Ankylosing spondylitis

Patients with active ankylosing spondylitis (AS) experienced rapid clinical response to the oral Janus kinase (JAK) inhibitor tofacitinib (Xeljanz) in a phase 3, randomized, double-blind, placebo-controlled study.

Tofacitinib was significantly more effective than was placebo at primary and secondary endpoints. Adverse events were more frequent with tofacitinib than with placebo, but there were no new safety risks.

Results were presented at the virtual annual meeting of the American College of Rheumatology by Atul Deodhar, MD, medical director of rheumatology clinics at Oregon Health and Science University, Portland.

At week 16, 56.4% of patients who received tofacitinib met ASAS20 criteria (Assessment of Ankylosing Spondylitis, a validated measure of 20% improvement), compared with 29.4% in the placebo group (P < .0001). The percentage of ASAS40 responders at week 16 was also significantly greater with tofacitinib (40.6%) than placebo (12.5%) (P < .0001).

The trial, sponsored by Pfizer, enrolled 269 adults with active AS who had a poor response to or were intolerant of at least two NSAIDs. Most in the active treatment and placebo groups were men (about 85%); the average age was 41 years. Most (77%) had no prior exposure to biologic disease-modifying antirheumatic drugs.

“Symptom duration was about 13 years,” Dr. Deodhar said.

In the 4-month double-blind phase, patients were randomly assigned in a 1:1 ratio to receive either tofacitinib 5 mg twice a day or placebo. After 16 weeks, all patients received open-label tofacitinib until week 48.

Safety was a secondary endpoint, Dr. Deodhar said.

In the tofacitinib group, 72 patients (54.1%) experienced adverse events (AEs), compared with 70 patients in the placebo group (51.5%). Two patients in the treatment group experienced severe AEs; none in the placebo group did so. In the treatment group, three patients left the trial because of AEs; in the placebo group, one patient did so.

The most common AEs were upper respiratory tract infection and nasopharyngitis.

“There were no unexpected side effects in this study,” Dr. Deodhar said. He noted that the risks were similar to known risks for those taking the drug for rheumatoid arthritis and psoriatic arthritis.

With tofacitinib there were no deaths, thromboembolic events, malignancies, major cardiac events, or gastrointestinal perforation. By week 48, three patients in the tofacitinib group had nonserious herpes zoster versus one in the placebo group.

“There’s a lot of hand-wringing” about why a JAK inhibitor would be effective for AS, inasmuch as it does not target the tumor necrosis factor [TNF] pathway or interleukin-17,” Dr. Deodhar said.

“Somehow, JAK inhibitor drugs are downstream, affecting several cytokines that we know are important in the pathogenesis and the phenotypic expression of the disease,” he said.

Sonali Khandelwal, MD, of Rush University, Chicago, who did not take part in the research, said in an interview that tofacitinib holds promise as a much-needed option.

“JAK inhibitors have been used with success in RA, and it is reassuring to see these phase 3 data for AS,” especially for those patients whose disease was not well controlled with other approved agents, she said.

She added that oral administration is a plus for patients.

“AS, like all other chronic rheumatologic conditions, has no cure,” Dr. Khandelwal noted. “The advent of biologics has changed the course of these conditions, but not one drug works for everyone.”

She said it would be helpful if future trials were to compare the safety and efficacy of tofacitinib with those of biologics that have already been approved for AS, such as anti-TNF agents and IL-17 antagonists.

The study was sponsored by Pfizer. Dr. Deodhar reported relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB. Dr. Khandelwal disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with active ankylosing spondylitis (AS) experienced rapid clinical response to the oral Janus kinase (JAK) inhibitor tofacitinib (Xeljanz) in a phase 3, randomized, double-blind, placebo-controlled study.

Tofacitinib was significantly more effective than was placebo at primary and secondary endpoints. Adverse events were more frequent with tofacitinib than with placebo, but there were no new safety risks.

Results were presented at the virtual annual meeting of the American College of Rheumatology by Atul Deodhar, MD, medical director of rheumatology clinics at Oregon Health and Science University, Portland.

At week 16, 56.4% of patients who received tofacitinib met ASAS20 criteria (Assessment of Ankylosing Spondylitis, a validated measure of 20% improvement), compared with 29.4% in the placebo group (P < .0001). The percentage of ASAS40 responders at week 16 was also significantly greater with tofacitinib (40.6%) than placebo (12.5%) (P < .0001).

The trial, sponsored by Pfizer, enrolled 269 adults with active AS who had a poor response to or were intolerant of at least two NSAIDs. Most in the active treatment and placebo groups were men (about 85%); the average age was 41 years. Most (77%) had no prior exposure to biologic disease-modifying antirheumatic drugs.

“Symptom duration was about 13 years,” Dr. Deodhar said.

In the 4-month double-blind phase, patients were randomly assigned in a 1:1 ratio to receive either tofacitinib 5 mg twice a day or placebo. After 16 weeks, all patients received open-label tofacitinib until week 48.

Safety was a secondary endpoint, Dr. Deodhar said.

In the tofacitinib group, 72 patients (54.1%) experienced adverse events (AEs), compared with 70 patients in the placebo group (51.5%). Two patients in the treatment group experienced severe AEs; none in the placebo group did so. In the treatment group, three patients left the trial because of AEs; in the placebo group, one patient did so.

The most common AEs were upper respiratory tract infection and nasopharyngitis.

“There were no unexpected side effects in this study,” Dr. Deodhar said. He noted that the risks were similar to known risks for those taking the drug for rheumatoid arthritis and psoriatic arthritis.

With tofacitinib there were no deaths, thromboembolic events, malignancies, major cardiac events, or gastrointestinal perforation. By week 48, three patients in the tofacitinib group had nonserious herpes zoster versus one in the placebo group.

“There’s a lot of hand-wringing” about why a JAK inhibitor would be effective for AS, inasmuch as it does not target the tumor necrosis factor [TNF] pathway or interleukin-17,” Dr. Deodhar said.

“Somehow, JAK inhibitor drugs are downstream, affecting several cytokines that we know are important in the pathogenesis and the phenotypic expression of the disease,” he said.

Sonali Khandelwal, MD, of Rush University, Chicago, who did not take part in the research, said in an interview that tofacitinib holds promise as a much-needed option.

“JAK inhibitors have been used with success in RA, and it is reassuring to see these phase 3 data for AS,” especially for those patients whose disease was not well controlled with other approved agents, she said.

She added that oral administration is a plus for patients.

“AS, like all other chronic rheumatologic conditions, has no cure,” Dr. Khandelwal noted. “The advent of biologics has changed the course of these conditions, but not one drug works for everyone.”

She said it would be helpful if future trials were to compare the safety and efficacy of tofacitinib with those of biologics that have already been approved for AS, such as anti-TNF agents and IL-17 antagonists.

The study was sponsored by Pfizer. Dr. Deodhar reported relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB. Dr. Khandelwal disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients with active ankylosing spondylitis (AS) experienced rapid clinical response to the oral Janus kinase (JAK) inhibitor tofacitinib (Xeljanz) in a phase 3, randomized, double-blind, placebo-controlled study.

Tofacitinib was significantly more effective than was placebo at primary and secondary endpoints. Adverse events were more frequent with tofacitinib than with placebo, but there were no new safety risks.

Results were presented at the virtual annual meeting of the American College of Rheumatology by Atul Deodhar, MD, medical director of rheumatology clinics at Oregon Health and Science University, Portland.

At week 16, 56.4% of patients who received tofacitinib met ASAS20 criteria (Assessment of Ankylosing Spondylitis, a validated measure of 20% improvement), compared with 29.4% in the placebo group (P < .0001). The percentage of ASAS40 responders at week 16 was also significantly greater with tofacitinib (40.6%) than placebo (12.5%) (P < .0001).

The trial, sponsored by Pfizer, enrolled 269 adults with active AS who had a poor response to or were intolerant of at least two NSAIDs. Most in the active treatment and placebo groups were men (about 85%); the average age was 41 years. Most (77%) had no prior exposure to biologic disease-modifying antirheumatic drugs.

“Symptom duration was about 13 years,” Dr. Deodhar said.

In the 4-month double-blind phase, patients were randomly assigned in a 1:1 ratio to receive either tofacitinib 5 mg twice a day or placebo. After 16 weeks, all patients received open-label tofacitinib until week 48.

Safety was a secondary endpoint, Dr. Deodhar said.

In the tofacitinib group, 72 patients (54.1%) experienced adverse events (AEs), compared with 70 patients in the placebo group (51.5%). Two patients in the treatment group experienced severe AEs; none in the placebo group did so. In the treatment group, three patients left the trial because of AEs; in the placebo group, one patient did so.

The most common AEs were upper respiratory tract infection and nasopharyngitis.

“There were no unexpected side effects in this study,” Dr. Deodhar said. He noted that the risks were similar to known risks for those taking the drug for rheumatoid arthritis and psoriatic arthritis.

With tofacitinib there were no deaths, thromboembolic events, malignancies, major cardiac events, or gastrointestinal perforation. By week 48, three patients in the tofacitinib group had nonserious herpes zoster versus one in the placebo group.

“There’s a lot of hand-wringing” about why a JAK inhibitor would be effective for AS, inasmuch as it does not target the tumor necrosis factor [TNF] pathway or interleukin-17,” Dr. Deodhar said.

