrix and chondrocytes. Under ideal conditions, hemostasis is maintained with balance between degradation and synthesis of extracellular matrix proteins. In the aging cartilage, a reduction of total proteoglycan synthesis occurs, decreasing its capacity to retain water. Matrix proteins are modified, leading to the accumulation of advanced glycation end products (AGEs). This process is irreversible, and AGEs cannot be removed from the articular cartilage. Chondrocytes respond to AGEs with increased catabolic activity and cytokine release. Initial chondral edema and matrix degradation leads to stress fractures in the collagen network and fissuring of the cartilage. Eventually, the microfractures lead to fragmenting of the cartilage, formation of loose bodies, and synovial inflammation. Sclerosis occurs in the subchondral bone, with accelerated bone turnover leading to osteophyte formation.⁸

Treatment

Unfortunately, no pharmacologic or nonpharmacologic therapy has been shown to reverse or halt the progression of OA. A comprehensive approach to the treatment of patients with OA is imperative for reducing disability and improving quality of life. Several sources have published guidelines for the management of OA.^9-11 More recently, comprehensive clinical practice guidelines have been published regarding nonsurgical management of hip and knee OA in the veteran population.¹²

Initially, a conservative approach is generally recommended with reduction of modifiable risk factors and patient education. Weight loss, aerobic conditioning, and physical therapy can improve function and stability. Notably, a weight reduction of 5% has been associated with an 18% to 24% improvement in knee OA.⁶ A supervised walking exercise program can be extremely beneficial for patients, with several studies showing improvement in pain, ambulatory function, and psychological well-being. Bracing devices and orthotic footwear can be helpful for compartmental unloading of the knee. The use of ambulatory assist devices (eg, canes, walkers) and splinting may also be of benefit. Topical lidocaine, capsaicin, and topical nonsteroidal anti-inflammatory drugs (NSAIDs) therapy can be useful adjuncts.

Medications are used mainly to provide analgesia and improve function while causing the fewest adverse effects (AEs) (Table 2). Contrary to conventional teaching, acetaminophen may not be as effective in the treatment of OA as previously thought. A recently published metaanalysis comparing treatments for knee OA revealed acetaminophen to be the least effective agent.¹³ Another meta-analysis showed that acetaminophen provided clinically insignificant pain relief in OA of the hip and knee.¹⁴ However, acetaminophen may be useful in the treatment of mild OA or in patients with contraindications to other oral therapies. Nonsteroidal anti-inflammatory drug therapy is more effective in a patient with inflammatory OA symptoms (eg, effusion, erosive OA) and can be added to acetaminophen if ineffective alone. Gastrointestinal protection against ulceration may be warranted, and use of NSAIDs may be contraindicated in the patient with high bleeding risk, renal insufficiency, or cardiovascular disease. In patients with low cardiac risk, celecoxib can be effective. Patients who have a contraindication to NSAIDs may find benefit from other analgesic agents, such as tramadol or duloxetine. Intra-articular corticosteroid injections can be particularly helpful for patients with a single osteoarthritic joint that has been unresponsive to oral or topical analgesics. Opioid analgesics may be used as a last resort when all other agents and therapies have failed. Most patients who require opioid therapy are awaiting surgical repair or are not surgical candidates.

Use of nutritional supplements such as glucosamine and chondroitin sulfate in the treatment of primary knee OA is controversial. These agents are not regulated by the FDA and their potency, purity, and safety are not guaranteed. Furthermore, the bioavailability of oral glucosamine and chondroitin sulfate is particularly poor, and studies have revealed conflicting evidence on their ability to reduce pain in patients with OA. Nonetheless, some evidence exists for cartilage proteoglycan integration and synthesis with glucosamine and chondroitin compounds. Most patients taking these supplements experience few AEs, and some report good responses to therapy. Some patients allergic to shellfish may experience a reaction to glucosamine products.

Hyaluronate injections can be recommended for patients with moderate OA who have failed standard medical treatment. Most clinical trials of hyaluronate suggest an analgesic benefit comparable with NSAID therapy and corticosteroid injections, but high-quality studies are lacking.

Colchicine may be effective in patients with inflammatory or noninflammatory OA. Two small studies showed colchicine to be beneficial in the treatment of primary OA of the knee.^15,16 Hydroxychloroquine may be helpful in the treatment of inflammatory OA.

Loss of joint function or severe pain refractory to medical treatment in a patient with OA likely requires surgical intervention. Patients who have difficulty ambulating more than a reasonable distance (ie, 1 block) or cannot stand in place for more than several minutes due to severe pain should be considered for total joint replacement. Patients often report awaking with severe pain at night or pain that significantly impedes their activities of daily living. In these patients, total joint replacement can be extremely beneficial and life altering.

Conclusion

Osteoarthritis is the most common arthritic disease and has a very high prevalence in the veteran population. Aging, obesity, prior trauma, and activity level are the common risk factors for the development of OA. Patterns of disease are recognizable by history, examination, and prominent radiographic features. Causes of secondary OA are important to recognize and treat. The pathogenesis of OA involves a disrupted homeostatic process leading to cartilage degradation, microfracture, subchondral sclerosis, and osteophyte formation. Treatment is unique to the individual and should include a comprehensive strategy involving patient education, exercise or physical therapy, and analgesia. Patients with severe osteoarthritis that significantly impacts activities of daily living may benefit from surgery.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Osteoarthritis (OA) is one of the most common diseases affecting the general population and is characterized by progressive, noninflammatory degenerative changes primarily involving the hips, knees, spine, hands, and feet. Among veterans the incidence and prevalence of OA is considerably higher than the incidence found in the general population. A study examining active-duty service members between 1999 and 2008 reported a 19-fold higher incidence in service members aged > 40 years compared with those aged < 20 years.1 In addition, women and African American service members seem to have a higher incidence of OA compared with other populations. Overall, the economic burden of OA is estimated to approach or exceed $60 billion annually and will continue to increase due to longer life expectancies in veterans.^2,3 Much of this burden relates to a lack of disease-modifying treatment and inadequacy of analgesic therapy.

Patterns of Osteoarthritis

The strongest risk factor associated with OA is age. Osteoarthritis is the most common cause of pain and disability in the elderly population.⁴ A heritable component seems to be associated with primary OA as shown by family risk studies.⁵ Estrogenic effects seem to protect younger women, whereas postmenopausal women are at greater risk after age 50 years. Previous joint trauma and activities have a large impact on the risk of developing OA later, particularly those activities and occupations requiring high-impact joint loading, such as those often seen in veterans. Other modifiable risk factors include smoking and obesity. The risk for knee OA has been found to increase 30-fold in patients with a body mass index > 30.⁶

Several OA disease patterns exist. The disorder can be characterized as primary or secondary. Primary OA classically presents in the aging male or postmenopausal female involving the apophyseal joints of the lumbar and cervical spine; base of the thumb (first carpometacarpal,[CMC] joint); proximal or distal interphalangeal joints (PIPs and DIPs) of the hand, knee, or hip; or the first metatarsophalangeal joint. The disease may be localized to 1 joint (localized OA) or involve multiple joints (generalized OA). The disease is more common in men aged < 45 years and more common in women aged > 45 years. In either sex, progression with age is a prominent feature.

Rarely, patients may present with inflammatory arthritis in a distribution typical of OA that is not associated with psoriasis or another disease. This form is known as inflammatory or erosive OA. A minority of cases present with rapidly progressive hip or knee degeneration, the cause of which is unknown. Osteoarthritis involving the metacarpophalangeal joints (MCPs), wrists, elbows, shoulders, or ankles is much less common. Patients with radiographic evidence of OA at these sites should be evaluated for a cause of secondary OA.

Patients often develop secondary OA in the setting of inflammatory arthritis, crystal-induced arthritis, and other systemic diseases. Causes of secondary OA should be considered when OA manifests in an atypical joint. Common causes of secondary OA are outlined in Table 1. A careful history may undercover a prior diagnosis of gout, calcium pyrophosphate deposition disease, or infectious arthritis in the affected joint. An important metabolic cause of secondary OA is hemochromatosis, which can lead to osteophytic change primarily in the second and third MCPs. Patients with diabetes mellitus-associated neuropathy may develop destructive changes in the foot (Charcot joint).

Symptoms and Examination

Osteoarthritis encompasses a wide spectrum of common conditions with similar pathophysiology. Most of these conditions share similar historic features, including pain during or after use and stiffness after prolonged periods of inactivity. Other common symptoms include swelling, joint locking or “cracking,” instability, and joint fatigue. Patients may perceive OA discomfort in different ways. Whereas one patient with knee OA may describe a sharp, gnawing pain, another may experience painless swelling and instability. Although OA is mainly considered a localized disease, patients may present with multiple areas of pain, suggesting a more generalized pattern. Patients with OA may have short periods of morning stiffness and “gelling,” but prolonged stiffness suggests the presence of inflammatory arthritis.

Examination of the osteoarthritic joint is performed with thorough palpation and range of motion testing. Evidence of joint swelling may be present near the joint line with pain on palpation. Palpable crepitus is commonly noted with restricted range of motion, usually inducing pain at the maximal range. Osteophytes or chondrophytes at the joint line may be tender and are commonly mistaken for joint swelling. In the hands, bony hypertrophy of the PIP and DIP joints may be noted (Bouchard’s and Heberden’s nodes, respectively). Pain at the base of the thumb is a common complaint in patients with OA of the CMC joint.

Most cases of OA can be diagnosed by taking a history and a physical examination without further investigation; however, plain radiographs are frequently obtained to confirm the diagnosis. Joint inflammation, when present, is usually mild. Occasionally, patients may present with evidence of warmth, effusion, and severe pain with restriction of motion. Patients with these symptoms should undergo prompt arthrocentesis to rule out infection, crystal-associated arthritis, hemarthrosis, or other inflammatory causes.

Radiographic Features

Plain radiographs are extremely helpful in denoting the extent of OA in a particular joint. Radiographic features of OA include narrowing of the joint space, osteophyte formation, and subchondral bone abnormalities. Narrowing of the joint space and alignment abnormalities occur due to loss of articular cartilage. Changes in the subchondral bone include sclerosis and cystic lesions. Erosive changes, ankylosis, and calcification of the articular cartilage are typically absent.

In the hands, a particular pattern is noted involving the PIP and DIP joints with characteristic sparing of the MCPs (Figure 1A). The first CMC joint is also commonly involved, with bony osteophyte formation and joint space loss. In the knee and hip, loss of joint space with subchondral bone cyst and osteophyte formation is common (Figure 1B).

The cervical and/or lumbar spine may reveal spondylosis, disc space narrowing, and osteophytes. More than 50% of people aged > 65 years have radiologic evidence of OA. However, radiographic evidence of OA is at least twice as common as symptomatic OA, warranting careful consideration when contemplating treatment.⁷

Pathogenesis

Normal articular cartilage is a complex tissue composed of extracellular matrix and chondrocytes. Under ideal conditions, hemostasis is maintained with balance between degradation and synthesis of extracellular matrix proteins. In the aging cartilage, a reduction of total proteoglycan synthesis occurs, decreasing its capacity to retain water. Matrix proteins are modified, leading to the accumulation of advanced glycation end products (AGEs). This process is irreversible, and AGEs cannot be removed from the articular cartilage. Chondrocytes respond to AGEs with increased catabolic activity and cytokine release. Initial chondral edema and matrix degradation leads to stress fractures in the collagen network and fissuring of the cartilage. Eventually, the microfractures lead to fragmenting of the cartilage, formation of loose bodies, and synovial inflammation. Sclerosis occurs in the subchondral bone, with accelerated bone turnover leading to osteophyte formation.⁸

Treatment

Unfortunately, no pharmacologic or nonpharmacologic therapy has been shown to reverse or halt the progression of OA. A comprehensive approach to the treatment of patients with OA is imperative for reducing disability and improving quality of life. Several sources have published guidelines for the management of OA.^9-11 More recently, comprehensive clinical practice guidelines have been published regarding nonsurgical management of hip and knee OA in the veteran population.¹²

Initially, a conservative approach is generally recommended with reduction of modifiable risk factors and patient education. Weight loss, aerobic conditioning, and physical therapy can improve function and stability. Notably, a weight reduction of 5% has been associated with an 18% to 24% improvement in knee OA.⁶ A supervised walking exercise program can be extremely beneficial for patients, with several studies showing improvement in pain, ambulatory function, and psychological well-being. Bracing devices and orthotic footwear can be helpful for compartmental unloading of the knee. The use of ambulatory assist devices (eg, canes, walkers) and splinting may also be of benefit. Topical lidocaine, capsaicin, and topical nonsteroidal anti-inflammatory drugs (NSAIDs) therapy can be useful adjuncts.

Medications are used mainly to provide analgesia and improve function while causing the fewest adverse effects (AEs) (Table 2). Contrary to conventional teaching, acetaminophen may not be as effective in the treatment of OA as previously thought. A recently published metaanalysis comparing treatments for knee OA revealed acetaminophen to be the least effective agent.¹³ Another meta-analysis showed that acetaminophen provided clinically insignificant pain relief in OA of the hip and knee.¹⁴ However, acetaminophen may be useful in the treatment of mild OA or in patients with contraindications to other oral therapies. Nonsteroidal anti-inflammatory drug therapy is more effective in a patient with inflammatory OA symptoms (eg, effusion, erosive OA) and can be added to acetaminophen if ineffective alone. Gastrointestinal protection against ulceration may be warranted, and use of NSAIDs may be contraindicated in the patient with high bleeding risk, renal insufficiency, or cardiovascular disease. In patients with low cardiac risk, celecoxib can be effective. Patients who have a contraindication to NSAIDs may find benefit from other analgesic agents, such as tramadol or duloxetine. Intra-articular corticosteroid injections can be particularly helpful for patients with a single osteoarthritic joint that has been unresponsive to oral or topical analgesics. Opioid analgesics may be used as a last resort when all other agents and therapies have failed. Most patients who require opioid therapy are awaiting surgical repair or are not surgical candidates.

Use of nutritional supplements such as glucosamine and chondroitin sulfate in the treatment of primary knee OA is controversial. These agents are not regulated by the FDA and their potency, purity, and safety are not guaranteed. Furthermore, the bioavailability of oral glucosamine and chondroitin sulfate is particularly poor, and studies have revealed conflicting evidence on their ability to reduce pain in patients with OA. Nonetheless, some evidence exists for cartilage proteoglycan integration and synthesis with glucosamine and chondroitin compounds. Most patients taking these supplements experience few AEs, and some report good responses to therapy. Some patients allergic to shellfish may experience a reaction to glucosamine products.

Hyaluronate injections can be recommended for patients with moderate OA who have failed standard medical treatment. Most clinical trials of hyaluronate suggest an analgesic benefit comparable with NSAID therapy and corticosteroid injections, but high-quality studies are lacking.

Colchicine may be effective in patients with inflammatory or noninflammatory OA. Two small studies showed colchicine to be beneficial in the treatment of primary OA of the knee.^15,16 Hydroxychloroquine may be helpful in the treatment of inflammatory OA.

Loss of joint function or severe pain refractory to medical treatment in a patient with OA likely requires surgical intervention. Patients who have difficulty ambulating more than a reasonable distance (ie, 1 block) or cannot stand in place for more than several minutes due to severe pain should be considered for total joint replacement. Patients often report awaking with severe pain at night or pain that significantly impedes their activities of daily living. In these patients, total joint replacement can be extremely beneficial and life altering.

Conclusion

Osteoarthritis is the most common arthritic disease and has a very high prevalence in the veteran population. Aging, obesity, prior trauma, and activity level are the common risk factors for the development of OA. Patterns of disease are recognizable by history, examination, and prominent radiographic features. Causes of secondary OA are important to recognize and treat. The pathogenesis of OA involves a disrupted homeostatic process leading to cartilage degradation, microfracture, subchondral sclerosis, and osteophyte formation. Treatment is unique to the individual and should include a comprehensive strategy involving patient education, exercise or physical therapy, and analgesia. Patients with severe osteoarthritis that significantly impacts activities of daily living may benefit from surgery.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Osteoarthritis (OA) is one of the most common diseases affecting the general population and is characterized by progressive, noninflammatory degenerative changes primarily involving the hips, knees, spine, hands, and feet. Among veterans the incidence and prevalence of OA is considerably higher than the incidence found in the general population. A study examining active-duty service members between 1999 and 2008 reported a 19-fold higher incidence in service members aged > 40 years compared with those aged < 20 years.1 In addition, women and African American service members seem to have a higher incidence of OA compared with other populations. Overall, the economic burden of OA is estimated to approach or exceed $60 billion annually and will continue to increase due to longer life expectancies in veterans.^2,3 Much of this burden relates to a lack of disease-modifying treatment and inadequacy of analgesic therapy.

Patterns of Osteoarthritis

The strongest risk factor associated with OA is age. Osteoarthritis is the most common cause of pain and disability in the elderly population.⁴ A heritable component seems to be associated with primary OA as shown by family risk studies.⁵ Estrogenic effects seem to protect younger women, whereas postmenopausal women are at greater risk after age 50 years. Previous joint trauma and activities have a large impact on the risk of developing OA later, particularly those activities and occupations requiring high-impact joint loading, such as those often seen in veterans. Other modifiable risk factors include smoking and obesity. The risk for knee OA has been found to increase 30-fold in patients with a body mass index > 30.⁶

Several OA disease patterns exist. The disorder can be characterized as primary or secondary. Primary OA classically presents in the aging male or postmenopausal female involving the apophyseal joints of the lumbar and cervical spine; base of the thumb (first carpometacarpal,[CMC] joint); proximal or distal interphalangeal joints (PIPs and DIPs) of the hand, knee, or hip; or the first metatarsophalangeal joint. The disease may be localized to 1 joint (localized OA) or involve multiple joints (generalized OA). The disease is more common in men aged < 45 years and more common in women aged > 45 years. In either sex, progression with age is a prominent feature.

Rarely, patients may present with inflammatory arthritis in a distribution typical of OA that is not associated with psoriasis or another disease. This form is known as inflammatory or erosive OA. A minority of cases present with rapidly progressive hip or knee degeneration, the cause of which is unknown. Osteoarthritis involving the metacarpophalangeal joints (MCPs), wrists, elbows, shoulders, or ankles is much less common. Patients with radiographic evidence of OA at these sites should be evaluated for a cause of secondary OA.

Patients often develop secondary OA in the setting of inflammatory arthritis, crystal-induced arthritis, and other systemic diseases. Causes of secondary OA should be considered when OA manifests in an atypical joint. Common causes of secondary OA are outlined in Table 1. A careful history may undercover a prior diagnosis of gout, calcium pyrophosphate deposition disease, or infectious arthritis in the affected joint. An important metabolic cause of secondary OA is hemochromatosis, which can lead to osteophytic change primarily in the second and third MCPs. Patients with diabetes mellitus-associated neuropathy may develop destructive changes in the foot (Charcot joint).

Symptoms and Examination

Osteoarthritis encompasses a wide spectrum of common conditions with similar pathophysiology. Most of these conditions share similar historic features, including pain during or after use and stiffness after prolonged periods of inactivity. Other common symptoms include swelling, joint locking or “cracking,” instability, and joint fatigue. Patients may perceive OA discomfort in different ways. Whereas one patient with knee OA may describe a sharp, gnawing pain, another may experience painless swelling and instability. Although OA is mainly considered a localized disease, patients may present with multiple areas of pain, suggesting a more generalized pattern. Patients with OA may have short periods of morning stiffness and “gelling,” but prolonged stiffness suggests the presence of inflammatory arthritis.

Examination of the osteoarthritic joint is performed with thorough palpation and range of motion testing. Evidence of joint swelling may be present near the joint line with pain on palpation. Palpable crepitus is commonly noted with restricted range of motion, usually inducing pain at the maximal range. Osteophytes or chondrophytes at the joint line may be tender and are commonly mistaken for joint swelling. In the hands, bony hypertrophy of the PIP and DIP joints may be noted (Bouchard’s and Heberden’s nodes, respectively). Pain at the base of the thumb is a common complaint in patients with OA of the CMC joint.

Most cases of OA can be diagnosed by taking a history and a physical examination without further investigation; however, plain radiographs are frequently obtained to confirm the diagnosis. Joint inflammation, when present, is usually mild. Occasionally, patients may present with evidence of warmth, effusion, and severe pain with restriction of motion. Patients with these symptoms should undergo prompt arthrocentesis to rule out infection, crystal-associated arthritis, hemarthrosis, or other inflammatory causes.

Radiographic Features

Plain radiographs are extremely helpful in denoting the extent of OA in a particular joint. Radiographic features of OA include narrowing of the joint space, osteophyte formation, and subchondral bone abnormalities. Narrowing of the joint space and alignment abnormalities occur due to loss of articular cartilage. Changes in the subchondral bone include sclerosis and cystic lesions. Erosive changes, ankylosis, and calcification of the articular cartilage are typically absent.

In the hands, a particular pattern is noted involving the PIP and DIP joints with characteristic sparing of the MCPs (Figure 1A). The first CMC joint is also commonly involved, with bony osteophyte formation and joint space loss. In the knee and hip, loss of joint space with subchondral bone cyst and osteophyte formation is common (Figure 1B).

The cervical and/or lumbar spine may reveal spondylosis, disc space narrowing, and osteophytes. More than 50% of people aged > 65 years have radiologic evidence of OA. However, radiographic evidence of OA is at least twice as common as symptomatic OA, warranting careful consideration when contemplating treatment.⁷

Pathogenesis

Normal articular cartilage is a complex tissue composed of extracellular matrix and chondrocytes. Under ideal conditions, hemostasis is maintained with balance between degradation and synthesis of extracellular matrix proteins. In the aging cartilage, a reduction of total proteoglycan synthesis occurs, decreasing its capacity to retain water. Matrix proteins are modified, leading to the accumulation of advanced glycation end products (AGEs). This process is irreversible, and AGEs cannot be removed from the articular cartilage. Chondrocytes respond to AGEs with increased catabolic activity and cytokine release. Initial chondral edema and matrix degradation leads to stress fractures in the collagen network and fissuring of the cartilage. Eventually, the microfractures lead to fragmenting of the cartilage, formation of loose bodies, and synovial inflammation. Sclerosis occurs in the subchondral bone, with accelerated bone turnover leading to osteophyte formation.⁸

Treatment

Unfortunately, no pharmacologic or nonpharmacologic therapy has been shown to reverse or halt the progression of OA. A comprehensive approach to the treatment of patients with OA is imperative for reducing disability and improving quality of life. Several sources have published guidelines for the management of OA.^9-11 More recently, comprehensive clinical practice guidelines have been published regarding nonsurgical management of hip and knee OA in the veteran population.¹²

Initially, a conservative approach is generally recommended with reduction of modifiable risk factors and patient education. Weight loss, aerobic conditioning, and physical therapy can improve function and stability. Notably, a weight reduction of 5% has been associated with an 18% to 24% improvement in knee OA.⁶ A supervised walking exercise program can be extremely beneficial for patients, with several studies showing improvement in pain, ambulatory function, and psychological well-being. Bracing devices and orthotic footwear can be helpful for compartmental unloading of the knee. The use of ambulatory assist devices (eg, canes, walkers) and splinting may also be of benefit. Topical lidocaine, capsaicin, and topical nonsteroidal anti-inflammatory drugs (NSAIDs) therapy can be useful adjuncts.

Medications are used mainly to provide analgesia and improve function while causing the fewest adverse effects (AEs) (Table 2). Contrary to conventional teaching, acetaminophen may not be as effective in the treatment of OA as previously thought. A recently published metaanalysis comparing treatments for knee OA revealed acetaminophen to be the least effective agent.¹³ Another meta-analysis showed that acetaminophen provided clinically insignificant pain relief in OA of the hip and knee.¹⁴ However, acetaminophen may be useful in the treatment of mild OA or in patients with contraindications to other oral therapies. Nonsteroidal anti-inflammatory drug therapy is more effective in a patient with inflammatory OA symptoms (eg, effusion, erosive OA) and can be added to acetaminophen if ineffective alone. Gastrointestinal protection against ulceration may be warranted, and use of NSAIDs may be contraindicated in the patient with high bleeding risk, renal insufficiency, or cardiovascular disease. In patients with low cardiac risk, celecoxib can be effective. Patients who have a contraindication to NSAIDs may find benefit from other analgesic agents, such as tramadol or duloxetine. Intra-articular corticosteroid injections can be particularly helpful for patients with a single osteoarthritic joint that has been unresponsive to oral or topical analgesics. Opioid analgesics may be used as a last resort when all other agents and therapies have failed. Most patients who require opioid therapy are awaiting surgical repair or are not surgical candidates.

