Rheumatoid Arthritis

Patients with rheumatoid arthritis treated with tofacitinib (Xeljanz) were 69% less likely to develop interstitial lung disease (ILD), compared with those treated with adalimumab (Humira), according to a new retrospective study.

About 10% of RA patients develop ILD, but data on how different biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) may affect the risk of developing ILD is lacking, the authors wrote. Identifying treatments that may have protective effects could be useful when prescribing treatments for patients with RA who are at higher risk for ILD, first author Matthew C. Baker, MD, clinical chief in the division of immunology and rheumatology at Stanford (Calif.) University, said in an interview.

In the analysis, published in JAMA Network Open researchers used the Optum Clinformatics Data Mart to identify claims data for patients with RA who were taking b/tsDMARDs from December 2003 to December 2019. Patients were excluded if they had a preexisting diagnosis of ILD or if they had less than 1 year of continuous enrollment in the data set.

The researchers identified 28,559 patients with RA who were treated with adalimumab (13,326), abatacept (Orencia; 5,676), rituximab (Rituxan; 5,444), tocilizumab (Actemra; 2,548), and tofacitinib (1,565). More than three-fourths of patients were female (78%), and their average age was 55.6 years old. During the study period, 276 developed ILD. An adjusted model showed a 69% lower incidence of ILD in patients treated with tofacitinib, compared with those treated with adalimumab (adjusted hazard ratio, 0.31; 95% confidence interval, 0.12-0.78; P = .009). An additional sensitivity analysis also showed a similar reduction in ILD risk in those taking tofacitinib, compared with adalimumab (aHR, 0.32; 95% CI, 0.13-0.82; P < .001). There was no significant difference in risk of developing ILD in the abatacept, rituximab, or tocilizumab groups, compared with the adalimumab group.

“Patients who generally looked similar with RA, but were given different treatments, had different risks of developing ILD,” Dr. Baker said. “Based on what we found, most of the biologic therapies had similar rates of developing ILD, but the JAK inhibitor tofacitinib had a reduced risk.” Additional research is necessary to see if tofacitinib shows the same benefit in prospective studies, he said.

“Even though this wasn’t a clinical trial, it suggested that one of the medications that we use to treat RA could potentially prevent the development of ILD,” Elizabeth Volkmann, MD, codirector of the Connective Tissue Disease-Related Interstitial Lung Disease Program at the University of California, Los Angeles, told this news organization. She was not involved with the study.

With retrospective studies, it is difficult to account for all confounding factors, even with adjusted models, she said. For example, the authors did not have data on patients’ history of smoking, a known risk factor for ILD that could have affected which treatment was selected, they acknowledged. The tofacitinib group was also smaller than other treatment groups, which “may have contributed to a small number of events,” the authors wrote. “However, the follow-up time was similar across all groups, and we used Cox proportional hazard models to investigate the association between time-to-event and use of treatment while controlling for the other baseline characteristics.”

Both Dr. Baker and Dr. Volkmann agreed that future research could also investigate whether tofacitinib prevents the progression of ILD in patients with RA who already have the lung condition. “That’s never been looked at before,” Dr. Volkmann said.

Dr. Baker and a coauthor received support for this work from grants from the National Institutes of Health. Dr. Baker and Dr. Volkmann report no relevant financial relationships.

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

Patients with rheumatoid arthritis treated with tofacitinib (Xeljanz) were 69% less likely to develop interstitial lung disease (ILD), compared with those treated with adalimumab (Humira), according to a new retrospective study.

About 10% of RA patients develop ILD, but data on how different biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) may affect the risk of developing ILD is lacking, the authors wrote. Identifying treatments that may have protective effects could be useful when prescribing treatments for patients with RA who are at higher risk for ILD, first author Matthew C. Baker, MD, clinical chief in the division of immunology and rheumatology at Stanford (Calif.) University, said in an interview.

In the analysis, published in JAMA Network Open researchers used the Optum Clinformatics Data Mart to identify claims data for patients with RA who were taking b/tsDMARDs from December 2003 to December 2019. Patients were excluded if they had a preexisting diagnosis of ILD or if they had less than 1 year of continuous enrollment in the data set.

