Immunology

HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.

Sharon Worcester/MDedge News

At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.

GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.

All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.

The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m² along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.

All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.

Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.

An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.

Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.

“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”

Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.

Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.

“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.

Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.

“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.

All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.

The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.

“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.

For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.

The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.

“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Dimitrova reported having no financial disclosures.

[email protected]

SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.

HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.

Sharon Worcester/MDedge News

At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.

GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.

All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.

The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m² along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.

All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.

Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.

An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.

Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.

“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”

Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.

Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.

“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.

Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.

“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.

All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.

The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.

“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.

For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.

The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.

“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Dimitrova reported having no financial disclosures.

[email protected]

SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.

HOUSTON – Allogeneic hematopoietic stem cell transplantation (allo-HCT) following a novel reduced-intensity conditioning regimen was largely successful in a heterogeneous cohort of 29 adults and children with primary immunodeficiency in a prospective clinical trial.

Sharon Worcester/MDedge News

At 1 year after transplant, overall survival was 98% and the estimated graft failure–free and graft-versus-host disease (GVHD)–free survival was 82% among the participants, who had various underlying primary immunodeficiencies (PIDs), Dimana Dimitrova, MD, reported at the Transplantation and Cellular Therapy Meetings.

GVHD-free survival was defined in this National Institutes of Health study as the absence of steroid-refractory grade 3-4 acute GVHD and chronic GVHD, noted Dr. Dimitrova of the NIH.

All patients, including 19 adults and 10 children (median age, 25 years), received a serotherapy-free, radiation-free, reduced-intensity conditioning regimen designed to optimize immune reconstitution, minimize toxicity and GVHD, reduce the risk of infectious complications, and enable successful use of alternative donors.

The conditioning platform included pentostatin on day –11 and day –7 at 4 mg/m² along with 8 days of low-dose cyclophosphamide and 2 days of pharmacokinetically dosed busulfan at 4,600 mmol/min. GVHD prophylaxis included posttransplantation cyclophosphamide, mycophenolate mofetil (MMF), and sirolimus.

All patients received T cell–replete bone marrow or peripheral blood stem cell allografts; 72% received alternative donor grafts, Dr. Dimitrova said.

Two patients died, including one with bacterial sepsis and invasive aspergillosis who died on day +44 and one with presumed viral encephalitis who died on day +110. The patients were high risk overall (median HCT–comorbidity index score of 3, with a range of 0-11), and the two who died had HCT-CI scores of 6 and 8, respectively.

An additional accidental death occurred at 18 months after transplant “in the setting of continued remission, good graft function, and no transplant-related complications,” she said.

Neutrophil recovery occurred at a median of 17 days after transplant; three patients experienced graft failure, including one primary failure with autologous recovery on day +14 and two secondary graft failures.

“Two patients with known underlying difficult-to-engraft diseases required second transplants using different nonmyeloabalative platforms, and nevertheless required donor lymphocyte infusions to avoid threatened secondary graft failure,” she said. “The third patient actually had sufficiently improved infectious disease control and has not needed a second transplant to date.”

Overall GVHD incidence using the novel platform has been extremely low, she said, noting that 14% of patients had grade 2-4 GVHD and 3% had grade 3-4 acute GVHD. There was no steroid-refractory GVHD or chronic GVHD.

Among the infectious complications, other than those that led to the two deaths, were cytomegalovirus reactivation in 7 of 16 patients at risk, BK virus–associated hemorrhagic cystitis in 19 of 22 patients at risk, and a suspected case of viral cardiomyopathy that ultimately resolved.

“Importantly, although many patients had Epstein-Barr virus [EBV] control issues prior to transplant, no patients received preemptive EBV-directed therapy, and no patients had EBV-PTLD [posttransplant lymphoproliferative disorder],” she said.

Additionally, blood stream infections were detected in five patients, there were two cases of confirmed aspergillosis, and one child developed cutaneous candidiasis. Other complications and toxicities appeared to relate to underlying pretransplant issues in the affected organ or exuberant immune responses to existing infection.

“Phenotype reversal was evident to some degree in all evaluable patients, even in those with mixed chimerism or unknown underlying genetic defect,” Dr. Dimitrova said.

All 10 patients with malignancy or lymphoproliferative disease as an additional indication for allo-HCT remain in remission, and most patients who required immunoglobulin replacement therapy prior to transplant have been able to discontinue it, she noted.

The findings of this study are of note, because while it has been known for decades that allo-HCT is a potentially curative therapy for patients with PIDs that arise from defects in cells of hematopoietic origin, it frequently fails because of complicating factors or is not an option, Dr. Dimitrova said.

“These patients will often enter transplant with multiple comorbidities and disease sequelae, particularly as diagnosis of PIDs increases in older children and adults following years of illness,” she explained, adding that related donor options may be limited if family members are also affected.

For this reason, and with the goal of improving access to allo-HCT to all who require it, the novel conditioning platform used in this study was developed.

The platform was well tolerated overall, Dr. Dimitrova said, emphasizing the “notably low” GVHD rates.

“Currently we are investigating reduced MMF with the goal of promoting earlier immune reconstitution, and a separate protocol has opened that includes several modifications to this platform aimed at patients with increased risk of graft failure who may not tolerate mixed chimerism early on,” she said, noting that both protocols are currently enrolling.

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Dimitrova reported having no financial disclosures.

[email protected]

SOURCE: Dimitrova D et al. TCT 2019, Abstract 54.

SAN FRANCISCO – A peanut or egg allergy diagnosed when infants were 1 year of age often resolved by the time they turned 6, in a longitudinal, population-based study of more than 5,000 Australian children.

Mitchel L. Zoler/MDedge News

Among 131 infants diagnosed with a peanut allergy when they were 1 year old and then followed with repeat testing 5 years later, 41 (31%) had complete resolution of their peanut allergy, while the allergy persisted in the other 90 children, Rachel L. Peters, PhD, said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. The study also followed 404 infants diagnosed with an egg allergy at 1 year of age and found that by age 6 the allergy had resolved in 368 (91%), while persisting in 36 children, said Dr. Peters, an epidemiologist at Murdoch Children’s Research Institute in Parkville, Australia.


The analysis also identified risk factors that linked with an increased rate of allergy persistence. For peanut allergy persistence beyond the first year, the correlating factors were early-onset eczema, tree nut allergy, and a stronger peanut allergy identified by a greater than 4-mm reaction to a peanut skin-prick test. Factors that linked with an increased rate of persistent egg allergy were eczema, peanut allergy, gastrointestinal or respiratory reaction symptoms to milk, and reaction on an oral food challenge elicited by a low dose (less than 0.5 mL) of milk.

A consequence of the frequent resolution of these food allergies was that a positive skin-prick test reaction to either peanut or egg at 1 year old was poorly predictive of allergy status at age 6, while skin-prick tests at age 6 worked well for identifying a persistent food allergy at that age.

The analyses that Dr. Peters and her associates ran used data collected in the HealthNuts study, a comprehensive, prospective, population-based study of food allergies in children that enrolled 5,276 infants at 1 year old. The HealthNuts researchers enrolled infants at immunization clinics in the Melbourne area, with enrollment stratified to represent the people who live in that region (Clin Exp Allergy. 2010 Oct;40[10]:1516-22).

[email protected]

On Twitter @mitchelzoler

SOURCE: Peters R et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB421.

SAN FRANCISCO – A peanut or egg allergy diagnosed when infants were 1 year of age often resolved by the time they turned 6, in a longitudinal, population-based study of more than 5,000 Australian children.

Mitchel L. Zoler/MDedge News

Among 131 infants diagnosed with a peanut allergy when they were 1 year old and then followed with repeat testing 5 years later, 41 (31%) had complete resolution of their peanut allergy, while the allergy persisted in the other 90 children, Rachel L. Peters, PhD, said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. The study also followed 404 infants diagnosed with an egg allergy at 1 year of age and found that by age 6 the allergy had resolved in 368 (91%), while persisting in 36 children, said Dr. Peters, an epidemiologist at Murdoch Children’s Research Institute in Parkville, Australia.


The analysis also identified risk factors that linked with an increased rate of allergy persistence. For peanut allergy persistence beyond the first year, the correlating factors were early-onset eczema, tree nut allergy, and a stronger peanut allergy identified by a greater than 4-mm reaction to a peanut skin-prick test. Factors that linked with an increased rate of persistent egg allergy were eczema, peanut allergy, gastrointestinal or respiratory reaction symptoms to milk, and reaction on an oral food challenge elicited by a low dose (less than 0.5 mL) of milk.

A consequence of the frequent resolution of these food allergies was that a positive skin-prick test reaction to either peanut or egg at 1 year old was poorly predictive of allergy status at age 6, while skin-prick tests at age 6 worked well for identifying a persistent food allergy at that age.

The analyses that Dr. Peters and her associates ran used data collected in the HealthNuts study, a comprehensive, prospective, population-based study of food allergies in children that enrolled 5,276 infants at 1 year old. The HealthNuts researchers enrolled infants at immunization clinics in the Melbourne area, with enrollment stratified to represent the people who live in that region (Clin Exp Allergy. 2010 Oct;40[10]:1516-22).

[email protected]

On Twitter @mitchelzoler

SOURCE: Peters R et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB421.

SAN FRANCISCO – A peanut or egg allergy diagnosed when infants were 1 year of age often resolved by the time they turned 6, in a longitudinal, population-based study of more than 5,000 Australian children.

Mitchel L. Zoler/MDedge News

Among 131 infants diagnosed with a peanut allergy when they were 1 year old and then followed with repeat testing 5 years later, 41 (31%) had complete resolution of their peanut allergy, while the allergy persisted in the other 90 children, Rachel L. Peters, PhD, said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. The study also followed 404 infants diagnosed with an egg allergy at 1 year of age and found that by age 6 the allergy had resolved in 368 (91%), while persisting in 36 children, said Dr. Peters, an epidemiologist at Murdoch Children’s Research Institute in Parkville, Australia.


The analysis also identified risk factors that linked with an increased rate of allergy persistence. For peanut allergy persistence beyond the first year, the correlating factors were early-onset eczema, tree nut allergy, and a stronger peanut allergy identified by a greater than 4-mm reaction to a peanut skin-prick test. Factors that linked with an increased rate of persistent egg allergy were eczema, peanut allergy, gastrointestinal or respiratory reaction symptoms to milk, and reaction on an oral food challenge elicited by a low dose (less than 0.5 mL) of milk.

A consequence of the frequent resolution of these food allergies was that a positive skin-prick test reaction to either peanut or egg at 1 year old was poorly predictive of allergy status at age 6, while skin-prick tests at age 6 worked well for identifying a persistent food allergy at that age.

The analyses that Dr. Peters and her associates ran used data collected in the HealthNuts study, a comprehensive, prospective, population-based study of food allergies in children that enrolled 5,276 infants at 1 year old. The HealthNuts researchers enrolled infants at immunization clinics in the Melbourne area, with enrollment stratified to represent the people who live in that region (Clin Exp Allergy. 2010 Oct;40[10]:1516-22).

[email protected]

On Twitter @mitchelzoler

SOURCE: Peters R et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB421.

Laboratory tests are often ordered inappropriately for patients in whom a rheumatologic illness is suspected; this occurs in both primary and secondary care.¹ Some tests are available both singly and as part of a battery of tests screening healthy people without symptoms.

The problem: negative test results are by no means always reassuring, and false-positive results raise the risks of unnecessary anxiety for patients and clinicians, needless referrals, and potential morbidity due to further unnecessary testing and exposure to wrong treatments.² Clinicians should be aware of the pitfalls of these tests in order to choose them wisely and interpret the results correctly.

This article provides practical guidance on requesting and interpreting some common tests in rheumatology, with the aid of case vignettes.

RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE ANTIBODY

A 41-year-old woman, previously in good health, presents to her primary care practitioner with a 6-week history of pain and swelling in her hands and early morning stiffness lasting about 2 hours. She denies having any extraarticular symptoms. Physical examination reveals synovitis across her right metacarpophalangeal joints, proximal interphalangeal joint of the left middle finger, and left wrist. The primary care physician is concerned that her symptoms might be due to rheumatoid arthritis.

Would testing for rheumatoid factor and anticitrullinated peptide antibody be useful in this patient?

Rheumatoid factor is an antibody (immunoglobulin M, IgG, or IgA) targeted against the Fc fragment of IgG.³ It was so named because it was originally detected in patients with rheumatoid arthritis, but it is neither sensitive nor specific for this condition. A meta-analysis of more than 5,000 patients with rheumatoid arthritis reported that rheumatoid factor testing had a sensitivity of 69% and specificity of 85%.⁴

Anticitrullinated peptide antibody, on the other hand, is much more specific for rheumatoid arthritis (95%), as it is seldom seen in other conditions, but its sensitivity is similar to that of rheumatoid factor (68%).^4–6 A positive result would thus lend strength to the diagnosis of rheumatoid arthritis, but a negative result would not exclude it.

Approach to early arthritis

When faced with a patient with early arthritis, some key questions to ask include^7,8:

Is this an inflammatory or a mechanical problem? Inflammatory arthritis is suggested by joint swelling that is not due to trauma or bony hypertrophy, early morning stiffness lasting longer than 30 minutes, and elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein). Involvement of the small joints of the hands and feet may be suggested by pain on compression of the metacarpophalangeal and metatarsophalangeal joints, respectively.

Is there a definite identifiable underlying cause for the inflammatory arthritis? The pattern of development of joint symptoms or the presence of extraarticular symptoms may suggest an underlying problem such as gout, psoriatic arthritis, systemic lupus erythematosus, or sarcoidosis.

If the arthritis is undifferentiated (ie, there is no definite identifiable cause), is it likely to remit or persist? This is perhaps the most important question to ask in order to prognosticate. Patients with risk factors for persistent disease, ie, for development of rheumatoid arthritis, should be referred to a rheumatologist early for timely institution of disease-modifying antirheumatic drug therapy.⁹ Multiple studies have shown that patients in whom this therapy is started early have much better clinical, functional, and radiologic outcomes than those in whom it is delayed.^10–12

The revised American College of Rheumatology and European League Against Rheumatism criteria¹³ include the following factors as predictors of persistence:

• Number of involved joints (with greater weight given to involvement of small joints)
• Duration of symptoms 6 weeks or longer
• Elevated acute-phase response (erythrocyte sedimentation rate or C-reactive protein level)
• A positive serologic test (either rheumatoid factor or anticitrullinated peptide antibody).

If both rheumatoid factor and anticitrullinated peptide antibody are positive in a patient with early undifferentiated arthritis, the risk of progression to rheumatoid arthritis is almost 100%, thus underscoring the importance of testing for these antibodies.^5,6 Referral to a rheumatologist should, however, not be delayed in patients with negative test results (more than one-third of patients with rheumatoid arthritis may be negative for both), and should be considered in those with inflammatory joint symptoms persisting longer than 6 weeks, especially with involvement of the small joints (sparing the distal interphalangeals) and elevated acute-phase response.

Rheumatoid factor in healthy people without symptoms

In some countries, testing for rheumatoid factor is offered as part of a battery of screening tests in healthy people who have no symptoms, a practice that should be strongly discouraged.

Multiple studies, both prospective and retrospective, have demonstrated that both rheumatoid factor and anticitrullinated peptide antibody may be present several years before the clinical diagnosis of rheumatoid arthritis.^6,14–16 But the risk of developing rheumatoid arthritis for asymptomatic individuals who are rheumatoid factor-positive depends on the rheumatoid factor titer, positive family history of rheumatoid arthritis in first-degree relatives, and copresence of anticitrullinated peptide antibody. The absolute risk, nevertheless, is still very small. In some, there might be an alternative explanation such as undiagnosed Sjögren syndrome or hepatitis C.

In any event, no strategy is currently available that is proven to prevent the development of rheumatoid arthritis, and there is no role for disease-modifying therapy during the preclinical phase.¹⁶

Back to our patient

Blood testing in our patient reveals normal complete blood cell counts, aminotransferase levels, and serum creatinine concentration; findings on urinalysis are normal. Her erythrocyte sedimentation rate is 56 mm/hour (reference range 0–15), and her C-reactive protein level is 26 mg/dL (normal < 3). Testing is negative for rheumatoid factor and anticitrullinated peptide antibody.

Although her rheumatoid factor and anticitrullinated peptide antibody tests are negative, she is referred to a rheumatologist because she has predictors of persistent disease, ie, symptom duration of 6 weeks, involvement of the small joints of the hands, and elevated erythrocyte sedimentation rate and C-reactive protein. The rheumatologist checks her parvovirus serology, which is negative.

The patient is given parenteral depot corticosteroid therapy, to which she responds briefly. Because her symptoms persist and continue to worsen, methotrexate treatment is started after an additional 6 weeks.

A 37-year-old woman presents to her primary care physician with the complaint of tiredness. She has a family history of systemic lupus erythematosus in her sister and maternal aunt. She is understandably worried about lupus because of the family history and is asking to be tested for it.

Would testing for antinuclear antibody be reasonable?

Antinuclear antibody is not a single antibody but rather a family of autoantibodies that are directed against nuclear constituents such as single- or double-stranded deoxyribonucleic acid (dsDNA), histones, centromeres, proteins complexed with ribonucleic acid (RNA), and enzymes such as topoisomerase.^17,18

Protein antigens complexed with RNA and some enzymes in the nucleus are also known as extractable nuclear antigens (ENAs). They include Ro, La, Sm, Jo-1, RNP, and ScL-70 and are named after the patient in whom they were first discovered (Robert, Lavine, Smith, and John), the antigen that is targeted (ribonucleoprotein or RNP), and the disease with which they are associated (anti-ScL-70 or antitopoisomerase in diffuse cutaneous scleroderma).

Antinuclear antibody testing is commonly requested to exclude connective tissue diseases such as lupus, but the clinician needs to be aware of the following points:

Antinuclear antibody may be encountered in conditions other than lupus

These include¹⁹:

• Other autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and myasthenia gravis
• Infection with organisms that share the epitope with self-antigens (molecular mimicry)
• Cancers
• Drugs such as hydralazine, procainamide, and minocycline.

Antinuclear antibody might also be produced by the healthy immune system from time to time to clear the nuclear debris that is extruded from aging cells.

A study in healthy individuals²⁰ reported a prevalence of positive antinuclear antibody of 32% at a titer of 1/40, 15% at a titer of 1/80, 7% at a titer of 1/160, and 3% at a titer of 1/320. Importantly, a positive result was more common among family members of patients with autoimmune connective tissue diseases.²¹ Hence, a positive antinuclear antibody result does not always mean lupus.

Antinuclear antibody testing is highly sensitive for lupus

With current laboratory methods, antinuclear antibody testing has a sensitivity close to 100%. Hence, a negative result virtually rules out lupus.

Two methods are commonly used to test for antinuclear antibody: indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).²² While human epithelial (Hep2) cells are used as the source of antigen in immunofluorescence, purified nuclear antigens coated on multiple-well plates are used in ELISA.

Although ELISA is simpler to perform, immunofluorescence has a slightly better sensitivity (because the Hep2 cells express a wide range of antigens) and is still considered the gold standard. As expected, the higher sensitivity occurs at the cost of reduced specificity (about 60%), so antinuclear antibody will also be detected in all the other conditions listed above.²³

To improve the specificity of antinuclear antibody testing, laboratories report titers (the highest dilution of the test serum that tested positive); a cutoff of greater than 1/80 is generally considered significant.

Do not order antinuclear antibody testing indiscriminately

To sum up, the antinuclear antibody test should be requested only in patients with involvement of multiple organ systems. Although a negative result would make it extremely unlikely that the clinical presentation is due to lupus, a positive result is insufficient on its own to make a diagnosis of lupus.

Diagnosing lupus is straightforward when patients present with a specific manifestation such as inflammatory arthritis, photosensitive skin rash, hemolytic anemia, thrombocytopenia, or nephritis, or with specific antibodies such as those against dsDNA or Sm. Patients who present with nonspecific symptoms such as arthralgia or tiredness with a positive antinuclear antibody and negative anti-dsDNA and anti-Sm may present difficulties even for the specialist.^25–27

Back to our patient

Our patient denies arthralgia. She has no extraarticular symptoms such as skin rashes, oral ulcers, sicca symptoms, muscle weakness, Raynaud phenomenon, pleuritic chest pain, or breathlessness. Findings on physical examination and urinalysis are unremarkable.

Her primary care physician decides to check her complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level. Although she is reassured that her tiredness is not due to lupus, she insists on getting an antinuclear antibody test.

Her complete blood cell counts are normal. Her erythrocyte sedimentation rate is 6 mm/hour. However, her thyroid-stimulating hormone level is elevated, and subsequent testing shows low free thyroxine and positive thyroid peroxidase antibodies. The antinuclear antibody is positive in a titer of 1/80 and negative for anti-dsDNA and anti-ENA.

We explain to her that the positive antinuclear antibody is most likely related to her autoimmune thyroid disease. She is referred to an endocrinologist.

A 24-year-old woman presents to the emergency department with acute unprovoked deep vein thrombosis in her right leg, confirmed by ultrasonography. She has no history of previous thrombosis, and the relevant family history is unremarkable. She has never been pregnant. Her platelet count is 84 × 10⁹/L (reference range 150–400), and her baseline activated partial thromboplastin time is prolonged at 62 seconds (reference range 23.0–32.4). The rest of her blood counts and her prothrombin time, liver enzyme levels, and serum creatinine level are normal.

Should this patient be tested for antiphospholipid antibodies?

Antiphospholipid antibodies are important because of their association with thrombotic risk (both venous and arterial) and pregnancy morbidity. The name is a misnomer, as these antibodies are targeted against some proteins that are bound to phospholipids and not only to the phospholipids themselves.

According to the modified Sapporo criteria for the classification of antiphospholipid syndrome,²⁸ antiphospholipid antibodies should remain persistently positive on at least 2 separate occasions at least 12 weeks apart for the result to be considered significant because some infections and drugs may be associated with the transient presence of antiphospholipid antibodies.