Use of nutritional supplements such as glucosamine and chondroitin sulfate in the treatment of primary knee OA is controversial. These agents are not regulated by the FDA and their potency, purity, and safety are not guaranteed. Furthermore, the bioavailability of oral glucosamine and chondroitin sulfate is particularly poor, and studies have revealed conflicting evidence on their ability to reduce pain in patients with OA. Nonetheless, some evidence exists for cartilage proteoglycan integration and synthesis with glucosamine and chondroitin compounds. Most patients taking these supplements experience few AEs, and some report good responses to therapy. Some patients allergic to shellfish may experience a reaction to glucosamine products.

Hyaluronate injections can be recommended for patients with moderate OA who have failed standard medical treatment. Most clinical trials of hyaluronate suggest an analgesic benefit comparable with NSAID therapy and corticosteroid injections, but high-quality studies are lacking.

Colchicine may be effective in patients with inflammatory or noninflammatory OA. Two small studies showed colchicine to be beneficial in the treatment of primary OA of the knee.^15,16 Hydroxychloroquine may be helpful in the treatment of inflammatory OA.

Loss of joint function or severe pain refractory to medical treatment in a patient with OA likely requires surgical intervention. Patients who have difficulty ambulating more than a reasonable distance (ie, 1 block) or cannot stand in place for more than several minutes due to severe pain should be considered for total joint replacement. Patients often report awaking with severe pain at night or pain that significantly impedes their activities of daily living. In these patients, total joint replacement can be extremely beneficial and life altering.

Conclusion

Osteoarthritis is the most common arthritic disease and has a very high prevalence in the veteran population. Aging, obesity, prior trauma, and activity level are the common risk factors for the development of OA. Patterns of disease are recognizable by history, examination, and prominent radiographic features. Causes of secondary OA are important to recognize and treat. The pathogenesis of OA involves a disrupted homeostatic process leading to cartilage degradation, microfracture, subchondral sclerosis, and osteophyte formation. Treatment is unique to the individual and should include a comprehensive strategy involving patient education, exercise or physical therapy, and analgesia. Patients with severe osteoarthritis that significantly impacts activities of daily living may benefit from surgery.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Psoriasis is a commonly encountered systemic condition, usually presenting with chronic erythematous plaques with an overlying silvery white scale.¹ Extracutaneous manifestations, such as joint or spine (axial) involvement, can occur along with this skin disorder. Psoriatic arthritis (PsA) is a chronic, heterogeneous disorder characterized by inflammatory arthritis in patients with psoriasis.^2,3 Until recently treatment of PsA has been limited to a few medications.

Continuing investigations into the pathogenesis of PsA have revealed new treatment options, targeting molecules at the cellular level. Over the past few years, additional medications have been approved, giving providers more options in treating patients with psoriasis and PsA. Furthermore, a multidisciplinary approach by both rheumatologists and dermatologists in evaluating and managing patients at VA clinics has helped optimize care of these patients by providing timely evaluation and treatment at the same visit.

Psoriasis Presentation and Diagnosis

Genetic predisposition and certain environmental factors (trauma, infection, medications) are known to trigger psoriasis, which can present in many forms.⁴ Chronic plaque psoriasis, or psoriasis vulgaris, is the most common skin pattern with a classic presentation of sharply demarcated erythematous plaques with overlying silver scale.⁴ It affects the scalp, lower back, umbilicus, genitals, and extensor surfaces of the elbows and knees. Guttate psoriasis is recognized by its multiple small papules and plaques in a droplike pattern. Pustular psoriasis usually presents with widespread pustules. On the other hand, erythrodermic psoriasis manifests as diffuse erythema involving multiple skin areas.⁴ Erythematous psoriatic plaques, which are predominantly in the intertriginous areas or skin folds (inguinal, perineal, genital, intergluteal, axillary, or inframammary), are known as inverse psoriasis.

A psoriasis diagnosis is made by taking a history and a physical examination. Rarely, a skin biopsy of the lesions will be required for an atypical presentation. The course of the disease is unpredictable, variable, and dependent on the type of psoriasis. Psoriasis vulgaris is a chronic condition, whereas guttate psoriasis is often self-limited.⁴ A poorer prognosis is seen in patients with erythrodermic and generalized pustular psoriasis.⁴

Psoriatic Arthritis Presentation, Classification, and Diagnosis

Prevalence of PsA is not known, but it is estimated to be from 0.3% to 1% of the U.S. population. In the psoriasis population, PsA is reported to range from 7% to 42%,³ although more recently, these numbers have been found to be in the 15% to 25% range (unpublished observations). This type of inflammatory arthritis can develop at any age but usually is seen between the ages of 30 and 50 years, with men being affected equally or a little more than are women.³ Clinical symptoms usually include pain and stiffness of affected joints, > 30 minutes of morning stiffness, and fatigue.

The presentation of joint involvement can vary widely. Five subtypes of arthritis were identified by Moll and Wright in 1973, which included arthritis with predominant distal interphalangeal involvement, arthritis mutilans, symmetric polyarthritis (> 5 joints), asymmetric oligoarthritis (1-4 joints), and predominant spondylitis (axial).⁵ Patients with PsA may also have evidence of spondylitis (inflammation of vertebra) or sacroiliitis (inflammation of the sacroiliac joints) with back pain > 3 months, hip or buttock pain, nighttime pain, or pain that improves with activity but worsens with rest.6 The cervical spine is more frequently involved than is the lumbar spine in patients with PsA.³

Psoriatic arthritis can have a diverse presentation not only with the affected joints, but also involving nails, tendons, and ligaments. An entire digit of the hand or foot can become swollen, known as dactylitis, or “sausage digit.” Inflammation at the insertion of tendons or ligaments, known as enthesitis, is also seen in PsA. Most common sites include the Achilles tendon, plantar fascia, and ligamentous insertions around the pelvic bones.³ Nail changes that are typically seen in patients with psoriasis can be seen in PsA as well, including pitting, ridging, hyperkeratosis, and onycholysis.³ Ocular inflammation which is classically seen with other spondyloarthropathies, can be seen in patients with PsA as well, frequently manifesting as conjunctivitis.^2,3

Psoriatic arthritis is commonly classified under the broader category of seronegative spondyloarthropathies, given the low frequency of a positive rheumatoid factor.³ Currently, there are no laboratory tests that can help with a PsA diagnosis.³ Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein may be elevated, indicating active inflammation.

Radiographic data, such as X-rays of the hands and feet, can confirm the clinical distribution of joint involvement and show evidence of erosive changes. Further destructive changes include osteolysis (bone resorption) that may cause the classic pencil-in-cup deformity, typically seen in arthritis mutilans (Figure 1).³ Other radiographic evidence of PsA can include proliferative changes with new bone formation seen along the shaft of the metacarpal and metatarsal bones.³ Patients with axial involvement can have evidence of asymmetric sacroiliitis, which can be seen on radiographs. Asymmetric syndesmophytes, or bony outgrowths, can also be seen throughout the axial spine.³

Diagnosis is based on the history and clinical presentation of a patient with the help of laboratory work and radiographs. Other forms of arthritis (such as rheumatoid arthritis, crystal arthropathies, osteoarthritis, ankylosing spondylitis) should be excluded. Given the varied presentation of PsA, classification criteria have been developed to assist in clinical research. Classification Criteria for Psoriatic Arthritis (CASPAR) have been developed and validated as an adjunct to clinical diagnosis and a source for clinical research (Table 1).⁷ Musculoskeletal pain in patients with psoriasis can be due to causes other than PsA, such as osteoarthritis and gout. A close working relationship in a combined rheumatology/dermatology clinic is vital to providing optimal diagnostic and treatment care for patients with psoriasis and PsA.⁸

The etiology of PsA is currently unknown, although many genetic, environmental, and immunologic factors have been identified that play a role in the pathogenesis of the disease. In this setting, immunologically mediated processes that cause inflammation occur in the synovium of joints, enthesium, bone, and skin of patients with PsA.⁹ Studies have shown that activated T cells and T-cell–derived cytokines play an important role in cartilage degradation, joint damage, and stimulating bone resorption.⁹

One particular proinflammatory cytokine, tumor necrosis factor alpha (TNFα), has been the target for many treatment modalities for several years. With new and ongoing research into the PsA pathogenesis, other treatment options have been discovered, targeting different cytokines and T cells that are involved in the disease process. This has led to drug trials and recent FDA approvals of several new medications, which provide further options for clinicians in managing and treating PsA.

Management of Psoriasis

Choice of therapy is determined by the extent and severity of psoriasis (body surface area [BSA] involvement) as well as the patient’s comorbidities and preferences.⁴ Providers have a wide spectrum of effective therapies to prescribe, both topically and systemically. Topical therapy options include corticosteroids, vitamin D3 and analogs (calcipotriene), anthralin, tar, tazarotene (third-generation retinoid), and calcineurin inhibitors (tacromlimus).⁴ Phototherapy with or without saltwater baths helps improve skin lesions.

These treatments are beneficial for all patients with psoriasis, but the disease can be controlled with monotherapy in patients with mild-to-moderate disease (< 10% BSA). Limiting these treatment options are some long-term effects of the medications because of the potential for toxicity as well as decreasing efficacy of the medication over time.4 For patients with more BSA involvement (> 10%), systemic treatment options include methotrexate (MTX), systemic retinoids (acitretin), calcineurin inhibitors (cyclosporine), and biologics. Many of these systemic treatment options overlap for patients with both psoriasis and PsA, and topical treatments can be used adjunctively to better control the skin disease.

Management of Psoriatic Arthritis

It is important to identify PsA and begin treatment early, because it has been shown that patients tend to fare better in their disease course if treated early.¹⁰ Once a diagnosis of PsA is made, disease activity needs to be determined by clinical examination and radiographs of joints. Scoring systems, by assessing bone erosions and deformities on joint radiographs, can aide with this assessment. Based on these, PsA can be categorized as mild, moderate, or severe. Several disease activity measures that have been developed for clinical trials in monitoring of disease activity can be used as an aide in the office setting. These tools are still being studied to determine the optimal measure of disease activity.

NSAIDs and Glucocorticoids

Controlling inflammation and providing pain relief are the primary treatment goals for patients with PsA. In mild, predominantly peripheral PsA, nonsteroidal antiinflammatory drugs (NSAIDs) can be used, but they do not halt disease progression. If the disease is controlled and not progressing, NSAIDs may be used as the only treatment. However, if symptoms persist and/or there is more joint involvement, the next level of therapy should be sought. Intra-articular corticosteroids for symptomatic relief can be given if only a few joints are affected. Oral corticosteroids can be used occasionally in patients with multiple joint aches, but they are typically avoided or tapered slowly to avoid worsening the patient’s skin psoriasis or having it evolve into a more severe form, such as pustular psoriasis.¹⁰ All these treatments can alleviate symptoms, but they do not prevent the progression of disease.

Disease-Modifying Antirheumatic Drugs

For patients who fail NSAIDs or present initially with more joint involvement (polyarthritis or > 5 swollen joints), traditional disease-modifying antirheumatic drugs (DMARDs) should be started (Table 2). Methotrexate is one of the first-line DMARD prescriptions. It is commonly used because of its effectiveness in treating both skin and joint involvement, despite limited evidence of its efficacy in controlled clinical trials for slowing the progression of joint damage in PsA.^2,9-11 Methotrexate can be given orally or subcutaneously (SC) every week. Routine laboratory monitoring is required given the known effects of MTX on liver and bone marrow suppression. Clinical monitoring is needed as well due to its well-known risk for pulmonary toxicity and teratogenicity.²

Leflunomide is another traditional oral DMARD that is administered daily. It has be shown to be effective in PsA, with only a modest effect in improving skin lesions.¹² Laboratory monitoring is identical to that required with MTX. Adverse effects (AEs) include diarrhea and increased risk of elevated transaminases.⁹ Sulfasalazine (SSZ) is also used as a traditional DMARD and shown to have an effective clinical response in treating peripheral arthritis but not in axial or skin disease.^9,12 Not all studies have shown effective responses to SSZ. The primary AE is gastrointestinal, making this a frequently discontinued medication.² Cyclosporine is more commonly used in psoriasis but can be used on its own or with MTX for treating patients with PsA.¹⁰ It is often not tolerated well and frequently discontinued, due to major AEs, including hypertension and renal dysfunction.^2,10

These traditional DMARDs are usually given for 3 to 6 months.¹³ After this initial period, the patient’s clinical response is reassessed, and the need for changing therapy to another DMARD or biologic is determined.

Biologic Therapies

With the discovery of TNFα as a potent cytokine in inflammatory arthritis came a new class of medications that has provided patients and providers with more effective treatment options. This category of medications is known as tumor necrosis factor inhibitors (TNFis). Five medications have been developed that target TNFα, each in its own way: etanercept, infliximab, adalimumab, golimumab, and certrolizumab pegol. These medications were initially studied in patients with rheumatoid arthritis, with further clinical trials performed for treatment of PsA. Each is prescribed differently: Adalimumab and certrolizumab are given SC every 2 weeks, etanercept is given weekly, and golimumab is given once a month. Infliximab is the only medication prescribed as an infusion, which is administered every 8 weeks after receiving 3 loading doses.

Studies have shown that all TNFis are effective in treating PsA: improving joint disease activity, inhibiting progression of structural damage, and improving function and overall quality of life^.10 The TNFi drugs also improve psoriasis along with dactylitis, enthesitis, and nail changes.¹³ Patients with
axial disease benefit from TNFi, but the evidence of TNFi effectiveness is extrapolated from studies in axial spondyloarthritis.^13,14 Tumor necrosis
factor inhibitors can be used as monotherapy, although there is some evidence for using TNFi drugs with MTX in PsA. Combination therapy can potentially prolong the survival of the TNFi drug or prevent formation of antidrug antibodies.^14,15

The current evidence for monotherapy vs combination therapy in patients with PsA is not consistent, and no formal guidelines have been developed to guide physicians one way or another. The TNFi drugs are generally well tolerated, although the patient needs to learn how to self-inject if given the SC route. Adverse effects include infusion or injection site reactions and infections. Prior to starting a TNFi, it is prudent to screen for latent tuberculosis infection as well as hepatitis B and C, given the risk of reactivation. Clinical response is monitored for 3 months, and if remission or low disease activity is not reached, a different TNFi may be tried.¹³ Importantly, patients receiving infliximab without clinical improvement in 3 months may have their dose and frequency increased before switching to an alternative TNFi. Some studies show that a trial of a second TNFi has a less potent response than with a first TNFi, and the drug survival is shorter in duration.¹³

One of the newest biologic agents approved for treating PsA is ustekinumab, a human monoclonal antibody (MAB) that inhibits receptor binding of cytokines interleukin (IL)-12 and IL-23. These cytokines have been identified in patients with psoriasis and PsA as further promoting inflammation. Ustekinumab recently received approval for the treatment of PsA and is given SC every 12 weeks after 2 initial doses. Further studies have also confirmed ustekinumab significantly suppressed radiographic progression of joint damage in patients with active PsA.¹⁵ Notable AEs included infections, but there have been no cases of tuberculosis or opportunistic infections reported.¹⁶

The most recent FDA-approved medication for PsA is apremilast. It is a phosphodiesterase-4 inhibitor, which causes the suppression of other proinflammatory mediators and cytokines active in the immune system.¹⁰ It is given orally, uptitrating the doses over a few days until the twice-daily maintenance dosing is achieved. It is generally well tolerated with nausea and diarrhea as the most common AEs.¹⁷ Further studies need to be conducted to assess whether this agent is able to prevent or decrease joint damage.

Other potential treatment options are currently undergoing trials to assess their efficacy and safety in treating psoriasis and/or PsA. One class targets the IL-17 cytokine pathway and includes brodalumab, a monoclonal antibody (MAB) anti-IL-17 receptor, ixekizumab and secukinumab, both MABs anti-IL-17A. Secukinumab has already received FDA approval for the treatment of plaque psoriasis (2015). Other agents currently undergoing trials are abatacept (cytotoxic T-lymphocyte antigen 4-Ig), a recombinant human fusion protein that blocks the co-stimulation of T cells9 and tofacitinib, a janus kinase inhibitor.¹⁸ Early studies show patients achieving a response with these medications, but further long-term studies are needed.¹⁹

Treatment Recommendations

Treatment approaches differ for patients with only psoriasis and patients with psoriasis and PsA, although some treatment modalities overlap. Recommendations for PsA have been set for each domain affected (Figure 2). The treatment approach is based on several factors, including severity or the degree of disease activity, any joint damage, and the patient’s comorbidities. Certain comorbidities are associated with PsA—cardiovascular disease, obesity, metabolic syndrome, diabetes, inflammatory bowel disease, fatty liver disease, chronic viral infections (hepatitis B or C), and kidney disease. These comorbidities can affect the choice of therapy for the patient.^20,21 Other factors affecting treatment choices include patient preference regarding mode and frequency of administration of the medication, potential AEs, requirements of laboratory monitoring or regular doctor visits, and the cost of medications.^10,22

In treating patients with psoriasis and PsA, a multidisciplinary approach is needed. Because skin manifestations of psoriasis usually develop prior to arthritis symptoms in most patients, primary care providers and dermatologists can routinely screen patients for arthritis.¹⁰ Rheumatologists can confirm arthritis and musculoskeletal involvement, but the treatment and management of these patients will need to be in collaboration with a dermatologist. The goal of comanagement is to choose appropriate therapies that may be able to treat both the skin and musculoskeletal manifestations.

A multidisciplinary approach can also limit polypharmacy, control costs, and reduce AEs. The existence of VA combined rheumatology and dermatology clinics makes this an invaluable experience for the veteran with direct and focused patient management. In addition to controlling disease activity, the goal of treatment is to improve function and the patient’s quality of life, halting structural joint damage to prevent disability.¹⁰ Physical and occupational therapies play an important role in PsA management as does exercise. Patients should be educated about their disease and treatment options discussed. It is also important to identify and reduce significant comorbidities, such as cardiovascular disease, to decrease mortality and improve life expectancy.¹⁰

Conclusion

Psoriasis is a distinct disease entity but can occur along with extracutaneous features. Patients with psoriasis need to be screened for PsA, and it is important to diagnose PsA early to begin appropriate treatment. Disease activity, severity, and any joint damage will determine therapy. Over the past decade, new treatment options have become available that provide more choices for patients than those of the standard DMARDs. The TNFis have proven to be efficacious in treating psoriasis and PsA. With a better understanding of pathogenesis of these diseases, new medications have been discovered targeting different parts of the immune system involved in dysregulation and ultimately inflammation. Additional clinical research is needed to provide physicians with more effective ways of controlling these diseases. Ultimately, the management of PsA is not solely based on medications, but the authors’ VA experience highlights the importance of a multispecialty approach to the management of psoriasis and PsA.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Psoriasis is a commonly encountered systemic condition, usually presenting with chronic erythematous plaques with an overlying silvery white scale.¹ Extracutaneous manifestations, such as joint or spine (axial) involvement, can occur along with this skin disorder. Psoriatic arthritis (PsA) is a chronic, heterogeneous disorder characterized by inflammatory arthritis in patients with psoriasis.^2,3 Until recently treatment of PsA has been limited to a few medications.

Continuing investigations into the pathogenesis of PsA have revealed new treatment options, targeting molecules at the cellular level. Over the past few years, additional medications have been approved, giving providers more options in treating patients with psoriasis and PsA. Furthermore, a multidisciplinary approach by both rheumatologists and dermatologists in evaluating and managing patients at VA clinics has helped optimize care of these patients by providing timely evaluation and treatment at the same visit.

Psoriasis Presentation and Diagnosis

Genetic predisposition and certain environmental factors (trauma, infection, medications) are known to trigger psoriasis, which can present in many forms.⁴ Chronic plaque psoriasis, or psoriasis vulgaris, is the most common skin pattern with a classic presentation of sharply demarcated erythematous plaques with overlying silver scale.⁴ It affects the scalp, lower back, umbilicus, genitals, and extensor surfaces of the elbows and knees. Guttate psoriasis is recognized by its multiple small papules and plaques in a droplike pattern. Pustular psoriasis usually presents with widespread pustules. On the other hand, erythrodermic psoriasis manifests as diffuse erythema involving multiple skin areas.⁴ Erythematous psoriatic plaques, which are predominantly in the intertriginous areas or skin folds (inguinal, perineal, genital, intergluteal, axillary, or inframammary), are known as inverse psoriasis.

A psoriasis diagnosis is made by taking a history and a physical examination. Rarely, a skin biopsy of the lesions will be required for an atypical presentation. The course of the disease is unpredictable, variable, and dependent on the type of psoriasis. Psoriasis vulgaris is a chronic condition, whereas guttate psoriasis is often self-limited.⁴ A poorer prognosis is seen in patients with erythrodermic and generalized pustular psoriasis.⁴

Psoriatic Arthritis Presentation, Classification, and Diagnosis

Prevalence of PsA is not known, but it is estimated to be from 0.3% to 1% of the U.S. population. In the psoriasis population, PsA is reported to range from 7% to 42%,³ although more recently, these numbers have been found to be in the 15% to 25% range (unpublished observations). This type of inflammatory arthritis can develop at any age but usually is seen between the ages of 30 and 50 years, with men being affected equally or a little more than are women.³ Clinical symptoms usually include pain and stiffness of affected joints, > 30 minutes of morning stiffness, and fatigue.

The presentation of joint involvement can vary widely. Five subtypes of arthritis were identified by Moll and Wright in 1973, which included arthritis with predominant distal interphalangeal involvement, arthritis mutilans, symmetric polyarthritis (> 5 joints), asymmetric oligoarthritis (1-4 joints), and predominant spondylitis (axial).⁵ Patients with PsA may also have evidence of spondylitis (inflammation of vertebra) or sacroiliitis (inflammation of the sacroiliac joints) with back pain > 3 months, hip or buttock pain, nighttime pain, or pain that improves with activity but worsens with rest.6 The cervical spine is more frequently involved than is the lumbar spine in patients with PsA.³

Psoriatic arthritis can have a diverse presentation not only with the affected joints, but also involving nails, tendons, and ligaments. An entire digit of the hand or foot can become swollen, known as dactylitis, or “sausage digit.” Inflammation at the insertion of tendons or ligaments, known as enthesitis, is also seen in PsA. Most common sites include the Achilles tendon, plantar fascia, and ligamentous insertions around the pelvic bones.³ Nail changes that are typically seen in patients with psoriasis can be seen in PsA as well, including pitting, ridging, hyperkeratosis, and onycholysis.³ Ocular inflammation which is classically seen with other spondyloarthropathies, can be seen in patients with PsA as well, frequently manifesting as conjunctivitis.^2,3

Psoriatic arthritis is commonly classified under the broader category of seronegative spondyloarthropathies, given the low frequency of a positive rheumatoid factor.³ Currently, there are no laboratory tests that can help with a PsA diagnosis.³ Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein may be elevated, indicating active inflammation.

Radiographic data, such as X-rays of the hands and feet, can confirm the clinical distribution of joint involvement and show evidence of erosive changes. Further destructive changes include osteolysis (bone resorption) that may cause the classic pencil-in-cup deformity, typically seen in arthritis mutilans (Figure 1).³ Other radiographic evidence of PsA can include proliferative changes with new bone formation seen along the shaft of the metacarpal and metatarsal bones.³ Patients with axial involvement can have evidence of asymmetric sacroiliitis, which can be seen on radiographs. Asymmetric syndesmophytes, or bony outgrowths, can also be seen throughout the axial spine.³

Diagnosis is based on the history and clinical presentation of a patient with the help of laboratory work and radiographs. Other forms of arthritis (such as rheumatoid arthritis, crystal arthropathies, osteoarthritis, ankylosing spondylitis) should be excluded. Given the varied presentation of PsA, classification criteria have been developed to assist in clinical research. Classification Criteria for Psoriatic Arthritis (CASPAR) have been developed and validated as an adjunct to clinical diagnosis and a source for clinical research (Table 1).⁷ Musculoskeletal pain in patients with psoriasis can be due to causes other than PsA, such as osteoarthritis and gout. A close working relationship in a combined rheumatology/dermatology clinic is vital to providing optimal diagnostic and treatment care for patients with psoriasis and PsA.⁸

The etiology of PsA is currently unknown, although many genetic, environmental, and immunologic factors have been identified that play a role in the pathogenesis of the disease. In this setting, immunologically mediated processes that cause inflammation occur in the synovium of joints, enthesium, bone, and skin of patients with PsA.⁹ Studies have shown that activated T cells and T-cell–derived cytokines play an important role in cartilage degradation, joint damage, and stimulating bone resorption.⁹

One particular proinflammatory cytokine, tumor necrosis factor alpha (TNFα), has been the target for many treatment modalities for several years. With new and ongoing research into the PsA pathogenesis, other treatment options have been discovered, targeting different cytokines and T cells that are involved in the disease process. This has led to drug trials and recent FDA approvals of several new medications, which provide further options for clinicians in managing and treating PsA.