“Somehow, JAK inhibitor drugs are downstream, affecting several cytokines that we know are important in the pathogenesis and the phenotypic expression of the disease,” he said.

Sonali Khandelwal, MD, of Rush University, Chicago, who did not take part in the research, said in an interview that tofacitinib holds promise as a much-needed option.

“JAK inhibitors have been used with success in RA, and it is reassuring to see these phase 3 data for AS,” especially for those patients whose disease was not well controlled with other approved agents, she said.

She added that oral administration is a plus for patients.

“AS, like all other chronic rheumatologic conditions, has no cure,” Dr. Khandelwal noted. “The advent of biologics has changed the course of these conditions, but not one drug works for everyone.”

She said it would be helpful if future trials were to compare the safety and efficacy of tofacitinib with those of biologics that have already been approved for AS, such as anti-TNF agents and IL-17 antagonists.

The study was sponsored by Pfizer. Dr. Deodhar reported relationships with AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB. Dr. Khandelwal disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Among people with COVID-19, those with systemic autoimmune rheumatic diseases had an elevated 30-day risk of hospitalization, ICU admission, need for mechanical ventilation, and acute kidney injury, compared to a group without rheumatic diseases at 4 months in a match-controlled study.

When investigators expanded the study to 6 months, the difference in need for mechanical ventilation disappeared. However, relative risk for venous thromboembolism (VTE) emerged as 74% higher among people with COVID-19 and with rheumatic disease, said Kristin D’Silva, MD, who presented the findings during a plenary session at the virtual annual meeting of the American College of Rheumatology. She noted that rheumatic disease itself could contribute to VTE risk.

Comorbidities including hypertension, diabetes, and asthma were more common among people with systemic autoimmune rheumatic diseases (SARDs). After adjustment for comorbidities, “the risks of hospitalization and ICU admission were attenuated, suggesting comorbidities are likely key mediators of the increased risk of severe COVID-19 outcomes observed in SARDs patients versus comparators,” Dr. D’Silva, a rheumatology fellow at Massachusetts General Hospital in Boston, said in an interview.

“The risk of venous thromboembolism persisted even after adjusting for comorbidities,” Dr. D’Silva said. Patients with SARDs should be closely monitored for VTE during COVID-19 infection, she added. “Patients with significant cardiovascular, pulmonary, and metabolic comorbidities should be closely monitored for severe COVID-19.”

At the same time, a systematic review of 15 published studies revealed a low incidence of COVID-19 infection among people with rheumatic disease. Furthermore, most experienced a mild clinical course and low mortality, Akhil Sood, MD, said when presenting results of his poster at the meeting.

Underlying immunosuppression, chronic inflammation, comorbidities, and disparities based on racial, ethnic, and socioeconomic status could predispose people with rheumatic disease to poorer COVID-19 outcomes. However, the risks and outcomes of COVID-19 infection among this population “are not well understood,” said Dr. Sood, a second-year resident in internal medicine at the University of Texas Medical Branch in Galveston.

Elevated risks in match-controlled study

Dr. D’Silva and colleagues examined a COVID-19 population and compared 716 people with SARDs and another 716 people from the general public at 4 months, as well as 2,379 people each in similar groups at 6 months. They used real-time electronic medical record data from the TriNetX research network to identify ICD-10 codes for inflammatory arthritis, connective tissue diseases, and systemic vasculitis. They also used ICD-10 codes and positive PCR tests to identify people with COVID-19.

Mean age was 57 years and women accounted for 79% of both groups evaluated at 4 months. Those with SARDs were 23% more likely to be hospitalized (relative risk, 1.23; 95% confidence interval, 1.01-1.50). This group was 75% more likely to be admitted to the ICU (RR, 1.75; 95% CI, 1.11-2.75), 77% more likely to require mechanical ventilation (RR, 1.77; 95% CI, 1.06-2.96), and 83% more likely to experience acute kidney injury (RR, 1.83; 95% CI, 1.11-3.00).

Risk of death was not significantly higher in the SARDs group (RR, 1.16; 95% CI, 0.73-1.86).

When Dr. D’Silva expanded the study to more people at 6 months, they added additional 30-day outcomes of interest: renal replacement therapy, VTE, and ischemic stroke. Risk of need for renal replacement therapy, for example, was 81% higher in the SARDs group (RR, 1.81; 95% CI, 1.07-3.07). Risk of stroke was not significantly different between groups.The improvement in mechanical ventilation risk between 4 and 6 months was not completely unexpected, Dr. D’Silva said. The relative risk dropped from 1.77 to 1.05. “This is not particularly surprising given national trends in the general population reporting decreased severe outcomes of COVID-19 including mortality as the pandemic progresses. This is likely multifactorial including changes in COVID-19 management (such as increasing use of nonintubated prone positioning rather than early intubation and treatments such as dexamethasone and remdesivir), decreased strain on hospitals and staffing compared to the early crisis phase of the pandemic, and higher testing capacity leading to detection of milder cases.”

When the 6-month analysis was further adjusted for comorbidities and a history of prior hospitalization within 1 year, only risk for acute kidney injury and VTE remained significant with relative risks of 1.33 and 1.60, respectively, likely because comorbidities are causal intermediates of COVID-19 30-day outcomes rather than confounders.

When asked to comment on the results, session comoderator Victoria K. Shanmugam, MD, said in an interview that the study “is of great interest both to rheumatologists and to patients with rheumatic disease.”

The higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney injury, and heart failure “is an important finding with implications for how our patients navigate risk during this pandemic,” said Dr. Shanmugam, director of the division of rheumatology at George Washington University in Washington.
 

Lower risks emerge in systematic review

The 15 observational studies in the systematic review included 11,815 participants. A total of 179, or 1.5%, tested positive for COVID-19.

“The incidence of COVID-19 infection among patients with rheumatic disease was low,” Dr. Sood said.

Within the COVID-19-positive group, almost 50% required hospitalization, 10% required ICU admission, and 8% died. The pooled event rate for hospitalization was 0.440 (95% CI, 0.296-0.596), while for ICU admission it was 0.132 (95% CI, 0.087-0.194) and for death it was 0.125 (95% CI, 0.082-0.182).
 

Different calculations of risk

The two studies seem to offer contradictory findings, but the disparities could be explained by study design differences. For example, Dr. D’Silva’s study evaluated a population with COVID-19 and compared those with SARDs versus a matched group from the general public. Dr. Sood and colleagues assessed study populations with rheumatic disease and assessed incidence of SARS-CoV-2 infection and difference in outcomes.

“We are asking very different questions,” Dr. D’Silva said.

“The study by D’Silva et al. was able to account for different factors to reduce confounding,” Dr. Sood said, adding that Dr. D’Silva and colleagues included a high proportion of minorities, compared with a less diverse population in the systematic review, which featured a large number of studies from Italy.

The authors of the two studies had no relevant financial disclosures to report.

SOURCES: D’Silva K et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0430, and Sood A et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0008.

Among people with COVID-19, those with systemic autoimmune rheumatic diseases had an elevated 30-day risk of hospitalization, ICU admission, need for mechanical ventilation, and acute kidney injury, compared to a group without rheumatic diseases at 4 months in a match-controlled study.

When investigators expanded the study to 6 months, the difference in need for mechanical ventilation disappeared. However, relative risk for venous thromboembolism (VTE) emerged as 74% higher among people with COVID-19 and with rheumatic disease, said Kristin D’Silva, MD, who presented the findings during a plenary session at the virtual annual meeting of the American College of Rheumatology. She noted that rheumatic disease itself could contribute to VTE risk.

Comorbidities including hypertension, diabetes, and asthma were more common among people with systemic autoimmune rheumatic diseases (SARDs). After adjustment for comorbidities, “the risks of hospitalization and ICU admission were attenuated, suggesting comorbidities are likely key mediators of the increased risk of severe COVID-19 outcomes observed in SARDs patients versus comparators,” Dr. D’Silva, a rheumatology fellow at Massachusetts General Hospital in Boston, said in an interview.

“The risk of venous thromboembolism persisted even after adjusting for comorbidities,” Dr. D’Silva said. Patients with SARDs should be closely monitored for VTE during COVID-19 infection, she added. “Patients with significant cardiovascular, pulmonary, and metabolic comorbidities should be closely monitored for severe COVID-19.”

At the same time, a systematic review of 15 published studies revealed a low incidence of COVID-19 infection among people with rheumatic disease. Furthermore, most experienced a mild clinical course and low mortality, Akhil Sood, MD, said when presenting results of his poster at the meeting.

Underlying immunosuppression, chronic inflammation, comorbidities, and disparities based on racial, ethnic, and socioeconomic status could predispose people with rheumatic disease to poorer COVID-19 outcomes. However, the risks and outcomes of COVID-19 infection among this population “are not well understood,” said Dr. Sood, a second-year resident in internal medicine at the University of Texas Medical Branch in Galveston.

Elevated risks in match-controlled study

Dr. D’Silva and colleagues examined a COVID-19 population and compared 716 people with SARDs and another 716 people from the general public at 4 months, as well as 2,379 people each in similar groups at 6 months. They used real-time electronic medical record data from the TriNetX research network to identify ICD-10 codes for inflammatory arthritis, connective tissue diseases, and systemic vasculitis. They also used ICD-10 codes and positive PCR tests to identify people with COVID-19.