Screening for antiphospholipid antibodies should include testing for IgM and IgG anticardiolipin antibodies, lupus anticoagulant, and IgM and IgG beta-2 glycoprotein I antibodies.^29,30

Anticardiolipin antibodies

Anticardiolipin (aCL) antibodies may be targeted either against beta-2 glycoprotein I (beta-2GPI) that is bound to cardiolipin (a phospholipid) or against cardiolipin alone; the former is more specific. Antibodies directed against cardiolipin alone are usually transient and are associated with infections and drugs. The result is considered significant only when anticardiolipin antibodies are present in a medium to high titer (> 40 IgG phospholipid units or IgM phospholipid units, or > 99th percentile).

Lupus anticoagulant

The antibody with “lupus anticoagulant activity” is targeted against prothrombin plus phospholipid or beta-2GPI plus phospholipid. The test for it is a functional assay involving 3 steps:

Demonstrating the prolongation of a phospholipid-dependent coagulation assay like the activated partial thromboplastin time (aPTT). (This may explain the prolongation of aPTT in the patient described in the vignette.) Although the presence of lupus anticoagulant is associated with thrombosis, it is called an “anticoagulant” because of this in vitro prolongation of phospholipid-dependent coagulation assays.

Mixing study. The phospholipid-dependent coagulation assay could be prolonged because of either the deficiency of a coagulation factor or the presence of the antiphospholipid antibodies. This can be differentiated by mixing the patient’s plasma with normal plasma (which will have all the clotting factors) in a 1:1 ratio. If the coagulation assay remains prolonged after the addition of normal plasma, clotting factor deficiency can be excluded.

Addition of a phospholipid. If the prolongation of the coagulation assay is due to the presence of an antiphospholipid antibody, addition of extra phospholipid will correct this.

Beta-2 glycoprotein I antibody (anti-beta-2GPI)

The beta-2GPI that is not bound to the cardiolipin can be detected by separately testing for beta-2GPI (the anticardiolipin test only detects the beta-2GPI that is bound to the cardiolipin). The result is considered significant if beta-2GPI is present in a medium to high titer (> 99th percentile).

Studies have shown that antiphospholipid antibodies may be present in 1% to 5% of apparently healthy people in the general population.³¹ These are usually low-titer anticardiolipin or anti-beta-GPI IgM antibodies that are not associated with thrombosis or adverse pregnancy outcomes. Hence, the term antiphospholipid syndrome should be reserved for those who have had at least 1 episode of thrombosis or pregnancy morbidity and persistent antiphospholipid antibodies, and not those who have asymptomatic or transient antiphospholipid antibodies.

Triple positivity (positive anticardiolipin, lupus anticoagulant, and anti-beta-2GPI) seems to be associated with the highest risk of thrombosis, with a 10-year cumulative incidence of 37.1% (95% confidence interval [CI] 19.9–54.3) for a first thrombotic event,³² and 44.2% (95% CI 38.6–49.8) for recurrent thrombosis.³³

The association with thrombosis is stronger for lupus anticoagulant than with the other 2 antibodies, with different studies³⁴ finding an odds ratio ranging from 5 to 16. A positive lupus anticoagulant test with or without a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a high-risk profile, while a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a moderate-risk profile. A low titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a low-risk profile that may not be associated with thrombosis.³⁵

Antiphospholipid syndrome is important to recognize because of the need for long-term anticoagulation to prevent recurrence.³⁶ It may be primary, when it occurs on its own, or secondary, when it occurs in association with another autoimmune disease such as lupus.

Venous events in antiphospholipid syndrome most commonly manifest as lower-limb deep vein thrombosis or pulmonary embolism, while arterial events most commonly manifest as stroke or transient ischemic attack.³⁷ Obstetric manifestations may include not only miscarriage and stillbirth, but also preterm delivery, intrauterine growth retardation, and preeclampsia, all occurring due to placental insufficiency.

The frequency of antiphospholipid antibodies has been estimated as 13.5% in patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% for those with pregnancy morbidity.³⁸

Some noncriteria manifestations have also been recognized in antiphospholipid syndrome, such as thrombocytopenia, cardiac vegetations (Libman-Sachs endocarditis), livedo reticularis, and nephropathy.

Back to our patient

Our patient’s anticardiolipin IgG test is negative, while her lupus anticoagulant and beta-2GPI IgG are positive. She has no clinical or laboratory features suggesting lupus.

She is started on warfarin. After 3 months, the warfarin is interrupted for several days, and she is retested for all 3 antiphospholipid antibodies. Her beta-2GPI I IgG and lupus anticoagulant tests are again positive. Because of the persistent antiphospholipid antibody positivity and clinical history of deep vein thrombosis, her condition is diagnosed as primary antiphospholipid syndrome. She is advised to continue anticoagulant therapy indefinitely.

A 34-year-old man who is an injecting drug user presents with a 2-week history of fever, malaise, and generalized arthralgia. There are no localizing symptoms of infection. Notable findings on examination include a temperature of 38.0°C (100.4°F), needle track marks in his arms, nonblanching vasculitic rash in his legs, and a systolic murmur over the precordium.

His white blood cell count is 15.3 × 10⁹/L (reference range 3.7–11.0), and his C-reactive protein level is 234 mg/dL (normal < 3). Otherwise, results of blood cell counts, liver enzyme tests, renal function tests, urinalysis, and chest radiography are normal.

Two sets of blood cultures are drawn. Transthoracic echocardiography and the antineutrophil cytoplasmic antibody (ANCA) test are requested, as are screening tests for human immunodeficiency virus, hepatitis B, and hepatitis C.

Was the ANCA test indicated in this patient?

ANCAs are autoantibodies against antigens located in the cytoplasmic granules of neutrophils and monocytes. They are associated with small-vessel vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and isolated pauciimmune crescentic glomerulonephritis, all collectively known as ANCA-associated vasculitis (AAV).³⁹

Laboratory methods to detect ANCA include indirect immunofluorescence and antigen-specific enzyme immunoassays. Indirect immunofluorescence only tells us whether or not an antibody that is targeting a cytoplasmic antigen is present. Based on the indirect immunofluorescent pattern, ANCA can be classified as follows:

• Perinuclear or p-ANCA (if the targeted antigen is located just around the nucleus and extends into it)
• Cytoplasmic or c-ANCA (if the targeted antigen is located farther away from the nucleus)
• Atypical ANCA (if the indirect immunofluorescent pattern does not fit with either p-ANCA or c-ANCA).

Indirect immunofluorescence does not give information about the exact antigen that is targeted; this can only be obtained by performing 1 of the antigen-specific immunoassays. The target antigen for c-ANCA is usually proteinase-3 (PR3), while that for p-ANCA could be myeloperoxidase (MPO), cathepsin, lysozyme, lactoferrin, or bactericidal permeability inhibitor. Anti-PR3 is highly specific for GPA, while anti-MPO is usually associated with MPA and EGPA. Less commonly, anti-PR3 may be seen in patients with MPA and anti-MPO in those with GPA. Hence, there is an increasing trend toward classifying ANCA-associated vasculitis into PR3-associated or MPO-associated vasculitis rather than as GPA, MPA, EGPA, or renal-limited vasculitis.⁴⁰

Several audits have shown that the ANCA test is widely misused and requested indiscriminately to rule out vasculitis. This results in a lower positive predictive value, possible harm to patients due to increased false-positive rates, and increased burden on the laboratory.^41–43 At least 2 separate groups have demonstrated that a gating policy that refuses ANCA testing in patients without clinical evidence of systemic vasculitis can reduce the number of inappropriate requests, improve the diagnostic yield, and make it more clinically relevant and cost-effective.^44,45

The clinician should bear in mind that:

Current guidelines recommend using one of the antigen-specific assays for PR3 and MPO as the primary screening method.⁴⁸ Until recently, indirect immunofluorescence was used to screen for ANCA-associated vasculitis, and positive results were confirmed by ELISA to detect ANCAs specific for PR3 and MPO,⁴⁹ but this is no longer recommended because of recent evidence suggesting a large variability between the different indirect immunofluorescent methods and improved diagnostic performance of the antigen-specific assays.

In a large multicenter study by Damoiseaux et al, the specificity with the different antigen-specific immunoassays was 98% to 99% for PR3-ANCA and 96% to 99% for MPO-ANCA.⁵⁰

ANCA-associated vasculitis should not be considered excluded if the PR3 and MPO-ANCA are negative. In the Damoiseaux study, about 11% to 15% of patients with GPA and 8% to 24% of patients with MPA tested negative for both PR3 and MPO-ANCA.⁵⁰

If the ANCA result is negative and clinical suspicion for ANCA-associated vasculitis is high, the clinician may wish to consider requesting another immunoassay method or indirect immunofluorescence. Results of indirect immunofluorescent testing results may be positive in those with a negative immunoassay, and vice versa.

Thus, the ANCA result should always be interpreted in the context of the whole clinical picture.⁵¹ Biopsy should still be considered the gold standard for the diagnosis of ANCA-associated vasculitis. The ANCA titer can help to improve clinical interpretation, because the likelihood of ANCA-associated vasculitis increases with higher levels of PR3 and MPO-ANCA.⁵²

Back to our patient

Our patient’s blood cultures grow methicillin-sensitive Staphylococcus aureus in both sets after 48 hours. Transthoracic echocardiography reveals vegetations around the tricuspid valve, with no evidence of valvular regurgitation. The diagnosis is right-sided infective endocarditis. He is started on appropriate antibiotics.

Tests for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. The ANCA test is positive for MPO-ANCA at 28 IU/mL (normal < 10).

The positive ANCA is thought to be related to the infective endocarditis. His vasculitis is most likely secondary to infective endocarditis and not ANCA-associated vasculitis. The ANCA test need not have been requested in the first place.

A 22-year-old man presents to his primary care physician with a 4-month history of gradually worsening low back pain associated with early morning stiffness lasting more than 2 hours. He has no peripheral joint symptoms.

In the last 2 years, he has had 2 separate episodes of uveitis. There is a family history of ankylosing spondylitis in his father. Examination reveals global restriction of lumbar movements but is otherwise unremarkable. Magnetic resonance imaging (MRI) of the lumbar spine and sacroiliac joints is normal.

Should this patient be tested for human leukocyte antigen-B27 (HLA-B27)?

The major histocompatibility complex (MHC) is a gene complex that is present in all animals. It encodes proteins that help with immunologic tolerance. HLA simply refers to the human version of the MHC.⁵³ The HLA gene complex, located on chromosome 6, is categorized into class I, class II, and class III. HLA-B is one of the 3 class I genes. Thus, a positive HLA-B27 result simply means that the particular gene is present in that person.

HLA-B27 is strongly associated with ankylosing spondylitis, also known as axial spondyloarthropathy.⁵⁴ Other genes also contribute to the pathogenesis of ankylosing spondylitis, but HLA-B27 is present in more than 90% of patients with this disease and is by far considered the most important. The association is not as strong for peripheral spondyloarthropathy, with studies reporting a frequency of up to 75% for reactive arthritis and inflammatory bowel disease-associated arthritis, and up to 50% for psoriatic arthritis and uveitis.⁵⁵

About 9% of healthy, asymptomatic individuals may have HLA-B27, so the mere presence of this gene is not evidence of disease.⁵⁶ There may be up to a 20-fold increased risk of ankylosing spondylitis among those who are HLA-B27-positive.⁵⁷

Some HLA genes have many different alleles, each of which is given a number (explaining the number 27 that follows the B). Closely related alleles that differ from one another by only a few amino-acid substitutions are then categorized together, thus accounting for more than 100 subtypes of HLA-B27 (designated from HLA-B*2701 to HLA-B*27106). These subtypes vary in frequency among different racial groups, and the population prevalence of ankylosing spondylitis parallels the frequency of HLA-B27.⁵⁸ The most common subtype seen in white people and American Indians is B*2705. HLA-B27 is rare in blacks, explaining the rarity of ankylosing spondylitis in this population. Further examples include HLA-B*2704, which is seen in Asians, and HLA-B*2702, seen in Mediterranean populations. Not all subtypes of HLA-B27 are associated with disease, and some, like HLA-B*2706, may also be protective.

When should the clinician consider testing for HLA-B27?

Peripheral spondyloarthropathy may present with arthritis, enthesitis (eg, heel pain due to inflammation at the site of insertion of the Achilles tendon or plantar fascia), or dactylitis (“sausage” swelling of the whole finger or toe due to extension of inflammation beyond the margins of the joint). Other clues may include psoriasis, inflammatory bowel disease, history of preceding gastrointestinal or genitourinary infection, family history of similar conditions, and history of recurrent uveitis.

For the initial assessment of patients who have inflammatory back pain, plain radiography of the sacroiliac joints is considered the gold standard.⁵⁹ If plain radiography does not show evidence of sacroiliitis, MRI of the sacroiliac joints should be considered. While plain radiography can reveal only structural changes such as sclerosis, erosions, and ankylosis, MRI is useful to evaluate for early inflammatory changes such as bone marrow edema. Imaging the lumbar spine is not necessary, as the sacroiliac joints are almost invariably involved in axial spondyloarthropathy, and lesions seldom occur in the lumbar spine in isolation.⁶⁰

The diagnosis of ankylosing spondylitis previously relied on confirmatory imaging features, but based on the new International Society classification criteria,^61–63 which can be applied to patients with more than 3 months of back pain and age of onset of symptoms before age 45, patients can be classified as having 1 of the following:

• Radiographic axial spondyloarthropathy, if they have evidence of sacroiliitis on imaging plus 1 other feature of spondyloarthropathy
• Nonradiographic axial spondyloarthropathy, if they have a positive HLA-B27 plus 2 other features of spondyloarthropathy (Table 7).

These new criteria have a sensitivity of 82.9% and specificity of 84.4%.^62,63 The disease burden of radiographic and nonradiographic axial spondyloarthropathy has been shown to be similar, suggesting that they are part of the same disease spectrum. Thus, the HLA-B27 test is useful to make a diagnosis of axial spondyloarthropathy even in the absence of imaging features and could be requested in patients with 2 or more features of spondyloarthropathy. In the absence of imaging features and a negative HLA-B27 result, however, the patient cannot be classified as having axial spondyloarthropathy.

Back to our patient

The absence of radiographic evidence would not exclude axial spondyloarthropathy in our patient. The HLA-B27 test is requested because of the inflammatory back pain and the presence of 2 spondyloarthropathy features (uveitis and the family history) and is reported to be positive. His disease is classified as nonradiographic axial spondyloarthropathy.

He is started on regular naproxen and is referred to a physiotherapist. After 1 month, he reports significant symptomatic improvement. He asks if he can be retested for HLA-B27 to see if it has become negative. We tell him that there is no point in repeating it, as it is a gene and will not disappear.

SUMMARY: CONSIDER THE CLINICAL PICTURE

When approaching a patient suspected of having a rheumatologic disease, a clinician should first consider the clinical presentation and the intended purpose of each test. The tests, in general, might serve several purposes. They might help to:

Increase the likelihood of the diagnosis in question. For example, a positive rheumatoid factor or anticitrullinated peptide antibody can help diagnose rheumatoid arthritis in a patient with early polyarthritis, a positive HLA-B27 can help diagnose ankylosing spondylitis in patients with inflammatory back pain and normal imaging, and a positive ANCA can help diagnose ANCA-associated vasculitis in a patient with glomerulonephritis.

Reduce the likelihood of the diagnosis in question. For example, a negative antinuclear antibody test reduces the likelihood of lupus in a patient with joint pains.

Monitor the condition. For example DNA antibodies can be used to monitor the activity of lupus.

Plan the treatment strategy. For example, one might consider lifelong anticoagulation if antiphospholipid antibodies are persistently positive in a patient with thrombosis.

Prognosticate. For example, positive rheumatoid factor and anticitrullinated peptide antibody increase the risk of erosive rheumatoid arthritis.

If the test was requested in the absence of a clear indication and the result is positive, it is important to bear in mind the potential pitfalls associated with that test and not attach a diagnostic label prematurely. None of the tests can confirm or exclude a condition, so the results should always be interpreted in the context of the whole clinical picture.   

Laboratory tests are often ordered inappropriately for patients in whom a rheumatologic illness is suspected; this occurs in both primary and secondary care.¹ Some tests are available both singly and as part of a battery of tests screening healthy people without symptoms.

The problem: negative test results are by no means always reassuring, and false-positive results raise the risks of unnecessary anxiety for patients and clinicians, needless referrals, and potential morbidity due to further unnecessary testing and exposure to wrong treatments.² Clinicians should be aware of the pitfalls of these tests in order to choose them wisely and interpret the results correctly.

This article provides practical guidance on requesting and interpreting some common tests in rheumatology, with the aid of case vignettes.

RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE ANTIBODY

A 41-year-old woman, previously in good health, presents to her primary care practitioner with a 6-week history of pain and swelling in her hands and early morning stiffness lasting about 2 hours. She denies having any extraarticular symptoms. Physical examination reveals synovitis across her right metacarpophalangeal joints, proximal interphalangeal joint of the left middle finger, and left wrist. The primary care physician is concerned that her symptoms might be due to rheumatoid arthritis.

Would testing for rheumatoid factor and anticitrullinated peptide antibody be useful in this patient?

Rheumatoid factor is an antibody (immunoglobulin M, IgG, or IgA) targeted against the Fc fragment of IgG.³ It was so named because it was originally detected in patients with rheumatoid arthritis, but it is neither sensitive nor specific for this condition. A meta-analysis of more than 5,000 patients with rheumatoid arthritis reported that rheumatoid factor testing had a sensitivity of 69% and specificity of 85%.⁴

Anticitrullinated peptide antibody, on the other hand, is much more specific for rheumatoid arthritis (95%), as it is seldom seen in other conditions, but its sensitivity is similar to that of rheumatoid factor (68%).^4–6 A positive result would thus lend strength to the diagnosis of rheumatoid arthritis, but a negative result would not exclude it.

Approach to early arthritis

When faced with a patient with early arthritis, some key questions to ask include^7,8:

Is this an inflammatory or a mechanical problem? Inflammatory arthritis is suggested by joint swelling that is not due to trauma or bony hypertrophy, early morning stiffness lasting longer than 30 minutes, and elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein). Involvement of the small joints of the hands and feet may be suggested by pain on compression of the metacarpophalangeal and metatarsophalangeal joints, respectively.

Is there a definite identifiable underlying cause for the inflammatory arthritis? The pattern of development of joint symptoms or the presence of extraarticular symptoms may suggest an underlying problem such as gout, psoriatic arthritis, systemic lupus erythematosus, or sarcoidosis.

If the arthritis is undifferentiated (ie, there is no definite identifiable cause), is it likely to remit or persist? This is perhaps the most important question to ask in order to prognosticate. Patients with risk factors for persistent disease, ie, for development of rheumatoid arthritis, should be referred to a rheumatologist early for timely institution of disease-modifying antirheumatic drug therapy.⁹ Multiple studies have shown that patients in whom this therapy is started early have much better clinical, functional, and radiologic outcomes than those in whom it is delayed.^10–12

The revised American College of Rheumatology and European League Against Rheumatism criteria¹³ include the following factors as predictors of persistence:

• Number of involved joints (with greater weight given to involvement of small joints)
• Duration of symptoms 6 weeks or longer
• Elevated acute-phase response (erythrocyte sedimentation rate or C-reactive protein level)
• A positive serologic test (either rheumatoid factor or anticitrullinated peptide antibody).

If both rheumatoid factor and anticitrullinated peptide antibody are positive in a patient with early undifferentiated arthritis, the risk of progression to rheumatoid arthritis is almost 100%, thus underscoring the importance of testing for these antibodies.^5,6 Referral to a rheumatologist should, however, not be delayed in patients with negative test results (more than one-third of patients with rheumatoid arthritis may be negative for both), and should be considered in those with inflammatory joint symptoms persisting longer than 6 weeks, especially with involvement of the small joints (sparing the distal interphalangeals) and elevated acute-phase response.

Rheumatoid factor in healthy people without symptoms

In some countries, testing for rheumatoid factor is offered as part of a battery of screening tests in healthy people who have no symptoms, a practice that should be strongly discouraged.

Multiple studies, both prospective and retrospective, have demonstrated that both rheumatoid factor and anticitrullinated peptide antibody may be present several years before the clinical diagnosis of rheumatoid arthritis.^6,14–16 But the risk of developing rheumatoid arthritis for asymptomatic individuals who are rheumatoid factor-positive depends on the rheumatoid factor titer, positive family history of rheumatoid arthritis in first-degree relatives, and copresence of anticitrullinated peptide antibody. The absolute risk, nevertheless, is still very small. In some, there might be an alternative explanation such as undiagnosed Sjögren syndrome or hepatitis C.

In any event, no strategy is currently available that is proven to prevent the development of rheumatoid arthritis, and there is no role for disease-modifying therapy during the preclinical phase.¹⁶

Back to our patient

Blood testing in our patient reveals normal complete blood cell counts, aminotransferase levels, and serum creatinine concentration; findings on urinalysis are normal. Her erythrocyte sedimentation rate is 56 mm/hour (reference range 0–15), and her C-reactive protein level is 26 mg/dL (normal < 3). Testing is negative for rheumatoid factor and anticitrullinated peptide antibody.

Although her rheumatoid factor and anticitrullinated peptide antibody tests are negative, she is referred to a rheumatologist because she has predictors of persistent disease, ie, symptom duration of 6 weeks, involvement of the small joints of the hands, and elevated erythrocyte sedimentation rate and C-reactive protein. The rheumatologist checks her parvovirus serology, which is negative.

The patient is given parenteral depot corticosteroid therapy, to which she responds briefly. Because her symptoms persist and continue to worsen, methotrexate treatment is started after an additional 6 weeks.