Management of Psoriasis

Choice of therapy is determined by the extent and severity of psoriasis (body surface area [BSA] involvement) as well as the patient’s comorbidities and preferences.⁴ Providers have a wide spectrum of effective therapies to prescribe, both topically and systemically. Topical therapy options include corticosteroids, vitamin D3 and analogs (calcipotriene), anthralin, tar, tazarotene (third-generation retinoid), and calcineurin inhibitors (tacromlimus).⁴ Phototherapy with or without saltwater baths helps improve skin lesions.

These treatments are beneficial for all patients with psoriasis, but the disease can be controlled with monotherapy in patients with mild-to-moderate disease (< 10% BSA). Limiting these treatment options are some long-term effects of the medications because of the potential for toxicity as well as decreasing efficacy of the medication over time.4 For patients with more BSA involvement (> 10%), systemic treatment options include methotrexate (MTX), systemic retinoids (acitretin), calcineurin inhibitors (cyclosporine), and biologics. Many of these systemic treatment options overlap for patients with both psoriasis and PsA, and topical treatments can be used adjunctively to better control the skin disease.

Management of Psoriatic Arthritis

It is important to identify PsA and begin treatment early, because it has been shown that patients tend to fare better in their disease course if treated early.¹⁰ Once a diagnosis of PsA is made, disease activity needs to be determined by clinical examination and radiographs of joints. Scoring systems, by assessing bone erosions and deformities on joint radiographs, can aide with this assessment. Based on these, PsA can be categorized as mild, moderate, or severe. Several disease activity measures that have been developed for clinical trials in monitoring of disease activity can be used as an aide in the office setting. These tools are still being studied to determine the optimal measure of disease activity.

NSAIDs and Glucocorticoids

Controlling inflammation and providing pain relief are the primary treatment goals for patients with PsA. In mild, predominantly peripheral PsA, nonsteroidal antiinflammatory drugs (NSAIDs) can be used, but they do not halt disease progression. If the disease is controlled and not progressing, NSAIDs may be used as the only treatment. However, if symptoms persist and/or there is more joint involvement, the next level of therapy should be sought. Intra-articular corticosteroids for symptomatic relief can be given if only a few joints are affected. Oral corticosteroids can be used occasionally in patients with multiple joint aches, but they are typically avoided or tapered slowly to avoid worsening the patient’s skin psoriasis or having it evolve into a more severe form, such as pustular psoriasis.¹⁰ All these treatments can alleviate symptoms, but they do not prevent the progression of disease.

Disease-Modifying Antirheumatic Drugs

For patients who fail NSAIDs or present initially with more joint involvement (polyarthritis or > 5 swollen joints), traditional disease-modifying antirheumatic drugs (DMARDs) should be started (Table 2). Methotrexate is one of the first-line DMARD prescriptions. It is commonly used because of its effectiveness in treating both skin and joint involvement, despite limited evidence of its efficacy in controlled clinical trials for slowing the progression of joint damage in PsA.^2,9-11 Methotrexate can be given orally or subcutaneously (SC) every week. Routine laboratory monitoring is required given the known effects of MTX on liver and bone marrow suppression. Clinical monitoring is needed as well due to its well-known risk for pulmonary toxicity and teratogenicity.²

Leflunomide is another traditional oral DMARD that is administered daily. It has be shown to be effective in PsA, with only a modest effect in improving skin lesions.¹² Laboratory monitoring is identical to that required with MTX. Adverse effects (AEs) include diarrhea and increased risk of elevated transaminases.⁹ Sulfasalazine (SSZ) is also used as a traditional DMARD and shown to have an effective clinical response in treating peripheral arthritis but not in axial or skin disease.^9,12 Not all studies have shown effective responses to SSZ. The primary AE is gastrointestinal, making this a frequently discontinued medication.² Cyclosporine is more commonly used in psoriasis but can be used on its own or with MTX for treating patients with PsA.¹⁰ It is often not tolerated well and frequently discontinued, due to major AEs, including hypertension and renal dysfunction.^2,10

These traditional DMARDs are usually given for 3 to 6 months.¹³ After this initial period, the patient’s clinical response is reassessed, and the need for changing therapy to another DMARD or biologic is determined.

Biologic Therapies

With the discovery of TNFα as a potent cytokine in inflammatory arthritis came a new class of medications that has provided patients and providers with more effective treatment options. This category of medications is known as tumor necrosis factor inhibitors (TNFis). Five medications have been developed that target TNFα, each in its own way: etanercept, infliximab, adalimumab, golimumab, and certrolizumab pegol. These medications were initially studied in patients with rheumatoid arthritis, with further clinical trials performed for treatment of PsA. Each is prescribed differently: Adalimumab and certrolizumab are given SC every 2 weeks, etanercept is given weekly, and golimumab is given once a month. Infliximab is the only medication prescribed as an infusion, which is administered every 8 weeks after receiving 3 loading doses.

Studies have shown that all TNFis are effective in treating PsA: improving joint disease activity, inhibiting progression of structural damage, and improving function and overall quality of life^.10 The TNFi drugs also improve psoriasis along with dactylitis, enthesitis, and nail changes.¹³ Patients with
axial disease benefit from TNFi, but the evidence of TNFi effectiveness is extrapolated from studies in axial spondyloarthritis.^13,14 Tumor necrosis
factor inhibitors can be used as monotherapy, although there is some evidence for using TNFi drugs with MTX in PsA. Combination therapy can potentially prolong the survival of the TNFi drug or prevent formation of antidrug antibodies.^14,15

The current evidence for monotherapy vs combination therapy in patients with PsA is not consistent, and no formal guidelines have been developed to guide physicians one way or another. The TNFi drugs are generally well tolerated, although the patient needs to learn how to self-inject if given the SC route. Adverse effects include infusion or injection site reactions and infections. Prior to starting a TNFi, it is prudent to screen for latent tuberculosis infection as well as hepatitis B and C, given the risk of reactivation. Clinical response is monitored for 3 months, and if remission or low disease activity is not reached, a different TNFi may be tried.¹³ Importantly, patients receiving infliximab without clinical improvement in 3 months may have their dose and frequency increased before switching to an alternative TNFi. Some studies show that a trial of a second TNFi has a less potent response than with a first TNFi, and the drug survival is shorter in duration.¹³

One of the newest biologic agents approved for treating PsA is ustekinumab, a human monoclonal antibody (MAB) that inhibits receptor binding of cytokines interleukin (IL)-12 and IL-23. These cytokines have been identified in patients with psoriasis and PsA as further promoting inflammation. Ustekinumab recently received approval for the treatment of PsA and is given SC every 12 weeks after 2 initial doses. Further studies have also confirmed ustekinumab significantly suppressed radiographic progression of joint damage in patients with active PsA.¹⁵ Notable AEs included infections, but there have been no cases of tuberculosis or opportunistic infections reported.¹⁶

The most recent FDA-approved medication for PsA is apremilast. It is a phosphodiesterase-4 inhibitor, which causes the suppression of other proinflammatory mediators and cytokines active in the immune system.¹⁰ It is given orally, uptitrating the doses over a few days until the twice-daily maintenance dosing is achieved. It is generally well tolerated with nausea and diarrhea as the most common AEs.¹⁷ Further studies need to be conducted to assess whether this agent is able to prevent or decrease joint damage.

Other potential treatment options are currently undergoing trials to assess their efficacy and safety in treating psoriasis and/or PsA. One class targets the IL-17 cytokine pathway and includes brodalumab, a monoclonal antibody (MAB) anti-IL-17 receptor, ixekizumab and secukinumab, both MABs anti-IL-17A. Secukinumab has already received FDA approval for the treatment of plaque psoriasis (2015). Other agents currently undergoing trials are abatacept (cytotoxic T-lymphocyte antigen 4-Ig), a recombinant human fusion protein that blocks the co-stimulation of T cells9 and tofacitinib, a janus kinase inhibitor.¹⁸ Early studies show patients achieving a response with these medications, but further long-term studies are needed.¹⁹

Treatment Recommendations

Treatment approaches differ for patients with only psoriasis and patients with psoriasis and PsA, although some treatment modalities overlap. Recommendations for PsA have been set for each domain affected (Figure 2). The treatment approach is based on several factors, including severity or the degree of disease activity, any joint damage, and the patient’s comorbidities. Certain comorbidities are associated with PsA—cardiovascular disease, obesity, metabolic syndrome, diabetes, inflammatory bowel disease, fatty liver disease, chronic viral infections (hepatitis B or C), and kidney disease. These comorbidities can affect the choice of therapy for the patient.^20,21 Other factors affecting treatment choices include patient preference regarding mode and frequency of administration of the medication, potential AEs, requirements of laboratory monitoring or regular doctor visits, and the cost of medications.^10,22

In treating patients with psoriasis and PsA, a multidisciplinary approach is needed. Because skin manifestations of psoriasis usually develop prior to arthritis symptoms in most patients, primary care providers and dermatologists can routinely screen patients for arthritis.¹⁰ Rheumatologists can confirm arthritis and musculoskeletal involvement, but the treatment and management of these patients will need to be in collaboration with a dermatologist. The goal of comanagement is to choose appropriate therapies that may be able to treat both the skin and musculoskeletal manifestations.

A multidisciplinary approach can also limit polypharmacy, control costs, and reduce AEs. The existence of VA combined rheumatology and dermatology clinics makes this an invaluable experience for the veteran with direct and focused patient management. In addition to controlling disease activity, the goal of treatment is to improve function and the patient’s quality of life, halting structural joint damage to prevent disability.¹⁰ Physical and occupational therapies play an important role in PsA management as does exercise. Patients should be educated about their disease and treatment options discussed. It is also important to identify and reduce significant comorbidities, such as cardiovascular disease, to decrease mortality and improve life expectancy.¹⁰

Conclusion

Psoriasis is a distinct disease entity but can occur along with extracutaneous features. Patients with psoriasis need to be screened for PsA, and it is important to diagnose PsA early to begin appropriate treatment. Disease activity, severity, and any joint damage will determine therapy. Over the past decade, new treatment options have become available that provide more choices for patients than those of the standard DMARDs. The TNFis have proven to be efficacious in treating psoriasis and PsA. With a better understanding of pathogenesis of these diseases, new medications have been discovered targeting different parts of the immune system involved in dysregulation and ultimately inflammation. Additional clinical research is needed to provide physicians with more effective ways of controlling these diseases. Ultimately, the management of PsA is not solely based on medications, but the authors’ VA experience highlights the importance of a multispecialty approach to the management of psoriasis and PsA.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Psoriasis is a commonly encountered systemic condition, usually presenting with chronic erythematous plaques with an overlying silvery white scale.¹ Extracutaneous manifestations, such as joint or spine (axial) involvement, can occur along with this skin disorder. Psoriatic arthritis (PsA) is a chronic, heterogeneous disorder characterized by inflammatory arthritis in patients with psoriasis.^2,3 Until recently treatment of PsA has been limited to a few medications.

Continuing investigations into the pathogenesis of PsA have revealed new treatment options, targeting molecules at the cellular level. Over the past few years, additional medications have been approved, giving providers more options in treating patients with psoriasis and PsA. Furthermore, a multidisciplinary approach by both rheumatologists and dermatologists in evaluating and managing patients at VA clinics has helped optimize care of these patients by providing timely evaluation and treatment at the same visit.

Psoriasis Presentation and Diagnosis

Genetic predisposition and certain environmental factors (trauma, infection, medications) are known to trigger psoriasis, which can present in many forms.⁴ Chronic plaque psoriasis, or psoriasis vulgaris, is the most common skin pattern with a classic presentation of sharply demarcated erythematous plaques with overlying silver scale.⁴ It affects the scalp, lower back, umbilicus, genitals, and extensor surfaces of the elbows and knees. Guttate psoriasis is recognized by its multiple small papules and plaques in a droplike pattern. Pustular psoriasis usually presents with widespread pustules. On the other hand, erythrodermic psoriasis manifests as diffuse erythema involving multiple skin areas.⁴ Erythematous psoriatic plaques, which are predominantly in the intertriginous areas or skin folds (inguinal, perineal, genital, intergluteal, axillary, or inframammary), are known as inverse psoriasis.

A psoriasis diagnosis is made by taking a history and a physical examination. Rarely, a skin biopsy of the lesions will be required for an atypical presentation. The course of the disease is unpredictable, variable, and dependent on the type of psoriasis. Psoriasis vulgaris is a chronic condition, whereas guttate psoriasis is often self-limited.⁴ A poorer prognosis is seen in patients with erythrodermic and generalized pustular psoriasis.⁴

Psoriatic Arthritis Presentation, Classification, and Diagnosis

Prevalence of PsA is not known, but it is estimated to be from 0.3% to 1% of the U.S. population. In the psoriasis population, PsA is reported to range from 7% to 42%,³ although more recently, these numbers have been found to be in the 15% to 25% range (unpublished observations). This type of inflammatory arthritis can develop at any age but usually is seen between the ages of 30 and 50 years, with men being affected equally or a little more than are women.³ Clinical symptoms usually include pain and stiffness of affected joints, > 30 minutes of morning stiffness, and fatigue.

The presentation of joint involvement can vary widely. Five subtypes of arthritis were identified by Moll and Wright in 1973, which included arthritis with predominant distal interphalangeal involvement, arthritis mutilans, symmetric polyarthritis (> 5 joints), asymmetric oligoarthritis (1-4 joints), and predominant spondylitis (axial).⁵ Patients with PsA may also have evidence of spondylitis (inflammation of vertebra) or sacroiliitis (inflammation of the sacroiliac joints) with back pain > 3 months, hip or buttock pain, nighttime pain, or pain that improves with activity but worsens with rest.6 The cervical spine is more frequently involved than is the lumbar spine in patients with PsA.³

Psoriatic arthritis can have a diverse presentation not only with the affected joints, but also involving nails, tendons, and ligaments. An entire digit of the hand or foot can become swollen, known as dactylitis, or “sausage digit.” Inflammation at the insertion of tendons or ligaments, known as enthesitis, is also seen in PsA. Most common sites include the Achilles tendon, plantar fascia, and ligamentous insertions around the pelvic bones.³ Nail changes that are typically seen in patients with psoriasis can be seen in PsA as well, including pitting, ridging, hyperkeratosis, and onycholysis.³ Ocular inflammation which is classically seen with other spondyloarthropathies, can be seen in patients with PsA as well, frequently manifesting as conjunctivitis.^2,3

Psoriatic arthritis is commonly classified under the broader category of seronegative spondyloarthropathies, given the low frequency of a positive rheumatoid factor.³ Currently, there are no laboratory tests that can help with a PsA diagnosis.³ Acute-phase reactants such as erythrocyte sedimentation rate and C-reactive protein may be elevated, indicating active inflammation.

Radiographic data, such as X-rays of the hands and feet, can confirm the clinical distribution of joint involvement and show evidence of erosive changes. Further destructive changes include osteolysis (bone resorption) that may cause the classic pencil-in-cup deformity, typically seen in arthritis mutilans (Figure 1).³ Other radiographic evidence of PsA can include proliferative changes with new bone formation seen along the shaft of the metacarpal and metatarsal bones.³ Patients with axial involvement can have evidence of asymmetric sacroiliitis, which can be seen on radiographs. Asymmetric syndesmophytes, or bony outgrowths, can also be seen throughout the axial spine.³

Diagnosis is based on the history and clinical presentation of a patient with the help of laboratory work and radiographs. Other forms of arthritis (such as rheumatoid arthritis, crystal arthropathies, osteoarthritis, ankylosing spondylitis) should be excluded. Given the varied presentation of PsA, classification criteria have been developed to assist in clinical research. Classification Criteria for Psoriatic Arthritis (CASPAR) have been developed and validated as an adjunct to clinical diagnosis and a source for clinical research (Table 1).⁷ Musculoskeletal pain in patients with psoriasis can be due to causes other than PsA, such as osteoarthritis and gout. A close working relationship in a combined rheumatology/dermatology clinic is vital to providing optimal diagnostic and treatment care for patients with psoriasis and PsA.⁸

The etiology of PsA is currently unknown, although many genetic, environmental, and immunologic factors have been identified that play a role in the pathogenesis of the disease. In this setting, immunologically mediated processes that cause inflammation occur in the synovium of joints, enthesium, bone, and skin of patients with PsA.⁹ Studies have shown that activated T cells and T-cell–derived cytokines play an important role in cartilage degradation, joint damage, and stimulating bone resorption.⁹

One particular proinflammatory cytokine, tumor necrosis factor alpha (TNFα), has been the target for many treatment modalities for several years. With new and ongoing research into the PsA pathogenesis, other treatment options have been discovered, targeting different cytokines and T cells that are involved in the disease process. This has led to drug trials and recent FDA approvals of several new medications, which provide further options for clinicians in managing and treating PsA.

Management of Psoriasis

Choice of therapy is determined by the extent and severity of psoriasis (body surface area [BSA] involvement) as well as the patient’s comorbidities and preferences.⁴ Providers have a wide spectrum of effective therapies to prescribe, both topically and systemically. Topical therapy options include corticosteroids, vitamin D3 and analogs (calcipotriene), anthralin, tar, tazarotene (third-generation retinoid), and calcineurin inhibitors (tacromlimus).⁴ Phototherapy with or without saltwater baths helps improve skin lesions.

These treatments are beneficial for all patients with psoriasis, but the disease can be controlled with monotherapy in patients with mild-to-moderate disease (< 10% BSA). Limiting these treatment options are some long-term effects of the medications because of the potential for toxicity as well as decreasing efficacy of the medication over time.4 For patients with more BSA involvement (> 10%), systemic treatment options include methotrexate (MTX), systemic retinoids (acitretin), calcineurin inhibitors (cyclosporine), and biologics. Many of these systemic treatment options overlap for patients with both psoriasis and PsA, and topical treatments can be used adjunctively to better control the skin disease.

Management of Psoriatic Arthritis

It is important to identify PsA and begin treatment early, because it has been shown that patients tend to fare better in their disease course if treated early.¹⁰ Once a diagnosis of PsA is made, disease activity needs to be determined by clinical examination and radiographs of joints. Scoring systems, by assessing bone erosions and deformities on joint radiographs, can aide with this assessment. Based on these, PsA can be categorized as mild, moderate, or severe. Several disease activity measures that have been developed for clinical trials in monitoring of disease activity can be used as an aide in the office setting. These tools are still being studied to determine the optimal measure of disease activity.

NSAIDs and Glucocorticoids

Controlling inflammation and providing pain relief are the primary treatment goals for patients with PsA. In mild, predominantly peripheral PsA, nonsteroidal antiinflammatory drugs (NSAIDs) can be used, but they do not halt disease progression. If the disease is controlled and not progressing, NSAIDs may be used as the only treatment. However, if symptoms persist and/or there is more joint involvement, the next level of therapy should be sought. Intra-articular corticosteroids for symptomatic relief can be given if only a few joints are affected. Oral corticosteroids can be used occasionally in patients with multiple joint aches, but they are typically avoided or tapered slowly to avoid worsening the patient’s skin psoriasis or having it evolve into a more severe form, such as pustular psoriasis.¹⁰ All these treatments can alleviate symptoms, but they do not prevent the progression of disease.

Disease-Modifying Antirheumatic Drugs

For patients who fail NSAIDs or present initially with more joint involvement (polyarthritis or > 5 swollen joints), traditional disease-modifying antirheumatic drugs (DMARDs) should be started (Table 2). Methotrexate is one of the first-line DMARD prescriptions. It is commonly used because of its effectiveness in treating both skin and joint involvement, despite limited evidence of its efficacy in controlled clinical trials for slowing the progression of joint damage in PsA.^2,9-11 Methotrexate can be given orally or subcutaneously (SC) every week. Routine laboratory monitoring is required given the known effects of MTX on liver and bone marrow suppression. Clinical monitoring is needed as well due to its well-known risk for pulmonary toxicity and teratogenicity.²

Leflunomide is another traditional oral DMARD that is administered daily. It has be shown to be effective in PsA, with only a modest effect in improving skin lesions.¹² Laboratory monitoring is identical to that required with MTX. Adverse effects (AEs) include diarrhea and increased risk of elevated transaminases.⁹ Sulfasalazine (SSZ) is also used as a traditional DMARD and shown to have an effective clinical response in treating peripheral arthritis but not in axial or skin disease.^9,12 Not all studies have shown effective responses to SSZ. The primary AE is gastrointestinal, making this a frequently discontinued medication.² Cyclosporine is more commonly used in psoriasis but can be used on its own or with MTX for treating patients with PsA.¹⁰ It is often not tolerated well and frequently discontinued, due to major AEs, including hypertension and renal dysfunction.^2,10

These traditional DMARDs are usually given for 3 to 6 months.¹³ After this initial period, the patient’s clinical response is reassessed, and the need for changing therapy to another DMARD or biologic is determined.

Biologic Therapies

With the discovery of TNFα as a potent cytokine in inflammatory arthritis came a new class of medications that has provided patients and providers with more effective treatment options. This category of medications is known as tumor necrosis factor inhibitors (TNFis). Five medications have been developed that target TNFα, each in its own way: etanercept, infliximab, adalimumab, golimumab, and certrolizumab pegol. These medications were initially studied in patients with rheumatoid arthritis, with further clinical trials performed for treatment of PsA. Each is prescribed differently: Adalimumab and certrolizumab are given SC every 2 weeks, etanercept is given weekly, and golimumab is given once a month. Infliximab is the only medication prescribed as an infusion, which is administered every 8 weeks after receiving 3 loading doses.

Studies have shown that all TNFis are effective in treating PsA: improving joint disease activity, inhibiting progression of structural damage, and improving function and overall quality of life^.10 The TNFi drugs also improve psoriasis along with dactylitis, enthesitis, and nail changes.¹³ Patients with
axial disease benefit from TNFi, but the evidence of TNFi effectiveness is extrapolated from studies in axial spondyloarthritis.^13,14 Tumor necrosis
factor inhibitors can be used as monotherapy, although there is some evidence for using TNFi drugs with MTX in PsA. Combination therapy can potentially prolong the survival of the TNFi drug or prevent formation of antidrug antibodies.^14,15

The current evidence for monotherapy vs combination therapy in patients with PsA is not consistent, and no formal guidelines have been developed to guide physicians one way or another. The TNFi drugs are generally well tolerated, although the patient needs to learn how to self-inject if given the SC route. Adverse effects include infusion or injection site reactions and infections. Prior to starting a TNFi, it is prudent to screen for latent tuberculosis infection as well as hepatitis B and C, given the risk of reactivation. Clinical response is monitored for 3 months, and if remission or low disease activity is not reached, a different TNFi may be tried.¹³ Importantly, patients receiving infliximab without clinical improvement in 3 months may have their dose and frequency increased before switching to an alternative TNFi. Some studies show that a trial of a second TNFi has a less potent response than with a first TNFi, and the drug survival is shorter in duration.¹³

One of the newest biologic agents approved for treating PsA is ustekinumab, a human monoclonal antibody (MAB) that inhibits receptor binding of cytokines interleukin (IL)-12 and IL-23. These cytokines have been identified in patients with psoriasis and PsA as further promoting inflammation. Ustekinumab recently received approval for the treatment of PsA and is given SC every 12 weeks after 2 initial doses. Further studies have also confirmed ustekinumab significantly suppressed radiographic progression of joint damage in patients with active PsA.¹⁵ Notable AEs included infections, but there have been no cases of tuberculosis or opportunistic infections reported.¹⁶

The most recent FDA-approved medication for PsA is apremilast. It is a phosphodiesterase-4 inhibitor, which causes the suppression of other proinflammatory mediators and cytokines active in the immune system.¹⁰ It is given orally, uptitrating the doses over a few days until the twice-daily maintenance dosing is achieved. It is generally well tolerated with nausea and diarrhea as the most common AEs.¹⁷ Further studies need to be conducted to assess whether this agent is able to prevent or decrease joint damage.