The researchers identified 28,559 patients with RA who were treated with adalimumab (13,326), abatacept (Orencia; 5,676), rituximab (Rituxan; 5,444), tocilizumab (Actemra; 2,548), and tofacitinib (1,565). More than three-fourths of patients were female (78%), and their average age was 55.6 years old. During the study period, 276 developed ILD. An adjusted model showed a 69% lower incidence of ILD in patients treated with tofacitinib, compared with those treated with adalimumab (adjusted hazard ratio, 0.31; 95% confidence interval, 0.12-0.78; P = .009). An additional sensitivity analysis also showed a similar reduction in ILD risk in those taking tofacitinib, compared with adalimumab (aHR, 0.32; 95% CI, 0.13-0.82; P < .001). There was no significant difference in risk of developing ILD in the abatacept, rituximab, or tocilizumab groups, compared with the adalimumab group.

“Patients who generally looked similar with RA, but were given different treatments, had different risks of developing ILD,” Dr. Baker said. “Based on what we found, most of the biologic therapies had similar rates of developing ILD, but the JAK inhibitor tofacitinib had a reduced risk.” Additional research is necessary to see if tofacitinib shows the same benefit in prospective studies, he said.

“Even though this wasn’t a clinical trial, it suggested that one of the medications that we use to treat RA could potentially prevent the development of ILD,” Elizabeth Volkmann, MD, codirector of the Connective Tissue Disease-Related Interstitial Lung Disease Program at the University of California, Los Angeles, told this news organization. She was not involved with the study.

With retrospective studies, it is difficult to account for all confounding factors, even with adjusted models, she said. For example, the authors did not have data on patients’ history of smoking, a known risk factor for ILD that could have affected which treatment was selected, they acknowledged. The tofacitinib group was also smaller than other treatment groups, which “may have contributed to a small number of events,” the authors wrote. “However, the follow-up time was similar across all groups, and we used Cox proportional hazard models to investigate the association between time-to-event and use of treatment while controlling for the other baseline characteristics.”

Both Dr. Baker and Dr. Volkmann agreed that future research could also investigate whether tofacitinib prevents the progression of ILD in patients with RA who already have the lung condition. “That’s never been looked at before,” Dr. Volkmann said.

Dr. Baker and a coauthor received support for this work from grants from the National Institutes of Health. Dr. Baker and Dr. Volkmann report no relevant financial relationships.

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

Patients with rheumatoid arthritis treated with tofacitinib (Xeljanz) were 69% less likely to develop interstitial lung disease (ILD), compared with those treated with adalimumab (Humira), according to a new retrospective study.

About 10% of RA patients develop ILD, but data on how different biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) may affect the risk of developing ILD is lacking, the authors wrote. Identifying treatments that may have protective effects could be useful when prescribing treatments for patients with RA who are at higher risk for ILD, first author Matthew C. Baker, MD, clinical chief in the division of immunology and rheumatology at Stanford (Calif.) University, said in an interview.

In the analysis, published in JAMA Network Open researchers used the Optum Clinformatics Data Mart to identify claims data for patients with RA who were taking b/tsDMARDs from December 2003 to December 2019. Patients were excluded if they had a preexisting diagnosis of ILD or if they had less than 1 year of continuous enrollment in the data set.

The researchers identified 28,559 patients with RA who were treated with adalimumab (13,326), abatacept (Orencia; 5,676), rituximab (Rituxan; 5,444), tocilizumab (Actemra; 2,548), and tofacitinib (1,565). More than three-fourths of patients were female (78%), and their average age was 55.6 years old. During the study period, 276 developed ILD. An adjusted model showed a 69% lower incidence of ILD in patients treated with tofacitinib, compared with those treated with adalimumab (adjusted hazard ratio, 0.31; 95% confidence interval, 0.12-0.78; P = .009). An additional sensitivity analysis also showed a similar reduction in ILD risk in those taking tofacitinib, compared with adalimumab (aHR, 0.32; 95% CI, 0.13-0.82; P < .001). There was no significant difference in risk of developing ILD in the abatacept, rituximab, or tocilizumab groups, compared with the adalimumab group.

“Patients who generally looked similar with RA, but were given different treatments, had different risks of developing ILD,” Dr. Baker said. “Based on what we found, most of the biologic therapies had similar rates of developing ILD, but the JAK inhibitor tofacitinib had a reduced risk.” Additional research is necessary to see if tofacitinib shows the same benefit in prospective studies, he said.

“Even though this wasn’t a clinical trial, it suggested that one of the medications that we use to treat RA could potentially prevent the development of ILD,” Elizabeth Volkmann, MD, codirector of the Connective Tissue Disease-Related Interstitial Lung Disease Program at the University of California, Los Angeles, told this news organization. She was not involved with the study.