A 37-year-old woman presents to her primary care physician with the complaint of tiredness. She has a family history of systemic lupus erythematosus in her sister and maternal aunt. She is understandably worried about lupus because of the family history and is asking to be tested for it.

Would testing for antinuclear antibody be reasonable?

Antinuclear antibody is not a single antibody but rather a family of autoantibodies that are directed against nuclear constituents such as single- or double-stranded deoxyribonucleic acid (dsDNA), histones, centromeres, proteins complexed with ribonucleic acid (RNA), and enzymes such as topoisomerase.^17,18

Protein antigens complexed with RNA and some enzymes in the nucleus are also known as extractable nuclear antigens (ENAs). They include Ro, La, Sm, Jo-1, RNP, and ScL-70 and are named after the patient in whom they were first discovered (Robert, Lavine, Smith, and John), the antigen that is targeted (ribonucleoprotein or RNP), and the disease with which they are associated (anti-ScL-70 or antitopoisomerase in diffuse cutaneous scleroderma).

Antinuclear antibody testing is commonly requested to exclude connective tissue diseases such as lupus, but the clinician needs to be aware of the following points:

Antinuclear antibody may be encountered in conditions other than lupus

These include¹⁹:

• Other autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and myasthenia gravis
• Infection with organisms that share the epitope with self-antigens (molecular mimicry)
• Cancers
• Drugs such as hydralazine, procainamide, and minocycline.

Antinuclear antibody might also be produced by the healthy immune system from time to time to clear the nuclear debris that is extruded from aging cells.

A study in healthy individuals²⁰ reported a prevalence of positive antinuclear antibody of 32% at a titer of 1/40, 15% at a titer of 1/80, 7% at a titer of 1/160, and 3% at a titer of 1/320. Importantly, a positive result was more common among family members of patients with autoimmune connective tissue diseases.²¹ Hence, a positive antinuclear antibody result does not always mean lupus.

Antinuclear antibody testing is highly sensitive for lupus

With current laboratory methods, antinuclear antibody testing has a sensitivity close to 100%. Hence, a negative result virtually rules out lupus.

Two methods are commonly used to test for antinuclear antibody: indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).²² While human epithelial (Hep2) cells are used as the source of antigen in immunofluorescence, purified nuclear antigens coated on multiple-well plates are used in ELISA.

Although ELISA is simpler to perform, immunofluorescence has a slightly better sensitivity (because the Hep2 cells express a wide range of antigens) and is still considered the gold standard. As expected, the higher sensitivity occurs at the cost of reduced specificity (about 60%), so antinuclear antibody will also be detected in all the other conditions listed above.²³

To improve the specificity of antinuclear antibody testing, laboratories report titers (the highest dilution of the test serum that tested positive); a cutoff of greater than 1/80 is generally considered significant.

Do not order antinuclear antibody testing indiscriminately

To sum up, the antinuclear antibody test should be requested only in patients with involvement of multiple organ systems. Although a negative result would make it extremely unlikely that the clinical presentation is due to lupus, a positive result is insufficient on its own to make a diagnosis of lupus.

Diagnosing lupus is straightforward when patients present with a specific manifestation such as inflammatory arthritis, photosensitive skin rash, hemolytic anemia, thrombocytopenia, or nephritis, or with specific antibodies such as those against dsDNA or Sm. Patients who present with nonspecific symptoms such as arthralgia or tiredness with a positive antinuclear antibody and negative anti-dsDNA and anti-Sm may present difficulties even for the specialist.^25–27

Back to our patient

Our patient denies arthralgia. She has no extraarticular symptoms such as skin rashes, oral ulcers, sicca symptoms, muscle weakness, Raynaud phenomenon, pleuritic chest pain, or breathlessness. Findings on physical examination and urinalysis are unremarkable.

Her primary care physician decides to check her complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level. Although she is reassured that her tiredness is not due to lupus, she insists on getting an antinuclear antibody test.

Her complete blood cell counts are normal. Her erythrocyte sedimentation rate is 6 mm/hour. However, her thyroid-stimulating hormone level is elevated, and subsequent testing shows low free thyroxine and positive thyroid peroxidase antibodies. The antinuclear antibody is positive in a titer of 1/80 and negative for anti-dsDNA and anti-ENA.

We explain to her that the positive antinuclear antibody is most likely related to her autoimmune thyroid disease. She is referred to an endocrinologist.

A 24-year-old woman presents to the emergency department with acute unprovoked deep vein thrombosis in her right leg, confirmed by ultrasonography. She has no history of previous thrombosis, and the relevant family history is unremarkable. She has never been pregnant. Her platelet count is 84 × 10⁹/L (reference range 150–400), and her baseline activated partial thromboplastin time is prolonged at 62 seconds (reference range 23.0–32.4). The rest of her blood counts and her prothrombin time, liver enzyme levels, and serum creatinine level are normal.

Should this patient be tested for antiphospholipid antibodies?

Antiphospholipid antibodies are important because of their association with thrombotic risk (both venous and arterial) and pregnancy morbidity. The name is a misnomer, as these antibodies are targeted against some proteins that are bound to phospholipids and not only to the phospholipids themselves.

According to the modified Sapporo criteria for the classification of antiphospholipid syndrome,²⁸ antiphospholipid antibodies should remain persistently positive on at least 2 separate occasions at least 12 weeks apart for the result to be considered significant because some infections and drugs may be associated with the transient presence of antiphospholipid antibodies.

Screening for antiphospholipid antibodies should include testing for IgM and IgG anticardiolipin antibodies, lupus anticoagulant, and IgM and IgG beta-2 glycoprotein I antibodies.^29,30

Anticardiolipin antibodies

Anticardiolipin (aCL) antibodies may be targeted either against beta-2 glycoprotein I (beta-2GPI) that is bound to cardiolipin (a phospholipid) or against cardiolipin alone; the former is more specific. Antibodies directed against cardiolipin alone are usually transient and are associated with infections and drugs. The result is considered significant only when anticardiolipin antibodies are present in a medium to high titer (> 40 IgG phospholipid units or IgM phospholipid units, or > 99th percentile).

Lupus anticoagulant

The antibody with “lupus anticoagulant activity” is targeted against prothrombin plus phospholipid or beta-2GPI plus phospholipid. The test for it is a functional assay involving 3 steps:

Demonstrating the prolongation of a phospholipid-dependent coagulation assay like the activated partial thromboplastin time (aPTT). (This may explain the prolongation of aPTT in the patient described in the vignette.) Although the presence of lupus anticoagulant is associated with thrombosis, it is called an “anticoagulant” because of this in vitro prolongation of phospholipid-dependent coagulation assays.

Mixing study. The phospholipid-dependent coagulation assay could be prolonged because of either the deficiency of a coagulation factor or the presence of the antiphospholipid antibodies. This can be differentiated by mixing the patient’s plasma with normal plasma (which will have all the clotting factors) in a 1:1 ratio. If the coagulation assay remains prolonged after the addition of normal plasma, clotting factor deficiency can be excluded.

Addition of a phospholipid. If the prolongation of the coagulation assay is due to the presence of an antiphospholipid antibody, addition of extra phospholipid will correct this.

Beta-2 glycoprotein I antibody (anti-beta-2GPI)

The beta-2GPI that is not bound to the cardiolipin can be detected by separately testing for beta-2GPI (the anticardiolipin test only detects the beta-2GPI that is bound to the cardiolipin). The result is considered significant if beta-2GPI is present in a medium to high titer (> 99th percentile).

Studies have shown that antiphospholipid antibodies may be present in 1% to 5% of apparently healthy people in the general population.³¹ These are usually low-titer anticardiolipin or anti-beta-GPI IgM antibodies that are not associated with thrombosis or adverse pregnancy outcomes. Hence, the term antiphospholipid syndrome should be reserved for those who have had at least 1 episode of thrombosis or pregnancy morbidity and persistent antiphospholipid antibodies, and not those who have asymptomatic or transient antiphospholipid antibodies.

Triple positivity (positive anticardiolipin, lupus anticoagulant, and anti-beta-2GPI) seems to be associated with the highest risk of thrombosis, with a 10-year cumulative incidence of 37.1% (95% confidence interval [CI] 19.9–54.3) for a first thrombotic event,³² and 44.2% (95% CI 38.6–49.8) for recurrent thrombosis.³³

The association with thrombosis is stronger for lupus anticoagulant than with the other 2 antibodies, with different studies³⁴ finding an odds ratio ranging from 5 to 16. A positive lupus anticoagulant test with or without a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a high-risk profile, while a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a moderate-risk profile. A low titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a low-risk profile that may not be associated with thrombosis.³⁵

Antiphospholipid syndrome is important to recognize because of the need for long-term anticoagulation to prevent recurrence.³⁶ It may be primary, when it occurs on its own, or secondary, when it occurs in association with another autoimmune disease such as lupus.

Venous events in antiphospholipid syndrome most commonly manifest as lower-limb deep vein thrombosis or pulmonary embolism, while arterial events most commonly manifest as stroke or transient ischemic attack.³⁷ Obstetric manifestations may include not only miscarriage and stillbirth, but also preterm delivery, intrauterine growth retardation, and preeclampsia, all occurring due to placental insufficiency.

The frequency of antiphospholipid antibodies has been estimated as 13.5% in patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% for those with pregnancy morbidity.³⁸

Some noncriteria manifestations have also been recognized in antiphospholipid syndrome, such as thrombocytopenia, cardiac vegetations (Libman-Sachs endocarditis), livedo reticularis, and nephropathy.

Back to our patient

Our patient’s anticardiolipin IgG test is negative, while her lupus anticoagulant and beta-2GPI IgG are positive. She has no clinical or laboratory features suggesting lupus.

She is started on warfarin. After 3 months, the warfarin is interrupted for several days, and she is retested for all 3 antiphospholipid antibodies. Her beta-2GPI I IgG and lupus anticoagulant tests are again positive. Because of the persistent antiphospholipid antibody positivity and clinical history of deep vein thrombosis, her condition is diagnosed as primary antiphospholipid syndrome. She is advised to continue anticoagulant therapy indefinitely.

A 34-year-old man who is an injecting drug user presents with a 2-week history of fever, malaise, and generalized arthralgia. There are no localizing symptoms of infection. Notable findings on examination include a temperature of 38.0°C (100.4°F), needle track marks in his arms, nonblanching vasculitic rash in his legs, and a systolic murmur over the precordium.

His white blood cell count is 15.3 × 10⁹/L (reference range 3.7–11.0), and his C-reactive protein level is 234 mg/dL (normal < 3). Otherwise, results of blood cell counts, liver enzyme tests, renal function tests, urinalysis, and chest radiography are normal.

Two sets of blood cultures are drawn. Transthoracic echocardiography and the antineutrophil cytoplasmic antibody (ANCA) test are requested, as are screening tests for human immunodeficiency virus, hepatitis B, and hepatitis C.

Was the ANCA test indicated in this patient?

ANCAs are autoantibodies against antigens located in the cytoplasmic granules of neutrophils and monocytes. They are associated with small-vessel vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and isolated pauciimmune crescentic glomerulonephritis, all collectively known as ANCA-associated vasculitis (AAV).³⁹

Laboratory methods to detect ANCA include indirect immunofluorescence and antigen-specific enzyme immunoassays. Indirect immunofluorescence only tells us whether or not an antibody that is targeting a cytoplasmic antigen is present. Based on the indirect immunofluorescent pattern, ANCA can be classified as follows:

• Perinuclear or p-ANCA (if the targeted antigen is located just around the nucleus and extends into it)
• Cytoplasmic or c-ANCA (if the targeted antigen is located farther away from the nucleus)
• Atypical ANCA (if the indirect immunofluorescent pattern does not fit with either p-ANCA or c-ANCA).

Indirect immunofluorescence does not give information about the exact antigen that is targeted; this can only be obtained by performing 1 of the antigen-specific immunoassays. The target antigen for c-ANCA is usually proteinase-3 (PR3), while that for p-ANCA could be myeloperoxidase (MPO), cathepsin, lysozyme, lactoferrin, or bactericidal permeability inhibitor. Anti-PR3 is highly specific for GPA, while anti-MPO is usually associated with MPA and EGPA. Less commonly, anti-PR3 may be seen in patients with MPA and anti-MPO in those with GPA. Hence, there is an increasing trend toward classifying ANCA-associated vasculitis into PR3-associated or MPO-associated vasculitis rather than as GPA, MPA, EGPA, or renal-limited vasculitis.⁴⁰

Several audits have shown that the ANCA test is widely misused and requested indiscriminately to rule out vasculitis. This results in a lower positive predictive value, possible harm to patients due to increased false-positive rates, and increased burden on the laboratory.^41–43 At least 2 separate groups have demonstrated that a gating policy that refuses ANCA testing in patients without clinical evidence of systemic vasculitis can reduce the number of inappropriate requests, improve the diagnostic yield, and make it more clinically relevant and cost-effective.^44,45

The clinician should bear in mind that:

Current guidelines recommend using one of the antigen-specific assays for PR3 and MPO as the primary screening method.⁴⁸ Until recently, indirect immunofluorescence was used to screen for ANCA-associated vasculitis, and positive results were confirmed by ELISA to detect ANCAs specific for PR3 and MPO,⁴⁹ but this is no longer recommended because of recent evidence suggesting a large variability between the different indirect immunofluorescent methods and improved diagnostic performance of the antigen-specific assays.

In a large multicenter study by Damoiseaux et al, the specificity with the different antigen-specific immunoassays was 98% to 99% for PR3-ANCA and 96% to 99% for MPO-ANCA.⁵⁰

ANCA-associated vasculitis should not be considered excluded if the PR3 and MPO-ANCA are negative. In the Damoiseaux study, about 11% to 15% of patients with GPA and 8% to 24% of patients with MPA tested negative for both PR3 and MPO-ANCA.⁵⁰

If the ANCA result is negative and clinical suspicion for ANCA-associated vasculitis is high, the clinician may wish to consider requesting another immunoassay method or indirect immunofluorescence. Results of indirect immunofluorescent testing results may be positive in those with a negative immunoassay, and vice versa.

Thus, the ANCA result should always be interpreted in the context of the whole clinical picture.⁵¹ Biopsy should still be considered the gold standard for the diagnosis of ANCA-associated vasculitis. The ANCA titer can help to improve clinical interpretation, because the likelihood of ANCA-associated vasculitis increases with higher levels of PR3 and MPO-ANCA.⁵²

Back to our patient

Our patient’s blood cultures grow methicillin-sensitive Staphylococcus aureus in both sets after 48 hours. Transthoracic echocardiography reveals vegetations around the tricuspid valve, with no evidence of valvular regurgitation. The diagnosis is right-sided infective endocarditis. He is started on appropriate antibiotics.

Tests for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. The ANCA test is positive for MPO-ANCA at 28 IU/mL (normal < 10).

The positive ANCA is thought to be related to the infective endocarditis. His vasculitis is most likely secondary to infective endocarditis and not ANCA-associated vasculitis. The ANCA test need not have been requested in the first place.

A 22-year-old man presents to his primary care physician with a 4-month history of gradually worsening low back pain associated with early morning stiffness lasting more than 2 hours. He has no peripheral joint symptoms.

In the last 2 years, he has had 2 separate episodes of uveitis. There is a family history of ankylosing spondylitis in his father. Examination reveals global restriction of lumbar movements but is otherwise unremarkable. Magnetic resonance imaging (MRI) of the lumbar spine and sacroiliac joints is normal.

Should this patient be tested for human leukocyte antigen-B27 (HLA-B27)?

The major histocompatibility complex (MHC) is a gene complex that is present in all animals. It encodes proteins that help with immunologic tolerance. HLA simply refers to the human version of the MHC.⁵³ The HLA gene complex, located on chromosome 6, is categorized into class I, class II, and class III. HLA-B is one of the 3 class I genes. Thus, a positive HLA-B27 result simply means that the particular gene is present in that person.

HLA-B27 is strongly associated with ankylosing spondylitis, also known as axial spondyloarthropathy.⁵⁴ Other genes also contribute to the pathogenesis of ankylosing spondylitis, but HLA-B27 is present in more than 90% of patients with this disease and is by far considered the most important. The association is not as strong for peripheral spondyloarthropathy, with studies reporting a frequency of up to 75% for reactive arthritis and inflammatory bowel disease-associated arthritis, and up to 50% for psoriatic arthritis and uveitis.⁵⁵

About 9% of healthy, asymptomatic individuals may have HLA-B27, so the mere presence of this gene is not evidence of disease.⁵⁶ There may be up to a 20-fold increased risk of ankylosing spondylitis among those who are HLA-B27-positive.⁵⁷

Some HLA genes have many different alleles, each of which is given a number (explaining the number 27 that follows the B). Closely related alleles that differ from one another by only a few amino-acid substitutions are then categorized together, thus accounting for more than 100 subtypes of HLA-B27 (designated from HLA-B*2701 to HLA-B*27106). These subtypes vary in frequency among different racial groups, and the population prevalence of ankylosing spondylitis parallels the frequency of HLA-B27.⁵⁸ The most common subtype seen in white people and American Indians is B*2705. HLA-B27 is rare in blacks, explaining the rarity of ankylosing spondylitis in this population. Further examples include HLA-B*2704, which is seen in Asians, and HLA-B*2702, seen in Mediterranean populations. Not all subtypes of HLA-B27 are associated with disease, and some, like HLA-B*2706, may also be protective.

When should the clinician consider testing for HLA-B27?

Peripheral spondyloarthropathy may present with arthritis, enthesitis (eg, heel pain due to inflammation at the site of insertion of the Achilles tendon or plantar fascia), or dactylitis (“sausage” swelling of the whole finger or toe due to extension of inflammation beyond the margins of the joint). Other clues may include psoriasis, inflammatory bowel disease, history of preceding gastrointestinal or genitourinary infection, family history of similar conditions, and history of recurrent uveitis.

For the initial assessment of patients who have inflammatory back pain, plain radiography of the sacroiliac joints is considered the gold standard.⁵⁹ If plain radiography does not show evidence of sacroiliitis, MRI of the sacroiliac joints should be considered. While plain radiography can reveal only structural changes such as sclerosis, erosions, and ankylosis, MRI is useful to evaluate for early inflammatory changes such as bone marrow edema. Imaging the lumbar spine is not necessary, as the sacroiliac joints are almost invariably involved in axial spondyloarthropathy, and lesions seldom occur in the lumbar spine in isolation.⁶⁰

The diagnosis of ankylosing spondylitis previously relied on confirmatory imaging features, but based on the new International Society classification criteria,^61–63 which can be applied to patients with more than 3 months of back pain and age of onset of symptoms before age 45, patients can be classified as having 1 of the following:

• Radiographic axial spondyloarthropathy, if they have evidence of sacroiliitis on imaging plus 1 other feature of spondyloarthropathy
• Nonradiographic axial spondyloarthropathy, if they have a positive HLA-B27 plus 2 other features of spondyloarthropathy (Table 7).

These new criteria have a sensitivity of 82.9% and specificity of 84.4%.^62,63 The disease burden of radiographic and nonradiographic axial spondyloarthropathy has been shown to be similar, suggesting that they are part of the same disease spectrum. Thus, the HLA-B27 test is useful to make a diagnosis of axial spondyloarthropathy even in the absence of imaging features and could be requested in patients with 2 or more features of spondyloarthropathy. In the absence of imaging features and a negative HLA-B27 result, however, the patient cannot be classified as having axial spondyloarthropathy.

Back to our patient

The absence of radiographic evidence would not exclude axial spondyloarthropathy in our patient. The HLA-B27 test is requested because of the inflammatory back pain and the presence of 2 spondyloarthropathy features (uveitis and the family history) and is reported to be positive. His disease is classified as nonradiographic axial spondyloarthropathy.

He is started on regular naproxen and is referred to a physiotherapist. After 1 month, he reports significant symptomatic improvement. He asks if he can be retested for HLA-B27 to see if it has become negative. We tell him that there is no point in repeating it, as it is a gene and will not disappear.

SUMMARY: CONSIDER THE CLINICAL PICTURE

When approaching a patient suspected of having a rheumatologic disease, a clinician should first consider the clinical presentation and the intended purpose of each test. The tests, in general, might serve several purposes. They might help to:

Increase the likelihood of the diagnosis in question. For example, a positive rheumatoid factor or anticitrullinated peptide antibody can help diagnose rheumatoid arthritis in a patient with early polyarthritis, a positive HLA-B27 can help diagnose ankylosing spondylitis in patients with inflammatory back pain and normal imaging, and a positive ANCA can help diagnose ANCA-associated vasculitis in a patient with glomerulonephritis.

Reduce the likelihood of the diagnosis in question. For example, a negative antinuclear antibody test reduces the likelihood of lupus in a patient with joint pains.

Monitor the condition. For example DNA antibodies can be used to monitor the activity of lupus.

Plan the treatment strategy. For example, one might consider lifelong anticoagulation if antiphospholipid antibodies are persistently positive in a patient with thrombosis.

Prognosticate. For example, positive rheumatoid factor and anticitrullinated peptide antibody increase the risk of erosive rheumatoid arthritis.

If the test was requested in the absence of a clear indication and the result is positive, it is important to bear in mind the potential pitfalls associated with that test and not attach a diagnostic label prematurely. None of the tests can confirm or exclude a condition, so the results should always be interpreted in the context of the whole clinical picture.   

Laboratory tests are often ordered inappropriately for patients in whom a rheumatologic illness is suspected; this occurs in both primary and secondary care.¹ Some tests are available both singly and as part of a battery of tests screening healthy people without symptoms.

The problem: negative test results are by no means always reassuring, and false-positive results raise the risks of unnecessary anxiety for patients and clinicians, needless referrals, and potential morbidity due to further unnecessary testing and exposure to wrong treatments.² Clinicians should be aware of the pitfalls of these tests in order to choose them wisely and interpret the results correctly.

This article provides practical guidance on requesting and interpreting some common tests in rheumatology, with the aid of case vignettes.

RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE ANTIBODY

A 41-year-old woman, previously in good health, presents to her primary care practitioner with a 6-week history of pain and swelling in her hands and early morning stiffness lasting about 2 hours. She denies having any extraarticular symptoms. Physical examination reveals synovitis across her right metacarpophalangeal joints, proximal interphalangeal joint of the left middle finger, and left wrist. The primary care physician is concerned that her symptoms might be due to rheumatoid arthritis.

Would testing for rheumatoid factor and anticitrullinated peptide antibody be useful in this patient?

Rheumatoid factor is an antibody (immunoglobulin M, IgG, or IgA) targeted against the Fc fragment of IgG.³ It was so named because it was originally detected in patients with rheumatoid arthritis, but it is neither sensitive nor specific for this condition. A meta-analysis of more than 5,000 patients with rheumatoid arthritis reported that rheumatoid factor testing had a sensitivity of 69% and specificity of 85%.⁴

Anticitrullinated peptide antibody, on the other hand, is much more specific for rheumatoid arthritis (95%), as it is seldom seen in other conditions, but its sensitivity is similar to that of rheumatoid factor (68%).^4–6 A positive result would thus lend strength to the diagnosis of rheumatoid arthritis, but a negative result would not exclude it.

Approach to early arthritis

When faced with a patient with early arthritis, some key questions to ask include^7,8:

Is this an inflammatory or a mechanical problem? Inflammatory arthritis is suggested by joint swelling that is not due to trauma or bony hypertrophy, early morning stiffness lasting longer than 30 minutes, and elevated inflammatory markers (erythrocyte sedimentation rate or C-reactive protein). Involvement of the small joints of the hands and feet may be suggested by pain on compression of the metacarpophalangeal and metatarsophalangeal joints, respectively.

Is there a definite identifiable underlying cause for the inflammatory arthritis? The pattern of development of joint symptoms or the presence of extraarticular symptoms may suggest an underlying problem such as gout, psoriatic arthritis, systemic lupus erythematosus, or sarcoidosis.

If the arthritis is undifferentiated (ie, there is no definite identifiable cause), is it likely to remit or persist? This is perhaps the most important question to ask in order to prognosticate. Patients with risk factors for persistent disease, ie, for development of rheumatoid arthritis, should be referred to a rheumatologist early for timely institution of disease-modifying antirheumatic drug therapy.⁹ Multiple studies have shown that patients in whom this therapy is started early have much better clinical, functional, and radiologic outcomes than those in whom it is delayed.^10–12

The revised American College of Rheumatology and European League Against Rheumatism criteria¹³ include the following factors as predictors of persistence:

• Number of involved joints (with greater weight given to involvement of small joints)
• Duration of symptoms 6 weeks or longer
• Elevated acute-phase response (erythrocyte sedimentation rate or C-reactive protein level)
• A positive serologic test (either rheumatoid factor or anticitrullinated peptide antibody).

If both rheumatoid factor and anticitrullinated peptide antibody are positive in a patient with early undifferentiated arthritis, the risk of progression to rheumatoid arthritis is almost 100%, thus underscoring the importance of testing for these antibodies.^5,6 Referral to a rheumatologist should, however, not be delayed in patients with negative test results (more than one-third of patients with rheumatoid arthritis may be negative for both), and should be considered in those with inflammatory joint symptoms persisting longer than 6 weeks, especially with involvement of the small joints (sparing the distal interphalangeals) and elevated acute-phase response.

Rheumatoid factor in healthy people without symptoms

In some countries, testing for rheumatoid factor is offered as part of a battery of screening tests in healthy people who have no symptoms, a practice that should be strongly discouraged.

Multiple studies, both prospective and retrospective, have demonstrated that both rheumatoid factor and anticitrullinated peptide antibody may be present several years before the clinical diagnosis of rheumatoid arthritis.^6,14–16 But the risk of developing rheumatoid arthritis for asymptomatic individuals who are rheumatoid factor-positive depends on the rheumatoid factor titer, positive family history of rheumatoid arthritis in first-degree relatives, and copresence of anticitrullinated peptide antibody. The absolute risk, nevertheless, is still very small. In some, there might be an alternative explanation such as undiagnosed Sjögren syndrome or hepatitis C.

In any event, no strategy is currently available that is proven to prevent the development of rheumatoid arthritis, and there is no role for disease-modifying therapy during the preclinical phase.¹⁶

Back to our patient

Blood testing in our patient reveals normal complete blood cell counts, aminotransferase levels, and serum creatinine concentration; findings on urinalysis are normal. Her erythrocyte sedimentation rate is 56 mm/hour (reference range 0–15), and her C-reactive protein level is 26 mg/dL (normal < 3). Testing is negative for rheumatoid factor and anticitrullinated peptide antibody.

Although her rheumatoid factor and anticitrullinated peptide antibody tests are negative, she is referred to a rheumatologist because she has predictors of persistent disease, ie, symptom duration of 6 weeks, involvement of the small joints of the hands, and elevated erythrocyte sedimentation rate and C-reactive protein. The rheumatologist checks her parvovirus serology, which is negative.

The patient is given parenteral depot corticosteroid therapy, to which she responds briefly. Because her symptoms persist and continue to worsen, methotrexate treatment is started after an additional 6 weeks.

A 37-year-old woman presents to her primary care physician with the complaint of tiredness. She has a family history of systemic lupus erythematosus in her sister and maternal aunt. She is understandably worried about lupus because of the family history and is asking to be tested for it.

Would testing for antinuclear antibody be reasonable?

Antinuclear antibody is not a single antibody but rather a family of autoantibodies that are directed against nuclear constituents such as single- or double-stranded deoxyribonucleic acid (dsDNA), histones, centromeres, proteins complexed with ribonucleic acid (RNA), and enzymes such as topoisomerase.^17,18

Protein antigens complexed with RNA and some enzymes in the nucleus are also known as extractable nuclear antigens (ENAs). They include Ro, La, Sm, Jo-1, RNP, and ScL-70 and are named after the patient in whom they were first discovered (Robert, Lavine, Smith, and John), the antigen that is targeted (ribonucleoprotein or RNP), and the disease with which they are associated (anti-ScL-70 or antitopoisomerase in diffuse cutaneous scleroderma).

Antinuclear antibody testing is commonly requested to exclude connective tissue diseases such as lupus, but the clinician needs to be aware of the following points:

Antinuclear antibody may be encountered in conditions other than lupus

These include¹⁹:

• Other autoimmune diseases such as rheumatoid arthritis, primary Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and myasthenia gravis
• Infection with organisms that share the epitope with self-antigens (molecular mimicry)
• Cancers
• Drugs such as hydralazine, procainamide, and minocycline.

Antinuclear antibody might also be produced by the healthy immune system from time to time to clear the nuclear debris that is extruded from aging cells.

A study in healthy individuals²⁰ reported a prevalence of positive antinuclear antibody of 32% at a titer of 1/40, 15% at a titer of 1/80, 7% at a titer of 1/160, and 3% at a titer of 1/320. Importantly, a positive result was more common among family members of patients with autoimmune connective tissue diseases.²¹ Hence, a positive antinuclear antibody result does not always mean lupus.

Antinuclear antibody testing is highly sensitive for lupus

With current laboratory methods, antinuclear antibody testing has a sensitivity close to 100%. Hence, a negative result virtually rules out lupus.

Two methods are commonly used to test for antinuclear antibody: indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).²² While human epithelial (Hep2) cells are used as the source of antigen in immunofluorescence, purified nuclear antigens coated on multiple-well plates are used in ELISA.

Although ELISA is simpler to perform, immunofluorescence has a slightly better sensitivity (because the Hep2 cells express a wide range of antigens) and is still considered the gold standard. As expected, the higher sensitivity occurs at the cost of reduced specificity (about 60%), so antinuclear antibody will also be detected in all the other conditions listed above.²³

To improve the specificity of antinuclear antibody testing, laboratories report titers (the highest dilution of the test serum that tested positive); a cutoff of greater than 1/80 is generally considered significant.

Do not order antinuclear antibody testing indiscriminately

To sum up, the antinuclear antibody test should be requested only in patients with involvement of multiple organ systems. Although a negative result would make it extremely unlikely that the clinical presentation is due to lupus, a positive result is insufficient on its own to make a diagnosis of lupus.

Diagnosing lupus is straightforward when patients present with a specific manifestation such as inflammatory arthritis, photosensitive skin rash, hemolytic anemia, thrombocytopenia, or nephritis, or with specific antibodies such as those against dsDNA or Sm. Patients who present with nonspecific symptoms such as arthralgia or tiredness with a positive antinuclear antibody and negative anti-dsDNA and anti-Sm may present difficulties even for the specialist.^25–27

Back to our patient

Our patient denies arthralgia. She has no extraarticular symptoms such as skin rashes, oral ulcers, sicca symptoms, muscle weakness, Raynaud phenomenon, pleuritic chest pain, or breathlessness. Findings on physical examination and urinalysis are unremarkable.

Her primary care physician decides to check her complete blood cell count, erythrocyte sedimentation rate, and thyroid-stimulating hormone level. Although she is reassured that her tiredness is not due to lupus, she insists on getting an antinuclear antibody test.

Her complete blood cell counts are normal. Her erythrocyte sedimentation rate is 6 mm/hour. However, her thyroid-stimulating hormone level is elevated, and subsequent testing shows low free thyroxine and positive thyroid peroxidase antibodies. The antinuclear antibody is positive in a titer of 1/80 and negative for anti-dsDNA and anti-ENA.

We explain to her that the positive antinuclear antibody is most likely related to her autoimmune thyroid disease. She is referred to an endocrinologist.

A 24-year-old woman presents to the emergency department with acute unprovoked deep vein thrombosis in her right leg, confirmed by ultrasonography. She has no history of previous thrombosis, and the relevant family history is unremarkable. She has never been pregnant. Her platelet count is 84 × 10⁹/L (reference range 150–400), and her baseline activated partial thromboplastin time is prolonged at 62 seconds (reference range 23.0–32.4). The rest of her blood counts and her prothrombin time, liver enzyme levels, and serum creatinine level are normal.

Should this patient be tested for antiphospholipid antibodies?

Antiphospholipid antibodies are important because of their association with thrombotic risk (both venous and arterial) and pregnancy morbidity. The name is a misnomer, as these antibodies are targeted against some proteins that are bound to phospholipids and not only to the phospholipids themselves.

According to the modified Sapporo criteria for the classification of antiphospholipid syndrome,²⁸ antiphospholipid antibodies should remain persistently positive on at least 2 separate occasions at least 12 weeks apart for the result to be considered significant because some infections and drugs may be associated with the transient presence of antiphospholipid antibodies.

Screening for antiphospholipid antibodies should include testing for IgM and IgG anticardiolipin antibodies, lupus anticoagulant, and IgM and IgG beta-2 glycoprotein I antibodies.^29,30

Anticardiolipin antibodies

Anticardiolipin (aCL) antibodies may be targeted either against beta-2 glycoprotein I (beta-2GPI) that is bound to cardiolipin (a phospholipid) or against cardiolipin alone; the former is more specific. Antibodies directed against cardiolipin alone are usually transient and are associated with infections and drugs. The result is considered significant only when anticardiolipin antibodies are present in a medium to high titer (> 40 IgG phospholipid units or IgM phospholipid units, or > 99th percentile).

Lupus anticoagulant

The antibody with “lupus anticoagulant activity” is targeted against prothrombin plus phospholipid or beta-2GPI plus phospholipid. The test for it is a functional assay involving 3 steps:

Demonstrating the prolongation of a phospholipid-dependent coagulation assay like the activated partial thromboplastin time (aPTT). (This may explain the prolongation of aPTT in the patient described in the vignette.) Although the presence of lupus anticoagulant is associated with thrombosis, it is called an “anticoagulant” because of this in vitro prolongation of phospholipid-dependent coagulation assays.

Mixing study. The phospholipid-dependent coagulation assay could be prolonged because of either the deficiency of a coagulation factor or the presence of the antiphospholipid antibodies. This can be differentiated by mixing the patient’s plasma with normal plasma (which will have all the clotting factors) in a 1:1 ratio. If the coagulation assay remains prolonged after the addition of normal plasma, clotting factor deficiency can be excluded.

Addition of a phospholipid. If the prolongation of the coagulation assay is due to the presence of an antiphospholipid antibody, addition of extra phospholipid will correct this.

Beta-2 glycoprotein I antibody (anti-beta-2GPI)

The beta-2GPI that is not bound to the cardiolipin can be detected by separately testing for beta-2GPI (the anticardiolipin test only detects the beta-2GPI that is bound to the cardiolipin). The result is considered significant if beta-2GPI is present in a medium to high titer (> 99th percentile).

Studies have shown that antiphospholipid antibodies may be present in 1% to 5% of apparently healthy people in the general population.³¹ These are usually low-titer anticardiolipin or anti-beta-GPI IgM antibodies that are not associated with thrombosis or adverse pregnancy outcomes. Hence, the term antiphospholipid syndrome should be reserved for those who have had at least 1 episode of thrombosis or pregnancy morbidity and persistent antiphospholipid antibodies, and not those who have asymptomatic or transient antiphospholipid antibodies.

Triple positivity (positive anticardiolipin, lupus anticoagulant, and anti-beta-2GPI) seems to be associated with the highest risk of thrombosis, with a 10-year cumulative incidence of 37.1% (95% confidence interval [CI] 19.9–54.3) for a first thrombotic event,³² and 44.2% (95% CI 38.6–49.8) for recurrent thrombosis.³³

The association with thrombosis is stronger for lupus anticoagulant than with the other 2 antibodies, with different studies³⁴ finding an odds ratio ranging from 5 to 16. A positive lupus anticoagulant test with or without a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a high-risk profile, while a moderate to high titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a moderate-risk profile. A low titer of anticardiolipin or anti-beta-2GPI IgM or IgG constitutes a low-risk profile that may not be associated with thrombosis.³⁵

Antiphospholipid syndrome is important to recognize because of the need for long-term anticoagulation to prevent recurrence.³⁶ It may be primary, when it occurs on its own, or secondary, when it occurs in association with another autoimmune disease such as lupus.

Venous events in antiphospholipid syndrome most commonly manifest as lower-limb deep vein thrombosis or pulmonary embolism, while arterial events most commonly manifest as stroke or transient ischemic attack.³⁷ Obstetric manifestations may include not only miscarriage and stillbirth, but also preterm delivery, intrauterine growth retardation, and preeclampsia, all occurring due to placental insufficiency.

The frequency of antiphospholipid antibodies has been estimated as 13.5% in patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% for those with pregnancy morbidity.³⁸

Some noncriteria manifestations have also been recognized in antiphospholipid syndrome, such as thrombocytopenia, cardiac vegetations (Libman-Sachs endocarditis), livedo reticularis, and nephropathy.

Back to our patient

Our patient’s anticardiolipin IgG test is negative, while her lupus anticoagulant and beta-2GPI IgG are positive. She has no clinical or laboratory features suggesting lupus.

She is started on warfarin. After 3 months, the warfarin is interrupted for several days, and she is retested for all 3 antiphospholipid antibodies. Her beta-2GPI I IgG and lupus anticoagulant tests are again positive. Because of the persistent antiphospholipid antibody positivity and clinical history of deep vein thrombosis, her condition is diagnosed as primary antiphospholipid syndrome. She is advised to continue anticoagulant therapy indefinitely.

A 34-year-old man who is an injecting drug user presents with a 2-week history of fever, malaise, and generalized arthralgia. There are no localizing symptoms of infection. Notable findings on examination include a temperature of 38.0°C (100.4°F), needle track marks in his arms, nonblanching vasculitic rash in his legs, and a systolic murmur over the precordium.

His white blood cell count is 15.3 × 10⁹/L (reference range 3.7–11.0), and his C-reactive protein level is 234 mg/dL (normal < 3). Otherwise, results of blood cell counts, liver enzyme tests, renal function tests, urinalysis, and chest radiography are normal.

Two sets of blood cultures are drawn. Transthoracic echocardiography and the antineutrophil cytoplasmic antibody (ANCA) test are requested, as are screening tests for human immunodeficiency virus, hepatitis B, and hepatitis C.

Was the ANCA test indicated in this patient?

ANCAs are autoantibodies against antigens located in the cytoplasmic granules of neutrophils and monocytes. They are associated with small-vessel vasculitides such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and isolated pauciimmune crescentic glomerulonephritis, all collectively known as ANCA-associated vasculitis (AAV).³⁹

Laboratory methods to detect ANCA include indirect immunofluorescence and antigen-specific enzyme immunoassays. Indirect immunofluorescence only tells us whether or not an antibody that is targeting a cytoplasmic antigen is present. Based on the indirect immunofluorescent pattern, ANCA can be classified as follows:

• Perinuclear or p-ANCA (if the targeted antigen is located just around the nucleus and extends into it)
• Cytoplasmic or c-ANCA (if the targeted antigen is located farther away from the nucleus)
• Atypical ANCA (if the indirect immunofluorescent pattern does not fit with either p-ANCA or c-ANCA).

Indirect immunofluorescence does not give information about the exact antigen that is targeted; this can only be obtained by performing 1 of the antigen-specific immunoassays. The target antigen for c-ANCA is usually proteinase-3 (PR3), while that for p-ANCA could be myeloperoxidase (MPO), cathepsin, lysozyme, lactoferrin, or bactericidal permeability inhibitor. Anti-PR3 is highly specific for GPA, while anti-MPO is usually associated with MPA and EGPA. Less commonly, anti-PR3 may be seen in patients with MPA and anti-MPO in those with GPA. Hence, there is an increasing trend toward classifying ANCA-associated vasculitis into PR3-associated or MPO-associated vasculitis rather than as GPA, MPA, EGPA, or renal-limited vasculitis.⁴⁰

Several audits have shown that the ANCA test is widely misused and requested indiscriminately to rule out vasculitis. This results in a lower positive predictive value, possible harm to patients due to increased false-positive rates, and increased burden on the laboratory.^41–43 At least 2 separate groups have demonstrated that a gating policy that refuses ANCA testing in patients without clinical evidence of systemic vasculitis can reduce the number of inappropriate requests, improve the diagnostic yield, and make it more clinically relevant and cost-effective.^44,45

The clinician should bear in mind that:

Current guidelines recommend using one of the antigen-specific assays for PR3 and MPO as the primary screening method.⁴⁸ Until recently, indirect immunofluorescence was used to screen for ANCA-associated vasculitis, and positive results were confirmed by ELISA to detect ANCAs specific for PR3 and MPO,⁴⁹ but this is no longer recommended because of recent evidence suggesting a large variability between the different indirect immunofluorescent methods and improved diagnostic performance of the antigen-specific assays.

In a large multicenter study by Damoiseaux et al, the specificity with the different antigen-specific immunoassays was 98% to 99% for PR3-ANCA and 96% to 99% for MPO-ANCA.⁵⁰

ANCA-associated vasculitis should not be considered excluded if the PR3 and MPO-ANCA are negative. In the Damoiseaux study, about 11% to 15% of patients with GPA and 8% to 24% of patients with MPA tested negative for both PR3 and MPO-ANCA.⁵⁰

If the ANCA result is negative and clinical suspicion for ANCA-associated vasculitis is high, the clinician may wish to consider requesting another immunoassay method or indirect immunofluorescence. Results of indirect immunofluorescent testing results may be positive in those with a negative immunoassay, and vice versa.

Thus, the ANCA result should always be interpreted in the context of the whole clinical picture.⁵¹ Biopsy should still be considered the gold standard for the diagnosis of ANCA-associated vasculitis. The ANCA titer can help to improve clinical interpretation, because the likelihood of ANCA-associated vasculitis increases with higher levels of PR3 and MPO-ANCA.⁵²

Back to our patient

Our patient’s blood cultures grow methicillin-sensitive Staphylococcus aureus in both sets after 48 hours. Transthoracic echocardiography reveals vegetations around the tricuspid valve, with no evidence of valvular regurgitation. The diagnosis is right-sided infective endocarditis. He is started on appropriate antibiotics.

Tests for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. The ANCA test is positive for MPO-ANCA at 28 IU/mL (normal < 10).

The positive ANCA is thought to be related to the infective endocarditis. His vasculitis is most likely secondary to infective endocarditis and not ANCA-associated vasculitis. The ANCA test need not have been requested in the first place.

A 22-year-old man presents to his primary care physician with a 4-month history of gradually worsening low back pain associated with early morning stiffness lasting more than 2 hours. He has no peripheral joint symptoms.

In the last 2 years, he has had 2 separate episodes of uveitis. There is a family history of ankylosing spondylitis in his father. Examination reveals global restriction of lumbar movements but is otherwise unremarkable. Magnetic resonance imaging (MRI) of the lumbar spine and sacroiliac joints is normal.

Should this patient be tested for human leukocyte antigen-B27 (HLA-B27)?

The major histocompatibility complex (MHC) is a gene complex that is present in all animals. It encodes proteins that help with immunologic tolerance. HLA simply refers to the human version of the MHC.⁵³ The HLA gene complex, located on chromosome 6, is categorized into class I, class II, and class III. HLA-B is one of the 3 class I genes. Thus, a positive HLA-B27 result simply means that the particular gene is present in that person.