Mean age was 57 years and women accounted for 79% of both groups evaluated at 4 months. Those with SARDs were 23% more likely to be hospitalized (relative risk, 1.23; 95% confidence interval, 1.01-1.50). This group was 75% more likely to be admitted to the ICU (RR, 1.75; 95% CI, 1.11-2.75), 77% more likely to require mechanical ventilation (RR, 1.77; 95% CI, 1.06-2.96), and 83% more likely to experience acute kidney injury (RR, 1.83; 95% CI, 1.11-3.00).

Risk of death was not significantly higher in the SARDs group (RR, 1.16; 95% CI, 0.73-1.86).

When Dr. D’Silva expanded the study to more people at 6 months, they added additional 30-day outcomes of interest: renal replacement therapy, VTE, and ischemic stroke. Risk of need for renal replacement therapy, for example, was 81% higher in the SARDs group (RR, 1.81; 95% CI, 1.07-3.07). Risk of stroke was not significantly different between groups.The improvement in mechanical ventilation risk between 4 and 6 months was not completely unexpected, Dr. D’Silva said. The relative risk dropped from 1.77 to 1.05. “This is not particularly surprising given national trends in the general population reporting decreased severe outcomes of COVID-19 including mortality as the pandemic progresses. This is likely multifactorial including changes in COVID-19 management (such as increasing use of nonintubated prone positioning rather than early intubation and treatments such as dexamethasone and remdesivir), decreased strain on hospitals and staffing compared to the early crisis phase of the pandemic, and higher testing capacity leading to detection of milder cases.”

When the 6-month analysis was further adjusted for comorbidities and a history of prior hospitalization within 1 year, only risk for acute kidney injury and VTE remained significant with relative risks of 1.33 and 1.60, respectively, likely because comorbidities are causal intermediates of COVID-19 30-day outcomes rather than confounders.

When asked to comment on the results, session comoderator Victoria K. Shanmugam, MD, said in an interview that the study “is of great interest both to rheumatologists and to patients with rheumatic disease.”

The higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney injury, and heart failure “is an important finding with implications for how our patients navigate risk during this pandemic,” said Dr. Shanmugam, director of the division of rheumatology at George Washington University in Washington.
 

Lower risks emerge in systematic review

The 15 observational studies in the systematic review included 11,815 participants. A total of 179, or 1.5%, tested positive for COVID-19.

“The incidence of COVID-19 infection among patients with rheumatic disease was low,” Dr. Sood said.

Within the COVID-19-positive group, almost 50% required hospitalization, 10% required ICU admission, and 8% died. The pooled event rate for hospitalization was 0.440 (95% CI, 0.296-0.596), while for ICU admission it was 0.132 (95% CI, 0.087-0.194) and for death it was 0.125 (95% CI, 0.082-0.182).
 

Different calculations of risk

The two studies seem to offer contradictory findings, but the disparities could be explained by study design differences. For example, Dr. D’Silva’s study evaluated a population with COVID-19 and compared those with SARDs versus a matched group from the general public. Dr. Sood and colleagues assessed study populations with rheumatic disease and assessed incidence of SARS-CoV-2 infection and difference in outcomes.

“We are asking very different questions,” Dr. D’Silva said.

“The study by D’Silva et al. was able to account for different factors to reduce confounding,” Dr. Sood said, adding that Dr. D’Silva and colleagues included a high proportion of minorities, compared with a less diverse population in the systematic review, which featured a large number of studies from Italy.

The authors of the two studies had no relevant financial disclosures to report.

SOURCES: D’Silva K et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0430, and Sood A et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0008.

Among people with COVID-19, those with systemic autoimmune rheumatic diseases had an elevated 30-day risk of hospitalization, ICU admission, need for mechanical ventilation, and acute kidney injury, compared to a group without rheumatic diseases at 4 months in a match-controlled study.

When investigators expanded the study to 6 months, the difference in need for mechanical ventilation disappeared. However, relative risk for venous thromboembolism (VTE) emerged as 74% higher among people with COVID-19 and with rheumatic disease, said Kristin D’Silva, MD, who presented the findings during a plenary session at the virtual annual meeting of the American College of Rheumatology. She noted that rheumatic disease itself could contribute to VTE risk.

Comorbidities including hypertension, diabetes, and asthma were more common among people with systemic autoimmune rheumatic diseases (SARDs). After adjustment for comorbidities, “the risks of hospitalization and ICU admission were attenuated, suggesting comorbidities are likely key mediators of the increased risk of severe COVID-19 outcomes observed in SARDs patients versus comparators,” Dr. D’Silva, a rheumatology fellow at Massachusetts General Hospital in Boston, said in an interview.

“The risk of venous thromboembolism persisted even after adjusting for comorbidities,” Dr. D’Silva said. Patients with SARDs should be closely monitored for VTE during COVID-19 infection, she added. “Patients with significant cardiovascular, pulmonary, and metabolic comorbidities should be closely monitored for severe COVID-19.”

At the same time, a systematic review of 15 published studies revealed a low incidence of COVID-19 infection among people with rheumatic disease. Furthermore, most experienced a mild clinical course and low mortality, Akhil Sood, MD, said when presenting results of his poster at the meeting.

Underlying immunosuppression, chronic inflammation, comorbidities, and disparities based on racial, ethnic, and socioeconomic status could predispose people with rheumatic disease to poorer COVID-19 outcomes. However, the risks and outcomes of COVID-19 infection among this population “are not well understood,” said Dr. Sood, a second-year resident in internal medicine at the University of Texas Medical Branch in Galveston.

Elevated risks in match-controlled study

Dr. D’Silva and colleagues examined a COVID-19 population and compared 716 people with SARDs and another 716 people from the general public at 4 months, as well as 2,379 people each in similar groups at 6 months. They used real-time electronic medical record data from the TriNetX research network to identify ICD-10 codes for inflammatory arthritis, connective tissue diseases, and systemic vasculitis. They also used ICD-10 codes and positive PCR tests to identify people with COVID-19.

Mean age was 57 years and women accounted for 79% of both groups evaluated at 4 months. Those with SARDs were 23% more likely to be hospitalized (relative risk, 1.23; 95% confidence interval, 1.01-1.50). This group was 75% more likely to be admitted to the ICU (RR, 1.75; 95% CI, 1.11-2.75), 77% more likely to require mechanical ventilation (RR, 1.77; 95% CI, 1.06-2.96), and 83% more likely to experience acute kidney injury (RR, 1.83; 95% CI, 1.11-3.00).

Risk of death was not significantly higher in the SARDs group (RR, 1.16; 95% CI, 0.73-1.86).

When Dr. D’Silva expanded the study to more people at 6 months, they added additional 30-day outcomes of interest: renal replacement therapy, VTE, and ischemic stroke. Risk of need for renal replacement therapy, for example, was 81% higher in the SARDs group (RR, 1.81; 95% CI, 1.07-3.07). Risk of stroke was not significantly different between groups.The improvement in mechanical ventilation risk between 4 and 6 months was not completely unexpected, Dr. D’Silva said. The relative risk dropped from 1.77 to 1.05. “This is not particularly surprising given national trends in the general population reporting decreased severe outcomes of COVID-19 including mortality as the pandemic progresses. This is likely multifactorial including changes in COVID-19 management (such as increasing use of nonintubated prone positioning rather than early intubation and treatments such as dexamethasone and remdesivir), decreased strain on hospitals and staffing compared to the early crisis phase of the pandemic, and higher testing capacity leading to detection of milder cases.”

When the 6-month analysis was further adjusted for comorbidities and a history of prior hospitalization within 1 year, only risk for acute kidney injury and VTE remained significant with relative risks of 1.33 and 1.60, respectively, likely because comorbidities are causal intermediates of COVID-19 30-day outcomes rather than confounders.

When asked to comment on the results, session comoderator Victoria K. Shanmugam, MD, said in an interview that the study “is of great interest both to rheumatologists and to patients with rheumatic disease.”

The higher risk of hospitalization, ICU admission, mechanical ventilation, acute kidney injury, and heart failure “is an important finding with implications for how our patients navigate risk during this pandemic,” said Dr. Shanmugam, director of the division of rheumatology at George Washington University in Washington.
 

Lower risks emerge in systematic review

The 15 observational studies in the systematic review included 11,815 participants. A total of 179, or 1.5%, tested positive for COVID-19.

“The incidence of COVID-19 infection among patients with rheumatic disease was low,” Dr. Sood said.

Within the COVID-19-positive group, almost 50% required hospitalization, 10% required ICU admission, and 8% died. The pooled event rate for hospitalization was 0.440 (95% CI, 0.296-0.596), while for ICU admission it was 0.132 (95% CI, 0.087-0.194) and for death it was 0.125 (95% CI, 0.082-0.182).
 

Different calculations of risk

The two studies seem to offer contradictory findings, but the disparities could be explained by study design differences. For example, Dr. D’Silva’s study evaluated a population with COVID-19 and compared those with SARDs versus a matched group from the general public. Dr. Sood and colleagues assessed study populations with rheumatic disease and assessed incidence of SARS-CoV-2 infection and difference in outcomes.

“We are asking very different questions,” Dr. D’Silva said.