With retrospective studies, it is difficult to account for all confounding factors, even with adjusted models, she said. For example, the authors did not have data on patients’ history of smoking, a known risk factor for ILD that could have affected which treatment was selected, they acknowledged. The tofacitinib group was also smaller than other treatment groups, which “may have contributed to a small number of events,” the authors wrote. “However, the follow-up time was similar across all groups, and we used Cox proportional hazard models to investigate the association between time-to-event and use of treatment while controlling for the other baseline characteristics.”

Both Dr. Baker and Dr. Volkmann agreed that future research could also investigate whether tofacitinib prevents the progression of ILD in patients with RA who already have the lung condition. “That’s never been looked at before,” Dr. Volkmann said.

Dr. Baker and a coauthor received support for this work from grants from the National Institutes of Health. Dr. Baker and Dr. Volkmann report no relevant financial relationships.

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

NEW ORLEANS – The efficacy and safety of Janus kinase (JAK) inhibitors for hair regrowth in adults with alopecia areata were reinforced by new results from clinical trials of two drugs presented at a late-breaker research session at the annual meeting of the American Academy of Dermatology.

Based on phase 3 studies that document robust hair growth in about one third of patients, deuruxolitinib (CTP-543), an inhibitor of the JAK1 and JAK2 enzymes, has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received U.S. approval almost 1 year ago.

In his talk on THRIVE-AA2, a phase 3 trial of the investigational medicine deuruxolitinib, the principal investigator, Brett A. King, MD, PhD, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.”

THRIVE-AA2 was the second of two phase 3 studies of deuruxolitinib. King was a principal investigator for both pivotal trials, called THRIVE-AA1 and THRIVE AA-2. He characterized the results of the two THRIVE trials as “comparable.”

Dr. King also was a principal investigator for the trials with baricitinib, called BRAVE-AA1 and BRAVE AA-2, which were published last year in the New England Journal of Medicine. The trials for both drugs had similar designs and endpoints.
 

Deuruxolitinib and the THRIVE studies

In the THRIVE-AA2 trial, 517 adult patients were enrolled with moderate to severe alopecia areata, defined as a SALT (Severity of Alopecia Tool) score of ≥ 50%, which signifies a hair loss of at least 50%. Like THRIVE-AA1, patients participated at treatment centers in North America and Europe. About two-thirds were female. The mean age was 39 years. The majority of patients had complete or near complete hair loss at baseline.

“Many of these patients are the ones we have historically characterized as having alopecia totalis or universalis,” Dr. King said.

Participating patients were randomly assigned to 8 mg deuruxolitinib twice daily, 12 mg deuruxolitinib twice daily, or placebo. The primary endpoint was a SALT score of ≤ 20% at week 24.

At 24 weeks, almost no patients in the placebo group (1%) vs. 33% and 38% in the 8 mg and 12 mg twice-daily groups, respectively, met the primary endpoint. Each active treatment group was highly significant vs. placebo.

Of the responders, the majority achieved complete or near complete hair growth as defined by a SALT score of ≤ 10%, Dr. King reported.

Based on a graph that showed a relatively steep climb over the entire 24-week study period, deuruxolitinib “had a really fast onset of action,” Dr. King said. By week 8, which was the time of the first assessment, both doses of deuruxolitinib were superior to placebo.

The majority of patients had complete or significant loss of eyebrows and eye lashes at baseline, but more than two-thirds of these patients had regrowth by week 24, Dr. King said. Again, no significant regrowth was observed in the placebo arm.

On the Satisfaction of Hair Patient Reported Outcomes (SPRO), more than half of patients on both doses reported being satisfied or very satisfied with the improvement when evaluated at 24 weeks.

“The patient satisfaction overshot what one would expect by looking at the SALT scores, but a lot of subjects were at the precipice of the primary endpoint, sitting on SALT scores of 21, 25, or 30,” Dr. King said.
 

High participation in extension trial

More than 90% of the patients assigned to deuruxolitinib completed the trial and have entered an open-label extension (OLE). Dr. King credited the substantial rates of hair growth and the low rate of significant adverse events for the high rate of transition to OLE. Those who experienced the response were motivated to maintain it.  

“This is a devastating disease. Patients want to get better,” Dr. King said.

There were no serious treatment-emergent adverse events associated with deuruxolitinib, including no thromboembolic events or other off-target events that have been reported previously with other JAK inhibitors in other disease states, such as rheumatoid arthritis. Although some adverse events, such as nasopharyngitis, were observed more often in those taking deuruxolitinib than placebo, there were “very few” discontinuations because of an adverse event, he said.