HLA-B27 is strongly associated with ankylosing spondylitis, also known as axial spondyloarthropathy.⁵⁴ Other genes also contribute to the pathogenesis of ankylosing spondylitis, but HLA-B27 is present in more than 90% of patients with this disease and is by far considered the most important. The association is not as strong for peripheral spondyloarthropathy, with studies reporting a frequency of up to 75% for reactive arthritis and inflammatory bowel disease-associated arthritis, and up to 50% for psoriatic arthritis and uveitis.⁵⁵

About 9% of healthy, asymptomatic individuals may have HLA-B27, so the mere presence of this gene is not evidence of disease.⁵⁶ There may be up to a 20-fold increased risk of ankylosing spondylitis among those who are HLA-B27-positive.⁵⁷

Some HLA genes have many different alleles, each of which is given a number (explaining the number 27 that follows the B). Closely related alleles that differ from one another by only a few amino-acid substitutions are then categorized together, thus accounting for more than 100 subtypes of HLA-B27 (designated from HLA-B*2701 to HLA-B*27106). These subtypes vary in frequency among different racial groups, and the population prevalence of ankylosing spondylitis parallels the frequency of HLA-B27.⁵⁸ The most common subtype seen in white people and American Indians is B*2705. HLA-B27 is rare in blacks, explaining the rarity of ankylosing spondylitis in this population. Further examples include HLA-B*2704, which is seen in Asians, and HLA-B*2702, seen in Mediterranean populations. Not all subtypes of HLA-B27 are associated with disease, and some, like HLA-B*2706, may also be protective.

When should the clinician consider testing for HLA-B27?

Peripheral spondyloarthropathy may present with arthritis, enthesitis (eg, heel pain due to inflammation at the site of insertion of the Achilles tendon or plantar fascia), or dactylitis (“sausage” swelling of the whole finger or toe due to extension of inflammation beyond the margins of the joint). Other clues may include psoriasis, inflammatory bowel disease, history of preceding gastrointestinal or genitourinary infection, family history of similar conditions, and history of recurrent uveitis.

For the initial assessment of patients who have inflammatory back pain, plain radiography of the sacroiliac joints is considered the gold standard.⁵⁹ If plain radiography does not show evidence of sacroiliitis, MRI of the sacroiliac joints should be considered. While plain radiography can reveal only structural changes such as sclerosis, erosions, and ankylosis, MRI is useful to evaluate for early inflammatory changes such as bone marrow edema. Imaging the lumbar spine is not necessary, as the sacroiliac joints are almost invariably involved in axial spondyloarthropathy, and lesions seldom occur in the lumbar spine in isolation.⁶⁰

The diagnosis of ankylosing spondylitis previously relied on confirmatory imaging features, but based on the new International Society classification criteria,^61–63 which can be applied to patients with more than 3 months of back pain and age of onset of symptoms before age 45, patients can be classified as having 1 of the following:

• Radiographic axial spondyloarthropathy, if they have evidence of sacroiliitis on imaging plus 1 other feature of spondyloarthropathy
• Nonradiographic axial spondyloarthropathy, if they have a positive HLA-B27 plus 2 other features of spondyloarthropathy (Table 7).

These new criteria have a sensitivity of 82.9% and specificity of 84.4%.^62,63 The disease burden of radiographic and nonradiographic axial spondyloarthropathy has been shown to be similar, suggesting that they are part of the same disease spectrum. Thus, the HLA-B27 test is useful to make a diagnosis of axial spondyloarthropathy even in the absence of imaging features and could be requested in patients with 2 or more features of spondyloarthropathy. In the absence of imaging features and a negative HLA-B27 result, however, the patient cannot be classified as having axial spondyloarthropathy.

Back to our patient

The absence of radiographic evidence would not exclude axial spondyloarthropathy in our patient. The HLA-B27 test is requested because of the inflammatory back pain and the presence of 2 spondyloarthropathy features (uveitis and the family history) and is reported to be positive. His disease is classified as nonradiographic axial spondyloarthropathy.

He is started on regular naproxen and is referred to a physiotherapist. After 1 month, he reports significant symptomatic improvement. He asks if he can be retested for HLA-B27 to see if it has become negative. We tell him that there is no point in repeating it, as it is a gene and will not disappear.

SUMMARY: CONSIDER THE CLINICAL PICTURE

When approaching a patient suspected of having a rheumatologic disease, a clinician should first consider the clinical presentation and the intended purpose of each test. The tests, in general, might serve several purposes. They might help to:

Increase the likelihood of the diagnosis in question. For example, a positive rheumatoid factor or anticitrullinated peptide antibody can help diagnose rheumatoid arthritis in a patient with early polyarthritis, a positive HLA-B27 can help diagnose ankylosing spondylitis in patients with inflammatory back pain and normal imaging, and a positive ANCA can help diagnose ANCA-associated vasculitis in a patient with glomerulonephritis.

Reduce the likelihood of the diagnosis in question. For example, a negative antinuclear antibody test reduces the likelihood of lupus in a patient with joint pains.

Monitor the condition. For example DNA antibodies can be used to monitor the activity of lupus.

Plan the treatment strategy. For example, one might consider lifelong anticoagulation if antiphospholipid antibodies are persistently positive in a patient with thrombosis.

Prognosticate. For example, positive rheumatoid factor and anticitrullinated peptide antibody increase the risk of erosive rheumatoid arthritis.

If the test was requested in the absence of a clear indication and the result is positive, it is important to bear in mind the potential pitfalls associated with that test and not attach a diagnostic label prematurely. None of the tests can confirm or exclude a condition, so the results should always be interpreted in the context of the whole clinical picture.   

SAN FRANCISCO – The estimated U.S. prevalence of sesame allergy appears to be at least 0.23% among both adults and children, roughly about 750,000 people, according to a recent, representative survey of more than 78,000 Americans, which shows sesame allergy apparently is common enough to prompt the Food and Drug Administration to require food labels that identify sesame as an ingredient or possible contaminant.

The sesame-allergy data also showed that sesame reactions were rated as having been severe by about a third of respondents, they caused about two-thirds of people who responded to sesame to go to an emergency department at least once (the highest rate for this outcome among all food allergies), and reactions had led to use of an epinephrine automated injector by about a quarter of people who responded to it, Christopher M. Warren said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

These findings document the public health importance of sesame allergy, which seems widespread and often severe enough to warrant making sesame the ninth allergen to require specific food labeling, said Ruchi S. Gupta, MD, senior author of the study and a professor of pediatrics and medicine at Northwestern University in Chicago.

“It seems to rank up with other food allergens regarding reaction severity,” Dr. Gupta said in a video interview. In October 2018, the FDA requested information on sesame allergy so that its staff could consider adding sesame to its list of major food allergens. The eight current major food allergens that require specific labeling are: peanut, tree nuts, eggs, milk, fish, shellfish, wheat, and soy. The 0.23% prevalence of sesame among U.S. residents makes it more common than certain tree nuts, and so the prevalence numbers also seem to justify adding sesame to the FDA’s labeling list because 750,000 is “a lot of people,” she noted.

An established surveying group based at the University of Chicago ran the data collection, which received responses from 53,575 U.S. household including 40,443 adults and 38,408 children. Dr. Gupta and her associates recently published information on the methods of the survey and other findings it made about U.S. food allergy rates (JAMA Network Open. 2019 Jan 4. doi: 10.1001/jamanetworkopen.2018.5630). The descriptions people provided about their food allergy diagnoses, and the effects these allergies had, underwent detailed review by a panel of experts who decide whether or not the evidence for an allergy was “convincing.” The 0.23% prevalence rate reported for sesame represented people for whom this allergy was convincingly demonstrated, reflected a confirmed physician diagnosis, or both, and hence it was a conservative estimate, Dr. Gupta said.

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Chadha AS et al. AAAAI 2019, Abstract 615.

SAN FRANCISCO – The estimated U.S. prevalence of sesame allergy appears to be at least 0.23% among both adults and children, roughly about 750,000 people, according to a recent, representative survey of more than 78,000 Americans, which shows sesame allergy apparently is common enough to prompt the Food and Drug Administration to require food labels that identify sesame as an ingredient or possible contaminant.

The sesame-allergy data also showed that sesame reactions were rated as having been severe by about a third of respondents, they caused about two-thirds of people who responded to sesame to go to an emergency department at least once (the highest rate for this outcome among all food allergies), and reactions had led to use of an epinephrine automated injector by about a quarter of people who responded to it, Christopher M. Warren said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

These findings document the public health importance of sesame allergy, which seems widespread and often severe enough to warrant making sesame the ninth allergen to require specific food labeling, said Ruchi S. Gupta, MD, senior author of the study and a professor of pediatrics and medicine at Northwestern University in Chicago.

“It seems to rank up with other food allergens regarding reaction severity,” Dr. Gupta said in a video interview. In October 2018, the FDA requested information on sesame allergy so that its staff could consider adding sesame to its list of major food allergens. The eight current major food allergens that require specific labeling are: peanut, tree nuts, eggs, milk, fish, shellfish, wheat, and soy. The 0.23% prevalence of sesame among U.S. residents makes it more common than certain tree nuts, and so the prevalence numbers also seem to justify adding sesame to the FDA’s labeling list because 750,000 is “a lot of people,” she noted.

An established surveying group based at the University of Chicago ran the data collection, which received responses from 53,575 U.S. household including 40,443 adults and 38,408 children. Dr. Gupta and her associates recently published information on the methods of the survey and other findings it made about U.S. food allergy rates (JAMA Network Open. 2019 Jan 4. doi: 10.1001/jamanetworkopen.2018.5630). The descriptions people provided about their food allergy diagnoses, and the effects these allergies had, underwent detailed review by a panel of experts who decide whether or not the evidence for an allergy was “convincing.” The 0.23% prevalence rate reported for sesame represented people for whom this allergy was convincingly demonstrated, reflected a confirmed physician diagnosis, or both, and hence it was a conservative estimate, Dr. Gupta said.

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Chadha AS et al. AAAAI 2019, Abstract 615.

SAN FRANCISCO – The estimated U.S. prevalence of sesame allergy appears to be at least 0.23% among both adults and children, roughly about 750,000 people, according to a recent, representative survey of more than 78,000 Americans, which shows sesame allergy apparently is common enough to prompt the Food and Drug Administration to require food labels that identify sesame as an ingredient or possible contaminant.

The sesame-allergy data also showed that sesame reactions were rated as having been severe by about a third of respondents, they caused about two-thirds of people who responded to sesame to go to an emergency department at least once (the highest rate for this outcome among all food allergies), and reactions had led to use of an epinephrine automated injector by about a quarter of people who responded to it, Christopher M. Warren said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

These findings document the public health importance of sesame allergy, which seems widespread and often severe enough to warrant making sesame the ninth allergen to require specific food labeling, said Ruchi S. Gupta, MD, senior author of the study and a professor of pediatrics and medicine at Northwestern University in Chicago.

“It seems to rank up with other food allergens regarding reaction severity,” Dr. Gupta said in a video interview. In October 2018, the FDA requested information on sesame allergy so that its staff could consider adding sesame to its list of major food allergens. The eight current major food allergens that require specific labeling are: peanut, tree nuts, eggs, milk, fish, shellfish, wheat, and soy. The 0.23% prevalence of sesame among U.S. residents makes it more common than certain tree nuts, and so the prevalence numbers also seem to justify adding sesame to the FDA’s labeling list because 750,000 is “a lot of people,” she noted.

An established surveying group based at the University of Chicago ran the data collection, which received responses from 53,575 U.S. household including 40,443 adults and 38,408 children. Dr. Gupta and her associates recently published information on the methods of the survey and other findings it made about U.S. food allergy rates (JAMA Network Open. 2019 Jan 4. doi: 10.1001/jamanetworkopen.2018.5630). The descriptions people provided about their food allergy diagnoses, and the effects these allergies had, underwent detailed review by a panel of experts who decide whether or not the evidence for an allergy was “convincing.” The 0.23% prevalence rate reported for sesame represented people for whom this allergy was convincingly demonstrated, reflected a confirmed physician diagnosis, or both, and hence it was a conservative estimate, Dr. Gupta said.

Mitchel L. Zoler/MDedge News

[email protected]

SOURCE: Chadha AS et al. AAAAI 2019, Abstract 615.

Global outbreaks of infectious diseases—such as smallpox, pertussis, dysentery, and scarlet fever—seem like fodder for the history books. It was centuries ago that epidemics wiped out large swathes of the world population. Many people living and raising children today have never witnessed the devastating effects of measles, mumps, polio, and influenza—diseases that have been substantially reduced or even eradicated.¹ Why? Because since the early 1900s, we have had scientifically developed and widely distributed vaccines at our disposal.

In context, it is incredible to realize that we are still in the beginning stages of vaccine research and development. From that perspective, it is perhaps not as surprising that some parents are hesitant to vaccinate their children—after all, do we really know everything we can and should know about inoculation? Parental resistance to or refusal of vaccination is further fueled by tainted research (Andrew Wakefield was forced to retract his findings that “validated” a link between thimerosal in vaccines and autism) and misinformation propagated on the Internet.²

But what has long been a source of frustration to those who support routine vaccination has, in recent years, started to become a public health issue. Measles outbreaks are no longer historical artifacts—they are real, as evidenced by the current rise in cases centered in Clark County, Washington. Through the first full week of February 2019, there were 101 confirmed cases of measles in the US, half of which occurred in Washington State—leading the governor to declare a public health emergency.³

This has, of course, reinvigorated the ongoing discussion about parental refusal to vaccinate. Enough has been said on this topic, by both public officials and private individuals, in a variety of venues over the years. So I’d like to focus instead on the role that individual health care providers can play in this situation.

Over the years, many of my colleagues have shared stories about parents who have refused to vaccinate their children. We know many things: These parents often fear complications from vaccination more than complications of disease. Many have religious or philosophical reasons for their reluctance or refusal to vaccinate their children. Some have concerns about vaccine safety or effectiveness. We know these things … but we don’t always know how to speak with parents about these issues.

It is somewhat ironic that the core motivation for hesitant parents and well-meaning clinicians is the same: care and protection of the child. The difficulty lies in the disparate view of what that entails. As NPs and PAs, though, our duty is to seek health benefits for and minimize harm to the patients in our care. Part of our role, when those patients are children, is to provide parents with the necessary risk-benefit information to help them make informed decisions. When the subject is vaccination, we must listen carefully and be respectful of parents’ concerns; we must recognize that their decision-making criteria may differ from ours.

So how can we bridge the gap with parents who “don’t see it the way we do”? We start by being honest with them about what is and isn’t known as far as the risks and benefits of vaccination in general or a vaccine in particular. This means acknowledging that although vaccines are very safe, they are not risk-free or 100% effective. But this also gives us the opportunity to provide them with validated data and to emphasize that the risks of any vaccine should not be considered in a silo but rather in comparison with the risks of the disease in question or of the lack of immunization.

Continue to: Helpfully, Leask and colleagues...

Helpfully, Leask and colleagues have classified parental positions on vaccination, which also provided the groundwork to offer strategies for communicating with each group.⁴ They identified five classes:

Unquestioning acceptors (30% to 40% of parents), who vaccinate their children and typically have no specific questions about the need for or safety of vaccines. Since this group tends to have a good relationship with their health care team but less detailed knowledge about vaccination, clinicians should continue to build rapport while providing scientific information about the vaccine being recommended or administered.⁴

Cautious acceptors (25% to 35%), who vaccinate their children despite having minor concerns. They tend to recognize the risk for adverse effects and hope their child will not be affected. In addition to building rapport, clinicians should provide verbal and numeric descriptions of relevant vaccine data and explain common adverse effects and disease risks.⁴

Hesitant vaccinators (20% to 30%), who are on the fence about the benefits and safety of vaccination. Their focus is more on the negative aspects, and they may not feel particularly trusting of their health care provider. Therefore, gaining trust is vital—parents in this group are eager to discuss their concerns with their clinician and have their questions answered satisfactorily. Motivational interviewing using a guiding style may be a helpful tool.⁴

Late or selective vaccinators (2% to 27%), who have significant doubts about the safety and necessity of vaccines, resulting in their choice to delay vaccination or select only some of the recommended vaccines for their child. These parents may require additional time—possibly a second appointment—in which to fully discuss their concerns. Be sure to provide up-to-date information on the risks and benefits of a vaccine, and use decision aids as appropriate.⁴

Continue to: Refusers...

Refusers (<2%), who have concerns about the number of vaccines children receive and conflicting feelings about whom to trust and how best to get answers to their questions. This group tends to demonstrate high knowledge levels about vaccination but may be the most argumentative when presented with information. Emphasize the importance of protecting the child from an infectious disease and reinforce the effectiveness of the vaccine. Use statistics rather than anecdotes. But above all, spend the time needed to provide refusers with a thorough understanding of the risks of not immunizing their child.⁴

Although it is not a universal sentiment, many parents confer trust on their health care providers. We can use this trust in a respectful, noncoercive, and non-condescending manner by providing research-supported facts about vaccines. Clinicians who listen with a compassionate ear will be in the best position to lead the hesitant, late or selective, or refusing parents to confidently make an informed decision that immunization is the best way to protect their children from vaccine-preventable diseases.⁴

Rather than yet again focusing on the negative, I’d like to ask: Have you had a success story of helping parents to choose vaccination for their children? How did you overcome their concerns? Share your experience with me at [email protected].

Global outbreaks of infectious diseases—such as smallpox, pertussis, dysentery, and scarlet fever—seem like fodder for the history books. It was centuries ago that epidemics wiped out large swathes of the world population. Many people living and raising children today have never witnessed the devastating effects of measles, mumps, polio, and influenza—diseases that have been substantially reduced or even eradicated.¹ Why? Because since the early 1900s, we have had scientifically developed and widely distributed vaccines at our disposal.

In context, it is incredible to realize that we are still in the beginning stages of vaccine research and development. From that perspective, it is perhaps not as surprising that some parents are hesitant to vaccinate their children—after all, do we really know everything we can and should know about inoculation? Parental resistance to or refusal of vaccination is further fueled by tainted research (Andrew Wakefield was forced to retract his findings that “validated” a link between thimerosal in vaccines and autism) and misinformation propagated on the Internet.²

But what has long been a source of frustration to those who support routine vaccination has, in recent years, started to become a public health issue. Measles outbreaks are no longer historical artifacts—they are real, as evidenced by the current rise in cases centered in Clark County, Washington. Through the first full week of February 2019, there were 101 confirmed cases of measles in the US, half of which occurred in Washington State—leading the governor to declare a public health emergency.³

This has, of course, reinvigorated the ongoing discussion about parental refusal to vaccinate. Enough has been said on this topic, by both public officials and private individuals, in a variety of venues over the years. So I’d like to focus instead on the role that individual health care providers can play in this situation.

Over the years, many of my colleagues have shared stories about parents who have refused to vaccinate their children. We know many things: These parents often fear complications from vaccination more than complications of disease. Many have religious or philosophical reasons for their reluctance or refusal to vaccinate their children. Some have concerns about vaccine safety or effectiveness. We know these things … but we don’t always know how to speak with parents about these issues.

It is somewhat ironic that the core motivation for hesitant parents and well-meaning clinicians is the same: care and protection of the child. The difficulty lies in the disparate view of what that entails. As NPs and PAs, though, our duty is to seek health benefits for and minimize harm to the patients in our care. Part of our role, when those patients are children, is to provide parents with the necessary risk-benefit information to help them make informed decisions. When the subject is vaccination, we must listen carefully and be respectful of parents’ concerns; we must recognize that their decision-making criteria may differ from ours.

So how can we bridge the gap with parents who “don’t see it the way we do”? We start by being honest with them about what is and isn’t known as far as the risks and benefits of vaccination in general or a vaccine in particular. This means acknowledging that although vaccines are very safe, they are not risk-free or 100% effective. But this also gives us the opportunity to provide them with validated data and to emphasize that the risks of any vaccine should not be considered in a silo but rather in comparison with the risks of the disease in question or of the lack of immunization.

Continue to: Helpfully, Leask and colleagues...

Helpfully, Leask and colleagues have classified parental positions on vaccination, which also provided the groundwork to offer strategies for communicating with each group.⁴ They identified five classes:

Unquestioning acceptors (30% to 40% of parents), who vaccinate their children and typically have no specific questions about the need for or safety of vaccines. Since this group tends to have a good relationship with their health care team but less detailed knowledge about vaccination, clinicians should continue to build rapport while providing scientific information about the vaccine being recommended or administered.⁴

Cautious acceptors (25% to 35%), who vaccinate their children despite having minor concerns. They tend to recognize the risk for adverse effects and hope their child will not be affected. In addition to building rapport, clinicians should provide verbal and numeric descriptions of relevant vaccine data and explain common adverse effects and disease risks.⁴

Hesitant vaccinators (20% to 30%), who are on the fence about the benefits and safety of vaccination. Their focus is more on the negative aspects, and they may not feel particularly trusting of their health care provider. Therefore, gaining trust is vital—parents in this group are eager to discuss their concerns with their clinician and have their questions answered satisfactorily. Motivational interviewing using a guiding style may be a helpful tool.⁴

Late or selective vaccinators (2% to 27%), who have significant doubts about the safety and necessity of vaccines, resulting in their choice to delay vaccination or select only some of the recommended vaccines for their child. These parents may require additional time—possibly a second appointment—in which to fully discuss their concerns. Be sure to provide up-to-date information on the risks and benefits of a vaccine, and use decision aids as appropriate.⁴

Continue to: Refusers...

Refusers (<2%), who have concerns about the number of vaccines children receive and conflicting feelings about whom to trust and how best to get answers to their questions. This group tends to demonstrate high knowledge levels about vaccination but may be the most argumentative when presented with information. Emphasize the importance of protecting the child from an infectious disease and reinforce the effectiveness of the vaccine. Use statistics rather than anecdotes. But above all, spend the time needed to provide refusers with a thorough understanding of the risks of not immunizing their child.⁴

Although it is not a universal sentiment, many parents confer trust on their health care providers. We can use this trust in a respectful, noncoercive, and non-condescending manner by providing research-supported facts about vaccines. Clinicians who listen with a compassionate ear will be in the best position to lead the hesitant, late or selective, or refusing parents to confidently make an informed decision that immunization is the best way to protect their children from vaccine-preventable diseases.⁴

Rather than yet again focusing on the negative, I’d like to ask: Have you had a success story of helping parents to choose vaccination for their children? How did you overcome their concerns? Share your experience with me at [email protected].