Other potential treatment options are currently undergoing trials to assess their efficacy and safety in treating psoriasis and/or PsA. One class targets the IL-17 cytokine pathway and includes brodalumab, a monoclonal antibody (MAB) anti-IL-17 receptor, ixekizumab and secukinumab, both MABs anti-IL-17A. Secukinumab has already received FDA approval for the treatment of plaque psoriasis (2015). Other agents currently undergoing trials are abatacept (cytotoxic T-lymphocyte antigen 4-Ig), a recombinant human fusion protein that blocks the co-stimulation of T cells9 and tofacitinib, a janus kinase inhibitor.¹⁸ Early studies show patients achieving a response with these medications, but further long-term studies are needed.¹⁹

Treatment Recommendations

Treatment approaches differ for patients with only psoriasis and patients with psoriasis and PsA, although some treatment modalities overlap. Recommendations for PsA have been set for each domain affected (Figure 2). The treatment approach is based on several factors, including severity or the degree of disease activity, any joint damage, and the patient’s comorbidities. Certain comorbidities are associated with PsA—cardiovascular disease, obesity, metabolic syndrome, diabetes, inflammatory bowel disease, fatty liver disease, chronic viral infections (hepatitis B or C), and kidney disease. These comorbidities can affect the choice of therapy for the patient.^20,21 Other factors affecting treatment choices include patient preference regarding mode and frequency of administration of the medication, potential AEs, requirements of laboratory monitoring or regular doctor visits, and the cost of medications.^10,22

In treating patients with psoriasis and PsA, a multidisciplinary approach is needed. Because skin manifestations of psoriasis usually develop prior to arthritis symptoms in most patients, primary care providers and dermatologists can routinely screen patients for arthritis.¹⁰ Rheumatologists can confirm arthritis and musculoskeletal involvement, but the treatment and management of these patients will need to be in collaboration with a dermatologist. The goal of comanagement is to choose appropriate therapies that may be able to treat both the skin and musculoskeletal manifestations.

A multidisciplinary approach can also limit polypharmacy, control costs, and reduce AEs. The existence of VA combined rheumatology and dermatology clinics makes this an invaluable experience for the veteran with direct and focused patient management. In addition to controlling disease activity, the goal of treatment is to improve function and the patient’s quality of life, halting structural joint damage to prevent disability.¹⁰ Physical and occupational therapies play an important role in PsA management as does exercise. Patients should be educated about their disease and treatment options discussed. It is also important to identify and reduce significant comorbidities, such as cardiovascular disease, to decrease mortality and improve life expectancy.¹⁰

Conclusion

Psoriasis is a distinct disease entity but can occur along with extracutaneous features. Patients with psoriasis need to be screened for PsA, and it is important to diagnose PsA early to begin appropriate treatment. Disease activity, severity, and any joint damage will determine therapy. Over the past decade, new treatment options have become available that provide more choices for patients than those of the standard DMARDs. The TNFis have proven to be efficacious in treating psoriasis and PsA. With a better understanding of pathogenesis of these diseases, new medications have been discovered targeting different parts of the immune system involved in dysregulation and ultimately inflammation. Additional clinical research is needed to provide physicians with more effective ways of controlling these diseases. Ultimately, the management of PsA is not solely based on medications, but the authors’ VA experience highlights the importance of a multispecialty approach to the management of psoriasis and PsA.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects— before administering pharmacologic therapy to patients.

Over the past 2 decades, an increasing number of rheumatologists have progressively incorporated ultrasound (US) as an invaluable diagnostic and monitoring tool into their clinical and research practice.^1,2 This imaging modality has become an established aid incorporated into the clinical evaluation of periarticular and articular structures involved in the diagnosis of several rheumatic disorders.

Ultrasound is a safe, noninvasive, patient-friendly imaging modality with a lack of contraindications and free of ionizing radiation. It allows real-time evaluation with dynamic assessment in a multiplanar view, assessment of multiple targets, and lower cost compared with magnetic resonance imaging (MRI) or computerized tomography scan. Above all, for the rheumatologist, US provides real-time scanning of all peripheral joints as many times as is required at the time of consultation. It is of great advantage in the assessment of a wide spectrum of abnormalities in rheumatic diseases with the potential of point-of-care imaging modality in the clinical evaluation and management of the patient. It facilitates a direct correlation between imaging findings and clinical data that improves the approach to a wide range of rheumatic diseases, from acute to chronic inflammatory arthritis, crystalline arthropathies, osteoarthritis (OA), spondyloarthropathies (SpA), vasculitis, and soft tissue syndromes. In addition, US is a bedside tool for performing accurate and safe diagnostic arthrocentesis, injections, and synovial biopsies.^3,4

Recently, a gradual attempt has been made to incorporate US into rheumatology disease classification or diagnostic criteria for rheumatoid arthritis (RA), polymyalgia rheumatica, gout, calcium pyrophosphate deposition disease (CPPD), and Sjögren’s syndrome.^5-10 Furthermore, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have produced evidence and expert opinion-based recommendations on the use of US in the clinical management of rheumatic diseases.^10-12 This article highlights the most common applications of US for assessment and management of different rheumatic diseases frequently encountered at the VAMC rheumatology inpatient and outpatient clinical service.

Evaluation of Inflammatory Arthritis

In RA and any other inflammatory arthritis, US has been used for the detection of joint effusions, synovitis, bone erosions, and tendon and enthesis involvement.^11,12 Ultrasound B-mode and power Doppler (PD) techniques have demonstrated a consistent and relevant role in optimizing the diagnosis, assessing the inflammatory activity, monitoring response to therapy, and predicting the inflammatory arthritis outcomes (Figures 1-3).^10-12 Ultrasound provides real-time information about the status of the synovial membrane, tendons, cartilage, bursae, and cortical bones, allowing an accurate assessment of the degree of inflammatory process in periarticular and articular tissues. Also, US can provide details about the characteristics of the collected fluid (ie, effusion or synovial hypertrophy), which is fundamental for the correct interpretation of the pathologic joint and/or soft tissue processes. The inflammatory process can be assessed by using PD mode, which detects and quantifies the vascular changes in the pannus due to vasodilation and the increased blood flow characteristic of active inflammation.^13,14

The Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) study group developed standardized sonopathologic definitions and scanning methods to be used in the daily rheumatologic practice and clinical trials (Table 1).¹⁵ Furthermore, it developed a semiquantitative scale to assess the degree of synovitis in US B-mode and PD mode (Table 2).¹⁵

The use of US to find subclinical synovitis in patients with RA considered to be in clinical remission is a new issue.¹⁶ Some reports have demonstrated progressive joint damage in these patients with evidence of active inflammation on PDUS despite clinical remission.^17,18 More prospective studies are required to provide a better understanding of the long-term effects of residual inflammation and the proper long-term treatment of these patients. Furthermore, the PD signal has been shown to be superior to the Disease Activity Score 28 (DAS-28) in evaluating disease activity, particularly in predicting joint damage.¹⁸

Ultrasound may be considered the gold standard imaging tool for the assessment of tendons in inflammatory arthritis and includes the detection of tenosynovitis and anatomical damage represented by the loss of the normal fibrillar echotexture and loss of definition of the tendon margins, which may occur in early disease.^19,20 Tenosynovitis of the extensor carpi ulnaris (ECU) detected by US has been shown to be an independent predictive factor of erosive joint damage, suggesting that ECU tenosynovitis represents a useful ultrasonographic landmark in the diagnosis of early RA.²¹

The availability of new nonbiologic and biologic therapies for inflammatory arthritis has raised the importance of identifying early changes, such as the detection of early erosions, which portend a poor long-term prognosis. The capability of US in identifying this lesion at an earlier stage compared with conventional radiography (CR) has allowed the early diagnosis and treatment of these patients before irreversible joint destruction occurs.²² In spite of all the supportive evidence of US utility in RA, it is not considered among the mandatory diagnostic criteria in the ACR/EULAR classification criteria for RA.⁵ Still, the addition of US findings to these criteria has increased the number of patients who fulfilled the 1987 ACR classification criteria for RA after 18 months of follow-up.²³ Despite extensive evidence of its utility in the diagnosis and monitoring of RA, further studies are still needed.

Spondyloarthritis

Similar to RA, SpA discloses sonographic findings of inflammatory arthritis; however, with more entheseal and tenosynovium involvement. Ultrasound has also been used in the early identification of characteristic changes of the skin and nail tissues, which can aid the global assessment of this heterogeneous disease, especially in psoriatic arthritis (PsA). The most common locations of enthesitis in SpA are the quadriceps and the Achilles enthesis.^24,25

Although US offers detailed imaging for the assessment of both tendons and enthesis, there is a lack of literature evaluating dactylitis. The OMERACT group recently released a composite measure of activity and severity of US dactylitis, which included newly defined elementary US lesions that may discern dactylitis of a digit.^26,27 Ultrasound has been compared with MRI in the detection of SpA-related synovitis of the hands and feet and has demonstrated competitive diagnostic sensitivity.²⁸ Ultrasound also shows higher sensitivity in detecting synovitis of the hands and feet compared with clinical examination and CR in PsA.^28,29 Unfortunately, there are no strongly validated US findings that can aid in the differential diagnosis of PsA against other chronic inflammatory arthritides. The presence of peritendinous extensor tendon inflammation was a highly specific sonographic feature of PsA, because it was present in 66% of metacarpophalangeal (MCP) joints as the only US sign of inflammation compared with patients with RA.³⁰

Another application of US is in the evaluation of subclinical inflammation at the enthesis in patients with a history of psoriasis without prior history of PsA.^27,31 In those patients with psoriatic nail changes, more subclinical enthesitis was found compared with patients with psoriasis without nail involvement.³² Furthermore, subclinical joint inflammation has also been described.³³ These findings suggest a possible predictive value in patients with psoriasis who should be monitored on a regular basis, because they are at risk of developing PsA.

Subclinical enthesitis by US imaging has been described in patients with recurrent anterior uveitis and inflammatory bowel disease.^34,35 In cases where SpA is suspected but diagnostic criteria are not fulfilled, the presence of one enthesis with increased PD signal highly predicts the eventual development of SpA.³⁶ Therefore, B-mode and PD evaluations of the entheses are critical in the identification of patients who are at an increased risk of developing SpA.³⁷ Treatment monitoring is performed by using a US scoring system in a follow-up evaluation of patients with PsA. Some of the scoring systems have evaluated changes in B-mode US lesions (enthesis and soft tissues, such as skin and nails), whereas others focus on changes in the PD signal.^37,38

The Five Targets Power Doppler for Psoriatic Disease PD scoring system comprises the assessment of PD signal in the joint, tendon with synovial sheath, enthesis, skin, and nails. Each of the targets is scored from 0 to 3 points, with a maximum of 15 total points. Some studies have shown that PDUS can provide valuable information in the evaluation of psoriatic plaques and onychopathy in patients with psoriasis and PsA.³⁹ The detection of a PD signal within the dermis and nail bed is equivalent to active inflammation in these sites.^39-41 However, further studies with larger cohorts proving inter- and intra-observer reliability are necessary to consolidate these findings and comfortably apply them in clinical practice.

Osteoarthritis

Increasingly US is studied for its validity and reliability in evaluating periarticular soft tissue and cartilage changes in knee OA. The associated US findings include a high prevalence of synovitis with a low prevalence of a PD signal, the presence of osteophytes, and joint space narrowing.^42,43 Increased PD signal, synovial hypertrophy, and joint effusion were observed in patients with radiographically erosive OA compared with those with radiographically nonerosive OA.⁴⁴

Bone erosions and inflammatory changes are also frequently detected by US in both erosive and nodal hand OA.⁴⁵ Compared with MRI, US has shown a good to excellent correlation in the assessment of osteophytes, bone erosions, synovitis, and tenosynovitis in erosive and hand nodal OA.⁴⁶ In comparison with CR, US has shown to have a higher sensitivity in the assessment of bony erosions, osteophytes, and space narrowing.⁴⁷ Ultrasound is able to detect changes in the earlier stages of cartilage erosion in OA, characterized by loss of the sharp contour and variations in the echogenicity of the cartilage matrix, asymmetric shrinkage, and ultimately the disappearance of the cartilaginous band, which is more evident in the later stages of OA.⁴⁵

Similar to RA management, US has been used to monitor disease activity and response to OA treatment. Patients who received intra-articular hyaluronic acid or intramuscular methylprednisolone for OA treatment were found to have a decrease of PD signal intensity and synovial effusion posttreatment.48 One could extrapolate these findings and conclude that US could be an additional tool for monitoring disease activity and assessing response to local and systemic treatments in OA.

Crystalline Arthropathies

Ultrasound application to crystal diseases facilitates the identification of microcrystalline deposits within the synovial membrane (joints), cartilage (both hyaline cartilage and fibrocartilage), and periarticular tissues (tendons, bursae, and soft tissues). Crystals appear as hyperechogenic spots of different sizes and shapes that can be seen in both articular and periarticular tissues.^49,50 The crystal deposition pattern on hyaline cartilage allows the differentiation between monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPP) crystals. The MSU crystals are deposited at the chondrosynovial (or superficial) margin of the hyaline cartilage and described sonographically as the double contour sign in gout, whereas CPP crystals are deposited within the intermediate layer of the hyaline cartilage and are seen as hyperechoic spots frequently described as rosary beads on US.^6,49,50

Other important sites that can be evaluated to determine the presence of CPP crystals include the menisci, symphysis pubis, and triangular fibrocartilage at the wrists, hips, and shoulders. Recent EULAR recommendations have incorporated US as part of the diagnostic imaging modality for the diagnosis of CPPD and more recently for gout.^6,51 Tophi are seen as MSU precipitates deposited in the joint cavity, tendons, and/or periarticular tissues such as bursae. They can show different echogenic signal. Soft tophi can demonstrate high PD signal due to high vascularization. On the other hand, hard tophi are hyperechoic on B-mode due to the presence of calcification, which does not allow passage of US waves, creating postacoustic shadowing.⁸ Studies have evaluated the predictive role of US in evaluating patients with asymptomatic hyperuricemia without any prior history of crystal-related joint disease and found tophaceous deposits in the triceps and patellar and quadriceps tendons.^52-55 Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout.^56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features.^56-57 Larger cohort studies are needed to confirm these findings.

An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. Therefore, diagnostic arthrocentesis, Gram stain, and culture, as well as evaluation of crystals under polarized microscopy, are still recommended.

Therapeutic Interventions

Real-time visualization of the injection needle by US allows reliable placement of the needle tip in the tissue or cavity of interest. Multiple studies have shown the low accuracy of palpation-guided injection for reaching the site of interest.^58,59 Some studies have shown a higher response rate to US-guided injections compared with palpation-guided as well as a higher rate of successful aspirations and clinical outcomes. Meta-analyses have demonstrated improved treatment response with the use of US-guided procedures compared with blinded injections.^60,61 Ultrasound-guided interventions are performed in both peripheral and axial joints.⁶² The most common US-guided procedures at the VA rheumatology clinic include arthrocentesis and intra-articular corticosteroid injections of small and medium-sized joints, such as MCP joints, elbows, wrists, and ankles.

Conclusions

Ultrasound is becoming a relevant part of rheumatology practice and research and can be regarded as a feasible and effective imaging technique that can allow real-time recognition of early anatomical changes, provide careful guidance for aspiration, and monitor local and/or systemic treatment response at the joint, tendon, enthesis, nail, and skin levels. Ultrasound is a user-friendly imaging modality readily applied at the bedside and considered an extension of the rheumatologist's physical examination.

The success of US depends on the individual operator. For this reason, structured educational programs during fellowship training programs and an efficient competency assessment system would facilitate proper implementation of US in rheumatology practice as performed by some but not all institutions.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Over the past 2 decades, an increasing number of rheumatologists have progressively incorporated ultrasound (US) as an invaluable diagnostic and monitoring tool into their clinical and research practice.^1,2 This imaging modality has become an established aid incorporated into the clinical evaluation of periarticular and articular structures involved in the diagnosis of several rheumatic disorders.

Ultrasound is a safe, noninvasive, patient-friendly imaging modality with a lack of contraindications and free of ionizing radiation. It allows real-time evaluation with dynamic assessment in a multiplanar view, assessment of multiple targets, and lower cost compared with magnetic resonance imaging (MRI) or computerized tomography scan. Above all, for the rheumatologist, US provides real-time scanning of all peripheral joints as many times as is required at the time of consultation. It is of great advantage in the assessment of a wide spectrum of abnormalities in rheumatic diseases with the potential of point-of-care imaging modality in the clinical evaluation and management of the patient. It facilitates a direct correlation between imaging findings and clinical data that improves the approach to a wide range of rheumatic diseases, from acute to chronic inflammatory arthritis, crystalline arthropathies, osteoarthritis (OA), spondyloarthropathies (SpA), vasculitis, and soft tissue syndromes. In addition, US is a bedside tool for performing accurate and safe diagnostic arthrocentesis, injections, and synovial biopsies.^3,4

Recently, a gradual attempt has been made to incorporate US into rheumatology disease classification or diagnostic criteria for rheumatoid arthritis (RA), polymyalgia rheumatica, gout, calcium pyrophosphate deposition disease (CPPD), and Sjögren’s syndrome.^5-10 Furthermore, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have produced evidence and expert opinion-based recommendations on the use of US in the clinical management of rheumatic diseases.^10-12 This article highlights the most common applications of US for assessment and management of different rheumatic diseases frequently encountered at the VAMC rheumatology inpatient and outpatient clinical service.

Evaluation of Inflammatory Arthritis

In RA and any other inflammatory arthritis, US has been used for the detection of joint effusions, synovitis, bone erosions, and tendon and enthesis involvement.^11,12 Ultrasound B-mode and power Doppler (PD) techniques have demonstrated a consistent and relevant role in optimizing the diagnosis, assessing the inflammatory activity, monitoring response to therapy, and predicting the inflammatory arthritis outcomes (Figures 1-3).^10-12 Ultrasound provides real-time information about the status of the synovial membrane, tendons, cartilage, bursae, and cortical bones, allowing an accurate assessment of the degree of inflammatory process in periarticular and articular tissues. Also, US can provide details about the characteristics of the collected fluid (ie, effusion or synovial hypertrophy), which is fundamental for the correct interpretation of the pathologic joint and/or soft tissue processes. The inflammatory process can be assessed by using PD mode, which detects and quantifies the vascular changes in the pannus due to vasodilation and the increased blood flow characteristic of active inflammation.^13,14

The Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) study group developed standardized sonopathologic definitions and scanning methods to be used in the daily rheumatologic practice and clinical trials (Table 1).¹⁵ Furthermore, it developed a semiquantitative scale to assess the degree of synovitis in US B-mode and PD mode (Table 2).¹⁵

The use of US to find subclinical synovitis in patients with RA considered to be in clinical remission is a new issue.¹⁶ Some reports have demonstrated progressive joint damage in these patients with evidence of active inflammation on PDUS despite clinical remission.^17,18 More prospective studies are required to provide a better understanding of the long-term effects of residual inflammation and the proper long-term treatment of these patients. Furthermore, the PD signal has been shown to be superior to the Disease Activity Score 28 (DAS-28) in evaluating disease activity, particularly in predicting joint damage.¹⁸

Ultrasound may be considered the gold standard imaging tool for the assessment of tendons in inflammatory arthritis and includes the detection of tenosynovitis and anatomical damage represented by the loss of the normal fibrillar echotexture and loss of definition of the tendon margins, which may occur in early disease.^19,20 Tenosynovitis of the extensor carpi ulnaris (ECU) detected by US has been shown to be an independent predictive factor of erosive joint damage, suggesting that ECU tenosynovitis represents a useful ultrasonographic landmark in the diagnosis of early RA.²¹

The availability of new nonbiologic and biologic therapies for inflammatory arthritis has raised the importance of identifying early changes, such as the detection of early erosions, which portend a poor long-term prognosis. The capability of US in identifying this lesion at an earlier stage compared with conventional radiography (CR) has allowed the early diagnosis and treatment of these patients before irreversible joint destruction occurs.²² In spite of all the supportive evidence of US utility in RA, it is not considered among the mandatory diagnostic criteria in the ACR/EULAR classification criteria for RA.⁵ Still, the addition of US findings to these criteria has increased the number of patients who fulfilled the 1987 ACR classification criteria for RA after 18 months of follow-up.²³ Despite extensive evidence of its utility in the diagnosis and monitoring of RA, further studies are still needed.

Spondyloarthritis

Similar to RA, SpA discloses sonographic findings of inflammatory arthritis; however, with more entheseal and tenosynovium involvement. Ultrasound has also been used in the early identification of characteristic changes of the skin and nail tissues, which can aid the global assessment of this heterogeneous disease, especially in psoriatic arthritis (PsA). The most common locations of enthesitis in SpA are the quadriceps and the Achilles enthesis.^24,25

Although US offers detailed imaging for the assessment of both tendons and enthesis, there is a lack of literature evaluating dactylitis. The OMERACT group recently released a composite measure of activity and severity of US dactylitis, which included newly defined elementary US lesions that may discern dactylitis of a digit.^26,27 Ultrasound has been compared with MRI in the detection of SpA-related synovitis of the hands and feet and has demonstrated competitive diagnostic sensitivity.²⁸ Ultrasound also shows higher sensitivity in detecting synovitis of the hands and feet compared with clinical examination and CR in PsA.^28,29 Unfortunately, there are no strongly validated US findings that can aid in the differential diagnosis of PsA against other chronic inflammatory arthritides. The presence of peritendinous extensor tendon inflammation was a highly specific sonographic feature of PsA, because it was present in 66% of metacarpophalangeal (MCP) joints as the only US sign of inflammation compared with patients with RA.³⁰

Another application of US is in the evaluation of subclinical inflammation at the enthesis in patients with a history of psoriasis without prior history of PsA.^27,31 In those patients with psoriatic nail changes, more subclinical enthesitis was found compared with patients with psoriasis without nail involvement.³² Furthermore, subclinical joint inflammation has also been described.³³ These findings suggest a possible predictive value in patients with psoriasis who should be monitored on a regular basis, because they are at risk of developing PsA.

Subclinical enthesitis by US imaging has been described in patients with recurrent anterior uveitis and inflammatory bowel disease.^34,35 In cases where SpA is suspected but diagnostic criteria are not fulfilled, the presence of one enthesis with increased PD signal highly predicts the eventual development of SpA.³⁶ Therefore, B-mode and PD evaluations of the entheses are critical in the identification of patients who are at an increased risk of developing SpA.³⁷ Treatment monitoring is performed by using a US scoring system in a follow-up evaluation of patients with PsA. Some of the scoring systems have evaluated changes in B-mode US lesions (enthesis and soft tissues, such as skin and nails), whereas others focus on changes in the PD signal.^37,38

The Five Targets Power Doppler for Psoriatic Disease PD scoring system comprises the assessment of PD signal in the joint, tendon with synovial sheath, enthesis, skin, and nails. Each of the targets is scored from 0 to 3 points, with a maximum of 15 total points. Some studies have shown that PDUS can provide valuable information in the evaluation of psoriatic plaques and onychopathy in patients with psoriasis and PsA.³⁹ The detection of a PD signal within the dermis and nail bed is equivalent to active inflammation in these sites.^39-41 However, further studies with larger cohorts proving inter- and intra-observer reliability are necessary to consolidate these findings and comfortably apply them in clinical practice.

Osteoarthritis

Increasingly US is studied for its validity and reliability in evaluating periarticular soft tissue and cartilage changes in knee OA. The associated US findings include a high prevalence of synovitis with a low prevalence of a PD signal, the presence of osteophytes, and joint space narrowing.^42,43 Increased PD signal, synovial hypertrophy, and joint effusion were observed in patients with radiographically erosive OA compared with those with radiographically nonerosive OA.⁴⁴

Bone erosions and inflammatory changes are also frequently detected by US in both erosive and nodal hand OA.⁴⁵ Compared with MRI, US has shown a good to excellent correlation in the assessment of osteophytes, bone erosions, synovitis, and tenosynovitis in erosive and hand nodal OA.⁴⁶ In comparison with CR, US has shown to have a higher sensitivity in the assessment of bony erosions, osteophytes, and space narrowing.⁴⁷ Ultrasound is able to detect changes in the earlier stages of cartilage erosion in OA, characterized by loss of the sharp contour and variations in the echogenicity of the cartilage matrix, asymmetric shrinkage, and ultimately the disappearance of the cartilaginous band, which is more evident in the later stages of OA.⁴⁵

Similar to RA management, US has been used to monitor disease activity and response to OA treatment. Patients who received intra-articular hyaluronic acid or intramuscular methylprednisolone for OA treatment were found to have a decrease of PD signal intensity and synovial effusion posttreatment.48 One could extrapolate these findings and conclude that US could be an additional tool for monitoring disease activity and assessing response to local and systemic treatments in OA.