“The study by D’Silva et al. was able to account for different factors to reduce confounding,” Dr. Sood said, adding that Dr. D’Silva and colleagues included a high proportion of minorities, compared with a less diverse population in the systematic review, which featured a large number of studies from Italy.

The authors of the two studies had no relevant financial disclosures to report.

SOURCES: D’Silva K et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0430, and Sood A et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0008.

Fully 48% of patients with autoimmune rheumatic diseases who developed persistent hypogammaglobulinemia after initiating treatment with immunomodulatory agents harbored gene variants associated with inborn errors of immunity, according to the findings of a single-center study published in Annals of the Rheumatic Diseases.

The results raise the possibility of a shared genetic etiology between “primary” and “secondary” hypogammaglobulinemia and suggest that some cases of autoimmune rheumatic disease may result from inborn errors of immunity. “In other words, a rheumatologist may be treating the rheumatic manifestations of a primary immunodeficiency disorder,” the study’s lead author, Georgios Sogkas, MD, PhD, said in an interview.

‘Striking’ findings suggest a future in personalized medicine

Experts who were not involved in the study called the results noteworthy. “The fact that half of patients with rheumatic disease who developed secondary hypogammaglobulinemia were found to have a functionally relevant mutation in a known PID gene is striking, albeit purely circumstantial given the absence of any functional or mechanistic data,” said Michael J. Ombrello, MD, principal investigator and head of the translational genetics and genomics unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, who was not involved in the study.

The findings, if they are validated by additional studies, might help clinicians personalize medicine by avoiding hypogammaglobulinemia-inducing immunomodulatory regimens in genetically predisposed patients, or by targeting Janus kinase (JAK) inhibitor therapy for patients with STAT3 gain-of-function variants, or PI3K delta inhibitors for patients with variants leading to hyperactivation of the PI3Kdelta gene, Dr. Sogkas said.

Dr. Ombrello agreed: “Whether the hypogammaglobulinemia is classified as primary or secondary, the presence of these genetic variants in half of patients with hypogammaglobulinemia suggests an opportunity to improve clinical care. Although far off at this point, one can imagine a day where genetic data allows a rheumatologist to identify new-onset rheumatic disease patients carrying PID gene mutations and cater their therapy and monitoring accordingly.”

If further research validates these findings, they would add to a growing body of support for incorporating expanded or universal exome or genome sequencing in the care of medically complex patients, such as those with rheumatic diseases, Dr. Ombrello said. However, he cautioned that the investigators could have “overstated” the relationship in their study between secondary hypogammaglobulinemia and immunomodulatory treatment. The fact that a small group of study participants (about 7%) developed hypogammaglobulinemia after initiating immunomodulatory therapy does not confirm a causal relationship, he emphasized. Common variable immune deficiency (CVID) can develop in adults as late as the fifth and sixth decade of life, he noted, making it “not implausible that a small number of rheumatic disease patients would develop CVID while under the care of a rheumatologist. Would these patients have developed hypogammaglobulinemia even without treatment with immunomodulators, purely related to their genetic mutations? If so, they would be better classified as having primary immune deficiency, although that distinction is largely one of semantics.”

‘Rheumatologists are obliged to step up’

Interestingly, only 23% of the patients with hypogammaglobulinemia in the study had a clinically significant history of infections even though only 9% were receiving prophylactic antibiotics. Such findings highlight the complexity of PIDs, according to experts. “A long generation ago, we thought of immunodeficiencies as infections. Now we see them as autoimmune diseases, inflammatory diseases, allergic diseases – the spectrum continues to enlarge,” said Leonard H. Calabrese, DO, the RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, who was not involved in the study.

Dr. Calabrese noted that more than 450 monogenic variants have been linked to inborn errors of immunity. “Because these [PIDs] can mimic autoinflammatory presentations, rheumatologists are obliged to step up and gain a greater understanding, to be able to recognize and diagnose them and sort them out.”

Future goals should include quantifying the prevalence of genetic variants underlying hypogammaglobulinemia among patients with rheumatic diseases, and better characterizing outcomes and phenotypes of patients harboring variants linked to inborn errors of immunity, Dr. Sogkas said. “Whether these patients actually have a different disease than what they are being treated for, I can’t tell from this paper, and that’s an important question for the future,” added Dr. Calabrese. “I also do wonder about the effects of different drugs,” he said, noting that many patients with PID-associated autosomal gene variants developed persistent secondary hypogammaglobulinemia after initiating methotrexate. “It makes me wonder whether some of these genes have a specific interaction with methotrexate,” he said. “That could be a biomarker for drug toxicity.”

Study funders included the German Research Foundation, the German multiorgan Autoimmunity Network, Hannover Medical School, the Rosemarie-Germscheid Foundation, the German Academic Exchange Service, HBRS, the Center for Infection Biology, and the German Center for Infection Research. The investigators reported having no competing interests.

SOURCE: Sogkas G et al. Ann Rheum Dis. 2020 Oct 12. doi: 10.1136/annrheumdis-2020-218280.

Fully 48% of patients with autoimmune rheumatic diseases who developed persistent hypogammaglobulinemia after initiating treatment with immunomodulatory agents harbored gene variants associated with inborn errors of immunity, according to the findings of a single-center study published in Annals of the Rheumatic Diseases.

The results raise the possibility of a shared genetic etiology between “primary” and “secondary” hypogammaglobulinemia and suggest that some cases of autoimmune rheumatic disease may result from inborn errors of immunity. “In other words, a rheumatologist may be treating the rheumatic manifestations of a primary immunodeficiency disorder,” the study’s lead author, Georgios Sogkas, MD, PhD, said in an interview.

‘Striking’ findings suggest a future in personalized medicine

Experts who were not involved in the study called the results noteworthy. “The fact that half of patients with rheumatic disease who developed secondary hypogammaglobulinemia were found to have a functionally relevant mutation in a known PID gene is striking, albeit purely circumstantial given the absence of any functional or mechanistic data,” said Michael J. Ombrello, MD, principal investigator and head of the translational genetics and genomics unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, who was not involved in the study.

The findings, if they are validated by additional studies, might help clinicians personalize medicine by avoiding hypogammaglobulinemia-inducing immunomodulatory regimens in genetically predisposed patients, or by targeting Janus kinase (JAK) inhibitor therapy for patients with STAT3 gain-of-function variants, or PI3K delta inhibitors for patients with variants leading to hyperactivation of the PI3Kdelta gene, Dr. Sogkas said.

Dr. Ombrello agreed: “Whether the hypogammaglobulinemia is classified as primary or secondary, the presence of these genetic variants in half of patients with hypogammaglobulinemia suggests an opportunity to improve clinical care. Although far off at this point, one can imagine a day where genetic data allows a rheumatologist to identify new-onset rheumatic disease patients carrying PID gene mutations and cater their therapy and monitoring accordingly.”

If further research validates these findings, they would add to a growing body of support for incorporating expanded or universal exome or genome sequencing in the care of medically complex patients, such as those with rheumatic diseases, Dr. Ombrello said. However, he cautioned that the investigators could have “overstated” the relationship in their study between secondary hypogammaglobulinemia and immunomodulatory treatment. The fact that a small group of study participants (about 7%) developed hypogammaglobulinemia after initiating immunomodulatory therapy does not confirm a causal relationship, he emphasized. Common variable immune deficiency (CVID) can develop in adults as late as the fifth and sixth decade of life, he noted, making it “not implausible that a small number of rheumatic disease patients would develop CVID while under the care of a rheumatologist. Would these patients have developed hypogammaglobulinemia even without treatment with immunomodulators, purely related to their genetic mutations? If so, they would be better classified as having primary immune deficiency, although that distinction is largely one of semantics.”

‘Rheumatologists are obliged to step up’

Interestingly, only 23% of the patients with hypogammaglobulinemia in the study had a clinically significant history of infections even though only 9% were receiving prophylactic antibiotics. Such findings highlight the complexity of PIDs, according to experts. “A long generation ago, we thought of immunodeficiencies as infections. Now we see them as autoimmune diseases, inflammatory diseases, allergic diseases – the spectrum continues to enlarge,” said Leonard H. Calabrese, DO, the RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, who was not involved in the study.

Dr. Calabrese noted that more than 450 monogenic variants have been linked to inborn errors of immunity. “Because these [PIDs] can mimic autoinflammatory presentations, rheumatologists are obliged to step up and gain a greater understanding, to be able to recognize and diagnose them and sort them out.”

Future goals should include quantifying the prevalence of genetic variants underlying hypogammaglobulinemia among patients with rheumatic diseases, and better characterizing outcomes and phenotypes of patients harboring variants linked to inborn errors of immunity, Dr. Sogkas said. “Whether these patients actually have a different disease than what they are being treated for, I can’t tell from this paper, and that’s an important question for the future,” added Dr. Calabrese. “I also do wonder about the effects of different drugs,” he said, noting that many patients with PID-associated autosomal gene variants developed persistent secondary hypogammaglobulinemia after initiating methotrexate. “It makes me wonder whether some of these genes have a specific interaction with methotrexate,” he said. “That could be a biomarker for drug toxicity.”

Study funders included the German Research Foundation, the German multiorgan Autoimmunity Network, Hannover Medical School, the Rosemarie-Germscheid Foundation, the German Academic Exchange Service, HBRS, the Center for Infection Biology, and the German Center for Infection Research. The investigators reported having no competing interests.