Global outbreaks of infectious diseases—such as smallpox, pertussis, dysentery, and scarlet fever—seem like fodder for the history books. It was centuries ago that epidemics wiped out large swathes of the world population. Many people living and raising children today have never witnessed the devastating effects of measles, mumps, polio, and influenza—diseases that have been substantially reduced or even eradicated.¹ Why? Because since the early 1900s, we have had scientifically developed and widely distributed vaccines at our disposal.

In context, it is incredible to realize that we are still in the beginning stages of vaccine research and development. From that perspective, it is perhaps not as surprising that some parents are hesitant to vaccinate their children—after all, do we really know everything we can and should know about inoculation? Parental resistance to or refusal of vaccination is further fueled by tainted research (Andrew Wakefield was forced to retract his findings that “validated” a link between thimerosal in vaccines and autism) and misinformation propagated on the Internet.²

But what has long been a source of frustration to those who support routine vaccination has, in recent years, started to become a public health issue. Measles outbreaks are no longer historical artifacts—they are real, as evidenced by the current rise in cases centered in Clark County, Washington. Through the first full week of February 2019, there were 101 confirmed cases of measles in the US, half of which occurred in Washington State—leading the governor to declare a public health emergency.³

This has, of course, reinvigorated the ongoing discussion about parental refusal to vaccinate. Enough has been said on this topic, by both public officials and private individuals, in a variety of venues over the years. So I’d like to focus instead on the role that individual health care providers can play in this situation.

Over the years, many of my colleagues have shared stories about parents who have refused to vaccinate their children. We know many things: These parents often fear complications from vaccination more than complications of disease. Many have religious or philosophical reasons for their reluctance or refusal to vaccinate their children. Some have concerns about vaccine safety or effectiveness. We know these things … but we don’t always know how to speak with parents about these issues.

It is somewhat ironic that the core motivation for hesitant parents and well-meaning clinicians is the same: care and protection of the child. The difficulty lies in the disparate view of what that entails. As NPs and PAs, though, our duty is to seek health benefits for and minimize harm to the patients in our care. Part of our role, when those patients are children, is to provide parents with the necessary risk-benefit information to help them make informed decisions. When the subject is vaccination, we must listen carefully and be respectful of parents’ concerns; we must recognize that their decision-making criteria may differ from ours.

So how can we bridge the gap with parents who “don’t see it the way we do”? We start by being honest with them about what is and isn’t known as far as the risks and benefits of vaccination in general or a vaccine in particular. This means acknowledging that although vaccines are very safe, they are not risk-free or 100% effective. But this also gives us the opportunity to provide them with validated data and to emphasize that the risks of any vaccine should not be considered in a silo but rather in comparison with the risks of the disease in question or of the lack of immunization.

Continue to: Helpfully, Leask and colleagues...

Helpfully, Leask and colleagues have classified parental positions on vaccination, which also provided the groundwork to offer strategies for communicating with each group.⁴ They identified five classes:

Unquestioning acceptors (30% to 40% of parents), who vaccinate their children and typically have no specific questions about the need for or safety of vaccines. Since this group tends to have a good relationship with their health care team but less detailed knowledge about vaccination, clinicians should continue to build rapport while providing scientific information about the vaccine being recommended or administered.⁴

Cautious acceptors (25% to 35%), who vaccinate their children despite having minor concerns. They tend to recognize the risk for adverse effects and hope their child will not be affected. In addition to building rapport, clinicians should provide verbal and numeric descriptions of relevant vaccine data and explain common adverse effects and disease risks.⁴

Hesitant vaccinators (20% to 30%), who are on the fence about the benefits and safety of vaccination. Their focus is more on the negative aspects, and they may not feel particularly trusting of their health care provider. Therefore, gaining trust is vital—parents in this group are eager to discuss their concerns with their clinician and have their questions answered satisfactorily. Motivational interviewing using a guiding style may be a helpful tool.⁴

Late or selective vaccinators (2% to 27%), who have significant doubts about the safety and necessity of vaccines, resulting in their choice to delay vaccination or select only some of the recommended vaccines for their child. These parents may require additional time—possibly a second appointment—in which to fully discuss their concerns. Be sure to provide up-to-date information on the risks and benefits of a vaccine, and use decision aids as appropriate.⁴

Continue to: Refusers...

Refusers (<2%), who have concerns about the number of vaccines children receive and conflicting feelings about whom to trust and how best to get answers to their questions. This group tends to demonstrate high knowledge levels about vaccination but may be the most argumentative when presented with information. Emphasize the importance of protecting the child from an infectious disease and reinforce the effectiveness of the vaccine. Use statistics rather than anecdotes. But above all, spend the time needed to provide refusers with a thorough understanding of the risks of not immunizing their child.⁴

Although it is not a universal sentiment, many parents confer trust on their health care providers. We can use this trust in a respectful, noncoercive, and non-condescending manner by providing research-supported facts about vaccines. Clinicians who listen with a compassionate ear will be in the best position to lead the hesitant, late or selective, or refusing parents to confidently make an informed decision that immunization is the best way to protect their children from vaccine-preventable diseases.⁴

Rather than yet again focusing on the negative, I’d like to ask: Have you had a success story of helping parents to choose vaccination for their children? How did you overcome their concerns? Share your experience with me at [email protected].

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

At a quick read, the messages from these articles may seem contradictory. But the biology is more complex in the setting of endogenous production of T₄ by the thyroid gland, which is regulated by TSH, which in turn is regulated in a feedback loop by the thyroid-produced T₄. In the setting of a fixed replacement dose of exogenous levothyroxine, the provided hormone affects the pituitary production of TSH, which likely will have no significant subsequent effect on the T₄ level. Thus, the feedback control loop is far simpler.

There has not been a definitive study demonstrating that thyroxine supplementation in patients with subclinical hypothyroidism results in a superior clinical outcome. There are hints that this may be the case, and Azim and Nasr cite some of these studies. Recognizing a few markedly different physiologic reasons why the TSH can be slightly elevated and the T₄ normal helps explain the lack of uniform clinical success with supplementation therapy and provides rationales for some management strategies.

Any biological variability in the responsiveness of the thyroid gland to TSH may affect the relationship between the levels of TSH and thyroid gland-released T₄. In theory, if the thyroid receptor has decreased affinity for TSH, a higher TSH concentration will be needed to get the thyroid gland to secrete the level of T₄ that the pituitary sensing mechanism deems normal for that individual. If the receptor affinity was decreased due to a gene polymorphism, this relationship between TSH and T₄ may be stable, and providing exogenous T₄ will result in a lower, “normalized” TSH level but may disrupt the thyroid-pituitary crosstalk and may even produce clinical hyperthyroidism.

A similar scenario exists in the setting of early thyroid gland failure, such as in Hashimoto thyroiditis. But in the latter scenario, the TSH-to-T₄ production relationship may be unstable over time, for as additional thyroid gland is destroyed, T₄ production will continue to decrease, the TSH will increase, and the thyroid gland may ultimately fail and hypothyroidism will occur. Hence the recommendation that in the setting of subclinical hypothyroidism and antiperoxidase antibodies, T₄ and TSH levels should be monitored regularly in order to detect early true thyroid gland failure when the T₄ level can no longer be maintained despite the increased stimulation of the gland by the elevated TSH. Analogous to this may be subclinical hypothyroidism in the elderly, in whom thyroid gland failure may develop, despite an increased TSH, from senescence rather than autoimmunity. What I am suggesting is that the natural history of all patients with subclinical hypothyroidism is not alike, and it thus should not be surprising that there does not seem to be a one-size-fits-all approach to management.

Symptoms in patients with subclinical hypothyroidism have not uniformly improved with T₄ treatment compared with placebo. Notably, most patients with subclinical hypothyroidism experience no symptoms. But consider the extremely common symptom of fatigue, which can be present for a myriad of defined and undefined reasons. This symptom may often lead physicians to check the TSH and, if that is even slightly elevated, to also check the T₄. It may also lead some physicians to routinely check the T₄. Subclinical hypothyroidism is also quite common; thus, by chance alone or because of the circadian timing of checking the TSH, a slightly elevated TSH and fatigue may coexist and yet be unrelated.

Additionally, a positive biochemical response to thyroxine supplementation, such as a lowering of cholesterol, does not prove that the patient was clinically hypothyroid prior to supplementation, any more than lowering a patient’s blood glucose with insulin proves that the patient was diabetic. The management of subclinical hypothyroidism should be nuanced and based on both clinical and laboratory parameters.

At a quick read, the messages from these articles may seem contradictory. But the biology is more complex in the setting of endogenous production of T₄ by the thyroid gland, which is regulated by TSH, which in turn is regulated in a feedback loop by the thyroid-produced T₄. In the setting of a fixed replacement dose of exogenous levothyroxine, the provided hormone affects the pituitary production of TSH, which likely will have no significant subsequent effect on the T₄ level. Thus, the feedback control loop is far simpler.

There has not been a definitive study demonstrating that thyroxine supplementation in patients with subclinical hypothyroidism results in a superior clinical outcome. There are hints that this may be the case, and Azim and Nasr cite some of these studies. Recognizing a few markedly different physiologic reasons why the TSH can be slightly elevated and the T₄ normal helps explain the lack of uniform clinical success with supplementation therapy and provides rationales for some management strategies.

Any biological variability in the responsiveness of the thyroid gland to TSH may affect the relationship between the levels of TSH and thyroid gland-released T₄. In theory, if the thyroid receptor has decreased affinity for TSH, a higher TSH concentration will be needed to get the thyroid gland to secrete the level of T₄ that the pituitary sensing mechanism deems normal for that individual. If the receptor affinity was decreased due to a gene polymorphism, this relationship between TSH and T₄ may be stable, and providing exogenous T₄ will result in a lower, “normalized” TSH level but may disrupt the thyroid-pituitary crosstalk and may even produce clinical hyperthyroidism.

A similar scenario exists in the setting of early thyroid gland failure, such as in Hashimoto thyroiditis. But in the latter scenario, the TSH-to-T₄ production relationship may be unstable over time, for as additional thyroid gland is destroyed, T₄ production will continue to decrease, the TSH will increase, and the thyroid gland may ultimately fail and hypothyroidism will occur. Hence the recommendation that in the setting of subclinical hypothyroidism and antiperoxidase antibodies, T₄ and TSH levels should be monitored regularly in order to detect early true thyroid gland failure when the T₄ level can no longer be maintained despite the increased stimulation of the gland by the elevated TSH. Analogous to this may be subclinical hypothyroidism in the elderly, in whom thyroid gland failure may develop, despite an increased TSH, from senescence rather than autoimmunity. What I am suggesting is that the natural history of all patients with subclinical hypothyroidism is not alike, and it thus should not be surprising that there does not seem to be a one-size-fits-all approach to management.

Symptoms in patients with subclinical hypothyroidism have not uniformly improved with T₄ treatment compared with placebo. Notably, most patients with subclinical hypothyroidism experience no symptoms. But consider the extremely common symptom of fatigue, which can be present for a myriad of defined and undefined reasons. This symptom may often lead physicians to check the TSH and, if that is even slightly elevated, to also check the T₄. It may also lead some physicians to routinely check the T₄. Subclinical hypothyroidism is also quite common; thus, by chance alone or because of the circadian timing of checking the TSH, a slightly elevated TSH and fatigue may coexist and yet be unrelated.

Additionally, a positive biochemical response to thyroxine supplementation, such as a lowering of cholesterol, does not prove that the patient was clinically hypothyroid prior to supplementation, any more than lowering a patient’s blood glucose with insulin proves that the patient was diabetic. The management of subclinical hypothyroidism should be nuanced and based on both clinical and laboratory parameters.

At a quick read, the messages from these articles may seem contradictory. But the biology is more complex in the setting of endogenous production of T₄ by the thyroid gland, which is regulated by TSH, which in turn is regulated in a feedback loop by the thyroid-produced T₄. In the setting of a fixed replacement dose of exogenous levothyroxine, the provided hormone affects the pituitary production of TSH, which likely will have no significant subsequent effect on the T₄ level. Thus, the feedback control loop is far simpler.

There has not been a definitive study demonstrating that thyroxine supplementation in patients with subclinical hypothyroidism results in a superior clinical outcome. There are hints that this may be the case, and Azim and Nasr cite some of these studies. Recognizing a few markedly different physiologic reasons why the TSH can be slightly elevated and the T₄ normal helps explain the lack of uniform clinical success with supplementation therapy and provides rationales for some management strategies.

Any biological variability in the responsiveness of the thyroid gland to TSH may affect the relationship between the levels of TSH and thyroid gland-released T₄. In theory, if the thyroid receptor has decreased affinity for TSH, a higher TSH concentration will be needed to get the thyroid gland to secrete the level of T₄ that the pituitary sensing mechanism deems normal for that individual. If the receptor affinity was decreased due to a gene polymorphism, this relationship between TSH and T₄ may be stable, and providing exogenous T₄ will result in a lower, “normalized” TSH level but may disrupt the thyroid-pituitary crosstalk and may even produce clinical hyperthyroidism.

A similar scenario exists in the setting of early thyroid gland failure, such as in Hashimoto thyroiditis. But in the latter scenario, the TSH-to-T₄ production relationship may be unstable over time, for as additional thyroid gland is destroyed, T₄ production will continue to decrease, the TSH will increase, and the thyroid gland may ultimately fail and hypothyroidism will occur. Hence the recommendation that in the setting of subclinical hypothyroidism and antiperoxidase antibodies, T₄ and TSH levels should be monitored regularly in order to detect early true thyroid gland failure when the T₄ level can no longer be maintained despite the increased stimulation of the gland by the elevated TSH. Analogous to this may be subclinical hypothyroidism in the elderly, in whom thyroid gland failure may develop, despite an increased TSH, from senescence rather than autoimmunity. What I am suggesting is that the natural history of all patients with subclinical hypothyroidism is not alike, and it thus should not be surprising that there does not seem to be a one-size-fits-all approach to management.

Symptoms in patients with subclinical hypothyroidism have not uniformly improved with T₄ treatment compared with placebo. Notably, most patients with subclinical hypothyroidism experience no symptoms. But consider the extremely common symptom of fatigue, which can be present for a myriad of defined and undefined reasons. This symptom may often lead physicians to check the TSH and, if that is even slightly elevated, to also check the T₄. It may also lead some physicians to routinely check the T₄. Subclinical hypothyroidism is also quite common; thus, by chance alone or because of the circadian timing of checking the TSH, a slightly elevated TSH and fatigue may coexist and yet be unrelated.

Additionally, a positive biochemical response to thyroxine supplementation, such as a lowering of cholesterol, does not prove that the patient was clinically hypothyroid prior to supplementation, any more than lowering a patient’s blood glucose with insulin proves that the patient was diabetic. The management of subclinical hypothyroidism should be nuanced and based on both clinical and laboratory parameters.

Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.
 

Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.
 

Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.
 

Taking aspirin and omega-3 polyunsaturated fatty acid did not reduce the colorectal adenoma among high-risk patients. Also today, New data reveal that college students are at greater risk of meningococcal B infection, children who survive Hodgkin lymphoma face a massive increased risk for second cancers down the road, and the 2018/19 flu season shows high activity in nine states.

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Apple Podcasts

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Taking aspirin and omega-3 polyunsaturated fatty acid did not reduce the colorectal adenoma among high-risk patients. Also today, New data reveal that college students are at greater risk of meningococcal B infection, children who survive Hodgkin lymphoma face a massive increased risk for second cancers down the road, and the 2018/19 flu season shows high activity in nine states.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Taking aspirin and omega-3 polyunsaturated fatty acid did not reduce the colorectal adenoma among high-risk patients. Also today, New data reveal that college students are at greater risk of meningococcal B infection, children who survive Hodgkin lymphoma face a massive increased risk for second cancers down the road, and the 2018/19 flu season shows high activity in nine states.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Anaphylaxis is potentially fatal but can be prevented if the trigger is identified and avoided, and death can be avoided if episodes are treated promptly.

A consensus definition of anaphylaxis has been difficult to achieve, with slight variations among international guidelines. The World Allergy Organization classifies anaphylaxis as immunologic, nonimmunologic, or idiopathic.¹ The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network highlight clinical symptoms and criteria.² The International Consensus on Food Allergy describes reactions as being immunoglobulin E (IgE)-mediated, cell-mediated, or a combination of the 2 mechanisms.³

Despite the subtle differences in these definitions, all 3 international organizations have a common recommendation for anaphylaxis: once it is diagnosed, epinephrine is the treatment of choice.

EPINEPHRINE IS THE TREATMENT OF CHOICE FOR ANAPHYLAXIS

Anaphylaxis commonly results from exposure to foods, medications, and Hymenoptera venom.⁴ Avoiding triggers is key in preventing anaphylaxis but is not always possible.

Although epinephrine is the cornerstone of the emergency treatment of anaphylaxis, many patients instead receive antihistamines and corticosteroids as initial therapy. Some take these medications on their own, and some receive them in emergency departments and outpatient clinics.⁵

Diphenhydramine, a histamine 1 receptor antagonist, is often used as a first-line medication. But diphenhydramine has a slow onset of action, taking 80 minutes after an oral dose to suppress a histamine-induced cutaneous flare by 50%, and taking 52 minutes with intramuscular administration.⁶ Corticosteroids also have a slow onset of action. These drugs cannot prevent death in anaphylaxis, a condition in which the median time to respiratory or cardiac arrest is 30 minutes after ingestion of food, 15 minutes after envenomation, and 5 minutes after iatrogenic reactions.⁷

Combination therapy with diphenhydra­mine and a histamine 2 receptor antagonist (eg, cimetidine, famotidine) is also commonly used,⁸ but this combination offers no advantage in terms of onset of action, and a Cochrane review could find no definitive evidence for or against the use of histamine 2 receptor antagonists.⁹

Because of their slow onset of action, all of these should be second-line therapies, given after epinephrine. Epinephrine is the first line of treatment because it has a maximal pharmacokinetic effect (time to maximal peak serum level) within 10 minutes of intramuscular injection into the thigh.^10,11

In addition, epinephrine acts on numerous receptors to antagonize the multiple pathologic effects of the mediators released during an anaphylactic episode. In contrast, antihistamines block only 1 mediator, while mediators other than histamine can be responsible for severe events and deaths.^12,13

It is crucial that epinephrine be given immediately, as delay has been associated with fatalities.¹⁴ In addition, guidelines recommend repeating epinephrine dosing after 5 to 15 minutes if the response to the first dose is suboptimal.^1,2 From 16% to 36% of patients may need a second dose.^15–18 Therefore, many physicians recommend that patients at risk of anaphylaxis keep not 1 but 2 epinephrine autoinjectors on hand at all times, and so say the US guidelines for the management of anaphylaxis.¹⁹

WHO SHOULD CARRY AN EPINEPHRINE AUTOINJECTOR?

All published guidelines recommend epinephrine as the drug of choice for anaphylaxis. And an epinephrine autoinjector is indicated for anyone who has experienced an anaphylactic event or is at risk of one, and these patients should carry it with them at all times. Such individuals include those with food allergy or Hymenoptera hypersensitivity.

Food allergy

The foods that most often cause anaphylaxis are peanuts, tree nuts, fish, shellfish, milk, and eggs, but any food can cause a reaction.

The prevalence of food allergy has increased over time, and treatments are limited. Some food desensitization protocols look promising but are still in the research stages. The best treatment at this time is to avoid the offending food, but there are accidental exposures.

Hymenoptera hypersensitivity

Patients who have had anaphylaxis after being stung by insects such as bees, wasps, yellow-faced hornets, white-faced hornets, yellow jackets, and fire ants should be evaluated by an allergist. Skin testing and serum IgE testing helps properly diagnose Hymenoptera hypersensitivity.

Once the diagnosis is confirmed, venom immunotherapy should be considered. Some patients choose only to carry an epinephrine autoinjector and to avoid these insects as much as possible. However, most patients also choose to receive venom immunotherapy, because 80% to 90% of those who receive this treatment for 3 to 5 years do not have a systemic reaction if they are stung again.²⁰

Regardless of whether they choose to undergo immunotherapy, sensitive patients should always carry an epinephrine autoinjector. This is also the case after treatment ends, since the therapy is not 100% effective.

In other patients who may be at increased risk, the mandate for an epinephrine autoinjector is less clear, and the decision to carry one is determined on an individual basis. Such individuals are those receiving allergen immunotherapy, with large local reactions to insect stings, with oral allergy syndrome, with mastocytosis, and with drug allergy. In these cases, the benefit vs the burden of carrying an autoinjector should be discussed with the patient.

Patients on allergen immunotherapy

National guidelines recommend that all patients who receive allergen immunotherapy be monitored in the clinic under a physician’s supervision for 30 minutes after the injection. Fortunately, life-threatening reactions occurring after 30 minutes are rare. But delayed systemic reactions can occur and may account for up to 50% of such events.²¹

Therefore, many physicians consider it prudent for patients on immunotherapy to carry an epinephrine autoinjector, but there is no consensus. A survey²² found that 13.5% of allergists did not prescribe the autoinjector for patients on immunotherapy, while 33.3% prescribed it for all their patients on immunotherapy, and the rest prescribed based on risk.

Since there are no national guidelines on epinephrine autoinjectors for patients on immunotherapy, the decision should be based on the patient’s risks and comorbidities and informed by discussion between the individual patient and his or her allergist.

Patients with large local reactions to insect stings

From 5% to 10% of patients who have large local reactions to insect stings are at risk of systemic reactions.²⁰

Patients with oral allergy syndrome

Oral allergy syndrome, also known as pollen-food allergy, causes itching and mild swelling of the mouth, lips, and throat after eating fresh fruits and vegetables. The prevalence ranges from 2% to 10% of patients with allergies.²³

A survey of allergists found that 20% of patients with oral allergy syndrome had experienced systemic symptoms.²⁴ The survey also showed that the decision to prescribe an epinephrine autoinjector to these patients was highly variable. Only about 30% of allergists recommend epinephrine autoinjectors to patients with oral allergy syndrome, while most believe that the decision should be based on the individual’s symptoms and risk.