Crystalline Arthropathies

Ultrasound application to crystal diseases facilitates the identification of microcrystalline deposits within the synovial membrane (joints), cartilage (both hyaline cartilage and fibrocartilage), and periarticular tissues (tendons, bursae, and soft tissues). Crystals appear as hyperechogenic spots of different sizes and shapes that can be seen in both articular and periarticular tissues.^49,50 The crystal deposition pattern on hyaline cartilage allows the differentiation between monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPP) crystals. The MSU crystals are deposited at the chondrosynovial (or superficial) margin of the hyaline cartilage and described sonographically as the double contour sign in gout, whereas CPP crystals are deposited within the intermediate layer of the hyaline cartilage and are seen as hyperechoic spots frequently described as rosary beads on US.^6,49,50

Other important sites that can be evaluated to determine the presence of CPP crystals include the menisci, symphysis pubis, and triangular fibrocartilage at the wrists, hips, and shoulders. Recent EULAR recommendations have incorporated US as part of the diagnostic imaging modality for the diagnosis of CPPD and more recently for gout.^6,51 Tophi are seen as MSU precipitates deposited in the joint cavity, tendons, and/or periarticular tissues such as bursae. They can show different echogenic signal. Soft tophi can demonstrate high PD signal due to high vascularization. On the other hand, hard tophi are hyperechoic on B-mode due to the presence of calcification, which does not allow passage of US waves, creating postacoustic shadowing.⁸ Studies have evaluated the predictive role of US in evaluating patients with asymptomatic hyperuricemia without any prior history of crystal-related joint disease and found tophaceous deposits in the triceps and patellar and quadriceps tendons.^52-55 Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout.^56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features.^56-57 Larger cohort studies are needed to confirm these findings.

An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. Therefore, diagnostic arthrocentesis, Gram stain, and culture, as well as evaluation of crystals under polarized microscopy, are still recommended.

Therapeutic Interventions

Real-time visualization of the injection needle by US allows reliable placement of the needle tip in the tissue or cavity of interest. Multiple studies have shown the low accuracy of palpation-guided injection for reaching the site of interest.^58,59 Some studies have shown a higher response rate to US-guided injections compared with palpation-guided as well as a higher rate of successful aspirations and clinical outcomes. Meta-analyses have demonstrated improved treatment response with the use of US-guided procedures compared with blinded injections.^60,61 Ultrasound-guided interventions are performed in both peripheral and axial joints.⁶² The most common US-guided procedures at the VA rheumatology clinic include arthrocentesis and intra-articular corticosteroid injections of small and medium-sized joints, such as MCP joints, elbows, wrists, and ankles.

Conclusions

Ultrasound is becoming a relevant part of rheumatology practice and research and can be regarded as a feasible and effective imaging technique that can allow real-time recognition of early anatomical changes, provide careful guidance for aspiration, and monitor local and/or systemic treatment response at the joint, tendon, enthesis, nail, and skin levels. Ultrasound is a user-friendly imaging modality readily applied at the bedside and considered an extension of the rheumatologist's physical examination.

The success of US depends on the individual operator. For this reason, structured educational programs during fellowship training programs and an efficient competency assessment system would facilitate proper implementation of US in rheumatology practice as performed by some but not all institutions.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Over the past 2 decades, an increasing number of rheumatologists have progressively incorporated ultrasound (US) as an invaluable diagnostic and monitoring tool into their clinical and research practice.^1,2 This imaging modality has become an established aid incorporated into the clinical evaluation of periarticular and articular structures involved in the diagnosis of several rheumatic disorders.

Ultrasound is a safe, noninvasive, patient-friendly imaging modality with a lack of contraindications and free of ionizing radiation. It allows real-time evaluation with dynamic assessment in a multiplanar view, assessment of multiple targets, and lower cost compared with magnetic resonance imaging (MRI) or computerized tomography scan. Above all, for the rheumatologist, US provides real-time scanning of all peripheral joints as many times as is required at the time of consultation. It is of great advantage in the assessment of a wide spectrum of abnormalities in rheumatic diseases with the potential of point-of-care imaging modality in the clinical evaluation and management of the patient. It facilitates a direct correlation between imaging findings and clinical data that improves the approach to a wide range of rheumatic diseases, from acute to chronic inflammatory arthritis, crystalline arthropathies, osteoarthritis (OA), spondyloarthropathies (SpA), vasculitis, and soft tissue syndromes. In addition, US is a bedside tool for performing accurate and safe diagnostic arthrocentesis, injections, and synovial biopsies.^3,4

Recently, a gradual attempt has been made to incorporate US into rheumatology disease classification or diagnostic criteria for rheumatoid arthritis (RA), polymyalgia rheumatica, gout, calcium pyrophosphate deposition disease (CPPD), and Sjögren’s syndrome.^5-10 Furthermore, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have produced evidence and expert opinion-based recommendations on the use of US in the clinical management of rheumatic diseases.^10-12 This article highlights the most common applications of US for assessment and management of different rheumatic diseases frequently encountered at the VAMC rheumatology inpatient and outpatient clinical service.

Evaluation of Inflammatory Arthritis

In RA and any other inflammatory arthritis, US has been used for the detection of joint effusions, synovitis, bone erosions, and tendon and enthesis involvement.^11,12 Ultrasound B-mode and power Doppler (PD) techniques have demonstrated a consistent and relevant role in optimizing the diagnosis, assessing the inflammatory activity, monitoring response to therapy, and predicting the inflammatory arthritis outcomes (Figures 1-3).^10-12 Ultrasound provides real-time information about the status of the synovial membrane, tendons, cartilage, bursae, and cortical bones, allowing an accurate assessment of the degree of inflammatory process in periarticular and articular tissues. Also, US can provide details about the characteristics of the collected fluid (ie, effusion or synovial hypertrophy), which is fundamental for the correct interpretation of the pathologic joint and/or soft tissue processes. The inflammatory process can be assessed by using PD mode, which detects and quantifies the vascular changes in the pannus due to vasodilation and the increased blood flow characteristic of active inflammation.^13,14

The Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) study group developed standardized sonopathologic definitions and scanning methods to be used in the daily rheumatologic practice and clinical trials (Table 1).¹⁵ Furthermore, it developed a semiquantitative scale to assess the degree of synovitis in US B-mode and PD mode (Table 2).¹⁵

The use of US to find subclinical synovitis in patients with RA considered to be in clinical remission is a new issue.¹⁶ Some reports have demonstrated progressive joint damage in these patients with evidence of active inflammation on PDUS despite clinical remission.^17,18 More prospective studies are required to provide a better understanding of the long-term effects of residual inflammation and the proper long-term treatment of these patients. Furthermore, the PD signal has been shown to be superior to the Disease Activity Score 28 (DAS-28) in evaluating disease activity, particularly in predicting joint damage.¹⁸

Ultrasound may be considered the gold standard imaging tool for the assessment of tendons in inflammatory arthritis and includes the detection of tenosynovitis and anatomical damage represented by the loss of the normal fibrillar echotexture and loss of definition of the tendon margins, which may occur in early disease.^19,20 Tenosynovitis of the extensor carpi ulnaris (ECU) detected by US has been shown to be an independent predictive factor of erosive joint damage, suggesting that ECU tenosynovitis represents a useful ultrasonographic landmark in the diagnosis of early RA.²¹

The availability of new nonbiologic and biologic therapies for inflammatory arthritis has raised the importance of identifying early changes, such as the detection of early erosions, which portend a poor long-term prognosis. The capability of US in identifying this lesion at an earlier stage compared with conventional radiography (CR) has allowed the early diagnosis and treatment of these patients before irreversible joint destruction occurs.²² In spite of all the supportive evidence of US utility in RA, it is not considered among the mandatory diagnostic criteria in the ACR/EULAR classification criteria for RA.⁵ Still, the addition of US findings to these criteria has increased the number of patients who fulfilled the 1987 ACR classification criteria for RA after 18 months of follow-up.²³ Despite extensive evidence of its utility in the diagnosis and monitoring of RA, further studies are still needed.

Spondyloarthritis

Similar to RA, SpA discloses sonographic findings of inflammatory arthritis; however, with more entheseal and tenosynovium involvement. Ultrasound has also been used in the early identification of characteristic changes of the skin and nail tissues, which can aid the global assessment of this heterogeneous disease, especially in psoriatic arthritis (PsA). The most common locations of enthesitis in SpA are the quadriceps and the Achilles enthesis.^24,25

Although US offers detailed imaging for the assessment of both tendons and enthesis, there is a lack of literature evaluating dactylitis. The OMERACT group recently released a composite measure of activity and severity of US dactylitis, which included newly defined elementary US lesions that may discern dactylitis of a digit.^26,27 Ultrasound has been compared with MRI in the detection of SpA-related synovitis of the hands and feet and has demonstrated competitive diagnostic sensitivity.²⁸ Ultrasound also shows higher sensitivity in detecting synovitis of the hands and feet compared with clinical examination and CR in PsA.^28,29 Unfortunately, there are no strongly validated US findings that can aid in the differential diagnosis of PsA against other chronic inflammatory arthritides. The presence of peritendinous extensor tendon inflammation was a highly specific sonographic feature of PsA, because it was present in 66% of metacarpophalangeal (MCP) joints as the only US sign of inflammation compared with patients with RA.³⁰

Another application of US is in the evaluation of subclinical inflammation at the enthesis in patients with a history of psoriasis without prior history of PsA.^27,31 In those patients with psoriatic nail changes, more subclinical enthesitis was found compared with patients with psoriasis without nail involvement.³² Furthermore, subclinical joint inflammation has also been described.³³ These findings suggest a possible predictive value in patients with psoriasis who should be monitored on a regular basis, because they are at risk of developing PsA.

Subclinical enthesitis by US imaging has been described in patients with recurrent anterior uveitis and inflammatory bowel disease.^34,35 In cases where SpA is suspected but diagnostic criteria are not fulfilled, the presence of one enthesis with increased PD signal highly predicts the eventual development of SpA.³⁶ Therefore, B-mode and PD evaluations of the entheses are critical in the identification of patients who are at an increased risk of developing SpA.³⁷ Treatment monitoring is performed by using a US scoring system in a follow-up evaluation of patients with PsA. Some of the scoring systems have evaluated changes in B-mode US lesions (enthesis and soft tissues, such as skin and nails), whereas others focus on changes in the PD signal.^37,38

The Five Targets Power Doppler for Psoriatic Disease PD scoring system comprises the assessment of PD signal in the joint, tendon with synovial sheath, enthesis, skin, and nails. Each of the targets is scored from 0 to 3 points, with a maximum of 15 total points. Some studies have shown that PDUS can provide valuable information in the evaluation of psoriatic plaques and onychopathy in patients with psoriasis and PsA.³⁹ The detection of a PD signal within the dermis and nail bed is equivalent to active inflammation in these sites.^39-41 However, further studies with larger cohorts proving inter- and intra-observer reliability are necessary to consolidate these findings and comfortably apply them in clinical practice.

Osteoarthritis

Increasingly US is studied for its validity and reliability in evaluating periarticular soft tissue and cartilage changes in knee OA. The associated US findings include a high prevalence of synovitis with a low prevalence of a PD signal, the presence of osteophytes, and joint space narrowing.^42,43 Increased PD signal, synovial hypertrophy, and joint effusion were observed in patients with radiographically erosive OA compared with those with radiographically nonerosive OA.⁴⁴

Bone erosions and inflammatory changes are also frequently detected by US in both erosive and nodal hand OA.⁴⁵ Compared with MRI, US has shown a good to excellent correlation in the assessment of osteophytes, bone erosions, synovitis, and tenosynovitis in erosive and hand nodal OA.⁴⁶ In comparison with CR, US has shown to have a higher sensitivity in the assessment of bony erosions, osteophytes, and space narrowing.⁴⁷ Ultrasound is able to detect changes in the earlier stages of cartilage erosion in OA, characterized by loss of the sharp contour and variations in the echogenicity of the cartilage matrix, asymmetric shrinkage, and ultimately the disappearance of the cartilaginous band, which is more evident in the later stages of OA.⁴⁵

Similar to RA management, US has been used to monitor disease activity and response to OA treatment. Patients who received intra-articular hyaluronic acid or intramuscular methylprednisolone for OA treatment were found to have a decrease of PD signal intensity and synovial effusion posttreatment.48 One could extrapolate these findings and conclude that US could be an additional tool for monitoring disease activity and assessing response to local and systemic treatments in OA.

Crystalline Arthropathies

Ultrasound application to crystal diseases facilitates the identification of microcrystalline deposits within the synovial membrane (joints), cartilage (both hyaline cartilage and fibrocartilage), and periarticular tissues (tendons, bursae, and soft tissues). Crystals appear as hyperechogenic spots of different sizes and shapes that can be seen in both articular and periarticular tissues.^49,50 The crystal deposition pattern on hyaline cartilage allows the differentiation between monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPP) crystals. The MSU crystals are deposited at the chondrosynovial (or superficial) margin of the hyaline cartilage and described sonographically as the double contour sign in gout, whereas CPP crystals are deposited within the intermediate layer of the hyaline cartilage and are seen as hyperechoic spots frequently described as rosary beads on US.^6,49,50

Other important sites that can be evaluated to determine the presence of CPP crystals include the menisci, symphysis pubis, and triangular fibrocartilage at the wrists, hips, and shoulders. Recent EULAR recommendations have incorporated US as part of the diagnostic imaging modality for the diagnosis of CPPD and more recently for gout.^6,51 Tophi are seen as MSU precipitates deposited in the joint cavity, tendons, and/or periarticular tissues such as bursae. They can show different echogenic signal. Soft tophi can demonstrate high PD signal due to high vascularization. On the other hand, hard tophi are hyperechoic on B-mode due to the presence of calcification, which does not allow passage of US waves, creating postacoustic shadowing.⁸ Studies have evaluated the predictive role of US in evaluating patients with asymptomatic hyperuricemia without any prior history of crystal-related joint disease and found tophaceous deposits in the triceps and patellar and quadriceps tendons.^52-55 Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout.^56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features.^56-57 Larger cohort studies are needed to confirm these findings.

An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. Therefore, diagnostic arthrocentesis, Gram stain, and culture, as well as evaluation of crystals under polarized microscopy, are still recommended.

Therapeutic Interventions

Real-time visualization of the injection needle by US allows reliable placement of the needle tip in the tissue or cavity of interest. Multiple studies have shown the low accuracy of palpation-guided injection for reaching the site of interest.^58,59 Some studies have shown a higher response rate to US-guided injections compared with palpation-guided as well as a higher rate of successful aspirations and clinical outcomes. Meta-analyses have demonstrated improved treatment response with the use of US-guided procedures compared with blinded injections.^60,61 Ultrasound-guided interventions are performed in both peripheral and axial joints.⁶² The most common US-guided procedures at the VA rheumatology clinic include arthrocentesis and intra-articular corticosteroid injections of small and medium-sized joints, such as MCP joints, elbows, wrists, and ankles.

Conclusions

Ultrasound is becoming a relevant part of rheumatology practice and research and can be regarded as a feasible and effective imaging technique that can allow real-time recognition of early anatomical changes, provide careful guidance for aspiration, and monitor local and/or systemic treatment response at the joint, tendon, enthesis, nail, and skin levels. Ultrasound is a user-friendly imaging modality readily applied at the bedside and considered an extension of the rheumatologist's physical examination.

The success of US depends on the individual operator. For this reason, structured educational programs during fellowship training programs and an efficient competency assessment system would facilitate proper implementation of US in rheumatology practice as performed by some but not all institutions.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Asthma is a chronic inflammatory disorder of the airways that leads to airflow obstruction and bronchial hyperresponsiveness. Clinical features of asthma include episodic cough, wheeze, and dyspnea, which may resolve with avoidance of triggers or therapy. Characteristic triggers of asthma are irritanttype airway exposures, including cold air, exercise, various environmental allergens, and work-related exposures. Work-related exposures are the etiology for occupational asthma and work-exacerbated asthma, accounting for up to 25% of adult-onset asthma.¹ It is imperative that clinicians evaluate the clinical history, pulmonary function testing, and response to prior therapies when caring for patients with asthma.

Asthma is common in active-duty service members, despite the diagnosis limiting entrance into the military, and there is potential for significant rates of underdiagnosis among new recruits.² Recent changes in military medical guidelines have allowed service members with well controlled asthma to remain on active duty.³ This potentially increases the number of service members with compromised respiratory status, which is concerning in light of the past decade of deployment to southwest Asia (SWA) and ongoing investigations into potential deployment-related irritant respiratory exposures.

Diagnosis

An accurate initial diagnosis is a critical starting point in the management of asthma. Many diseases can mimic asthma, including vocal cord dysfunction, chronic obstructive pulmonary disease (COPD), congestive heart failure, sarcoidosis, allergic bronchopulmonary aspergillosis
(ABPA), and eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (Table 1).⁴ Asthma-mimics, in particular ABPA and EGPA, are often diagnosed via careful longitudinal follow-up.

Characteristic symptoms of asthma include cough, wheeze, dyspnea, chest tightness, and sputum production. Symptoms should be described systematically in terms of onset, frequency, duration, diurnal variability, and seasonality. A careful review of systems should be conducted to exclude conditions such as COPD, pulmonary emboli, congestive heart failure, viral syndromes, acute infection, or hypersensitivity pneumonitis. Patients must be queried (carefully and often repeatedly) about potential triggers, including physical activity, hobbies, pets (including any animals owned by the patient, family members, or living on the property), and occupation.

Physical examination may reveal presence of nasal polyps, nasal mucosal swelling, increased secretions, wheezing, a prolonged expiratory phase, atopic dermatitis, or eczema. Further cardiac evaluation with transthoracic echocardiography may be considered in patients with a heart murmur. Digital clubbing is not characteristic of asthma and should prompt investigation of alternative inflammatory disease (connective tissue disease, interstitial lung disease, or bronchiectasis).

Pulmonary function testing including spirometry and bronchodilator response should be performed as demonstration of airflow limitation is crucial for the diagnosis of asthma.⁴ Spirometry should be performed in accordance with published standards and documented in the patient's medical record. Airflow limitation should be described in accordance with the Third National Health and Nutrition Examination Survey (NHANES III) references values as recommended by the American Thoracic Society and the European Respiratory Society (ATS/ERS) guidelines.^5-7 Obstruction is defined as an forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio less than the fifth percentile of the
normal distribution (lower limit of normal). Bronchodilator testing should also be performed to establish presence and degree of response to inhaled bronchodilator medication. A12% increase in the FEV1 with an absolute increase of 200 mL is considered significant in adults.⁷

It is important to note that although a positive bronchodilator response is highly suggestive of asthma in the appropriate clinical circumstance, it is not required for diagnosis, and inhaled bronchodilators may be useful in disease management even in the absence of a positive response. Patients with nonspecific reductions in the FVC, with symptoms not consistent with asthma, or not responding to typical asthma therapy are more likely to have been falsely diagnosed. These patients should have lung volumes and diffusion capacity of carbon monoxide measured to evaluate for other potential etiologies (eg, parenchymal lung disease, pulmonary vascular disease).⁴

Bronchoprovocation testing is useful for demonstrating airway hyperresponsiveness in a patient with symptoms suggestive of asthma, particularly those with normal baseline spirometry. Patients should have testing performed and interpreted in accordance with ATS
standards.⁸ Although methacholine challenge testing is preferred, other methods including cold air or eucapnic hyperventilation are also established. Exercise challenge testing, although less sensitive, remains a useful tool, particularly in patients with primarily exertional symptoms. It is important to note that a positive bronchoprovocation test result may occur in other conditions. Whereas a positive test is consistent with asthma, a negative test may be more useful to exclude the diagnosis^.8 Finally, chest imaging with plain film radiographs (posteroanterior and lateral views) is important to exclude parenchymal lung disease or mediastinal disorders. Further imaging with computed tomography is not indicated in the absence of atypical clinical features (such as abnormal plain films or failure to respond to therapy).

Management

The initial management of asthma in based on severity and follows a stepwise progression according to the 2007 National Asthma Education and Prevention Program.⁹ Severity is determined by the following factors: symptoms in the past 2 to 4 weeks, pulmonary function testing, and number of exacerbations requiring oral glucocorticoids (Table 2).

The initiation of therapy is based on the assessment of severity (Table 3). Patients with intermittent asthma are treated initially with short-acting beta-agonists (SABA) alone. Patients with known triggers are instructed to use beta-agonists about 20 minutes prior to a known trigger such as exercise.^4,9 For a patient with mild persistent asthma, the preferred controller medication is a low-dose inhaled corticosteroid (ICS). If a patient has moderate persistent asthma, the preferred controller medication becomes a lowdose ICS plus a long-acting beta agonist (LABA) or a medium-dose ICS. Severe persistent patients are treated with a medium-dose ICS and a LABA or a high-dose ICS.^4,9 In patients who need additional therapy beyond that described here, providers may consider adjunctive therapy with theophylline, leukotriene receptor antagonists (such as montelukast), or cromolyn/nedocromil.^4,9 If a patient has severe persistent asthma, anti-IgE therapy omalizumab can be considered if serum IgE levels are within the established range (30-700 IU/mL).¹⁰

Chronic asthma management relies on assessment and monitoring of functional impairment and response to therapy over time. Impairment is best assessed using a validated questionnaire assessing nighttime awakenings; frequency of as-needed bronchodilator therapy; limitation in home, school, or work activities; and perception of control or peak flow monitoring.⁴ One questionnaire that has been validated in the outpatient setting (as well as for home use via mail or telephone) is the Asthma Control Test.^11-14 The history obtained in clinic should assess risk factors for future exacerbations, such as the use of oral glucocorticoids, emergency department visits, hospitalizations, and admissions to the intensive care unit. For patients whose symptoms are not well controlled, a step up in therapy of one level should be performed. Therapy can be continued or stepped down (to minimize adverse effects) in those with adequate control.

Comorbid Conditions

Asthma management should also address comorbid conditions, including gastroesophageal reflux disease (GERD), allergic rhinosinusitis, obesity, and obstructive sleep apnea (OSA). Gastroesophageal reflux disease is common in asthmatics, and treatment may reduce exacerbations and symptoms, particularly in severe asthma.¹⁵ Allergic rhinitis/sinusitis is also common, and treatment may improve respiratory symptoms. Obesity is associated with an increased risk of developing asthma and may be associated with increased asthma severity.¹⁶ Patients with asthma and comorbid OSA should be encouraged to use continuous positive airway pressure (CPAP) with regular compliance (> 4 hours per night on > 70% of nights).¹⁷ Optimally, the goal for CPAP use should be 7 to 8 hours per night. Finally, patients with asthma are at higher risk for depression and other behavioral disorders, which may lead to poor compliance with therapy, adversely impacting disease severity and efficacy of medical care.¹⁸

Triggers

The avoidance of triggers may reduce the need for controller medications. Inhaled allergens or irritants (tobacco or wood smoke) may be suggested by a history of worsening at home or in the workplace (or during the work week).⁹ Allergy testing may be considered for identification of allergens— particularly indoor allergens such as dust mites, animal dander, molds, mice, and cockroaches. Nonselective beta blockers, aspirin, nonsteroidal anti-inflammatory drugs, or dietary sulfites may produce significant exacerbations in some patients with asthma. Administration of the flu vaccine is indicated in all asthma patients, and pneumococcal vaccination is indicated in all adult patients requiring controller medication due to significant risk of complications with pneumococcal infection or influenza.⁴

Patient Education

Patient education is an integral part of asthma management. Patients should be educated on roles of medications, appropriate technique for using a metered dose inhaler and spacer, self-monitoring of disease, identification of triggers and environmental control measures, and a plan for care during exacerbations. Patient education programs have been shown to be effective in reducing hospitalizations.¹⁹ Use of valved holding chambers is preferred.⁴ Investigation and education into the role of allergens in the patient’s disease is recommended. However, there is insufficient evidence to advocate a single specific avoidance strategy. Comprehensive, as opposed to limited, strategies are recommended. Immunotherapy is effective for patients with persistent asthma and identified inhaled allergen sensitivities.⁴ All patients should be queried about smoking history and advised strongly to quit smoking.

Pharmacotherapy

Medications used for asthma primarily include inhaled bronchodilators and ICS when controller therapy is required. Short-acting beta agonists should be used for quick relief of symptoms and can be used preemptively for triggers. The frequency of SABA use should be queried to assess control. In addition, patients should be instructed to seek medical attention should a SABA fail to achieve a quick and sustained response. Inhaled corticosteroids should be used as a first-line treatment to control persistent asthma with initial dosing based on severity. Long-acting beta agonists are the preferred add-on to ICS therapy for patients whose symptoms are not controlled with an ICS. Long-acting beta agonists should not be used for acute symptoms or without an ICS, regardless of asthma stage. They carry an FDA boxed warning regarding increased risk of severe asthma exacerbations and asthma-related deaths.²⁰

Leukotriene modifiers may provide benefit and should be used in stepwise fashion as an alternative to LABA in appropriately selected patients. Cromolyn may be considered as alternative to ICS in mild persistent asthma, but is rarely used. Theophylline may be considered if other options have not been successful. Serum levels should be maintained between 5 and 15 μg/mL, and routine monitoring is indicated due to significant toxicities and medication interactions. Omalizumab can be considered as adjunctive therapy in patients with elevated IgE in the prescribed target ranges (30-700 IU/mL) and sensitivity to relevant allergies. In patients with chronic, refractory symptoms there may be a role for oral corticosteroid therapy outside the setting of acute exacerbations. This decision should be individualized and balance the
benefits obtained from therapy against the risks of chronic steroid use (impaired glucose control, immunosuppression, poor wound healing, adverse effects on bone density, and adverse psychiatric effects).