The data of THRIVE-AA2 are wholly compatible with the previously reported 706-patient THRIVE-AA1, according to Dr. King. In THRIVE-AA1, the primary endpoint of SALT ≤ 20% was reached by 29.6%, 41.5%, and 0.8% of the 8 mg, 12 mg, and placebo groups, respectively. Patient satisfaction scores, safety, and tolerability were also similar, according to Dr. King.

The experience with deuruxolitinib in the THRIVE-AA phase 3 program is similar to the experience with baricitinib in the BRAVE-AA trials. Although they cannot be compared directly because of potential differences between study populations, the 4-mg dose of baricitinib also achieved SALT score ≤ 20 in about 35% of patients, he said. The proportion was lower in the 2-mg group but was also superior to the placebo group.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Responding to a question about payers reluctant to reimburse therapies for a “cosmetic” condition, Dr. King added that the effective treatments are “changing the landscape of how we think about this disease.” Dr. King believes these kinds of data show that “we are literally transforming lives forever.”
 

Baricitinib and the BRAVE studies

When baricitinib received regulatory approval for alopecia areata last year, it was not just the first JAK inhibitor approved for this disease, but the first systemic therapy of any kind, according to Maryanne Senna, MD, an assistant professor of dermatology at Harvard Medical School, Boston, and the director of the Lahey Hair Loss Center of Excellence, Burlington, Mass. Dr. Senna was a clinical investigator of BRAVE-AA1, as well as of THRIVE-AA2.

Providing an update on the BRAVE-AA program, Dr. Senna reported 104-week data that appear to support the idea of a life-changing benefit from JAK inhibitor therapy. This is because the effects appear durable.

In the data she presented at the AAD, responders and mixed responders at 52 weeks were followed to 104 weeks. Mixed responders were defined as those without a SALT response of ≤ 20 at week 52 but who had achieved this degree of hair regrowth at some earlier point.

Of the responders, 90% maintained their response at 104 weeks. In addition, many of the mixed responders and patients with a partial response but who never achieved a SALT score ≤ 20% gained additional hair growth, including complete or near complete hair growth, when maintained on treatment over the 2 years of follow-up.

“The follow-up suggests that, if you keep patients on treatment, you can get many of them to a meaningful response,” she said.

Meanwhile, “there have been no new safety signals,” Dr. Senna said. She based this statement not only of the 104-week data but on follow-up of up to 3.6 years among patients who have remained on treatment after participating in previous studies.

According to Dr. Senna, the off-target events that have been reported previously in other diseases with other JAK inhibitors, such as major adverse cardiovascular events and thromboembolic events, have not so far been observed in the BRAVE-AA phase 3 program.

Baricitinib, much like all but one of the JAK inhibitors with dermatologic indications, carries a black box warning that lists multiple risks for drugs in this class, based on a rheumatoid arthritis study.

The Food and Drug Administration has granted deuruxolitinib Breakthrough Therapy designation for the treatment of adult patients with moderate to severe alopecia areata and Fast Track designation for the treatment of alopecia areata, according to its manufacturer Concert Pharmaceuticals.

Dr. King reports financial relationships with more than 15 pharmaceutical companies, including Concert Pharmaceuticals, which provided the funding for the THRIVE-AA trial program, and for Eli Lilly, which provided funding for the BRAVE-AA trial program. Dr. Senna reports financial relationships with Arena pharmaceuticals, Follica, and both Concert Pharmaceuticals and Eli Lilly.

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

NEW ORLEANS – The efficacy and safety of Janus kinase (JAK) inhibitors for hair regrowth in adults with alopecia areata were reinforced by new results from clinical trials of two drugs presented at a late-breaker research session at the annual meeting of the American Academy of Dermatology.

Based on phase 3 studies that document robust hair growth in about one third of patients, deuruxolitinib (CTP-543), an inhibitor of the JAK1 and JAK2 enzymes, has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received U.S. approval almost 1 year ago.

In his talk on THRIVE-AA2, a phase 3 trial of the investigational medicine deuruxolitinib, the principal investigator, Brett A. King, MD, PhD, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.”

THRIVE-AA2 was the second of two phase 3 studies of deuruxolitinib. King was a principal investigator for both pivotal trials, called THRIVE-AA1 and THRIVE AA-2. He characterized the results of the two THRIVE trials as “comparable.”