More research is needed in the area of food allergy. Because data are limited, there are no national guidelines on whether these patients should carry an epinephrine autoinjector. We agree with the Joint Task Force on Practice Parameters¹⁴ recommendation that the decision be made on an individual basis following discussion between the patient and physician. 

Patients with mastocytosis

Patients with mastocytosis and a history of anaphylaxis are at increased risk for systemic reactions to Hymenoptera venom.

Patients with medication allergy

Once medication allergy has been diagnosed, avoidance is usually effective, obviating the need for an epinephrine autoinjector, although the physician has the option of prescribing one.

CAUTIONS, NOT CONTRAINDICATIONS

Physicians may be reluctant to prescribe an epinephrine autoinjector because of the risk of an adverse reaction in patients with hypertension, coronary artery disease, or arrhythmias, and in elderly patients taking multiple drugs, especially drugs that can interact with epinephrine. Nevertheless, there is no absolute contraindication to the use of epinephrine in anaphylaxis.

In patients with atherosclerosis and cardiovascular disease

Epinephrine increases vasoconstriction, heart rate, and cardiac force of contraction. These effects are beneficial during anaphylaxis, but in rare cases patients have experienced myocardial infarction and acute coronary syndrome after receiving intravenous epinephrine.²⁵ These incidents have naturally prompted reluctance to prescribe it in susceptible patients with coronary disease during anaphylaxis.

Yet epinephrine may not be solely to blame for these adverse responses. Mast cells are abundant in the heart, and their release of mediators can also result in adverse cardiac manifestations, including myocardial infarction.²⁶

Conversely, some drugs used to treat cardiovascular disease can worsen anaphylaxis.

Beta-blockers can cause bronchospasm and decrease cardiac contractility. They can also blunt the pharmacologic effects of epinephrine. There is concern that epinephrine may produce dangerous elevations of blood pressure in patients taking beta-blockers by unopposed alpha-adrenergic stimulation and reflex vagotonic effects.²⁷ And there is evidence that beta-blockers may increase the risk and severity of reactions. One study reported that patients taking beta-blockers are more than 8 times more likely to be hospitalized due to anaphylactoid reaction with bronchospasm.²⁸

Beta-blockers and, to a lesser extent, angiotensin-converting enzyme inhibitors have been shown to increase the risk of anaphylaxis in the emergency department.^29,30 However, some investigators have not found beta-blockers to be a risk factor. A study evaluating anaphylactoid reactions from contrast media found no statistically significant higher risk in patients taking beta-blockers.³¹ Similarly, a study of 3,178 patients on beta-blockers receiving venom immunotherapy or allergen immunotherapy found no increase in the frequency of systemic reactions.³² Nevertheless, overall, more studies support the hypothesis that beta-blockers may be an additional risk factor in anaphylaxis.³³

Thus, clinicians treating patients with cardiovascular disease and anaphylaxis face a dilemma. Although there is concern in this population, epinephrine should not be withheld in patients with cardiovascular disease who are experiencing an anaphylactic event.³³ If epinephrine is not administered, the patient could die.

Elderly patients on multiple medications

Older patients are also at risk of anaphylaxis. But clinicians are reluctant to treat older patients with epinephrine because of concerns about adverse effects.

Epinephrine dispensing rates vary substantially in different age groups: 1.44% for patients under age 17, 0.9% for those ages 17 to 64, and 0.32% for those age 65 or older.³⁴ A Canadian study of 492 patients with anaphylaxis in the emergency department showed that those over age 50 received epinephrine less often than younger patients (36.1% vs 60.5%).³⁵ Cardiovascular complications were more frequent in the older group, occurring in 4 (9.1%) of the 44 older patients who received epinephrine compared with 1 (0.4%) of the 225 younger patients who received it. On the other hand, the rate of adverse effects from subcutaneous epinephrine was no different in older asthma patients compared with younger patients.³⁶

Many older patients take multiple medications, raising concern about adverse effects. Commonly prescribed medications in the elderly can affect the actions of epinephrine. Monoamine oxidase inhibitors retard the catabolism of epinephrine. Tricyclic antidepressants may decrease the reuptake of catecholamines by neurons and thus interfere with the degradation of epinephrine. Digoxin has a narrow therapeutic window and can potentially increase the risk of arrhythmias when given with epinephrine.

Although the clinician must be cautious in treating older patients who have comorbidities, these are not sufficient to withhold prescribing an epinephrine autoinjector to elderly patients at risk of anaphylaxis.

Epinephrine autoinjectors come preloaded for prompt delivery of the drug. They are intended primarily for use by patients themselves in unsupervised settings in suspected anaphylaxis. Simplicity of use and safety must be considered in such a setting so that patients can use the device correctly and are not incorrectly dosed.

Several models are commercially available, with different ergonomic designs and sizes. EpiPen, the first one marketed in the United States, was introduced in 1987. One device (Auvi-Q) contains an audio chip that gives step-by-step instructions at the time of use. It is hoped that this device will reduce errors in usage during this stressful time for patients and caregivers.

In the United States, epinephrine autoinjectors contain either 0.15 or 0.30 mg of the drug, but some clinicians believe this may not be enough. The UK Resuscitation Council recommends 0.50 mg for patients over age 12,³⁷ and an epinephrine autoinjector with that dose is available in Europe.

Subcutaneous vs intramuscular delivery

The package insert for some epinephrine autoinjectors says the injector can be used to treat anaphylaxis by both subcutaneous and intramuscular administration. However, the routes are not equivalent.

The goal in anaphylaxis is to quickly achieve high tissue and plasma epinephrine concentrations, and studies have found that injection into the vastus lateralis muscle, but not the deltoid muscle, results in faster time to peak plasma concentration: 8 minutes for injection in the vastus lateralis muscle and 34 minutes for subcutaneous delivery.^10,11 In addition, injection in the vastus lateralis muscle results in a higher peak plasma concentration than the subcutaneous or deltoid route. Based on these data, intramuscular injection into the vastus lateralis muscle in the thigh appears to be the preferred route of administration of epinephrine.

Obese patients may need a longer needle

Research on the original autoinjector was conducted by the US military, which wanted a rapidly effective and easy-to-use antidote for battlefield exposure to poison gas. The resulting device had 2 separate spring-loaded syringes, 1 containing pralidoxime chloride and the other atropine sulfate. To enable its use through the thick fabric of a chemical warfare suit, the needles were 2.2 cm long.

The first commercial autoinjector to contain epinephrine was made by Survival Technology (Bethesda, MD) in the mid-1970s. The manufacturer considered a 2.2-cm needle to be too long, and the first commercially available epinephrine autoinjector, EpiPen, had a 1.43-cm needle for adult use.

Since then, needle lengths have ranged from 1.17 to 2.5 cm to accommodate different skin-to-muscle depths, with shorter needles for children and longer needles for obese adults.³⁸

However, the prevalence of obesity is high and continues to rise.³⁹ Obesity raises concern that the needles in epinephrine autoinjectors may be too short for the preferred intramuscular delivery, resulting in subcutaneous deposition.

A study that used computed tomography of the thigh found that 1 (2%) of 50 men and 21 (42%) of 50 women studied had a subcutaneous tissue depth greater than 1.43 cm, the needle length in EpiPen. These were not anaphylaxis patients, but the findings suggest that many patients—especially women—may be getting subcutaneous instead of intramuscular delivery with this device.⁴⁰

Another study that used ultrasonography showed that the 1.43-cm EpiPen needle was too short for 36 (31%) of 116 adults.⁴¹ Women were 6.4 times more likely than men to encounter this problem. Other risk factors include higher body mass index, short height, and thicker thighs.

Emerade, an injector with a 2.5-cm needle, is available in some European countries. A longer needle may be helpful in some cases. but we do not yet have enough data to determine the optimal needle length.

Conversely, some children may need shorter needles and may in fact be at risk of having the needle penetrate bone.⁴² The US Food and Drug Administration recently approved a shorter needle for an epinephrine autoinjector (Auvi-Q) to be used in children weighing 7.5 kg to 15 kg.

BARRIERS TO USING EPINEPHRINE AUTOINJECTORS

Many patients do not use their epinephrine autoinjector in times of anaphylaxis or do not have one with them. Common reasons cited by respondents in a survey⁴³ of 1,385 patients included the following:

They took an oral antihistamine instead (38%).

They never received a prescription for an epinephrine autoinjector (28%).

They thought their symptoms were mild and would resolve with time (13%).

They were afraid (6%). There are reports of accidental injection, typically into fingers, hands, and thumbs. Fortunately, most accidental injections do not require a hand surgeon evaluation or surgery.⁴⁴ Conservative therapy and monitoring of the injection site are sufficient in most cases.

They could not afford an epinephrine autoinjector (1%).⁴³ Mylan Pharmaceuticals infamously increased the price of its EpiPen to more than $600 for a package of 2 pens. Generic devices are available in the United States but are still too expensive for some patients and are cumbersome to carry.

However, even expensive epinephrine autoinjectors may be cost-effective. Epidemiologic studies have found that patients who did not use an epinephrine autoinjector incurred a higher burden of cost due to emergency department visits and inpatient hospitalizations.⁴⁵

As a do-it-yourself option, some resourceful patients are obtaining autoinjectors intended for insulin injection, replacing the needle, and filling the injector with epinephrine, at a cost of about $30. (The manufacturer does not endorse this off-label use of their device—www.owenmumford.com/us/patients/if-you-need-to-inject.) Least costly of all is to prescribe multidose vials of epinephrine and regular syringes and teach patients and their caregivers how to draw up the proper dose and give themselves an injection—in essence going back to what was done before 1987.

It was past its expiration date (2%).⁴³ Failure to refill the prescription is common. A California Kaiser Permanente study⁴⁶ showed that only 46% of patients refilled their epinephrine autoinjector prescription at least once, and the refill rate decreased over time: 43% at 1 to 2 year follow-up, 35% at 3 to 4 years, and 30% at 5 years or longer. Based on these data, it is imperative to educate patients regarding the importance of replacing the epinephrine autoinjector when the old one expires.

NEED FOR PATIENT EDUCATION

Even though prompt treatment with epinephrine decreases fatalities, it continues to be underused in the community. In addition, it is often prescribed without adequate training in its use and appropriate emphasis on the need to keep the device on hand at all times and to replace it in a timely manner if it is used or has expired. Physicians need to educate patients on how to avoid triggers and how to recognize symptoms of anaphylaxis whenever they prescribe an epinephrine autoinjector.

Anaphylaxis is potentially fatal but can be prevented if the trigger is identified and avoided, and death can be avoided if episodes are treated promptly.

A consensus definition of anaphylaxis has been difficult to achieve, with slight variations among international guidelines. The World Allergy Organization classifies anaphylaxis as immunologic, nonimmunologic, or idiopathic.¹ The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network highlight clinical symptoms and criteria.² The International Consensus on Food Allergy describes reactions as being immunoglobulin E (IgE)-mediated, cell-mediated, or a combination of the 2 mechanisms.³

Despite the subtle differences in these definitions, all 3 international organizations have a common recommendation for anaphylaxis: once it is diagnosed, epinephrine is the treatment of choice.

EPINEPHRINE IS THE TREATMENT OF CHOICE FOR ANAPHYLAXIS

Anaphylaxis commonly results from exposure to foods, medications, and Hymenoptera venom.⁴ Avoiding triggers is key in preventing anaphylaxis but is not always possible.

Although epinephrine is the cornerstone of the emergency treatment of anaphylaxis, many patients instead receive antihistamines and corticosteroids as initial therapy. Some take these medications on their own, and some receive them in emergency departments and outpatient clinics.⁵

Diphenhydramine, a histamine 1 receptor antagonist, is often used as a first-line medication. But diphenhydramine has a slow onset of action, taking 80 minutes after an oral dose to suppress a histamine-induced cutaneous flare by 50%, and taking 52 minutes with intramuscular administration.⁶ Corticosteroids also have a slow onset of action. These drugs cannot prevent death in anaphylaxis, a condition in which the median time to respiratory or cardiac arrest is 30 minutes after ingestion of food, 15 minutes after envenomation, and 5 minutes after iatrogenic reactions.⁷

Combination therapy with diphenhydra­mine and a histamine 2 receptor antagonist (eg, cimetidine, famotidine) is also commonly used,⁸ but this combination offers no advantage in terms of onset of action, and a Cochrane review could find no definitive evidence for or against the use of histamine 2 receptor antagonists.⁹

Because of their slow onset of action, all of these should be second-line therapies, given after epinephrine. Epinephrine is the first line of treatment because it has a maximal pharmacokinetic effect (time to maximal peak serum level) within 10 minutes of intramuscular injection into the thigh.^10,11

In addition, epinephrine acts on numerous receptors to antagonize the multiple pathologic effects of the mediators released during an anaphylactic episode. In contrast, antihistamines block only 1 mediator, while mediators other than histamine can be responsible for severe events and deaths.^12,13

It is crucial that epinephrine be given immediately, as delay has been associated with fatalities.¹⁴ In addition, guidelines recommend repeating epinephrine dosing after 5 to 15 minutes if the response to the first dose is suboptimal.^1,2 From 16% to 36% of patients may need a second dose.^15–18 Therefore, many physicians recommend that patients at risk of anaphylaxis keep not 1 but 2 epinephrine autoinjectors on hand at all times, and so say the US guidelines for the management of anaphylaxis.¹⁹

WHO SHOULD CARRY AN EPINEPHRINE AUTOINJECTOR?

All published guidelines recommend epinephrine as the drug of choice for anaphylaxis. And an epinephrine autoinjector is indicated for anyone who has experienced an anaphylactic event or is at risk of one, and these patients should carry it with them at all times. Such individuals include those with food allergy or Hymenoptera hypersensitivity.

Food allergy

The foods that most often cause anaphylaxis are peanuts, tree nuts, fish, shellfish, milk, and eggs, but any food can cause a reaction.

The prevalence of food allergy has increased over time, and treatments are limited. Some food desensitization protocols look promising but are still in the research stages. The best treatment at this time is to avoid the offending food, but there are accidental exposures.

Hymenoptera hypersensitivity

Patients who have had anaphylaxis after being stung by insects such as bees, wasps, yellow-faced hornets, white-faced hornets, yellow jackets, and fire ants should be evaluated by an allergist. Skin testing and serum IgE testing helps properly diagnose Hymenoptera hypersensitivity.

Once the diagnosis is confirmed, venom immunotherapy should be considered. Some patients choose only to carry an epinephrine autoinjector and to avoid these insects as much as possible. However, most patients also choose to receive venom immunotherapy, because 80% to 90% of those who receive this treatment for 3 to 5 years do not have a systemic reaction if they are stung again.²⁰

Regardless of whether they choose to undergo immunotherapy, sensitive patients should always carry an epinephrine autoinjector. This is also the case after treatment ends, since the therapy is not 100% effective.

In other patients who may be at increased risk, the mandate for an epinephrine autoinjector is less clear, and the decision to carry one is determined on an individual basis. Such individuals are those receiving allergen immunotherapy, with large local reactions to insect stings, with oral allergy syndrome, with mastocytosis, and with drug allergy. In these cases, the benefit vs the burden of carrying an autoinjector should be discussed with the patient.

Patients on allergen immunotherapy

National guidelines recommend that all patients who receive allergen immunotherapy be monitored in the clinic under a physician’s supervision for 30 minutes after the injection. Fortunately, life-threatening reactions occurring after 30 minutes are rare. But delayed systemic reactions can occur and may account for up to 50% of such events.²¹

Therefore, many physicians consider it prudent for patients on immunotherapy to carry an epinephrine autoinjector, but there is no consensus. A survey²² found that 13.5% of allergists did not prescribe the autoinjector for patients on immunotherapy, while 33.3% prescribed it for all their patients on immunotherapy, and the rest prescribed based on risk.

Since there are no national guidelines on epinephrine autoinjectors for patients on immunotherapy, the decision should be based on the patient’s risks and comorbidities and informed by discussion between the individual patient and his or her allergist.

Patients with large local reactions to insect stings

From 5% to 10% of patients who have large local reactions to insect stings are at risk of systemic reactions.²⁰

Patients with oral allergy syndrome

Oral allergy syndrome, also known as pollen-food allergy, causes itching and mild swelling of the mouth, lips, and throat after eating fresh fruits and vegetables. The prevalence ranges from 2% to 10% of patients with allergies.²³

A survey of allergists found that 20% of patients with oral allergy syndrome had experienced systemic symptoms.²⁴ The survey also showed that the decision to prescribe an epinephrine autoinjector to these patients was highly variable. Only about 30% of allergists recommend epinephrine autoinjectors to patients with oral allergy syndrome, while most believe that the decision should be based on the individual’s symptoms and risk.

More research is needed in the area of food allergy. Because data are limited, there are no national guidelines on whether these patients should carry an epinephrine autoinjector. We agree with the Joint Task Force on Practice Parameters¹⁴ recommendation that the decision be made on an individual basis following discussion between the patient and physician. 

Patients with mastocytosis

Patients with mastocytosis and a history of anaphylaxis are at increased risk for systemic reactions to Hymenoptera venom.

Patients with medication allergy

Once medication allergy has been diagnosed, avoidance is usually effective, obviating the need for an epinephrine autoinjector, although the physician has the option of prescribing one.

CAUTIONS, NOT CONTRAINDICATIONS

Physicians may be reluctant to prescribe an epinephrine autoinjector because of the risk of an adverse reaction in patients with hypertension, coronary artery disease, or arrhythmias, and in elderly patients taking multiple drugs, especially drugs that can interact with epinephrine. Nevertheless, there is no absolute contraindication to the use of epinephrine in anaphylaxis.

In patients with atherosclerosis and cardiovascular disease

Epinephrine increases vasoconstriction, heart rate, and cardiac force of contraction. These effects are beneficial during anaphylaxis, but in rare cases patients have experienced myocardial infarction and acute coronary syndrome after receiving intravenous epinephrine.²⁵ These incidents have naturally prompted reluctance to prescribe it in susceptible patients with coronary disease during anaphylaxis.

Yet epinephrine may not be solely to blame for these adverse responses. Mast cells are abundant in the heart, and their release of mediators can also result in adverse cardiac manifestations, including myocardial infarction.²⁶

Conversely, some drugs used to treat cardiovascular disease can worsen anaphylaxis.

Beta-blockers can cause bronchospasm and decrease cardiac contractility. They can also blunt the pharmacologic effects of epinephrine. There is concern that epinephrine may produce dangerous elevations of blood pressure in patients taking beta-blockers by unopposed alpha-adrenergic stimulation and reflex vagotonic effects.²⁷ And there is evidence that beta-blockers may increase the risk and severity of reactions. One study reported that patients taking beta-blockers are more than 8 times more likely to be hospitalized due to anaphylactoid reaction with bronchospasm.²⁸

Beta-blockers and, to a lesser extent, angiotensin-converting enzyme inhibitors have been shown to increase the risk of anaphylaxis in the emergency department.^29,30 However, some investigators have not found beta-blockers to be a risk factor. A study evaluating anaphylactoid reactions from contrast media found no statistically significant higher risk in patients taking beta-blockers.³¹ Similarly, a study of 3,178 patients on beta-blockers receiving venom immunotherapy or allergen immunotherapy found no increase in the frequency of systemic reactions.³² Nevertheless, overall, more studies support the hypothesis that beta-blockers may be an additional risk factor in anaphylaxis.³³

Thus, clinicians treating patients with cardiovascular disease and anaphylaxis face a dilemma. Although there is concern in this population, epinephrine should not be withheld in patients with cardiovascular disease who are experiencing an anaphylactic event.³³ If epinephrine is not administered, the patient could die.

Elderly patients on multiple medications

Older patients are also at risk of anaphylaxis. But clinicians are reluctant to treat older patients with epinephrine because of concerns about adverse effects.

Epinephrine dispensing rates vary substantially in different age groups: 1.44% for patients under age 17, 0.9% for those ages 17 to 64, and 0.32% for those age 65 or older.³⁴ A Canadian study of 492 patients with anaphylaxis in the emergency department showed that those over age 50 received epinephrine less often than younger patients (36.1% vs 60.5%).³⁵ Cardiovascular complications were more frequent in the older group, occurring in 4 (9.1%) of the 44 older patients who received epinephrine compared with 1 (0.4%) of the 225 younger patients who received it. On the other hand, the rate of adverse effects from subcutaneous epinephrine was no different in older asthma patients compared with younger patients.³⁶

Many older patients take multiple medications, raising concern about adverse effects. Commonly prescribed medications in the elderly can affect the actions of epinephrine. Monoamine oxidase inhibitors retard the catabolism of epinephrine. Tricyclic antidepressants may decrease the reuptake of catecholamines by neurons and thus interfere with the degradation of epinephrine. Digoxin has a narrow therapeutic window and can potentially increase the risk of arrhythmias when given with epinephrine.

Although the clinician must be cautious in treating older patients who have comorbidities, these are not sufficient to withhold prescribing an epinephrine autoinjector to elderly patients at risk of anaphylaxis.

Epinephrine autoinjectors come preloaded for prompt delivery of the drug. They are intended primarily for use by patients themselves in unsupervised settings in suspected anaphylaxis. Simplicity of use and safety must be considered in such a setting so that patients can use the device correctly and are not incorrectly dosed.

Several models are commercially available, with different ergonomic designs and sizes. EpiPen, the first one marketed in the United States, was introduced in 1987. One device (Auvi-Q) contains an audio chip that gives step-by-step instructions at the time of use. It is hoped that this device will reduce errors in usage during this stressful time for patients and caregivers.

In the United States, epinephrine autoinjectors contain either 0.15 or 0.30 mg of the drug, but some clinicians believe this may not be enough. The UK Resuscitation Council recommends 0.50 mg for patients over age 12,³⁷ and an epinephrine autoinjector with that dose is available in Europe.