Novel biologic therapies for asthma include antagonists of cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), and tumor necrosis factor (TNF)-α inhibitors. These agents have been evaluated in phase 2 and phase 3 studies thus far. The eosinophilic asthma phenotype is described as increased blood or sputum eosinophil levels correlating with disease activity. T-helper 2 cells that express IL-4, IL-5, and IL-13 coordinate eosinophilic inflammation in asthma.²¹

Mepolizumab (anti–IL-5) has been shown to be effective in reduction of exacerbations in patients with eosinophilic asthma phenotype, particularly those with frequent exacerbations.²² Reslizumab (humanized anti–IL-5) has been shown to significantly reduce symptoms and is currently undergoing phase 3 trials.²¹ Benralizumab is a humanized fucosylated IgG1κ monoclonal antibody (mAb) that binds IL-5Ra in order to induce apoptosis in eosinophils and basophils. It is currently under investigation for use in asthma and COPD.²¹

Lebrikizumab (anti–IL-13) has been shown to improve lung function in inadequately controlled asthma patients with elevated periostin levels.²³ Tralokinumab (anti–IL-13 humanized IgG4) improved FEV1 and reduced symptoms in patients with moderate to severe uncontrolled asthma in comparison with placebo.²⁴ Pitrakinra is a recombinant IL-4 variant that competitively inhibits the IL-4Rα receptor, inhibiting the function of both IL-4 and IL-13. This agent may prove beneficial in patients with atopic asthma.²¹

Dupilumab, a fully humanized mAb to the IL-4Rα/IL-13Rα receptor complex inhibiting actions of both IL-4 and IL-13 signaling, and has demonstrated > 80% relative reduction in asthma exacerbations, improved symptoms and led to improvement in FEV1 in patients with
moderate to severe asthma and increased serum or sputum eosinophils.²⁵ It may represent a promising avenue for future asthma research, as its initial investigation has shown both improvement in function and clinical outcomes. Ultimately, ongoing research will be needed to determine the long-term effects of these agents and whether they offer efficacy in asthma patients in general vs specific asthma-phenotypes.

The TNF-α inhibitors have also been investigated for use in asthma. TNF-α is an innate cytokine implicated in chronic inflammatory conditions, including rheumatoid arthritis and Crohn’s disease. Macrophages are a major source of TNF-α along with contributions from monocytes, dendritic cells, B lymphocytes, T cells,neutrophils, mast cells, and eosinophils. TNF-α has a proinflammatory effect on eosinophils, neutrophils, T cells, epithelial cells, and endothelial cells. Studies of asthma have revealed increased TNF-α within respiratory epithelial tissue biopsies and airway lavages of patients with severe asthma compared with those with good control. Etanercept, a soluble TNF-α receptor linked to human IgG1, has been reported to significantly improve symptoms and lung function in severe refractory asthma.²⁶
However golimumab, an anti-TNF biologic, was shown to have deleterious effects, including an increased rate of serious infections, potential increased risk of malignancy, and 1 death in the treatment group.²⁷ Identification of the correct patient population may improve clinical outcomes, but a potentially unfavorable risk benefit ratio may limit the future of anti–TNF-α therapy in severe asthma.

Considerations Unique to the Military

Active-duty personnel present unique challenges in the diagnosis and management of asthma. Service members should be questioned thoroughly on deployment and exposure history. A significant portion of the current military population has deployed to SWA in the past decade, many for multiple deployments. Research addressing respiratory complaints in the deployed military population is ongoing. To date, military research has demonstrated
that while many service members with deploymentrelated respiratory exposures have a paucity of objective findings after pulmonary medicine evaluation, some demonstrate functional limitations consistent with asthma or airway hyperresponsivenesss.²⁸ Further retrospective studies did not find a relationship between deployment and diagnosis rates or severity in asthma patients in the Army.²⁹ A comprehensive evaluation is recommended for service members with dyspnea to include investigating for potential asthma- or exercise-induced bronchospasm, in addition to diagnoses such as vocal cord dysfunction, GERD, and OSA.^28-30

A recent study in service members with respiratory complaints related to deployment included surgical lung biopsy; however, the clinical applicability of these results is unclear, given the lack of a firm association between the histologic diagnoses and clinical condition of the subjects.³¹ In general, it is not recommended to perform surgical lung biopsy for patients with deployment history to SWA in the absence of objective findings on chest imaging or significant changes in pulmonary function testing. Screening spirometry has been postulated as a way to improve monitoring for military members proximate to deployment and longitudinally. However, an unpublished cost analysis estimates that for the over 500,000 activeduty service members, screening spirometry would cost in the tens of millions of dollars.³² This analysis did not include the costs of follow-up specialty care or further
tests. Although screening spirometry does not appear to be feasible presently, research evaluating screening spirometry is in progress in the military.³³

If diagnosed with asthma, service members should be able to perform all required duties, wear protective gear, and have stable disease requiring infrequent, if any, oral corticosteroid treatment. According to U.S. Army retention regulations, soldiers diagnosed with asthma may be placed on temporary profile (duty restrictions) for up to 12 months when medically advised. If at the end of that trial the soldier is unable to wear a protective mask or pass the timed physical fitness run outdoors (on medications), then the soldier should be placed on a more restrictive physical profile and referred for a medical evaluation board. If able to pass the physical fitness run (or an alternate aerobic fitness event) within standards and perform all military training and duties on ICSs and bronchodilators, the soldier may be placed on a less restrictive temporary profile. If the soldier does not require medications or activity limitations, then no profile qualifications are required. Chronic asthma should also require a physical profile if it results in repetitive hospitalizations, emergency department visits, excessive time lost from duty, or repetitive use of oral corticosteroids.³

Conclusion

The evaluation and management of asthma in the military requires appropriate diagnosis, treatment, and longitudinal follow-up. The diagnosis should always be confirmed with pulmonary function and bronchoprovocation testing. Conditions mimicking asthma should be excluded, particularly when asthma does not respond to appropriate therapy. It is imperative that patients with asthma who do not demonstrate an expected course of improvement with therapy seek evaluation by a pulmonary disease specialist. This serves to re-evaluate whether the initial diagnosis was correct, assess for potential disease mimics and aggravating comorbidities, and ensure that asthma therapy is in accordance with published guidelines. Service members with asthma can remain on active duty when management with inhaled therapies allows them to meet standards and perform required duties.

Service members with asthma represent a unique and ever expanding patient population, given the role of potential respiratory exposures in SWA. Longitudinal follow-up is critical in conjunction with application of novel therapies as appropriate and understanding the impact of deployment-related respiratory exposures. These patients will continue to require care in the military health care system, the VA health care system, and in the private sector for decades to come.

Author disclosures
Dr. Morris is a paid speaker for Spiriva by Boehringer-Ingelheim. The other authors have no financial interests to disclose. None of the authors have any relevant conflicts of interest to disclose. This study was not supported by any funding or financial sponsorship.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner or Frontline Medical Communications Inc. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The opinions in this manuscript do not constitute endorsement by San Antonio Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense, or the U.S. Government of the information contained therein. The authors alone are responsible for the content and writing of the paper.

Asthma is a chronic inflammatory disorder of the airways that leads to airflow obstruction and bronchial hyperresponsiveness. Clinical features of asthma include episodic cough, wheeze, and dyspnea, which may resolve with avoidance of triggers or therapy. Characteristic triggers of asthma are irritanttype airway exposures, including cold air, exercise, various environmental allergens, and work-related exposures. Work-related exposures are the etiology for occupational asthma and work-exacerbated asthma, accounting for up to 25% of adult-onset asthma.¹ It is imperative that clinicians evaluate the clinical history, pulmonary function testing, and response to prior therapies when caring for patients with asthma.

Asthma is common in active-duty service members, despite the diagnosis limiting entrance into the military, and there is potential for significant rates of underdiagnosis among new recruits.² Recent changes in military medical guidelines have allowed service members with well controlled asthma to remain on active duty.³ This potentially increases the number of service members with compromised respiratory status, which is concerning in light of the past decade of deployment to southwest Asia (SWA) and ongoing investigations into potential deployment-related irritant respiratory exposures.

Diagnosis

An accurate initial diagnosis is a critical starting point in the management of asthma. Many diseases can mimic asthma, including vocal cord dysfunction, chronic obstructive pulmonary disease (COPD), congestive heart failure, sarcoidosis, allergic bronchopulmonary aspergillosis
(ABPA), and eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (Table 1).⁴ Asthma-mimics, in particular ABPA and EGPA, are often diagnosed via careful longitudinal follow-up.

Characteristic symptoms of asthma include cough, wheeze, dyspnea, chest tightness, and sputum production. Symptoms should be described systematically in terms of onset, frequency, duration, diurnal variability, and seasonality. A careful review of systems should be conducted to exclude conditions such as COPD, pulmonary emboli, congestive heart failure, viral syndromes, acute infection, or hypersensitivity pneumonitis. Patients must be queried (carefully and often repeatedly) about potential triggers, including physical activity, hobbies, pets (including any animals owned by the patient, family members, or living on the property), and occupation.

Physical examination may reveal presence of nasal polyps, nasal mucosal swelling, increased secretions, wheezing, a prolonged expiratory phase, atopic dermatitis, or eczema. Further cardiac evaluation with transthoracic echocardiography may be considered in patients with a heart murmur. Digital clubbing is not characteristic of asthma and should prompt investigation of alternative inflammatory disease (connective tissue disease, interstitial lung disease, or bronchiectasis).

Pulmonary function testing including spirometry and bronchodilator response should be performed as demonstration of airflow limitation is crucial for the diagnosis of asthma.⁴ Spirometry should be performed in accordance with published standards and documented in the patient's medical record. Airflow limitation should be described in accordance with the Third National Health and Nutrition Examination Survey (NHANES III) references values as recommended by the American Thoracic Society and the European Respiratory Society (ATS/ERS) guidelines.^5-7 Obstruction is defined as an forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio less than the fifth percentile of the
normal distribution (lower limit of normal). Bronchodilator testing should also be performed to establish presence and degree of response to inhaled bronchodilator medication. A12% increase in the FEV1 with an absolute increase of 200 mL is considered significant in adults.⁷

It is important to note that although a positive bronchodilator response is highly suggestive of asthma in the appropriate clinical circumstance, it is not required for diagnosis, and inhaled bronchodilators may be useful in disease management even in the absence of a positive response. Patients with nonspecific reductions in the FVC, with symptoms not consistent with asthma, or not responding to typical asthma therapy are more likely to have been falsely diagnosed. These patients should have lung volumes and diffusion capacity of carbon monoxide measured to evaluate for other potential etiologies (eg, parenchymal lung disease, pulmonary vascular disease).⁴

Bronchoprovocation testing is useful for demonstrating airway hyperresponsiveness in a patient with symptoms suggestive of asthma, particularly those with normal baseline spirometry. Patients should have testing performed and interpreted in accordance with ATS
standards.⁸ Although methacholine challenge testing is preferred, other methods including cold air or eucapnic hyperventilation are also established. Exercise challenge testing, although less sensitive, remains a useful tool, particularly in patients with primarily exertional symptoms. It is important to note that a positive bronchoprovocation test result may occur in other conditions. Whereas a positive test is consistent with asthma, a negative test may be more useful to exclude the diagnosis^.8 Finally, chest imaging with plain film radiographs (posteroanterior and lateral views) is important to exclude parenchymal lung disease or mediastinal disorders. Further imaging with computed tomography is not indicated in the absence of atypical clinical features (such as abnormal plain films or failure to respond to therapy).

Management

The initial management of asthma in based on severity and follows a stepwise progression according to the 2007 National Asthma Education and Prevention Program.⁹ Severity is determined by the following factors: symptoms in the past 2 to 4 weeks, pulmonary function testing, and number of exacerbations requiring oral glucocorticoids (Table 2).

The initiation of therapy is based on the assessment of severity (Table 3). Patients with intermittent asthma are treated initially with short-acting beta-agonists (SABA) alone. Patients with known triggers are instructed to use beta-agonists about 20 minutes prior to a known trigger such as exercise.^4,9 For a patient with mild persistent asthma, the preferred controller medication is a low-dose inhaled corticosteroid (ICS). If a patient has moderate persistent asthma, the preferred controller medication becomes a lowdose ICS plus a long-acting beta agonist (LABA) or a medium-dose ICS. Severe persistent patients are treated with a medium-dose ICS and a LABA or a high-dose ICS.^4,9 In patients who need additional therapy beyond that described here, providers may consider adjunctive therapy with theophylline, leukotriene receptor antagonists (such as montelukast), or cromolyn/nedocromil.^4,9 If a patient has severe persistent asthma, anti-IgE therapy omalizumab can be considered if serum IgE levels are within the established range (30-700 IU/mL).¹⁰

Chronic asthma management relies on assessment and monitoring of functional impairment and response to therapy over time. Impairment is best assessed using a validated questionnaire assessing nighttime awakenings; frequency of as-needed bronchodilator therapy; limitation in home, school, or work activities; and perception of control or peak flow monitoring.⁴ One questionnaire that has been validated in the outpatient setting (as well as for home use via mail or telephone) is the Asthma Control Test.^11-14 The history obtained in clinic should assess risk factors for future exacerbations, such as the use of oral glucocorticoids, emergency department visits, hospitalizations, and admissions to the intensive care unit. For patients whose symptoms are not well controlled, a step up in therapy of one level should be performed. Therapy can be continued or stepped down (to minimize adverse effects) in those with adequate control.

Comorbid Conditions

Asthma management should also address comorbid conditions, including gastroesophageal reflux disease (GERD), allergic rhinosinusitis, obesity, and obstructive sleep apnea (OSA). Gastroesophageal reflux disease is common in asthmatics, and treatment may reduce exacerbations and symptoms, particularly in severe asthma.¹⁵ Allergic rhinitis/sinusitis is also common, and treatment may improve respiratory symptoms. Obesity is associated with an increased risk of developing asthma and may be associated with increased asthma severity.¹⁶ Patients with asthma and comorbid OSA should be encouraged to use continuous positive airway pressure (CPAP) with regular compliance (> 4 hours per night on > 70% of nights).¹⁷ Optimally, the goal for CPAP use should be 7 to 8 hours per night. Finally, patients with asthma are at higher risk for depression and other behavioral disorders, which may lead to poor compliance with therapy, adversely impacting disease severity and efficacy of medical care.¹⁸

Triggers

The avoidance of triggers may reduce the need for controller medications. Inhaled allergens or irritants (tobacco or wood smoke) may be suggested by a history of worsening at home or in the workplace (or during the work week).⁹ Allergy testing may be considered for identification of allergens— particularly indoor allergens such as dust mites, animal dander, molds, mice, and cockroaches. Nonselective beta blockers, aspirin, nonsteroidal anti-inflammatory drugs, or dietary sulfites may produce significant exacerbations in some patients with asthma. Administration of the flu vaccine is indicated in all asthma patients, and pneumococcal vaccination is indicated in all adult patients requiring controller medication due to significant risk of complications with pneumococcal infection or influenza.⁴

Patient Education

Patient education is an integral part of asthma management. Patients should be educated on roles of medications, appropriate technique for using a metered dose inhaler and spacer, self-monitoring of disease, identification of triggers and environmental control measures, and a plan for care during exacerbations. Patient education programs have been shown to be effective in reducing hospitalizations.¹⁹ Use of valved holding chambers is preferred.⁴ Investigation and education into the role of allergens in the patient’s disease is recommended. However, there is insufficient evidence to advocate a single specific avoidance strategy. Comprehensive, as opposed to limited, strategies are recommended. Immunotherapy is effective for patients with persistent asthma and identified inhaled allergen sensitivities.⁴ All patients should be queried about smoking history and advised strongly to quit smoking.

Pharmacotherapy

Medications used for asthma primarily include inhaled bronchodilators and ICS when controller therapy is required. Short-acting beta agonists should be used for quick relief of symptoms and can be used preemptively for triggers. The frequency of SABA use should be queried to assess control. In addition, patients should be instructed to seek medical attention should a SABA fail to achieve a quick and sustained response. Inhaled corticosteroids should be used as a first-line treatment to control persistent asthma with initial dosing based on severity. Long-acting beta agonists are the preferred add-on to ICS therapy for patients whose symptoms are not controlled with an ICS. Long-acting beta agonists should not be used for acute symptoms or without an ICS, regardless of asthma stage. They carry an FDA boxed warning regarding increased risk of severe asthma exacerbations and asthma-related deaths.²⁰

Leukotriene modifiers may provide benefit and should be used in stepwise fashion as an alternative to LABA in appropriately selected patients. Cromolyn may be considered as alternative to ICS in mild persistent asthma, but is rarely used. Theophylline may be considered if other options have not been successful. Serum levels should be maintained between 5 and 15 μg/mL, and routine monitoring is indicated due to significant toxicities and medication interactions. Omalizumab can be considered as adjunctive therapy in patients with elevated IgE in the prescribed target ranges (30-700 IU/mL) and sensitivity to relevant allergies. In patients with chronic, refractory symptoms there may be a role for oral corticosteroid therapy outside the setting of acute exacerbations. This decision should be individualized and balance the
benefits obtained from therapy against the risks of chronic steroid use (impaired glucose control, immunosuppression, poor wound healing, adverse effects on bone density, and adverse psychiatric effects).

Novel biologic therapies for asthma include antagonists of cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), and tumor necrosis factor (TNF)-α inhibitors. These agents have been evaluated in phase 2 and phase 3 studies thus far. The eosinophilic asthma phenotype is described as increased blood or sputum eosinophil levels correlating with disease activity. T-helper 2 cells that express IL-4, IL-5, and IL-13 coordinate eosinophilic inflammation in asthma.²¹

Mepolizumab (anti–IL-5) has been shown to be effective in reduction of exacerbations in patients with eosinophilic asthma phenotype, particularly those with frequent exacerbations.²² Reslizumab (humanized anti–IL-5) has been shown to significantly reduce symptoms and is currently undergoing phase 3 trials.²¹ Benralizumab is a humanized fucosylated IgG1κ monoclonal antibody (mAb) that binds IL-5Ra in order to induce apoptosis in eosinophils and basophils. It is currently under investigation for use in asthma and COPD.²¹

Lebrikizumab (anti–IL-13) has been shown to improve lung function in inadequately controlled asthma patients with elevated periostin levels.²³ Tralokinumab (anti–IL-13 humanized IgG4) improved FEV1 and reduced symptoms in patients with moderate to severe uncontrolled asthma in comparison with placebo.²⁴ Pitrakinra is a recombinant IL-4 variant that competitively inhibits the IL-4Rα receptor, inhibiting the function of both IL-4 and IL-13. This agent may prove beneficial in patients with atopic asthma.²¹

Dupilumab, a fully humanized mAb to the IL-4Rα/IL-13Rα receptor complex inhibiting actions of both IL-4 and IL-13 signaling, and has demonstrated > 80% relative reduction in asthma exacerbations, improved symptoms and led to improvement in FEV1 in patients with
moderate to severe asthma and increased serum or sputum eosinophils.²⁵ It may represent a promising avenue for future asthma research, as its initial investigation has shown both improvement in function and clinical outcomes. Ultimately, ongoing research will be needed to determine the long-term effects of these agents and whether they offer efficacy in asthma patients in general vs specific asthma-phenotypes.

The TNF-α inhibitors have also been investigated for use in asthma. TNF-α is an innate cytokine implicated in chronic inflammatory conditions, including rheumatoid arthritis and Crohn’s disease. Macrophages are a major source of TNF-α along with contributions from monocytes, dendritic cells, B lymphocytes, T cells,neutrophils, mast cells, and eosinophils. TNF-α has a proinflammatory effect on eosinophils, neutrophils, T cells, epithelial cells, and endothelial cells. Studies of asthma have revealed increased TNF-α within respiratory epithelial tissue biopsies and airway lavages of patients with severe asthma compared with those with good control. Etanercept, a soluble TNF-α receptor linked to human IgG1, has been reported to significantly improve symptoms and lung function in severe refractory asthma.²⁶
However golimumab, an anti-TNF biologic, was shown to have deleterious effects, including an increased rate of serious infections, potential increased risk of malignancy, and 1 death in the treatment group.²⁷ Identification of the correct patient population may improve clinical outcomes, but a potentially unfavorable risk benefit ratio may limit the future of anti–TNF-α therapy in severe asthma.

Considerations Unique to the Military

Active-duty personnel present unique challenges in the diagnosis and management of asthma. Service members should be questioned thoroughly on deployment and exposure history. A significant portion of the current military population has deployed to SWA in the past decade, many for multiple deployments. Research addressing respiratory complaints in the deployed military population is ongoing. To date, military research has demonstrated
that while many service members with deploymentrelated respiratory exposures have a paucity of objective findings after pulmonary medicine evaluation, some demonstrate functional limitations consistent with asthma or airway hyperresponsivenesss.²⁸ Further retrospective studies did not find a relationship between deployment and diagnosis rates or severity in asthma patients in the Army.²⁹ A comprehensive evaluation is recommended for service members with dyspnea to include investigating for potential asthma- or exercise-induced bronchospasm, in addition to diagnoses such as vocal cord dysfunction, GERD, and OSA.^28-30

A recent study in service members with respiratory complaints related to deployment included surgical lung biopsy; however, the clinical applicability of these results is unclear, given the lack of a firm association between the histologic diagnoses and clinical condition of the subjects.³¹ In general, it is not recommended to perform surgical lung biopsy for patients with deployment history to SWA in the absence of objective findings on chest imaging or significant changes in pulmonary function testing. Screening spirometry has been postulated as a way to improve monitoring for military members proximate to deployment and longitudinally. However, an unpublished cost analysis estimates that for the over 500,000 activeduty service members, screening spirometry would cost in the tens of millions of dollars.³² This analysis did not include the costs of follow-up specialty care or further
tests. Although screening spirometry does not appear to be feasible presently, research evaluating screening spirometry is in progress in the military.³³

If diagnosed with asthma, service members should be able to perform all required duties, wear protective gear, and have stable disease requiring infrequent, if any, oral corticosteroid treatment. According to U.S. Army retention regulations, soldiers diagnosed with asthma may be placed on temporary profile (duty restrictions) for up to 12 months when medically advised. If at the end of that trial the soldier is unable to wear a protective mask or pass the timed physical fitness run outdoors (on medications), then the soldier should be placed on a more restrictive physical profile and referred for a medical evaluation board. If able to pass the physical fitness run (or an alternate aerobic fitness event) within standards and perform all military training and duties on ICSs and bronchodilators, the soldier may be placed on a less restrictive temporary profile. If the soldier does not require medications or activity limitations, then no profile qualifications are required. Chronic asthma should also require a physical profile if it results in repetitive hospitalizations, emergency department visits, excessive time lost from duty, or repetitive use of oral corticosteroids.³

Conclusion

The evaluation and management of asthma in the military requires appropriate diagnosis, treatment, and longitudinal follow-up. The diagnosis should always be confirmed with pulmonary function and bronchoprovocation testing. Conditions mimicking asthma should be excluded, particularly when asthma does not respond to appropriate therapy. It is imperative that patients with asthma who do not demonstrate an expected course of improvement with therapy seek evaluation by a pulmonary disease specialist. This serves to re-evaluate whether the initial diagnosis was correct, assess for potential disease mimics and aggravating comorbidities, and ensure that asthma therapy is in accordance with published guidelines. Service members with asthma can remain on active duty when management with inhaled therapies allows them to meet standards and perform required duties.

Service members with asthma represent a unique and ever expanding patient population, given the role of potential respiratory exposures in SWA. Longitudinal follow-up is critical in conjunction with application of novel therapies as appropriate and understanding the impact of deployment-related respiratory exposures. These patients will continue to require care in the military health care system, the VA health care system, and in the private sector for decades to come.

Author disclosures
Dr. Morris is a paid speaker for Spiriva by Boehringer-Ingelheim. The other authors have no financial interests to disclose. None of the authors have any relevant conflicts of interest to disclose. This study was not supported by any funding or financial sponsorship.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner or Frontline Medical Communications Inc. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The opinions in this manuscript do not constitute endorsement by San Antonio Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense, or the U.S. Government of the information contained therein. The authors alone are responsible for the content and writing of the paper.