SOURCE: Sogkas G et al. Ann Rheum Dis. 2020 Oct 12. doi: 10.1136/annrheumdis-2020-218280.

Fully 48% of patients with autoimmune rheumatic diseases who developed persistent hypogammaglobulinemia after initiating treatment with immunomodulatory agents harbored gene variants associated with inborn errors of immunity, according to the findings of a single-center study published in Annals of the Rheumatic Diseases.

The results raise the possibility of a shared genetic etiology between “primary” and “secondary” hypogammaglobulinemia and suggest that some cases of autoimmune rheumatic disease may result from inborn errors of immunity. “In other words, a rheumatologist may be treating the rheumatic manifestations of a primary immunodeficiency disorder,” the study’s lead author, Georgios Sogkas, MD, PhD, said in an interview.

‘Striking’ findings suggest a future in personalized medicine

Experts who were not involved in the study called the results noteworthy. “The fact that half of patients with rheumatic disease who developed secondary hypogammaglobulinemia were found to have a functionally relevant mutation in a known PID gene is striking, albeit purely circumstantial given the absence of any functional or mechanistic data,” said Michael J. Ombrello, MD, principal investigator and head of the translational genetics and genomics unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, who was not involved in the study.

The findings, if they are validated by additional studies, might help clinicians personalize medicine by avoiding hypogammaglobulinemia-inducing immunomodulatory regimens in genetically predisposed patients, or by targeting Janus kinase (JAK) inhibitor therapy for patients with STAT3 gain-of-function variants, or PI3K delta inhibitors for patients with variants leading to hyperactivation of the PI3Kdelta gene, Dr. Sogkas said.

Dr. Ombrello agreed: “Whether the hypogammaglobulinemia is classified as primary or secondary, the presence of these genetic variants in half of patients with hypogammaglobulinemia suggests an opportunity to improve clinical care. Although far off at this point, one can imagine a day where genetic data allows a rheumatologist to identify new-onset rheumatic disease patients carrying PID gene mutations and cater their therapy and monitoring accordingly.”

If further research validates these findings, they would add to a growing body of support for incorporating expanded or universal exome or genome sequencing in the care of medically complex patients, such as those with rheumatic diseases, Dr. Ombrello said. However, he cautioned that the investigators could have “overstated” the relationship in their study between secondary hypogammaglobulinemia and immunomodulatory treatment. The fact that a small group of study participants (about 7%) developed hypogammaglobulinemia after initiating immunomodulatory therapy does not confirm a causal relationship, he emphasized. Common variable immune deficiency (CVID) can develop in adults as late as the fifth and sixth decade of life, he noted, making it “not implausible that a small number of rheumatic disease patients would develop CVID while under the care of a rheumatologist. Would these patients have developed hypogammaglobulinemia even without treatment with immunomodulators, purely related to their genetic mutations? If so, they would be better classified as having primary immune deficiency, although that distinction is largely one of semantics.”

‘Rheumatologists are obliged to step up’

Interestingly, only 23% of the patients with hypogammaglobulinemia in the study had a clinically significant history of infections even though only 9% were receiving prophylactic antibiotics. Such findings highlight the complexity of PIDs, according to experts. “A long generation ago, we thought of immunodeficiencies as infections. Now we see them as autoimmune diseases, inflammatory diseases, allergic diseases – the spectrum continues to enlarge,” said Leonard H. Calabrese, DO, the RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, who was not involved in the study.

Dr. Calabrese noted that more than 450 monogenic variants have been linked to inborn errors of immunity. “Because these [PIDs] can mimic autoinflammatory presentations, rheumatologists are obliged to step up and gain a greater understanding, to be able to recognize and diagnose them and sort them out.”

Future goals should include quantifying the prevalence of genetic variants underlying hypogammaglobulinemia among patients with rheumatic diseases, and better characterizing outcomes and phenotypes of patients harboring variants linked to inborn errors of immunity, Dr. Sogkas said. “Whether these patients actually have a different disease than what they are being treated for, I can’t tell from this paper, and that’s an important question for the future,” added Dr. Calabrese. “I also do wonder about the effects of different drugs,” he said, noting that many patients with PID-associated autosomal gene variants developed persistent secondary hypogammaglobulinemia after initiating methotrexate. “It makes me wonder whether some of these genes have a specific interaction with methotrexate,” he said. “That could be a biomarker for drug toxicity.”

Study funders included the German Research Foundation, the German multiorgan Autoimmunity Network, Hannover Medical School, the Rosemarie-Germscheid Foundation, the German Academic Exchange Service, HBRS, the Center for Infection Biology, and the German Center for Infection Research. The investigators reported having no competing interests.

SOURCE: Sogkas G et al. Ann Rheum Dis. 2020 Oct 12. doi: 10.1136/annrheumdis-2020-218280.

Few patient characteristics of men and women with nonradiographic axial spondyloarthritis (nr-axSpA) appear to differ, yet women with the condition have a significantly lower response rate to treatment with tumor necrosis factor (TNF) inhibitors, according to results from a prospective cohort study.

Despite these similarities between the sexes, first author Regula Neuenschwander of the department of rheumatology at Zurich University Hospital and colleagues reported in Arthritis Research & Therapy that women treated with a TNF inhibitor were 81% less likely than men to have a 40% or greater improvement on Assessment of Spondyloarthritis International Society (ASAS) response criteria by 1 year. Statistically significant differences at baseline included women’s longer time to nr-axSpA diagnosis, slightly lower HLA-B27 positivity rate, higher mean baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, higher rate of current enthesitis, and lower mean body mass index (BMI).

With radiographic disease, women have been reported to more often “present with higher self-reported disease activity and functional impairment, a lower quality of life, less severe spinal radiographic changes, and more peripheral disease (arthritis and enthesitis),” whereas men more often have “objective markers of inflammation, such as elevated C-reactive protein (CRP) levels and magnetic resonance imaging (MRI) inflammation of the axial skeleton,” the researchers wrote. Radiographic disease also tends to occur more often in men, and some studies have reported men to have a greater response to TNF inhibitors. However, the current study sought to understand whether these differences between sexes exist in patients with nonradiographic disease.

The researchers included 495 patients (231 men and 264 women) with a clinical diagnosis of nr-axSpA in the Swiss Clinical Quality Management cohort during 2005-2018 who fulfilled ASAS classification criteria for axSpA and lacked definite radiographic sacroiliac joint changes according to the modified New York criteria. The radiographs were centrally digitized and independently scored in a blinded manner by a rotating group of two readers (out of six total).

Both women and men had a mean age of around 28 years at symptom onset, but women had a significantly longer diagnostic delay of 6.0 years vs. 4.7 years. Also, women were significantly less likely to be HLA-B27 positive (67.0% vs. 76.5%) and had a significantly higher mean BASDAI score at baseline (5.3 vs. 4.6). More women than men also showed signs of current enthesitis (79.6% vs. 64.0%), and women had a lower mean BMI (24.3 vs. 25.7 kg/m²). Concomitant clinically diagnosed fibromyalgia was higher in women than in men (13.1% vs. 2.7%), and when patients with fibromylagia (n = 25) were excluded the remaining differences in BASDAI were mainly because of fatigue and enthesitis, both of which occurred more often in women than in men.

A total of 163 patients without fibromyalgia started a first TNF inhibitor, and 120 had a follow-up visit at 1 year. An ASAS40 response is defined as 40% improvement in at least three of four domains on the ASAS response criteria: patient global assessment of disease activity for the past week, patient assessment of back pain over the past week, function (as assessed on the Bath Ankylosing Spondylitis Functional Index [BASFI]), and inflammation (mean of BASDAI questions 5 and 6). An ASAS40 response was achieved by 17% of women and 38% of men (odds ratio, 0.34; 95% confidence interval, 0.12-0.93), and this difference became more pronounced after adjustment for baseline differences in BASDAI, Maastricht Ankylosing Spondylitis Enthesitis Score, BMI, and diagnostic delay (OR, 0.19; 95% CI, 0.05-0.61). ASAS40 response rates were lower for patients with higher BMI but better for those with higher BASDAI levels. The researchers found comparable results when they excluded patients who stopped a TNF inhibitor because of other reasons for discontinuation and also when they counted patients who discontinued the TNF inhibitor because of remission as responders.

The sex difference in nr-axSpA patients’ treatment response to TNF inhibitors was even larger than the 56% lower odds the same group of researchers reported finding between women and men with radiographic disease in an earlier report, according to the new paper.

Given that this study and others in nr-axSpA patients have found higher remission rates to TNF inhibitor therapy in men versus women, the “current study therefore adds to available data to support the claim for future randomized controlled trials in axSpA to be sufficiently powered to detect potential sex differences,” the researchers said.

The authors acknowledged that a lack of MRI scans available for central scoring made it impossible to evaluate potential imaging misinterpretation, such as possible abnormalities mimicking mild sacroiliitis that have been reported to be more prevalent in women. It is also possible that some patients with fibromyalgia were missed because of screening for the condition by expert opinion of the treating rheumatologist “on a comorbidity questionnaire and not through fulfillment of classification criteria for fibromyalgia or via the use of a standardized fibromyalgia questionnaire,” they said.

The study was funded by the Stiftung für Rheumaforschung in Zurich. The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and by 11 pharmaceutical companies. Two study authors reported receiving consulting and/or speaking fees from some of those same companies.