Subcutaneous vs intramuscular delivery

The package insert for some epinephrine autoinjectors says the injector can be used to treat anaphylaxis by both subcutaneous and intramuscular administration. However, the routes are not equivalent.

The goal in anaphylaxis is to quickly achieve high tissue and plasma epinephrine concentrations, and studies have found that injection into the vastus lateralis muscle, but not the deltoid muscle, results in faster time to peak plasma concentration: 8 minutes for injection in the vastus lateralis muscle and 34 minutes for subcutaneous delivery.^10,11 In addition, injection in the vastus lateralis muscle results in a higher peak plasma concentration than the subcutaneous or deltoid route. Based on these data, intramuscular injection into the vastus lateralis muscle in the thigh appears to be the preferred route of administration of epinephrine.

Obese patients may need a longer needle

Research on the original autoinjector was conducted by the US military, which wanted a rapidly effective and easy-to-use antidote for battlefield exposure to poison gas. The resulting device had 2 separate spring-loaded syringes, 1 containing pralidoxime chloride and the other atropine sulfate. To enable its use through the thick fabric of a chemical warfare suit, the needles were 2.2 cm long.

The first commercial autoinjector to contain epinephrine was made by Survival Technology (Bethesda, MD) in the mid-1970s. The manufacturer considered a 2.2-cm needle to be too long, and the first commercially available epinephrine autoinjector, EpiPen, had a 1.43-cm needle for adult use.

Since then, needle lengths have ranged from 1.17 to 2.5 cm to accommodate different skin-to-muscle depths, with shorter needles for children and longer needles for obese adults.³⁸

However, the prevalence of obesity is high and continues to rise.³⁹ Obesity raises concern that the needles in epinephrine autoinjectors may be too short for the preferred intramuscular delivery, resulting in subcutaneous deposition.

A study that used computed tomography of the thigh found that 1 (2%) of 50 men and 21 (42%) of 50 women studied had a subcutaneous tissue depth greater than 1.43 cm, the needle length in EpiPen. These were not anaphylaxis patients, but the findings suggest that many patients—especially women—may be getting subcutaneous instead of intramuscular delivery with this device.⁴⁰

Another study that used ultrasonography showed that the 1.43-cm EpiPen needle was too short for 36 (31%) of 116 adults.⁴¹ Women were 6.4 times more likely than men to encounter this problem. Other risk factors include higher body mass index, short height, and thicker thighs.

Emerade, an injector with a 2.5-cm needle, is available in some European countries. A longer needle may be helpful in some cases. but we do not yet have enough data to determine the optimal needle length.

Conversely, some children may need shorter needles and may in fact be at risk of having the needle penetrate bone.⁴² The US Food and Drug Administration recently approved a shorter needle for an epinephrine autoinjector (Auvi-Q) to be used in children weighing 7.5 kg to 15 kg.

BARRIERS TO USING EPINEPHRINE AUTOINJECTORS

Many patients do not use their epinephrine autoinjector in times of anaphylaxis or do not have one with them. Common reasons cited by respondents in a survey⁴³ of 1,385 patients included the following:

They took an oral antihistamine instead (38%).

They never received a prescription for an epinephrine autoinjector (28%).

They thought their symptoms were mild and would resolve with time (13%).

They were afraid (6%). There are reports of accidental injection, typically into fingers, hands, and thumbs. Fortunately, most accidental injections do not require a hand surgeon evaluation or surgery.⁴⁴ Conservative therapy and monitoring of the injection site are sufficient in most cases.

They could not afford an epinephrine autoinjector (1%).⁴³ Mylan Pharmaceuticals infamously increased the price of its EpiPen to more than $600 for a package of 2 pens. Generic devices are available in the United States but are still too expensive for some patients and are cumbersome to carry.

However, even expensive epinephrine autoinjectors may be cost-effective. Epidemiologic studies have found that patients who did not use an epinephrine autoinjector incurred a higher burden of cost due to emergency department visits and inpatient hospitalizations.⁴⁵

As a do-it-yourself option, some resourceful patients are obtaining autoinjectors intended for insulin injection, replacing the needle, and filling the injector with epinephrine, at a cost of about $30. (The manufacturer does not endorse this off-label use of their device—www.owenmumford.com/us/patients/if-you-need-to-inject.) Least costly of all is to prescribe multidose vials of epinephrine and regular syringes and teach patients and their caregivers how to draw up the proper dose and give themselves an injection—in essence going back to what was done before 1987.

It was past its expiration date (2%).⁴³ Failure to refill the prescription is common. A California Kaiser Permanente study⁴⁶ showed that only 46% of patients refilled their epinephrine autoinjector prescription at least once, and the refill rate decreased over time: 43% at 1 to 2 year follow-up, 35% at 3 to 4 years, and 30% at 5 years or longer. Based on these data, it is imperative to educate patients regarding the importance of replacing the epinephrine autoinjector when the old one expires.

NEED FOR PATIENT EDUCATION

Even though prompt treatment with epinephrine decreases fatalities, it continues to be underused in the community. In addition, it is often prescribed without adequate training in its use and appropriate emphasis on the need to keep the device on hand at all times and to replace it in a timely manner if it is used or has expired. Physicians need to educate patients on how to avoid triggers and how to recognize symptoms of anaphylaxis whenever they prescribe an epinephrine autoinjector.

Anaphylaxis is potentially fatal but can be prevented if the trigger is identified and avoided, and death can be avoided if episodes are treated promptly.

A consensus definition of anaphylaxis has been difficult to achieve, with slight variations among international guidelines. The World Allergy Organization classifies anaphylaxis as immunologic, nonimmunologic, or idiopathic.¹ The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network highlight clinical symptoms and criteria.² The International Consensus on Food Allergy describes reactions as being immunoglobulin E (IgE)-mediated, cell-mediated, or a combination of the 2 mechanisms.³

Despite the subtle differences in these definitions, all 3 international organizations have a common recommendation for anaphylaxis: once it is diagnosed, epinephrine is the treatment of choice.

EPINEPHRINE IS THE TREATMENT OF CHOICE FOR ANAPHYLAXIS

Anaphylaxis commonly results from exposure to foods, medications, and Hymenoptera venom.⁴ Avoiding triggers is key in preventing anaphylaxis but is not always possible.

Although epinephrine is the cornerstone of the emergency treatment of anaphylaxis, many patients instead receive antihistamines and corticosteroids as initial therapy. Some take these medications on their own, and some receive them in emergency departments and outpatient clinics.⁵

Diphenhydramine, a histamine 1 receptor antagonist, is often used as a first-line medication. But diphenhydramine has a slow onset of action, taking 80 minutes after an oral dose to suppress a histamine-induced cutaneous flare by 50%, and taking 52 minutes with intramuscular administration.⁶ Corticosteroids also have a slow onset of action. These drugs cannot prevent death in anaphylaxis, a condition in which the median time to respiratory or cardiac arrest is 30 minutes after ingestion of food, 15 minutes after envenomation, and 5 minutes after iatrogenic reactions.⁷

Combination therapy with diphenhydra­mine and a histamine 2 receptor antagonist (eg, cimetidine, famotidine) is also commonly used,⁸ but this combination offers no advantage in terms of onset of action, and a Cochrane review could find no definitive evidence for or against the use of histamine 2 receptor antagonists.⁹

Because of their slow onset of action, all of these should be second-line therapies, given after epinephrine. Epinephrine is the first line of treatment because it has a maximal pharmacokinetic effect (time to maximal peak serum level) within 10 minutes of intramuscular injection into the thigh.^10,11

In addition, epinephrine acts on numerous receptors to antagonize the multiple pathologic effects of the mediators released during an anaphylactic episode. In contrast, antihistamines block only 1 mediator, while mediators other than histamine can be responsible for severe events and deaths.^12,13

It is crucial that epinephrine be given immediately, as delay has been associated with fatalities.¹⁴ In addition, guidelines recommend repeating epinephrine dosing after 5 to 15 minutes if the response to the first dose is suboptimal.^1,2 From 16% to 36% of patients may need a second dose.^15–18 Therefore, many physicians recommend that patients at risk of anaphylaxis keep not 1 but 2 epinephrine autoinjectors on hand at all times, and so say the US guidelines for the management of anaphylaxis.¹⁹

WHO SHOULD CARRY AN EPINEPHRINE AUTOINJECTOR?

All published guidelines recommend epinephrine as the drug of choice for anaphylaxis. And an epinephrine autoinjector is indicated for anyone who has experienced an anaphylactic event or is at risk of one, and these patients should carry it with them at all times. Such individuals include those with food allergy or Hymenoptera hypersensitivity.

Food allergy

The foods that most often cause anaphylaxis are peanuts, tree nuts, fish, shellfish, milk, and eggs, but any food can cause a reaction.

The prevalence of food allergy has increased over time, and treatments are limited. Some food desensitization protocols look promising but are still in the research stages. The best treatment at this time is to avoid the offending food, but there are accidental exposures.

Hymenoptera hypersensitivity

Patients who have had anaphylaxis after being stung by insects such as bees, wasps, yellow-faced hornets, white-faced hornets, yellow jackets, and fire ants should be evaluated by an allergist. Skin testing and serum IgE testing helps properly diagnose Hymenoptera hypersensitivity.

Once the diagnosis is confirmed, venom immunotherapy should be considered. Some patients choose only to carry an epinephrine autoinjector and to avoid these insects as much as possible. However, most patients also choose to receive venom immunotherapy, because 80% to 90% of those who receive this treatment for 3 to 5 years do not have a systemic reaction if they are stung again.²⁰

Regardless of whether they choose to undergo immunotherapy, sensitive patients should always carry an epinephrine autoinjector. This is also the case after treatment ends, since the therapy is not 100% effective.

In other patients who may be at increased risk, the mandate for an epinephrine autoinjector is less clear, and the decision to carry one is determined on an individual basis. Such individuals are those receiving allergen immunotherapy, with large local reactions to insect stings, with oral allergy syndrome, with mastocytosis, and with drug allergy. In these cases, the benefit vs the burden of carrying an autoinjector should be discussed with the patient.

Patients on allergen immunotherapy

National guidelines recommend that all patients who receive allergen immunotherapy be monitored in the clinic under a physician’s supervision for 30 minutes after the injection. Fortunately, life-threatening reactions occurring after 30 minutes are rare. But delayed systemic reactions can occur and may account for up to 50% of such events.²¹

Therefore, many physicians consider it prudent for patients on immunotherapy to carry an epinephrine autoinjector, but there is no consensus. A survey²² found that 13.5% of allergists did not prescribe the autoinjector for patients on immunotherapy, while 33.3% prescribed it for all their patients on immunotherapy, and the rest prescribed based on risk.

Since there are no national guidelines on epinephrine autoinjectors for patients on immunotherapy, the decision should be based on the patient’s risks and comorbidities and informed by discussion between the individual patient and his or her allergist.

Patients with large local reactions to insect stings

From 5% to 10% of patients who have large local reactions to insect stings are at risk of systemic reactions.²⁰

Patients with oral allergy syndrome

Oral allergy syndrome, also known as pollen-food allergy, causes itching and mild swelling of the mouth, lips, and throat after eating fresh fruits and vegetables. The prevalence ranges from 2% to 10% of patients with allergies.²³

A survey of allergists found that 20% of patients with oral allergy syndrome had experienced systemic symptoms.²⁴ The survey also showed that the decision to prescribe an epinephrine autoinjector to these patients was highly variable. Only about 30% of allergists recommend epinephrine autoinjectors to patients with oral allergy syndrome, while most believe that the decision should be based on the individual’s symptoms and risk.

More research is needed in the area of food allergy. Because data are limited, there are no national guidelines on whether these patients should carry an epinephrine autoinjector. We agree with the Joint Task Force on Practice Parameters¹⁴ recommendation that the decision be made on an individual basis following discussion between the patient and physician. 

Patients with mastocytosis

Patients with mastocytosis and a history of anaphylaxis are at increased risk for systemic reactions to Hymenoptera venom.

Patients with medication allergy

Once medication allergy has been diagnosed, avoidance is usually effective, obviating the need for an epinephrine autoinjector, although the physician has the option of prescribing one.

CAUTIONS, NOT CONTRAINDICATIONS

Physicians may be reluctant to prescribe an epinephrine autoinjector because of the risk of an adverse reaction in patients with hypertension, coronary artery disease, or arrhythmias, and in elderly patients taking multiple drugs, especially drugs that can interact with epinephrine. Nevertheless, there is no absolute contraindication to the use of epinephrine in anaphylaxis.

In patients with atherosclerosis and cardiovascular disease

Epinephrine increases vasoconstriction, heart rate, and cardiac force of contraction. These effects are beneficial during anaphylaxis, but in rare cases patients have experienced myocardial infarction and acute coronary syndrome after receiving intravenous epinephrine.²⁵ These incidents have naturally prompted reluctance to prescribe it in susceptible patients with coronary disease during anaphylaxis.

Yet epinephrine may not be solely to blame for these adverse responses. Mast cells are abundant in the heart, and their release of mediators can also result in adverse cardiac manifestations, including myocardial infarction.²⁶

Conversely, some drugs used to treat cardiovascular disease can worsen anaphylaxis.

Beta-blockers can cause bronchospasm and decrease cardiac contractility. They can also blunt the pharmacologic effects of epinephrine. There is concern that epinephrine may produce dangerous elevations of blood pressure in patients taking beta-blockers by unopposed alpha-adrenergic stimulation and reflex vagotonic effects.²⁷ And there is evidence that beta-blockers may increase the risk and severity of reactions. One study reported that patients taking beta-blockers are more than 8 times more likely to be hospitalized due to anaphylactoid reaction with bronchospasm.²⁸

Beta-blockers and, to a lesser extent, angiotensin-converting enzyme inhibitors have been shown to increase the risk of anaphylaxis in the emergency department.^29,30 However, some investigators have not found beta-blockers to be a risk factor. A study evaluating anaphylactoid reactions from contrast media found no statistically significant higher risk in patients taking beta-blockers.³¹ Similarly, a study of 3,178 patients on beta-blockers receiving venom immunotherapy or allergen immunotherapy found no increase in the frequency of systemic reactions.³² Nevertheless, overall, more studies support the hypothesis that beta-blockers may be an additional risk factor in anaphylaxis.³³

Thus, clinicians treating patients with cardiovascular disease and anaphylaxis face a dilemma. Although there is concern in this population, epinephrine should not be withheld in patients with cardiovascular disease who are experiencing an anaphylactic event.³³ If epinephrine is not administered, the patient could die.

Elderly patients on multiple medications

Older patients are also at risk of anaphylaxis. But clinicians are reluctant to treat older patients with epinephrine because of concerns about adverse effects.

Epinephrine dispensing rates vary substantially in different age groups: 1.44% for patients under age 17, 0.9% for those ages 17 to 64, and 0.32% for those age 65 or older.³⁴ A Canadian study of 492 patients with anaphylaxis in the emergency department showed that those over age 50 received epinephrine less often than younger patients (36.1% vs 60.5%).³⁵ Cardiovascular complications were more frequent in the older group, occurring in 4 (9.1%) of the 44 older patients who received epinephrine compared with 1 (0.4%) of the 225 younger patients who received it. On the other hand, the rate of adverse effects from subcutaneous epinephrine was no different in older asthma patients compared with younger patients.³⁶

Many older patients take multiple medications, raising concern about adverse effects. Commonly prescribed medications in the elderly can affect the actions of epinephrine. Monoamine oxidase inhibitors retard the catabolism of epinephrine. Tricyclic antidepressants may decrease the reuptake of catecholamines by neurons and thus interfere with the degradation of epinephrine. Digoxin has a narrow therapeutic window and can potentially increase the risk of arrhythmias when given with epinephrine.

Although the clinician must be cautious in treating older patients who have comorbidities, these are not sufficient to withhold prescribing an epinephrine autoinjector to elderly patients at risk of anaphylaxis.

Epinephrine autoinjectors come preloaded for prompt delivery of the drug. They are intended primarily for use by patients themselves in unsupervised settings in suspected anaphylaxis. Simplicity of use and safety must be considered in such a setting so that patients can use the device correctly and are not incorrectly dosed.

Several models are commercially available, with different ergonomic designs and sizes. EpiPen, the first one marketed in the United States, was introduced in 1987. One device (Auvi-Q) contains an audio chip that gives step-by-step instructions at the time of use. It is hoped that this device will reduce errors in usage during this stressful time for patients and caregivers.

In the United States, epinephrine autoinjectors contain either 0.15 or 0.30 mg of the drug, but some clinicians believe this may not be enough. The UK Resuscitation Council recommends 0.50 mg for patients over age 12,³⁷ and an epinephrine autoinjector with that dose is available in Europe.

Subcutaneous vs intramuscular delivery

The package insert for some epinephrine autoinjectors says the injector can be used to treat anaphylaxis by both subcutaneous and intramuscular administration. However, the routes are not equivalent.

The goal in anaphylaxis is to quickly achieve high tissue and plasma epinephrine concentrations, and studies have found that injection into the vastus lateralis muscle, but not the deltoid muscle, results in faster time to peak plasma concentration: 8 minutes for injection in the vastus lateralis muscle and 34 minutes for subcutaneous delivery.^10,11 In addition, injection in the vastus lateralis muscle results in a higher peak plasma concentration than the subcutaneous or deltoid route. Based on these data, intramuscular injection into the vastus lateralis muscle in the thigh appears to be the preferred route of administration of epinephrine.

Obese patients may need a longer needle

Research on the original autoinjector was conducted by the US military, which wanted a rapidly effective and easy-to-use antidote for battlefield exposure to poison gas. The resulting device had 2 separate spring-loaded syringes, 1 containing pralidoxime chloride and the other atropine sulfate. To enable its use through the thick fabric of a chemical warfare suit, the needles were 2.2 cm long.

The first commercial autoinjector to contain epinephrine was made by Survival Technology (Bethesda, MD) in the mid-1970s. The manufacturer considered a 2.2-cm needle to be too long, and the first commercially available epinephrine autoinjector, EpiPen, had a 1.43-cm needle for adult use.

Since then, needle lengths have ranged from 1.17 to 2.5 cm to accommodate different skin-to-muscle depths, with shorter needles for children and longer needles for obese adults.³⁸

However, the prevalence of obesity is high and continues to rise.³⁹ Obesity raises concern that the needles in epinephrine autoinjectors may be too short for the preferred intramuscular delivery, resulting in subcutaneous deposition.

A study that used computed tomography of the thigh found that 1 (2%) of 50 men and 21 (42%) of 50 women studied had a subcutaneous tissue depth greater than 1.43 cm, the needle length in EpiPen. These were not anaphylaxis patients, but the findings suggest that many patients—especially women—may be getting subcutaneous instead of intramuscular delivery with this device.⁴⁰

Another study that used ultrasonography showed that the 1.43-cm EpiPen needle was too short for 36 (31%) of 116 adults.⁴¹ Women were 6.4 times more likely than men to encounter this problem. Other risk factors include higher body mass index, short height, and thicker thighs.

Emerade, an injector with a 2.5-cm needle, is available in some European countries. A longer needle may be helpful in some cases. but we do not yet have enough data to determine the optimal needle length.

Conversely, some children may need shorter needles and may in fact be at risk of having the needle penetrate bone.⁴² The US Food and Drug Administration recently approved a shorter needle for an epinephrine autoinjector (Auvi-Q) to be used in children weighing 7.5 kg to 15 kg.

BARRIERS TO USING EPINEPHRINE AUTOINJECTORS

Many patients do not use their epinephrine autoinjector in times of anaphylaxis or do not have one with them. Common reasons cited by respondents in a survey⁴³ of 1,385 patients included the following:

They took an oral antihistamine instead (38%).

They never received a prescription for an epinephrine autoinjector (28%).

They thought their symptoms were mild and would resolve with time (13%).

They were afraid (6%). There are reports of accidental injection, typically into fingers, hands, and thumbs. Fortunately, most accidental injections do not require a hand surgeon evaluation or surgery.⁴⁴ Conservative therapy and monitoring of the injection site are sufficient in most cases.

They could not afford an epinephrine autoinjector (1%).⁴³ Mylan Pharmaceuticals infamously increased the price of its EpiPen to more than $600 for a package of 2 pens. Generic devices are available in the United States but are still too expensive for some patients and are cumbersome to carry.

However, even expensive epinephrine autoinjectors may be cost-effective. Epidemiologic studies have found that patients who did not use an epinephrine autoinjector incurred a higher burden of cost due to emergency department visits and inpatient hospitalizations.⁴⁵

As a do-it-yourself option, some resourceful patients are obtaining autoinjectors intended for insulin injection, replacing the needle, and filling the injector with epinephrine, at a cost of about $30. (The manufacturer does not endorse this off-label use of their device—www.owenmumford.com/us/patients/if-you-need-to-inject.) Least costly of all is to prescribe multidose vials of epinephrine and regular syringes and teach patients and their caregivers how to draw up the proper dose and give themselves an injection—in essence going back to what was done before 1987.

It was past its expiration date (2%).⁴³ Failure to refill the prescription is common. A California Kaiser Permanente study⁴⁶ showed that only 46% of patients refilled their epinephrine autoinjector prescription at least once, and the refill rate decreased over time: 43% at 1 to 2 year follow-up, 35% at 3 to 4 years, and 30% at 5 years or longer. Based on these data, it is imperative to educate patients regarding the importance of replacing the epinephrine autoinjector when the old one expires.

NEED FOR PATIENT EDUCATION

Even though prompt treatment with epinephrine decreases fatalities, it continues to be underused in the community. In addition, it is often prescribed without adequate training in its use and appropriate emphasis on the need to keep the device on hand at all times and to replace it in a timely manner if it is used or has expired. Physicians need to educate patients on how to avoid triggers and how to recognize symptoms of anaphylaxis whenever they prescribe an epinephrine autoinjector.