Asthma is a chronic inflammatory disorder of the airways that leads to airflow obstruction and bronchial hyperresponsiveness. Clinical features of asthma include episodic cough, wheeze, and dyspnea, which may resolve with avoidance of triggers or therapy. Characteristic triggers of asthma are irritanttype airway exposures, including cold air, exercise, various environmental allergens, and work-related exposures. Work-related exposures are the etiology for occupational asthma and work-exacerbated asthma, accounting for up to 25% of adult-onset asthma.¹ It is imperative that clinicians evaluate the clinical history, pulmonary function testing, and response to prior therapies when caring for patients with asthma.

Asthma is common in active-duty service members, despite the diagnosis limiting entrance into the military, and there is potential for significant rates of underdiagnosis among new recruits.² Recent changes in military medical guidelines have allowed service members with well controlled asthma to remain on active duty.³ This potentially increases the number of service members with compromised respiratory status, which is concerning in light of the past decade of deployment to southwest Asia (SWA) and ongoing investigations into potential deployment-related irritant respiratory exposures.

Diagnosis

An accurate initial diagnosis is a critical starting point in the management of asthma. Many diseases can mimic asthma, including vocal cord dysfunction, chronic obstructive pulmonary disease (COPD), congestive heart failure, sarcoidosis, allergic bronchopulmonary aspergillosis
(ABPA), and eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome (Table 1).⁴ Asthma-mimics, in particular ABPA and EGPA, are often diagnosed via careful longitudinal follow-up.

Characteristic symptoms of asthma include cough, wheeze, dyspnea, chest tightness, and sputum production. Symptoms should be described systematically in terms of onset, frequency, duration, diurnal variability, and seasonality. A careful review of systems should be conducted to exclude conditions such as COPD, pulmonary emboli, congestive heart failure, viral syndromes, acute infection, or hypersensitivity pneumonitis. Patients must be queried (carefully and often repeatedly) about potential triggers, including physical activity, hobbies, pets (including any animals owned by the patient, family members, or living on the property), and occupation.

Physical examination may reveal presence of nasal polyps, nasal mucosal swelling, increased secretions, wheezing, a prolonged expiratory phase, atopic dermatitis, or eczema. Further cardiac evaluation with transthoracic echocardiography may be considered in patients with a heart murmur. Digital clubbing is not characteristic of asthma and should prompt investigation of alternative inflammatory disease (connective tissue disease, interstitial lung disease, or bronchiectasis).

Pulmonary function testing including spirometry and bronchodilator response should be performed as demonstration of airflow limitation is crucial for the diagnosis of asthma.⁴ Spirometry should be performed in accordance with published standards and documented in the patient's medical record. Airflow limitation should be described in accordance with the Third National Health and Nutrition Examination Survey (NHANES III) references values as recommended by the American Thoracic Society and the European Respiratory Society (ATS/ERS) guidelines.^5-7 Obstruction is defined as an forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio less than the fifth percentile of the
normal distribution (lower limit of normal). Bronchodilator testing should also be performed to establish presence and degree of response to inhaled bronchodilator medication. A12% increase in the FEV1 with an absolute increase of 200 mL is considered significant in adults.⁷

It is important to note that although a positive bronchodilator response is highly suggestive of asthma in the appropriate clinical circumstance, it is not required for diagnosis, and inhaled bronchodilators may be useful in disease management even in the absence of a positive response. Patients with nonspecific reductions in the FVC, with symptoms not consistent with asthma, or not responding to typical asthma therapy are more likely to have been falsely diagnosed. These patients should have lung volumes and diffusion capacity of carbon monoxide measured to evaluate for other potential etiologies (eg, parenchymal lung disease, pulmonary vascular disease).⁴

Bronchoprovocation testing is useful for demonstrating airway hyperresponsiveness in a patient with symptoms suggestive of asthma, particularly those with normal baseline spirometry. Patients should have testing performed and interpreted in accordance with ATS
standards.⁸ Although methacholine challenge testing is preferred, other methods including cold air or eucapnic hyperventilation are also established. Exercise challenge testing, although less sensitive, remains a useful tool, particularly in patients with primarily exertional symptoms. It is important to note that a positive bronchoprovocation test result may occur in other conditions. Whereas a positive test is consistent with asthma, a negative test may be more useful to exclude the diagnosis^.8 Finally, chest imaging with plain film radiographs (posteroanterior and lateral views) is important to exclude parenchymal lung disease or mediastinal disorders. Further imaging with computed tomography is not indicated in the absence of atypical clinical features (such as abnormal plain films or failure to respond to therapy).

Management

The initial management of asthma in based on severity and follows a stepwise progression according to the 2007 National Asthma Education and Prevention Program.⁹ Severity is determined by the following factors: symptoms in the past 2 to 4 weeks, pulmonary function testing, and number of exacerbations requiring oral glucocorticoids (Table 2).

The initiation of therapy is based on the assessment of severity (Table 3). Patients with intermittent asthma are treated initially with short-acting beta-agonists (SABA) alone. Patients with known triggers are instructed to use beta-agonists about 20 minutes prior to a known trigger such as exercise.^4,9 For a patient with mild persistent asthma, the preferred controller medication is a low-dose inhaled corticosteroid (ICS). If a patient has moderate persistent asthma, the preferred controller medication becomes a lowdose ICS plus a long-acting beta agonist (LABA) or a medium-dose ICS. Severe persistent patients are treated with a medium-dose ICS and a LABA or a high-dose ICS.^4,9 In patients who need additional therapy beyond that described here, providers may consider adjunctive therapy with theophylline, leukotriene receptor antagonists (such as montelukast), or cromolyn/nedocromil.^4,9 If a patient has severe persistent asthma, anti-IgE therapy omalizumab can be considered if serum IgE levels are within the established range (30-700 IU/mL).¹⁰

Chronic asthma management relies on assessment and monitoring of functional impairment and response to therapy over time. Impairment is best assessed using a validated questionnaire assessing nighttime awakenings; frequency of as-needed bronchodilator therapy; limitation in home, school, or work activities; and perception of control or peak flow monitoring.⁴ One questionnaire that has been validated in the outpatient setting (as well as for home use via mail or telephone) is the Asthma Control Test.^11-14 The history obtained in clinic should assess risk factors for future exacerbations, such as the use of oral glucocorticoids, emergency department visits, hospitalizations, and admissions to the intensive care unit. For patients whose symptoms are not well controlled, a step up in therapy of one level should be performed. Therapy can be continued or stepped down (to minimize adverse effects) in those with adequate control.

Comorbid Conditions

Asthma management should also address comorbid conditions, including gastroesophageal reflux disease (GERD), allergic rhinosinusitis, obesity, and obstructive sleep apnea (OSA). Gastroesophageal reflux disease is common in asthmatics, and treatment may reduce exacerbations and symptoms, particularly in severe asthma.¹⁵ Allergic rhinitis/sinusitis is also common, and treatment may improve respiratory symptoms. Obesity is associated with an increased risk of developing asthma and may be associated with increased asthma severity.¹⁶ Patients with asthma and comorbid OSA should be encouraged to use continuous positive airway pressure (CPAP) with regular compliance (> 4 hours per night on > 70% of nights).¹⁷ Optimally, the goal for CPAP use should be 7 to 8 hours per night. Finally, patients with asthma are at higher risk for depression and other behavioral disorders, which may lead to poor compliance with therapy, adversely impacting disease severity and efficacy of medical care.¹⁸

Triggers

The avoidance of triggers may reduce the need for controller medications. Inhaled allergens or irritants (tobacco or wood smoke) may be suggested by a history of worsening at home or in the workplace (or during the work week).⁹ Allergy testing may be considered for identification of allergens— particularly indoor allergens such as dust mites, animal dander, molds, mice, and cockroaches. Nonselective beta blockers, aspirin, nonsteroidal anti-inflammatory drugs, or dietary sulfites may produce significant exacerbations in some patients with asthma. Administration of the flu vaccine is indicated in all asthma patients, and pneumococcal vaccination is indicated in all adult patients requiring controller medication due to significant risk of complications with pneumococcal infection or influenza.⁴

Patient Education

Patient education is an integral part of asthma management. Patients should be educated on roles of medications, appropriate technique for using a metered dose inhaler and spacer, self-monitoring of disease, identification of triggers and environmental control measures, and a plan for care during exacerbations. Patient education programs have been shown to be effective in reducing hospitalizations.¹⁹ Use of valved holding chambers is preferred.⁴ Investigation and education into the role of allergens in the patient’s disease is recommended. However, there is insufficient evidence to advocate a single specific avoidance strategy. Comprehensive, as opposed to limited, strategies are recommended. Immunotherapy is effective for patients with persistent asthma and identified inhaled allergen sensitivities.⁴ All patients should be queried about smoking history and advised strongly to quit smoking.

Pharmacotherapy

Medications used for asthma primarily include inhaled bronchodilators and ICS when controller therapy is required. Short-acting beta agonists should be used for quick relief of symptoms and can be used preemptively for triggers. The frequency of SABA use should be queried to assess control. In addition, patients should be instructed to seek medical attention should a SABA fail to achieve a quick and sustained response. Inhaled corticosteroids should be used as a first-line treatment to control persistent asthma with initial dosing based on severity. Long-acting beta agonists are the preferred add-on to ICS therapy for patients whose symptoms are not controlled with an ICS. Long-acting beta agonists should not be used for acute symptoms or without an ICS, regardless of asthma stage. They carry an FDA boxed warning regarding increased risk of severe asthma exacerbations and asthma-related deaths.²⁰

Leukotriene modifiers may provide benefit and should be used in stepwise fashion as an alternative to LABA in appropriately selected patients. Cromolyn may be considered as alternative to ICS in mild persistent asthma, but is rarely used. Theophylline may be considered if other options have not been successful. Serum levels should be maintained between 5 and 15 μg/mL, and routine monitoring is indicated due to significant toxicities and medication interactions. Omalizumab can be considered as adjunctive therapy in patients with elevated IgE in the prescribed target ranges (30-700 IU/mL) and sensitivity to relevant allergies. In patients with chronic, refractory symptoms there may be a role for oral corticosteroid therapy outside the setting of acute exacerbations. This decision should be individualized and balance the
benefits obtained from therapy against the risks of chronic steroid use (impaired glucose control, immunosuppression, poor wound healing, adverse effects on bone density, and adverse psychiatric effects).

Novel biologic therapies for asthma include antagonists of cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), and tumor necrosis factor (TNF)-α inhibitors. These agents have been evaluated in phase 2 and phase 3 studies thus far. The eosinophilic asthma phenotype is described as increased blood or sputum eosinophil levels correlating with disease activity. T-helper 2 cells that express IL-4, IL-5, and IL-13 coordinate eosinophilic inflammation in asthma.²¹

Mepolizumab (anti–IL-5) has been shown to be effective in reduction of exacerbations in patients with eosinophilic asthma phenotype, particularly those with frequent exacerbations.²² Reslizumab (humanized anti–IL-5) has been shown to significantly reduce symptoms and is currently undergoing phase 3 trials.²¹ Benralizumab is a humanized fucosylated IgG1κ monoclonal antibody (mAb) that binds IL-5Ra in order to induce apoptosis in eosinophils and basophils. It is currently under investigation for use in asthma and COPD.²¹

Lebrikizumab (anti–IL-13) has been shown to improve lung function in inadequately controlled asthma patients with elevated periostin levels.²³ Tralokinumab (anti–IL-13 humanized IgG4) improved FEV1 and reduced symptoms in patients with moderate to severe uncontrolled asthma in comparison with placebo.²⁴ Pitrakinra is a recombinant IL-4 variant that competitively inhibits the IL-4Rα receptor, inhibiting the function of both IL-4 and IL-13. This agent may prove beneficial in patients with atopic asthma.²¹

Dupilumab, a fully humanized mAb to the IL-4Rα/IL-13Rα receptor complex inhibiting actions of both IL-4 and IL-13 signaling, and has demonstrated > 80% relative reduction in asthma exacerbations, improved symptoms and led to improvement in FEV1 in patients with
moderate to severe asthma and increased serum or sputum eosinophils.²⁵ It may represent a promising avenue for future asthma research, as its initial investigation has shown both improvement in function and clinical outcomes. Ultimately, ongoing research will be needed to determine the long-term effects of these agents and whether they offer efficacy in asthma patients in general vs specific asthma-phenotypes.

The TNF-α inhibitors have also been investigated for use in asthma. TNF-α is an innate cytokine implicated in chronic inflammatory conditions, including rheumatoid arthritis and Crohn’s disease. Macrophages are a major source of TNF-α along with contributions from monocytes, dendritic cells, B lymphocytes, T cells,neutrophils, mast cells, and eosinophils. TNF-α has a proinflammatory effect on eosinophils, neutrophils, T cells, epithelial cells, and endothelial cells. Studies of asthma have revealed increased TNF-α within respiratory epithelial tissue biopsies and airway lavages of patients with severe asthma compared with those with good control. Etanercept, a soluble TNF-α receptor linked to human IgG1, has been reported to significantly improve symptoms and lung function in severe refractory asthma.²⁶
However golimumab, an anti-TNF biologic, was shown to have deleterious effects, including an increased rate of serious infections, potential increased risk of malignancy, and 1 death in the treatment group.²⁷ Identification of the correct patient population may improve clinical outcomes, but a potentially unfavorable risk benefit ratio may limit the future of anti–TNF-α therapy in severe asthma.

Considerations Unique to the Military

Active-duty personnel present unique challenges in the diagnosis and management of asthma. Service members should be questioned thoroughly on deployment and exposure history. A significant portion of the current military population has deployed to SWA in the past decade, many for multiple deployments. Research addressing respiratory complaints in the deployed military population is ongoing. To date, military research has demonstrated
that while many service members with deploymentrelated respiratory exposures have a paucity of objective findings after pulmonary medicine evaluation, some demonstrate functional limitations consistent with asthma or airway hyperresponsivenesss.²⁸ Further retrospective studies did not find a relationship between deployment and diagnosis rates or severity in asthma patients in the Army.²⁹ A comprehensive evaluation is recommended for service members with dyspnea to include investigating for potential asthma- or exercise-induced bronchospasm, in addition to diagnoses such as vocal cord dysfunction, GERD, and OSA.^28-30

A recent study in service members with respiratory complaints related to deployment included surgical lung biopsy; however, the clinical applicability of these results is unclear, given the lack of a firm association between the histologic diagnoses and clinical condition of the subjects.³¹ In general, it is not recommended to perform surgical lung biopsy for patients with deployment history to SWA in the absence of objective findings on chest imaging or significant changes in pulmonary function testing. Screening spirometry has been postulated as a way to improve monitoring for military members proximate to deployment and longitudinally. However, an unpublished cost analysis estimates that for the over 500,000 activeduty service members, screening spirometry would cost in the tens of millions of dollars.³² This analysis did not include the costs of follow-up specialty care or further
tests. Although screening spirometry does not appear to be feasible presently, research evaluating screening spirometry is in progress in the military.³³

If diagnosed with asthma, service members should be able to perform all required duties, wear protective gear, and have stable disease requiring infrequent, if any, oral corticosteroid treatment. According to U.S. Army retention regulations, soldiers diagnosed with asthma may be placed on temporary profile (duty restrictions) for up to 12 months when medically advised. If at the end of that trial the soldier is unable to wear a protective mask or pass the timed physical fitness run outdoors (on medications), then the soldier should be placed on a more restrictive physical profile and referred for a medical evaluation board. If able to pass the physical fitness run (or an alternate aerobic fitness event) within standards and perform all military training and duties on ICSs and bronchodilators, the soldier may be placed on a less restrictive temporary profile. If the soldier does not require medications or activity limitations, then no profile qualifications are required. Chronic asthma should also require a physical profile if it results in repetitive hospitalizations, emergency department visits, excessive time lost from duty, or repetitive use of oral corticosteroids.³

Conclusion

The evaluation and management of asthma in the military requires appropriate diagnosis, treatment, and longitudinal follow-up. The diagnosis should always be confirmed with pulmonary function and bronchoprovocation testing. Conditions mimicking asthma should be excluded, particularly when asthma does not respond to appropriate therapy. It is imperative that patients with asthma who do not demonstrate an expected course of improvement with therapy seek evaluation by a pulmonary disease specialist. This serves to re-evaluate whether the initial diagnosis was correct, assess for potential disease mimics and aggravating comorbidities, and ensure that asthma therapy is in accordance with published guidelines. Service members with asthma can remain on active duty when management with inhaled therapies allows them to meet standards and perform required duties.

Service members with asthma represent a unique and ever expanding patient population, given the role of potential respiratory exposures in SWA. Longitudinal follow-up is critical in conjunction with application of novel therapies as appropriate and understanding the impact of deployment-related respiratory exposures. These patients will continue to require care in the military health care system, the VA health care system, and in the private sector for decades to come.

Author disclosures
Dr. Morris is a paid speaker for Spiriva by Boehringer-Ingelheim. The other authors have no financial interests to disclose. None of the authors have any relevant conflicts of interest to disclose. This study was not supported by any funding or financial sponsorship.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner or Frontline Medical Communications Inc. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The opinions in this manuscript do not constitute endorsement by San Antonio Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, Department of Defense, or the U.S. Government of the information contained therein. The authors alone are responsible for the content and writing of the paper.

This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

Patient Evaluation

The practice guidelines of the National Comprehensive Cancer Network (NCCN) recommend using life expectancy in determining treatment.¹ Prostate cancer is considered to be an indolent disease, and active therapy may be more harmful than beneficial to older patients whose life expectancy is limited because of treatment-related sequelae. Therefore, an accurate estimation of life expectancy is important in devising treatment strategies for older patients.

Age should not be the only factor in determining the life expectancy of patients, because life expectancy varies widely based on the patient’s health status, including preexisting comorbidities. Chronologic life expectancy can be found in the Social Security Administration’s life tables. Individual life expectancy is then projected by adding 50% to or deducting 50% from the chronologic life expectancy for men in the highest and lowest quartile of health, respectively. The life expectancy from the life tables can be applied with no addition or subtraction for men in the middle 2 quartiles of health status (Figure 1).²

Geriatric Assessment

Despite the increasing incidence of prostate cancer in older adults, no particular guidelines for its management exist. Compared with younger patients, older
patients with prostate cancer need to weigh the benefits of treatment vs the risks to avoid any potential adverse treatment-related quality of life (QOL) decreases. Clearly, for some patients there are no significant benefits from treatment (eg, improved survival).

The Comprehensive Geriatric Assessment has been created to properly assess aging in correlation to individual and patient-centered biologic and clinical metrics.
Following extensive literature reviews, the International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recognized that the most important prognostic factors in evaluating health status in elderly patients with prostate cancer include comorbidities, functional dependence, and nutrition status.³ An important prognosticator of survival in prostate cancer is preexisting comorbidities. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) is considered the best metric currently available in assessing a patient’s death risk unrelated to cancer.

Another important factor influencing survival of older patients with prostate cancer is the patient’s level of independent activity. Independent functioning is evaluated
using (1) activities of daily living (ADL); and (2) the instrumental activities of daily living (IADL).^4-6

Health Status Subgroups

The SIOG recommendation for prostate cancer treatment in older patients is based on a complete assessment of existing comorbidities of patients using the CIRS-G,
IADL, and ADL scales as well as the nutritional status of each patient.^3,7-9 Based on these prognostic tools, the SIOG classifies the health status of elderly patients with prostate cancer into 4 prognostic health status categories: healthy, vulnerable, frail, and terminal.^10,11

Patient Characteristics

Older patients generally present with highrisk prostate cancer at diagnosis.^12,13 However, older patients are less likely to be treated with curative intent, resulting in
lower overall and disease-specific survivals. Nearly 40% of deaths due to prostate cancer occur in patients aged ≥ 75 years and 31% in the group aged ≥ 85 years.^12,14 Recent reports have demonstrated that curative radiotherapy or surgery improved survival outcomes as well as QOL in the elderly, comparable with those seen in younger patients.

Bechis and colleagues analyzed the relationship between survival of older patients with high-risk cancer and curative local therapy.¹⁵ Treatment modalities included radical prostatectomy, external-beam radiation therapy (EBRT), watchful waiting/active surveillance, and other modalities, including primary androgen deprivation therapy (ADT). The findings were: (1) older patients more frequently presented with high-risk disease as age increased; (2) therapeutic approaches varied but were based mainly on age at diagnosis rather than on cancer risk factors (Figures 2 and 3); and (3) ADT was used more frequently in older patients compared with its use in younger patients, irrespective of the risk score, including patients with high-risk disease.

Older patients were less likely to receive radical therapy, especially surgical treatment, regardless of risk category. Forty-four percent of patients aged > 70 years with high-risk disease died of any cause at a median 5.7 years, and 21% died of prostate cancer; whereas 47% of patients aged > 75 years with high-risk disease died at a median of 5.3 years, and 20% of those died of prostate cancer.

When older patients with high-risk disease received curative local therapy, however, the mortality rate decreased.

In a study by Sun and colleagues, 4,561 senior patients who received radical prostatectomy therapy were classified into 3 age groups (aged < 60 years, aged 60 to 70 years, and aged > 70 years) based on the year of surgery (before or after 2000). Therapy outcomes were compared among the 3 groups.¹⁶ The researchers found that seniors aged > 70 years who presented with high-risk disease had poorer therapeutic outcomes. A diagnosis of advancedstage cancer and a Gleason score > 7 were more often made in patients aged > 70 years vs that of their younger counterparts. They also found greater risk of failures for these patients in biochemical recurrence, distant metastasis, and disease-specific survivals.

Most clinicians typically ruled out active treatment based on chronologic age alone, without considering existing comorbidities and overall life expectancy. According
to a study by Daskivich and colleagues, only 16% of patients aged > 75 years were aggressively treated, whereas 84% of patients aged < 55 years received aggressive curative therapy, using radical prostatectomy, radiation therapy, or brachytherapy.¹⁷

Therapeutic Approaches

Current NCCN guidelines recommend active surveillance as an option for men with low- and intermediate-risk disease with a < 10-year life expectancy and the only option for men with a < 20-year life expectancy and a very low-risk of prostate cancer (stage T1c, Gleason ≤ 6, prostate specific antigen [PSA] < 10 ng/mL, < 3 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL²). Patients who are older and have significant comorbidities should be managed with active surveillance rather than with active treatment. In the practice setting, however, studies indicated that a substantial number of older men with limited life expectancy still received aggressive treatment for low-risk cancer. Active treatment tended to decrease with age but was still common among men aged > 80 years: 25% received active local therapy, 36% received primary ADT, and only 39% received no active treatment.¹⁸

Surgery

Surgical treatment is an active therapeutic option for some patients with localized disease. Mortalities were reduced using prostatectomy vs watchful waiting, including disease-specific mortality and rates of metastasis. As newer techniques develop, laparoscopic prostatectomy may be able to provide excellent therapeutic
outcomes with quick surgical recovery times and possibly less postoperative nerve damage. Compared with younger patients, older patients experienced comparable
outcomes after surgical therapy.19-21 Despite encouraging surgical outcomes, however, surgery is not generally offered to patients aged > 70 years because
of the presumed high risks related to possible surgical complications.

Radiation Therapies

External-beam radiation therapy has been a well-established, standard mode of radiotherapy for the past several decades, among various radiation modalities, including brachytherapy (high- and low-dose radioactive seed implant therapy), cyber-knife therapy, and proton therapy. If indicated, EBRT rather than surgery is generally suggested as an active treatment for patients with localized prostate cancer. In general, EBRT and radical prostatectomy are comparable in survival
outcomes, but EBRT is preferred for older patients because it is noninvasive.^21,22 Conventional EBRT technique has gradually progressed over the past several decades, advancing to 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), image-guided radiotherapy, and then most recently to RapidArc radiation therapy.

RapidArc radiotherapy is an advanced form of IMRT that increases dose conformity and significantly shortens daily treatment times. In contrast to the static conventional IMRT technique (requiring repeated stops to deliver radiation through a 360° rotation of the therapy machine around the patient), RapidArc radiotherapy continues to deliver radiation therapy to the targeted tumor lesion with no interruption while the therapy machine is rotating around the patient. Accordingly, radiation therapy time is much shorter (up to 8 times faster) compared with conventional IMRT radiotherapy.

Systemic Therapy

Androgen-deprivation therapy can slow cancer growth, as it inhibits androgen production, blocks androgen action, or both. For localized prostate cancers with intermittent- and high-risk for recurrence, radiation therapy combined with ADT (eg, leuprolide, goserelin, triptorelin) reduces mortality of patients compared with ADT alone. In addition, hormone therapy is used for advanced, recurrent, or metastatic prostate cancers.