[email protected]

SOURCE: Neuenschwander R et al. Arthritis Res Ther. 2020;22(1):233.

Few patient characteristics of men and women with nonradiographic axial spondyloarthritis (nr-axSpA) appear to differ, yet women with the condition have a significantly lower response rate to treatment with tumor necrosis factor (TNF) inhibitors, according to results from a prospective cohort study.

Despite these similarities between the sexes, first author Regula Neuenschwander of the department of rheumatology at Zurich University Hospital and colleagues reported in Arthritis Research & Therapy that women treated with a TNF inhibitor were 81% less likely than men to have a 40% or greater improvement on Assessment of Spondyloarthritis International Society (ASAS) response criteria by 1 year. Statistically significant differences at baseline included women’s longer time to nr-axSpA diagnosis, slightly lower HLA-B27 positivity rate, higher mean baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, higher rate of current enthesitis, and lower mean body mass index (BMI).

With radiographic disease, women have been reported to more often “present with higher self-reported disease activity and functional impairment, a lower quality of life, less severe spinal radiographic changes, and more peripheral disease (arthritis and enthesitis),” whereas men more often have “objective markers of inflammation, such as elevated C-reactive protein (CRP) levels and magnetic resonance imaging (MRI) inflammation of the axial skeleton,” the researchers wrote. Radiographic disease also tends to occur more often in men, and some studies have reported men to have a greater response to TNF inhibitors. However, the current study sought to understand whether these differences between sexes exist in patients with nonradiographic disease.

The researchers included 495 patients (231 men and 264 women) with a clinical diagnosis of nr-axSpA in the Swiss Clinical Quality Management cohort during 2005-2018 who fulfilled ASAS classification criteria for axSpA and lacked definite radiographic sacroiliac joint changes according to the modified New York criteria. The radiographs were centrally digitized and independently scored in a blinded manner by a rotating group of two readers (out of six total).

Both women and men had a mean age of around 28 years at symptom onset, but women had a significantly longer diagnostic delay of 6.0 years vs. 4.7 years. Also, women were significantly less likely to be HLA-B27 positive (67.0% vs. 76.5%) and had a significantly higher mean BASDAI score at baseline (5.3 vs. 4.6). More women than men also showed signs of current enthesitis (79.6% vs. 64.0%), and women had a lower mean BMI (24.3 vs. 25.7 kg/m²). Concomitant clinically diagnosed fibromyalgia was higher in women than in men (13.1% vs. 2.7%), and when patients with fibromylagia (n = 25) were excluded the remaining differences in BASDAI were mainly because of fatigue and enthesitis, both of which occurred more often in women than in men.

A total of 163 patients without fibromyalgia started a first TNF inhibitor, and 120 had a follow-up visit at 1 year. An ASAS40 response is defined as 40% improvement in at least three of four domains on the ASAS response criteria: patient global assessment of disease activity for the past week, patient assessment of back pain over the past week, function (as assessed on the Bath Ankylosing Spondylitis Functional Index [BASFI]), and inflammation (mean of BASDAI questions 5 and 6). An ASAS40 response was achieved by 17% of women and 38% of men (odds ratio, 0.34; 95% confidence interval, 0.12-0.93), and this difference became more pronounced after adjustment for baseline differences in BASDAI, Maastricht Ankylosing Spondylitis Enthesitis Score, BMI, and diagnostic delay (OR, 0.19; 95% CI, 0.05-0.61). ASAS40 response rates were lower for patients with higher BMI but better for those with higher BASDAI levels. The researchers found comparable results when they excluded patients who stopped a TNF inhibitor because of other reasons for discontinuation and also when they counted patients who discontinued the TNF inhibitor because of remission as responders.

The sex difference in nr-axSpA patients’ treatment response to TNF inhibitors was even larger than the 56% lower odds the same group of researchers reported finding between women and men with radiographic disease in an earlier report, according to the new paper.

Given that this study and others in nr-axSpA patients have found higher remission rates to TNF inhibitor therapy in men versus women, the “current study therefore adds to available data to support the claim for future randomized controlled trials in axSpA to be sufficiently powered to detect potential sex differences,” the researchers said.

The authors acknowledged that a lack of MRI scans available for central scoring made it impossible to evaluate potential imaging misinterpretation, such as possible abnormalities mimicking mild sacroiliitis that have been reported to be more prevalent in women. It is also possible that some patients with fibromyalgia were missed because of screening for the condition by expert opinion of the treating rheumatologist “on a comorbidity questionnaire and not through fulfillment of classification criteria for fibromyalgia or via the use of a standardized fibromyalgia questionnaire,” they said.

The study was funded by the Stiftung für Rheumaforschung in Zurich. The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and by 11 pharmaceutical companies. Two study authors reported receiving consulting and/or speaking fees from some of those same companies.

[email protected]

SOURCE: Neuenschwander R et al. Arthritis Res Ther. 2020;22(1):233.

Few patient characteristics of men and women with nonradiographic axial spondyloarthritis (nr-axSpA) appear to differ, yet women with the condition have a significantly lower response rate to treatment with tumor necrosis factor (TNF) inhibitors, according to results from a prospective cohort study.

Despite these similarities between the sexes, first author Regula Neuenschwander of the department of rheumatology at Zurich University Hospital and colleagues reported in Arthritis Research & Therapy that women treated with a TNF inhibitor were 81% less likely than men to have a 40% or greater improvement on Assessment of Spondyloarthritis International Society (ASAS) response criteria by 1 year. Statistically significant differences at baseline included women’s longer time to nr-axSpA diagnosis, slightly lower HLA-B27 positivity rate, higher mean baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, higher rate of current enthesitis, and lower mean body mass index (BMI).

With radiographic disease, women have been reported to more often “present with higher self-reported disease activity and functional impairment, a lower quality of life, less severe spinal radiographic changes, and more peripheral disease (arthritis and enthesitis),” whereas men more often have “objective markers of inflammation, such as elevated C-reactive protein (CRP) levels and magnetic resonance imaging (MRI) inflammation of the axial skeleton,” the researchers wrote. Radiographic disease also tends to occur more often in men, and some studies have reported men to have a greater response to TNF inhibitors. However, the current study sought to understand whether these differences between sexes exist in patients with nonradiographic disease.

The researchers included 495 patients (231 men and 264 women) with a clinical diagnosis of nr-axSpA in the Swiss Clinical Quality Management cohort during 2005-2018 who fulfilled ASAS classification criteria for axSpA and lacked definite radiographic sacroiliac joint changes according to the modified New York criteria. The radiographs were centrally digitized and independently scored in a blinded manner by a rotating group of two readers (out of six total).

Both women and men had a mean age of around 28 years at symptom onset, but women had a significantly longer diagnostic delay of 6.0 years vs. 4.7 years. Also, women were significantly less likely to be HLA-B27 positive (67.0% vs. 76.5%) and had a significantly higher mean BASDAI score at baseline (5.3 vs. 4.6). More women than men also showed signs of current enthesitis (79.6% vs. 64.0%), and women had a lower mean BMI (24.3 vs. 25.7 kg/m²). Concomitant clinically diagnosed fibromyalgia was higher in women than in men (13.1% vs. 2.7%), and when patients with fibromylagia (n = 25) were excluded the remaining differences in BASDAI were mainly because of fatigue and enthesitis, both of which occurred more often in women than in men.

A total of 163 patients without fibromyalgia started a first TNF inhibitor, and 120 had a follow-up visit at 1 year. An ASAS40 response is defined as 40% improvement in at least three of four domains on the ASAS response criteria: patient global assessment of disease activity for the past week, patient assessment of back pain over the past week, function (as assessed on the Bath Ankylosing Spondylitis Functional Index [BASFI]), and inflammation (mean of BASDAI questions 5 and 6). An ASAS40 response was achieved by 17% of women and 38% of men (odds ratio, 0.34; 95% confidence interval, 0.12-0.93), and this difference became more pronounced after adjustment for baseline differences in BASDAI, Maastricht Ankylosing Spondylitis Enthesitis Score, BMI, and diagnostic delay (OR, 0.19; 95% CI, 0.05-0.61). ASAS40 response rates were lower for patients with higher BMI but better for those with higher BASDAI levels. The researchers found comparable results when they excluded patients who stopped a TNF inhibitor because of other reasons for discontinuation and also when they counted patients who discontinued the TNF inhibitor because of remission as responders.

The sex difference in nr-axSpA patients’ treatment response to TNF inhibitors was even larger than the 56% lower odds the same group of researchers reported finding between women and men with radiographic disease in an earlier report, according to the new paper.

Given that this study and others in nr-axSpA patients have found higher remission rates to TNF inhibitor therapy in men versus women, the “current study therefore adds to available data to support the claim for future randomized controlled trials in axSpA to be sufficiently powered to detect potential sex differences,” the researchers said.

The authors acknowledged that a lack of MRI scans available for central scoring made it impossible to evaluate potential imaging misinterpretation, such as possible abnormalities mimicking mild sacroiliitis that have been reported to be more prevalent in women. It is also possible that some patients with fibromyalgia were missed because of screening for the condition by expert opinion of the treating rheumatologist “on a comorbidity questionnaire and not through fulfillment of classification criteria for fibromyalgia or via the use of a standardized fibromyalgia questionnaire,” they said.