Most advanced and roughly one-fifth of biologically recurrent cancers ultimately convert to castrationresistant prostate cancer and may potentially benefit from nonhormonal systemic chemotherapy. Docetaxel with or without prednisone is the agent of choice for castration-resistant symptomatic metastatic prostate cancer. Cabazitaxel is a secondgeneration taxane and approved for castration-resistantmetastatic prostate cancer. Other systemic drugs (hormonal) for chemotherapy-naïve, metastatic castration-resistant prostate cancer are abiraterone (androgen synthesis inhibitor) and enzalutamide (anti-androgen).

Low-Risk Prostate Cancers

Active surveillance would be a reasonable management option for older patients with low-risk, localized prostate cancer and limited life expectancy of < 10 years. Albertsen and colleagues reported that patients with welldifferentiated prostate cancer and limited life expectancy have little chance of death due to prostate cancer but are more likely die of other causes, such as preexisting comorbidities.²³ Bill-Axelson and colleagues reported a very similar cancer-specific mortality rate of only 2.5% for patients with well-differentiated prostate cancer who are receiving either active therapy or active surveillance.²⁴ In another study, Krakowsky and colleagues reported a 97% 10-year cancer-specific survival rate in 450 patients with a median age of 70 years, and in a randomized study, Holmberg and colleagues reported no differences in overall survival for patients aged > 65 years who were randomized to surgery or watchful waiting for early-stage prostate cancer.^25,26

The literature consistently reports cancer-specific survival rates approaching 100% for patients with low-risk prostate cancer. The main concern regarding aggressive
therapy for older patients with low-risk cancer and significant comorbidities, as well as limited life expectancy, is the real possibility of overtreatment and the resultant high risk of treatment-related complications and loss in QOL. For example, surgery can lead to varying degrees of incontinence, and radiation can lead to rectal bleeding from proctitis, both severely impacting patients’ QOL.

High-Risk Prostate Cancers

Older patients with high-risk prostate cancer generally do not receive curative therapy. Bechis and colleagues examined the influence of age on disease-specific mortality.¹⁵ They found that patients aged > 75 years were more likely to be diagnosed with high-risk prostate cancer and treated with conservative therapy, such as ADT or watchful waiting, often resulting in death. They also found that the choice of therapy in older patients was based primarily on age rather than on comorbidities or other disease factors. Trends for such undertreatment were most evident in healthy seniors with high-risk cancer. The undertreatment of older patients with lower comorbidities contributes to the higher disease-specific mortality seen in the elderly population. Such healthy older patients were often overlooked solely because of their age and might have been denied the opportunity to receive curative and life-saving therapy early.

Summary

Most prostate cancers develop in older patients, and nearly one-fourth of prostate cancers are diagnosed in patients who are aged > 75 years. In addition, older patients show a higher tendency to present with highrisk prostate cancer. Furthermore, older patients have a higher risk of death compared with that of younger
patients, although many of them still die of causes other than prostate cancer. The most important prognostic factors in older patients, as recognized by the SIOG Prostate Cancer Working Group, included comorbidities, dependence status, and nutrition status. Management decisions for older patients with prostate cancer should be individualized and formulated based on remaining life expectancy, the patient’s functional performance and health status, as well as coexisting comorbidities and patient-specific prognostic characteristics of the prostate cancer, such as stage, Gleason score, and PSA values.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic
therapy to patients.

Click here to read the digital edition.

This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

Patient Evaluation

The practice guidelines of the National Comprehensive Cancer Network (NCCN) recommend using life expectancy in determining treatment.¹ Prostate cancer is considered to be an indolent disease, and active therapy may be more harmful than beneficial to older patients whose life expectancy is limited because of treatment-related sequelae. Therefore, an accurate estimation of life expectancy is important in devising treatment strategies for older patients.

Age should not be the only factor in determining the life expectancy of patients, because life expectancy varies widely based on the patient’s health status, including preexisting comorbidities. Chronologic life expectancy can be found in the Social Security Administration’s life tables. Individual life expectancy is then projected by adding 50% to or deducting 50% from the chronologic life expectancy for men in the highest and lowest quartile of health, respectively. The life expectancy from the life tables can be applied with no addition or subtraction for men in the middle 2 quartiles of health status (Figure 1).²

Geriatric Assessment

Despite the increasing incidence of prostate cancer in older adults, no particular guidelines for its management exist. Compared with younger patients, older
patients with prostate cancer need to weigh the benefits of treatment vs the risks to avoid any potential adverse treatment-related quality of life (QOL) decreases. Clearly, for some patients there are no significant benefits from treatment (eg, improved survival).

The Comprehensive Geriatric Assessment has been created to properly assess aging in correlation to individual and patient-centered biologic and clinical metrics.
Following extensive literature reviews, the International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recognized that the most important prognostic factors in evaluating health status in elderly patients with prostate cancer include comorbidities, functional dependence, and nutrition status.³ An important prognosticator of survival in prostate cancer is preexisting comorbidities. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) is considered the best metric currently available in assessing a patient’s death risk unrelated to cancer.

Another important factor influencing survival of older patients with prostate cancer is the patient’s level of independent activity. Independent functioning is evaluated
using (1) activities of daily living (ADL); and (2) the instrumental activities of daily living (IADL).^4-6

Health Status Subgroups

The SIOG recommendation for prostate cancer treatment in older patients is based on a complete assessment of existing comorbidities of patients using the CIRS-G,
IADL, and ADL scales as well as the nutritional status of each patient.^3,7-9 Based on these prognostic tools, the SIOG classifies the health status of elderly patients with prostate cancer into 4 prognostic health status categories: healthy, vulnerable, frail, and terminal.^10,11

Patient Characteristics

Older patients generally present with highrisk prostate cancer at diagnosis.^12,13 However, older patients are less likely to be treated with curative intent, resulting in
lower overall and disease-specific survivals. Nearly 40% of deaths due to prostate cancer occur in patients aged ≥ 75 years and 31% in the group aged ≥ 85 years.^12,14 Recent reports have demonstrated that curative radiotherapy or surgery improved survival outcomes as well as QOL in the elderly, comparable with those seen in younger patients.

Bechis and colleagues analyzed the relationship between survival of older patients with high-risk cancer and curative local therapy.¹⁵ Treatment modalities included radical prostatectomy, external-beam radiation therapy (EBRT), watchful waiting/active surveillance, and other modalities, including primary androgen deprivation therapy (ADT). The findings were: (1) older patients more frequently presented with high-risk disease as age increased; (2) therapeutic approaches varied but were based mainly on age at diagnosis rather than on cancer risk factors (Figures 2 and 3); and (3) ADT was used more frequently in older patients compared with its use in younger patients, irrespective of the risk score, including patients with high-risk disease.

Older patients were less likely to receive radical therapy, especially surgical treatment, regardless of risk category. Forty-four percent of patients aged > 70 years with high-risk disease died of any cause at a median 5.7 years, and 21% died of prostate cancer; whereas 47% of patients aged > 75 years with high-risk disease died at a median of 5.3 years, and 20% of those died of prostate cancer.

When older patients with high-risk disease received curative local therapy, however, the mortality rate decreased.

In a study by Sun and colleagues, 4,561 senior patients who received radical prostatectomy therapy were classified into 3 age groups (aged < 60 years, aged 60 to 70 years, and aged > 70 years) based on the year of surgery (before or after 2000). Therapy outcomes were compared among the 3 groups.¹⁶ The researchers found that seniors aged > 70 years who presented with high-risk disease had poorer therapeutic outcomes. A diagnosis of advancedstage cancer and a Gleason score > 7 were more often made in patients aged > 70 years vs that of their younger counterparts. They also found greater risk of failures for these patients in biochemical recurrence, distant metastasis, and disease-specific survivals.

Most clinicians typically ruled out active treatment based on chronologic age alone, without considering existing comorbidities and overall life expectancy. According
to a study by Daskivich and colleagues, only 16% of patients aged > 75 years were aggressively treated, whereas 84% of patients aged < 55 years received aggressive curative therapy, using radical prostatectomy, radiation therapy, or brachytherapy.¹⁷

Therapeutic Approaches

Current NCCN guidelines recommend active surveillance as an option for men with low- and intermediate-risk disease with a < 10-year life expectancy and the only option for men with a < 20-year life expectancy and a very low-risk of prostate cancer (stage T1c, Gleason ≤ 6, prostate specific antigen [PSA] < 10 ng/mL, < 3 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL²). Patients who are older and have significant comorbidities should be managed with active surveillance rather than with active treatment. In the practice setting, however, studies indicated that a substantial number of older men with limited life expectancy still received aggressive treatment for low-risk cancer. Active treatment tended to decrease with age but was still common among men aged > 80 years: 25% received active local therapy, 36% received primary ADT, and only 39% received no active treatment.¹⁸

Surgery

Surgical treatment is an active therapeutic option for some patients with localized disease. Mortalities were reduced using prostatectomy vs watchful waiting, including disease-specific mortality and rates of metastasis. As newer techniques develop, laparoscopic prostatectomy may be able to provide excellent therapeutic
outcomes with quick surgical recovery times and possibly less postoperative nerve damage. Compared with younger patients, older patients experienced comparable
outcomes after surgical therapy.19-21 Despite encouraging surgical outcomes, however, surgery is not generally offered to patients aged > 70 years because
of the presumed high risks related to possible surgical complications.

Radiation Therapies

External-beam radiation therapy has been a well-established, standard mode of radiotherapy for the past several decades, among various radiation modalities, including brachytherapy (high- and low-dose radioactive seed implant therapy), cyber-knife therapy, and proton therapy. If indicated, EBRT rather than surgery is generally suggested as an active treatment for patients with localized prostate cancer. In general, EBRT and radical prostatectomy are comparable in survival
outcomes, but EBRT is preferred for older patients because it is noninvasive.^21,22 Conventional EBRT technique has gradually progressed over the past several decades, advancing to 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), image-guided radiotherapy, and then most recently to RapidArc radiation therapy.

RapidArc radiotherapy is an advanced form of IMRT that increases dose conformity and significantly shortens daily treatment times. In contrast to the static conventional IMRT technique (requiring repeated stops to deliver radiation through a 360° rotation of the therapy machine around the patient), RapidArc radiotherapy continues to deliver radiation therapy to the targeted tumor lesion with no interruption while the therapy machine is rotating around the patient. Accordingly, radiation therapy time is much shorter (up to 8 times faster) compared with conventional IMRT radiotherapy.

Systemic Therapy

Androgen-deprivation therapy can slow cancer growth, as it inhibits androgen production, blocks androgen action, or both. For localized prostate cancers with intermittent- and high-risk for recurrence, radiation therapy combined with ADT (eg, leuprolide, goserelin, triptorelin) reduces mortality of patients compared with ADT alone. In addition, hormone therapy is used for advanced, recurrent, or metastatic prostate cancers.

Most advanced and roughly one-fifth of biologically recurrent cancers ultimately convert to castrationresistant prostate cancer and may potentially benefit from nonhormonal systemic chemotherapy. Docetaxel with or without prednisone is the agent of choice for castration-resistant symptomatic metastatic prostate cancer. Cabazitaxel is a secondgeneration taxane and approved for castration-resistantmetastatic prostate cancer. Other systemic drugs (hormonal) for chemotherapy-naïve, metastatic castration-resistant prostate cancer are abiraterone (androgen synthesis inhibitor) and enzalutamide (anti-androgen).

Low-Risk Prostate Cancers

Active surveillance would be a reasonable management option for older patients with low-risk, localized prostate cancer and limited life expectancy of < 10 years. Albertsen and colleagues reported that patients with welldifferentiated prostate cancer and limited life expectancy have little chance of death due to prostate cancer but are more likely die of other causes, such as preexisting comorbidities.²³ Bill-Axelson and colleagues reported a very similar cancer-specific mortality rate of only 2.5% for patients with well-differentiated prostate cancer who are receiving either active therapy or active surveillance.²⁴ In another study, Krakowsky and colleagues reported a 97% 10-year cancer-specific survival rate in 450 patients with a median age of 70 years, and in a randomized study, Holmberg and colleagues reported no differences in overall survival for patients aged > 65 years who were randomized to surgery or watchful waiting for early-stage prostate cancer.^25,26

The literature consistently reports cancer-specific survival rates approaching 100% for patients with low-risk prostate cancer. The main concern regarding aggressive
therapy for older patients with low-risk cancer and significant comorbidities, as well as limited life expectancy, is the real possibility of overtreatment and the resultant high risk of treatment-related complications and loss in QOL. For example, surgery can lead to varying degrees of incontinence, and radiation can lead to rectal bleeding from proctitis, both severely impacting patients’ QOL.

High-Risk Prostate Cancers

Older patients with high-risk prostate cancer generally do not receive curative therapy. Bechis and colleagues examined the influence of age on disease-specific mortality.¹⁵ They found that patients aged > 75 years were more likely to be diagnosed with high-risk prostate cancer and treated with conservative therapy, such as ADT or watchful waiting, often resulting in death. They also found that the choice of therapy in older patients was based primarily on age rather than on comorbidities or other disease factors. Trends for such undertreatment were most evident in healthy seniors with high-risk cancer. The undertreatment of older patients with lower comorbidities contributes to the higher disease-specific mortality seen in the elderly population. Such healthy older patients were often overlooked solely because of their age and might have been denied the opportunity to receive curative and life-saving therapy early.

Summary

Most prostate cancers develop in older patients, and nearly one-fourth of prostate cancers are diagnosed in patients who are aged > 75 years. In addition, older patients show a higher tendency to present with highrisk prostate cancer. Furthermore, older patients have a higher risk of death compared with that of younger
patients, although many of them still die of causes other than prostate cancer. The most important prognostic factors in older patients, as recognized by the SIOG Prostate Cancer Working Group, included comorbidities, dependence status, and nutrition status. Management decisions for older patients with prostate cancer should be individualized and formulated based on remaining life expectancy, the patient’s functional performance and health status, as well as coexisting comorbidities and patient-specific prognostic characteristics of the prostate cancer, such as stage, Gleason score, and PSA values.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic
therapy to patients.

Click here to read the digital edition.

This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.

There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.

Patient Evaluation

The practice guidelines of the National Comprehensive Cancer Network (NCCN) recommend using life expectancy in determining treatment.¹ Prostate cancer is considered to be an indolent disease, and active therapy may be more harmful than beneficial to older patients whose life expectancy is limited because of treatment-related sequelae. Therefore, an accurate estimation of life expectancy is important in devising treatment strategies for older patients.

Age should not be the only factor in determining the life expectancy of patients, because life expectancy varies widely based on the patient’s health status, including preexisting comorbidities. Chronologic life expectancy can be found in the Social Security Administration’s life tables. Individual life expectancy is then projected by adding 50% to or deducting 50% from the chronologic life expectancy for men in the highest and lowest quartile of health, respectively. The life expectancy from the life tables can be applied with no addition or subtraction for men in the middle 2 quartiles of health status (Figure 1).²

Geriatric Assessment

Despite the increasing incidence of prostate cancer in older adults, no particular guidelines for its management exist. Compared with younger patients, older
patients with prostate cancer need to weigh the benefits of treatment vs the risks to avoid any potential adverse treatment-related quality of life (QOL) decreases. Clearly, for some patients there are no significant benefits from treatment (eg, improved survival).

The Comprehensive Geriatric Assessment has been created to properly assess aging in correlation to individual and patient-centered biologic and clinical metrics.
Following extensive literature reviews, the International Society of Geriatric Oncology (SIOG) Prostate Cancer Working Group recognized that the most important prognostic factors in evaluating health status in elderly patients with prostate cancer include comorbidities, functional dependence, and nutrition status.³ An important prognosticator of survival in prostate cancer is preexisting comorbidities. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) is considered the best metric currently available in assessing a patient’s death risk unrelated to cancer.

Another important factor influencing survival of older patients with prostate cancer is the patient’s level of independent activity. Independent functioning is evaluated
using (1) activities of daily living (ADL); and (2) the instrumental activities of daily living (IADL).^4-6

Health Status Subgroups

The SIOG recommendation for prostate cancer treatment in older patients is based on a complete assessment of existing comorbidities of patients using the CIRS-G,
IADL, and ADL scales as well as the nutritional status of each patient.^3,7-9 Based on these prognostic tools, the SIOG classifies the health status of elderly patients with prostate cancer into 4 prognostic health status categories: healthy, vulnerable, frail, and terminal.^10,11

Patient Characteristics

Older patients generally present with highrisk prostate cancer at diagnosis.^12,13 However, older patients are less likely to be treated with curative intent, resulting in
lower overall and disease-specific survivals. Nearly 40% of deaths due to prostate cancer occur in patients aged ≥ 75 years and 31% in the group aged ≥ 85 years.^12,14 Recent reports have demonstrated that curative radiotherapy or surgery improved survival outcomes as well as QOL in the elderly, comparable with those seen in younger patients.

Bechis and colleagues analyzed the relationship between survival of older patients with high-risk cancer and curative local therapy.¹⁵ Treatment modalities included radical prostatectomy, external-beam radiation therapy (EBRT), watchful waiting/active surveillance, and other modalities, including primary androgen deprivation therapy (ADT). The findings were: (1) older patients more frequently presented with high-risk disease as age increased; (2) therapeutic approaches varied but were based mainly on age at diagnosis rather than on cancer risk factors (Figures 2 and 3); and (3) ADT was used more frequently in older patients compared with its use in younger patients, irrespective of the risk score, including patients with high-risk disease.

Older patients were less likely to receive radical therapy, especially surgical treatment, regardless of risk category. Forty-four percent of patients aged > 70 years with high-risk disease died of any cause at a median 5.7 years, and 21% died of prostate cancer; whereas 47% of patients aged > 75 years with high-risk disease died at a median of 5.3 years, and 20% of those died of prostate cancer.

When older patients with high-risk disease received curative local therapy, however, the mortality rate decreased.

In a study by Sun and colleagues, 4,561 senior patients who received radical prostatectomy therapy were classified into 3 age groups (aged < 60 years, aged 60 to 70 years, and aged > 70 years) based on the year of surgery (before or after 2000). Therapy outcomes were compared among the 3 groups.¹⁶ The researchers found that seniors aged > 70 years who presented with high-risk disease had poorer therapeutic outcomes. A diagnosis of advancedstage cancer and a Gleason score > 7 were more often made in patients aged > 70 years vs that of their younger counterparts. They also found greater risk of failures for these patients in biochemical recurrence, distant metastasis, and disease-specific survivals.

Most clinicians typically ruled out active treatment based on chronologic age alone, without considering existing comorbidities and overall life expectancy. According
to a study by Daskivich and colleagues, only 16% of patients aged > 75 years were aggressively treated, whereas 84% of patients aged < 55 years received aggressive curative therapy, using radical prostatectomy, radiation therapy, or brachytherapy.¹⁷

Therapeutic Approaches

Current NCCN guidelines recommend active surveillance as an option for men with low- and intermediate-risk disease with a < 10-year life expectancy and the only option for men with a < 20-year life expectancy and a very low-risk of prostate cancer (stage T1c, Gleason ≤ 6, prostate specific antigen [PSA] < 10 ng/mL, < 3 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL²). Patients who are older and have significant comorbidities should be managed with active surveillance rather than with active treatment. In the practice setting, however, studies indicated that a substantial number of older men with limited life expectancy still received aggressive treatment for low-risk cancer. Active treatment tended to decrease with age but was still common among men aged > 80 years: 25% received active local therapy, 36% received primary ADT, and only 39% received no active treatment.¹⁸

Surgery

Surgical treatment is an active therapeutic option for some patients with localized disease. Mortalities were reduced using prostatectomy vs watchful waiting, including disease-specific mortality and rates of metastasis. As newer techniques develop, laparoscopic prostatectomy may be able to provide excellent therapeutic
outcomes with quick surgical recovery times and possibly less postoperative nerve damage. Compared with younger patients, older patients experienced comparable
outcomes after surgical therapy.19-21 Despite encouraging surgical outcomes, however, surgery is not generally offered to patients aged > 70 years because
of the presumed high risks related to possible surgical complications.

Radiation Therapies

External-beam radiation therapy has been a well-established, standard mode of radiotherapy for the past several decades, among various radiation modalities, including brachytherapy (high- and low-dose radioactive seed implant therapy), cyber-knife therapy, and proton therapy. If indicated, EBRT rather than surgery is generally suggested as an active treatment for patients with localized prostate cancer. In general, EBRT and radical prostatectomy are comparable in survival
outcomes, but EBRT is preferred for older patients because it is noninvasive.^21,22 Conventional EBRT technique has gradually progressed over the past several decades, advancing to 3D conformal radiotherapy, intensity-modulated radiation therapy (IMRT), image-guided radiotherapy, and then most recently to RapidArc radiation therapy.

RapidArc radiotherapy is an advanced form of IMRT that increases dose conformity and significantly shortens daily treatment times. In contrast to the static conventional IMRT technique (requiring repeated stops to deliver radiation through a 360° rotation of the therapy machine around the patient), RapidArc radiotherapy continues to deliver radiation therapy to the targeted tumor lesion with no interruption while the therapy machine is rotating around the patient. Accordingly, radiation therapy time is much shorter (up to 8 times faster) compared with conventional IMRT radiotherapy.

Systemic Therapy

Androgen-deprivation therapy can slow cancer growth, as it inhibits androgen production, blocks androgen action, or both. For localized prostate cancers with intermittent- and high-risk for recurrence, radiation therapy combined with ADT (eg, leuprolide, goserelin, triptorelin) reduces mortality of patients compared with ADT alone. In addition, hormone therapy is used for advanced, recurrent, or metastatic prostate cancers.

Most advanced and roughly one-fifth of biologically recurrent cancers ultimately convert to castrationresistant prostate cancer and may potentially benefit from nonhormonal systemic chemotherapy. Docetaxel with or without prednisone is the agent of choice for castration-resistant symptomatic metastatic prostate cancer. Cabazitaxel is a secondgeneration taxane and approved for castration-resistantmetastatic prostate cancer. Other systemic drugs (hormonal) for chemotherapy-naïve, metastatic castration-resistant prostate cancer are abiraterone (androgen synthesis inhibitor) and enzalutamide (anti-androgen).

Low-Risk Prostate Cancers

Active surveillance would be a reasonable management option for older patients with low-risk, localized prostate cancer and limited life expectancy of < 10 years. Albertsen and colleagues reported that patients with welldifferentiated prostate cancer and limited life expectancy have little chance of death due to prostate cancer but are more likely die of other causes, such as preexisting comorbidities.²³ Bill-Axelson and colleagues reported a very similar cancer-specific mortality rate of only 2.5% for patients with well-differentiated prostate cancer who are receiving either active therapy or active surveillance.²⁴ In another study, Krakowsky and colleagues reported a 97% 10-year cancer-specific survival rate in 450 patients with a median age of 70 years, and in a randomized study, Holmberg and colleagues reported no differences in overall survival for patients aged > 65 years who were randomized to surgery or watchful waiting for early-stage prostate cancer.^25,26

The literature consistently reports cancer-specific survival rates approaching 100% for patients with low-risk prostate cancer. The main concern regarding aggressive
therapy for older patients with low-risk cancer and significant comorbidities, as well as limited life expectancy, is the real possibility of overtreatment and the resultant high risk of treatment-related complications and loss in QOL. For example, surgery can lead to varying degrees of incontinence, and radiation can lead to rectal bleeding from proctitis, both severely impacting patients’ QOL.

High-Risk Prostate Cancers

Older patients with high-risk prostate cancer generally do not receive curative therapy. Bechis and colleagues examined the influence of age on disease-specific mortality.¹⁵ They found that patients aged > 75 years were more likely to be diagnosed with high-risk prostate cancer and treated with conservative therapy, such as ADT or watchful waiting, often resulting in death. They also found that the choice of therapy in older patients was based primarily on age rather than on comorbidities or other disease factors. Trends for such undertreatment were most evident in healthy seniors with high-risk cancer. The undertreatment of older patients with lower comorbidities contributes to the higher disease-specific mortality seen in the elderly population. Such healthy older patients were often overlooked solely because of their age and might have been denied the opportunity to receive curative and life-saving therapy early.

Summary

Most prostate cancers develop in older patients, and nearly one-fourth of prostate cancers are diagnosed in patients who are aged > 75 years. In addition, older patients show a higher tendency to present with highrisk prostate cancer. Furthermore, older patients have a higher risk of death compared with that of younger
patients, although many of them still die of causes other than prostate cancer. The most important prognostic factors in older patients, as recognized by the SIOG Prostate Cancer Working Group, included comorbidities, dependence status, and nutrition status. Management decisions for older patients with prostate cancer should be individualized and formulated based on remaining life expectancy, the patient’s functional performance and health status, as well as coexisting comorbidities and patient-specific prognostic characteristics of the prostate cancer, such as stage, Gleason score, and PSA values.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations— including indications, contraindications, warnings, and adverse effects—before administering pharmacologic
therapy to patients.

Click here to read the digital edition.