The study was funded by the Stiftung für Rheumaforschung in Zurich. The Swiss Clinical Quality Management Foundation is supported by the Swiss Society of Rheumatology and by 11 pharmaceutical companies. Two study authors reported receiving consulting and/or speaking fees from some of those same companies.

[email protected]

SOURCE: Neuenschwander R et al. Arthritis Res Ther. 2020;22(1):233.

The U.S. Food and Drug Administration released new warnings Oct. 15 that most nonsteroidal anti-inflammatory agents (NSAIDs) carry an elevated risk for kidney complications in unborn children when taken around weeks 20 or later in pregnancy.

Citing newly available research, the agency states the risk of low amniotic fluid (known as oligohydramnios) can occur, which in turn can cause rare but serious kidney problems in the offspring. Pregnancy complications also can result.

The FDA action expands on earlier warnings about agents in this drug class, which the FDA previously cautioned about taking after week 30 of pregnancy because of heart-related risks.

Manufacturers of both over-the-counter and prescription NSAIDs – including ibuprofen, naproxen, diclofenac, and celecoxib – will be required to update their labeling with the new warning.

Low-dose (81-mg) aspirin is excluded from this warning.

“Low-dose aspirin may be an important treatment for some women during pregnancy and should be taken under the direction of a healthcare professional,” the agency stated in a news release.

“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, states in the release. “To this end, the agency is using its regulatory authority to inform women and their healthcare providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”

Oligohydramnios can arise quickly – in as little as 2 days – or weeks after starting regular NSAID use in this patient population. The condition usually resolves if a pregnant woman stops taking the NSAID, the agency notes.

If a health care provider believes NSAIDs are necessary between about 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and shortest duration possible, the Drug Safety Communication notes.

As a reminder, health care professionals and patients should report side effects from NSAIDs to the FDA’s MedWatch program.

A version of this article originally appeared on Medscape.com.

The U.S. Food and Drug Administration released new warnings Oct. 15 that most nonsteroidal anti-inflammatory agents (NSAIDs) carry an elevated risk for kidney complications in unborn children when taken around weeks 20 or later in pregnancy.

Citing newly available research, the agency states the risk of low amniotic fluid (known as oligohydramnios) can occur, which in turn can cause rare but serious kidney problems in the offspring. Pregnancy complications also can result.

The FDA action expands on earlier warnings about agents in this drug class, which the FDA previously cautioned about taking after week 30 of pregnancy because of heart-related risks.

Manufacturers of both over-the-counter and prescription NSAIDs – including ibuprofen, naproxen, diclofenac, and celecoxib – will be required to update their labeling with the new warning.

Low-dose (81-mg) aspirin is excluded from this warning.

“Low-dose aspirin may be an important treatment for some women during pregnancy and should be taken under the direction of a healthcare professional,” the agency stated in a news release.

“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, states in the release. “To this end, the agency is using its regulatory authority to inform women and their healthcare providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”

Oligohydramnios can arise quickly – in as little as 2 days – or weeks after starting regular NSAID use in this patient population. The condition usually resolves if a pregnant woman stops taking the NSAID, the agency notes.

If a health care provider believes NSAIDs are necessary between about 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and shortest duration possible, the Drug Safety Communication notes.

As a reminder, health care professionals and patients should report side effects from NSAIDs to the FDA’s MedWatch program.

A version of this article originally appeared on Medscape.com.

The U.S. Food and Drug Administration released new warnings Oct. 15 that most nonsteroidal anti-inflammatory agents (NSAIDs) carry an elevated risk for kidney complications in unborn children when taken around weeks 20 or later in pregnancy.

Citing newly available research, the agency states the risk of low amniotic fluid (known as oligohydramnios) can occur, which in turn can cause rare but serious kidney problems in the offspring. Pregnancy complications also can result.

The FDA action expands on earlier warnings about agents in this drug class, which the FDA previously cautioned about taking after week 30 of pregnancy because of heart-related risks.

Manufacturers of both over-the-counter and prescription NSAIDs – including ibuprofen, naproxen, diclofenac, and celecoxib – will be required to update their labeling with the new warning.

Low-dose (81-mg) aspirin is excluded from this warning.

“Low-dose aspirin may be an important treatment for some women during pregnancy and should be taken under the direction of a healthcare professional,” the agency stated in a news release.

“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, states in the release. “To this end, the agency is using its regulatory authority to inform women and their healthcare providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”

Oligohydramnios can arise quickly – in as little as 2 days – or weeks after starting regular NSAID use in this patient population. The condition usually resolves if a pregnant woman stops taking the NSAID, the agency notes.

If a health care provider believes NSAIDs are necessary between about 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and shortest duration possible, the Drug Safety Communication notes.

As a reminder, health care professionals and patients should report side effects from NSAIDs to the FDA’s MedWatch program.

A version of this article originally appeared on Medscape.com.

The adjuvanted recombinant zoster vaccine Shingrix appears to be effective in older adults with autoimmune diseases who are not receiving treatment regimens that suppress the immune system, according to a post hoc analysis of patients in two clinical trials.

jarun011/thinkstock

A two-dose regimen of Shingrix was effective in 90.5% of a subset of patients in two phase 3 clinical trials of adults who were aged at least 50 years, according to Alemnew F. Dagnew, MD, of GlaxoSmithKline and colleagues. The lowest rates of effectiveness with Shingrix, for patients aged between 70-79 years, was 84.4%, the researchers reported in Rheumatology.

The CDC recommends adults aged at least 50 years receive two doses of Shingrix to help prevent reoccurrence of herpes zoster, or Zostavax (zoster vaccine live) if adults are allergic to components of the Shingrix vaccine or have tested negative for varicella zoster virus immunity.

Dr. Dagnew and colleagues evaluated Shingrix in 983 patients who received two doses of Shingrix and 960 patients who received placebo from the ZOE-50 and ZOE-70 trials, where each dose was administered at least 2 months apart. The mean age of patients in both groups was 68.8 years in the Shingrix group and 69.4 years in the placebo group, and more than half of patients in both Shingrix (59.9%) and placebo groups (60.8%) were women. About 7% of the patients in two clinical trial had a pIMD.

At enrollment, the most common preexisting immune-mediated disorders (pIMDs) were psoriasis (215 patients taking Shingrix vs. 239 patients on placebo), spondyloarthropathy (109 patients taking Shingrix vs. 89 patients on placebo), rheumatoid arthritis (96 patients taking Shingrix vs. 94 patients on placebo), and celiac disease (41 patients taking Shingrix vs. 34 patients on placebo). Dr. Dagnew and colleagues examined the subgroup of patients with pIMDs for safety and vaccine efficacy, which was defined as not developing herpes zoster before the second dose.

Overall, the efficacy of Shingrix was 90.5% across all age groups (95% confidence interval, 73.5%-97.5%), with the group aged between 70-79 years having the lowest rate of effectiveness (95% CI, 30.8%-98.3%). The rate of severe adverse events was 14.6% in the Shingrix group and 11.7% in the placebo group between the first Shingrix dose and for up to 1 year after the second dose. The most common adverse events were infections and infestations as well as cardiac disorders. “Our data show a balance between study groups in the frequency and nature of SAEs, confirming the favorable safety profile of [Shingrix] in populations with pIMDs,” Dr. Dagnew and colleagues wrote.

The researchers acknowledged that the ZOE-50/70 studies were underpowered to detect the efficacy and safety of Shingrix in individuals with pIMDs but said that the large number of participants in the studies let them estimate efficacy and adverse events for this subgroup. They also noted there was no randomization of pIMDs at enrollment, even though pIMDs occurred at similar rates between Shingrix and placebo groups.

This study was funded by GlaxoSmithKline; the company helped with conducting and analyzing the study and also provided the costs associated with publishing it. Five authors reported being an employee of GlaxoSmithKline during the time the work was conducted, and four of the five own stock in the company. One author is now an employee of UCB. One author reported having served on the advisory boards for Merck Sharp & Dohme, GlaxoSmithKline, and Curevo.

SOURCE: Dagnew AF et al. Rheumatology. 2020 Sep 10. doi: 10.1093/rheumatology/keaa424.

The adjuvanted recombinant zoster vaccine Shingrix appears to be effective in older adults with autoimmune diseases who are not receiving treatment regimens that suppress the immune system, according to a post hoc analysis of patients in two clinical trials.

jarun011/thinkstock

A two-dose regimen of Shingrix was effective in 90.5% of a subset of patients in two phase 3 clinical trials of adults who were aged at least 50 years, according to Alemnew F. Dagnew, MD, of GlaxoSmithKline and colleagues. The lowest rates of effectiveness with Shingrix, for patients aged between 70-79 years, was 84.4%, the researchers reported in Rheumatology.

The CDC recommends adults aged at least 50 years receive two doses of Shingrix to help prevent reoccurrence of herpes zoster, or Zostavax (zoster vaccine live) if adults are allergic to components of the Shingrix vaccine or have tested negative for varicella zoster virus immunity.

Dr. Dagnew and colleagues evaluated Shingrix in 983 patients who received two doses of Shingrix and 960 patients who received placebo from the ZOE-50 and ZOE-70 trials, where each dose was administered at least 2 months apart. The mean age of patients in both groups was 68.8 years in the Shingrix group and 69.4 years in the placebo group, and more than half of patients in both Shingrix (59.9%) and placebo groups (60.8%) were women. About 7% of the patients in two clinical trial had a pIMD.

At enrollment, the most common preexisting immune-mediated disorders (pIMDs) were psoriasis (215 patients taking Shingrix vs. 239 patients on placebo), spondyloarthropathy (109 patients taking Shingrix vs. 89 patients on placebo), rheumatoid arthritis (96 patients taking Shingrix vs. 94 patients on placebo), and celiac disease (41 patients taking Shingrix vs. 34 patients on placebo). Dr. Dagnew and colleagues examined the subgroup of patients with pIMDs for safety and vaccine efficacy, which was defined as not developing herpes zoster before the second dose.

Overall, the efficacy of Shingrix was 90.5% across all age groups (95% confidence interval, 73.5%-97.5%), with the group aged between 70-79 years having the lowest rate of effectiveness (95% CI, 30.8%-98.3%). The rate of severe adverse events was 14.6% in the Shingrix group and 11.7% in the placebo group between the first Shingrix dose and for up to 1 year after the second dose. The most common adverse events were infections and infestations as well as cardiac disorders. “Our data show a balance between study groups in the frequency and nature of SAEs, confirming the favorable safety profile of [Shingrix] in populations with pIMDs,” Dr. Dagnew and colleagues wrote.

The researchers acknowledged that the ZOE-50/70 studies were underpowered to detect the efficacy and safety of Shingrix in individuals with pIMDs but said that the large number of participants in the studies let them estimate efficacy and adverse events for this subgroup. They also noted there was no randomization of pIMDs at enrollment, even though pIMDs occurred at similar rates between Shingrix and placebo groups.

This study was funded by GlaxoSmithKline; the company helped with conducting and analyzing the study and also provided the costs associated with publishing it. Five authors reported being an employee of GlaxoSmithKline during the time the work was conducted, and four of the five own stock in the company. One author is now an employee of UCB. One author reported having served on the advisory boards for Merck Sharp & Dohme, GlaxoSmithKline, and Curevo.

SOURCE: Dagnew AF et al. Rheumatology. 2020 Sep 10. doi: 10.1093/rheumatology/keaa424.

The adjuvanted recombinant zoster vaccine Shingrix appears to be effective in older adults with autoimmune diseases who are not receiving treatment regimens that suppress the immune system, according to a post hoc analysis of patients in two clinical trials.

jarun011/thinkstock

A two-dose regimen of Shingrix was effective in 90.5% of a subset of patients in two phase 3 clinical trials of adults who were aged at least 50 years, according to Alemnew F. Dagnew, MD, of GlaxoSmithKline and colleagues. The lowest rates of effectiveness with Shingrix, for patients aged between 70-79 years, was 84.4%, the researchers reported in Rheumatology.

The CDC recommends adults aged at least 50 years receive two doses of Shingrix to help prevent reoccurrence of herpes zoster, or Zostavax (zoster vaccine live) if adults are allergic to components of the Shingrix vaccine or have tested negative for varicella zoster virus immunity.

Dr. Dagnew and colleagues evaluated Shingrix in 983 patients who received two doses of Shingrix and 960 patients who received placebo from the ZOE-50 and ZOE-70 trials, where each dose was administered at least 2 months apart. The mean age of patients in both groups was 68.8 years in the Shingrix group and 69.4 years in the placebo group, and more than half of patients in both Shingrix (59.9%) and placebo groups (60.8%) were women. About 7% of the patients in two clinical trial had a pIMD.

At enrollment, the most common preexisting immune-mediated disorders (pIMDs) were psoriasis (215 patients taking Shingrix vs. 239 patients on placebo), spondyloarthropathy (109 patients taking Shingrix vs. 89 patients on placebo), rheumatoid arthritis (96 patients taking Shingrix vs. 94 patients on placebo), and celiac disease (41 patients taking Shingrix vs. 34 patients on placebo). Dr. Dagnew and colleagues examined the subgroup of patients with pIMDs for safety and vaccine efficacy, which was defined as not developing herpes zoster before the second dose.

Overall, the efficacy of Shingrix was 90.5% across all age groups (95% confidence interval, 73.5%-97.5%), with the group aged between 70-79 years having the lowest rate of effectiveness (95% CI, 30.8%-98.3%). The rate of severe adverse events was 14.6% in the Shingrix group and 11.7% in the placebo group between the first Shingrix dose and for up to 1 year after the second dose. The most common adverse events were infections and infestations as well as cardiac disorders. “Our data show a balance between study groups in the frequency and nature of SAEs, confirming the favorable safety profile of [Shingrix] in populations with pIMDs,” Dr. Dagnew and colleagues wrote.

The researchers acknowledged that the ZOE-50/70 studies were underpowered to detect the efficacy and safety of Shingrix in individuals with pIMDs but said that the large number of participants in the studies let them estimate efficacy and adverse events for this subgroup. They also noted there was no randomization of pIMDs at enrollment, even though pIMDs occurred at similar rates between Shingrix and placebo groups.

This study was funded by GlaxoSmithKline; the company helped with conducting and analyzing the study and also provided the costs associated with publishing it. Five authors reported being an employee of GlaxoSmithKline during the time the work was conducted, and four of the five own stock in the company. One author is now an employee of UCB. One author reported having served on the advisory boards for Merck Sharp & Dohme, GlaxoSmithKline, and Curevo.

SOURCE: Dagnew AF et al. Rheumatology. 2020 Sep 10. doi: 10.1093/rheumatology/keaa424.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.

Monitor antidrug antibodies for their impact on drug clearance to maximize treatment outcomes in rheumatology patients treated with biologics, Niels Vande Casteele, PharmD, PhD, said in a virtual presentation at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.

Antidrug antibodies (ADAb) are associated with impaired drug efficacy and safety, he noted. Furthermore, he indicated that when ADAb bind to the drug, they can either block the activity of the drug directly and/or may cause the formation of complexes, leading to accelerated drug clearance and reduced drug exposure.

Dr. Vande Casteele, assistant professor in the department of medicine at the University of California, San Diego, outlined factors that contribute to immunogenicity, which occurs when the body reacts to neoantigens, or when there is a breakdown in immune tolerance, he said.

Genetics can play a key role in the risk for immunogenicity, as can the route of administration, dose, treatment duration, and concomitant diseases or medications, he explained.

In addition, product-related factors including sequence variation, glycosylation, host cells, contaminants and processing impurities, formulation, and handling and storage issues can impact immunogenicity, he noted.

For example, Dr. Vande Casteele cited a study in which the proportion of infliximab-treated patients with positive ADAbs was substantially higher among those receiving the drug intravenously, compared with those receiving it subcutaneously. As for treatment dosing, data on patients treated with infliximab have shown that maintenance therapy is associated with lower rates of immunogenicity, compared to episodic therapy, he said.

In terms of genetics, Dr. Vande Casteele cited a study published in January in Gastroenterology showing the presence of the HLA-DQA1*05 allele, carried by approximately 40% of the European population, significantly increased the rate of immunogenicity to infliximab and adalimumab in patients with Crohn’s disease (hazard ratio, 1.90).
 

Therapeutic drug monitoring and overcoming immunogenicity

Dr. Vande Casteele also reviewed how to measure ADAbs. “Antidrug antibody units and concentrations can differ across assays,” he said.

In clinical practice, “the majority of patients at the time of secondary loss of response will present with low drug exposure, and that is when you measure antidrug antibodies,” he said.

In rheumatology patients, the presence of ADAbs against anti–tumor necrosis factor monoclonal antibodies conveys a risk for treatment discontinuation, as well as “a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases,” Dr. Vande Casteele said.

However, “the combined use of anti–tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks,” he noted.

For therapeutic drug monitoring in patients with a secondary loss of response, “first, look at the trough concentration,” Dr. Vande Casteele said. “If it is optimal, then ADAbs are probably inconsequential.” If the trough is low or undetectable, examine ADAbs, he added. To manage ADAbs, data support the use of drug dose escalation in some cases. However, “you may be able to overcome the antidrug antibodies in some patients with dose escalation, but this is not always a cost-effective strategy in the long term,” and some patients fail a drug despite adequate drug concentration, which may mean they are failing the mechanism, and not because of pharmacokinetic-related issues, he said.

Dr. Vande Casteele cited a post hoc analysis of the TAXIT trial, published in Gastroenterology. It was the first prospective study to look at proactive therapeutic drug monitoring in patients with inflammatory bowel diseases treated with maintenance infliximab. This post hoc analysis showed that ADAbs were overcome with dose escalation in nearly 50% of patients in the lowest two ADAb quartiles at the start of the trial, and although ADAb were masked by dose escalation in the highest two quartiles, measurement with a drug-sensitive assay showed that ADAb never disappeared, he said.

Another strategy to try to overcome immunogenicity is to add an immunomodulator, Dr. Vande Casteele said. He cited a recent study published in Rheumatology showing that the effect of methotrexate was mediated through immunogenicity for immunogenic compounds such as adalimumab.

Importantly, there is a risk for immunogenicity across agents, he noted. “Patients who are antibody positive to the prior anti-TNF are at a higher risk of developing antibodies to subsequent anti-TNFs.”

Dr. Vande Casteele reported receiving research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv (formerly Robarts Clinical Trials), Celltrion, and Prometheus. Global Academy for Medical Education and this news organization are owned by the same parent company.