Dr. King also was a principal investigator for the trials with baricitinib, called BRAVE-AA1 and BRAVE AA-2, which were published last year in the New England Journal of Medicine. The trials for both drugs had similar designs and endpoints.
 

Deuruxolitinib and the THRIVE studies

In the THRIVE-AA2 trial, 517 adult patients were enrolled with moderate to severe alopecia areata, defined as a SALT (Severity of Alopecia Tool) score of ≥ 50%, which signifies a hair loss of at least 50%. Like THRIVE-AA1, patients participated at treatment centers in North America and Europe. About two-thirds were female. The mean age was 39 years. The majority of patients had complete or near complete hair loss at baseline.

“Many of these patients are the ones we have historically characterized as having alopecia totalis or universalis,” Dr. King said.

Participating patients were randomly assigned to 8 mg deuruxolitinib twice daily, 12 mg deuruxolitinib twice daily, or placebo. The primary endpoint was a SALT score of ≤ 20% at week 24.

At 24 weeks, almost no patients in the placebo group (1%) vs. 33% and 38% in the 8 mg and 12 mg twice-daily groups, respectively, met the primary endpoint. Each active treatment group was highly significant vs. placebo.

Of the responders, the majority achieved complete or near complete hair growth as defined by a SALT score of ≤ 10%, Dr. King reported.

Based on a graph that showed a relatively steep climb over the entire 24-week study period, deuruxolitinib “had a really fast onset of action,” Dr. King said. By week 8, which was the time of the first assessment, both doses of deuruxolitinib were superior to placebo.

The majority of patients had complete or significant loss of eyebrows and eye lashes at baseline, but more than two-thirds of these patients had regrowth by week 24, Dr. King said. Again, no significant regrowth was observed in the placebo arm.

On the Satisfaction of Hair Patient Reported Outcomes (SPRO), more than half of patients on both doses reported being satisfied or very satisfied with the improvement when evaluated at 24 weeks.

“The patient satisfaction overshot what one would expect by looking at the SALT scores, but a lot of subjects were at the precipice of the primary endpoint, sitting on SALT scores of 21, 25, or 30,” Dr. King said.
 

High participation in extension trial

More than 90% of the patients assigned to deuruxolitinib completed the trial and have entered an open-label extension (OLE). Dr. King credited the substantial rates of hair growth and the low rate of significant adverse events for the high rate of transition to OLE. Those who experienced the response were motivated to maintain it.  

“This is a devastating disease. Patients want to get better,” Dr. King said.

There were no serious treatment-emergent adverse events associated with deuruxolitinib, including no thromboembolic events or other off-target events that have been reported previously with other JAK inhibitors in other disease states, such as rheumatoid arthritis. Although some adverse events, such as nasopharyngitis, were observed more often in those taking deuruxolitinib than placebo, there were “very few” discontinuations because of an adverse event, he said.

The data of THRIVE-AA2 are wholly compatible with the previously reported 706-patient THRIVE-AA1, according to Dr. King. In THRIVE-AA1, the primary endpoint of SALT ≤ 20% was reached by 29.6%, 41.5%, and 0.8% of the 8 mg, 12 mg, and placebo groups, respectively. Patient satisfaction scores, safety, and tolerability were also similar, according to Dr. King.

The experience with deuruxolitinib in the THRIVE-AA phase 3 program is similar to the experience with baricitinib in the BRAVE-AA trials. Although they cannot be compared directly because of potential differences between study populations, the 4-mg dose of baricitinib also achieved SALT score ≤ 20 in about 35% of patients, he said. The proportion was lower in the 2-mg group but was also superior to the placebo group.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Responding to a question about payers reluctant to reimburse therapies for a “cosmetic” condition, Dr. King added that the effective treatments are “changing the landscape of how we think about this disease.” Dr. King believes these kinds of data show that “we are literally transforming lives forever.”
 

Baricitinib and the BRAVE studies

When baricitinib received regulatory approval for alopecia areata last year, it was not just the first JAK inhibitor approved for this disease, but the first systemic therapy of any kind, according to Maryanne Senna, MD, an assistant professor of dermatology at Harvard Medical School, Boston, and the director of the Lahey Hair Loss Center of Excellence, Burlington, Mass. Dr. Senna was a clinical investigator of BRAVE-AA1, as well as of THRIVE-AA2.

Providing an update on the BRAVE-AA program, Dr. Senna reported 104-week data that appear to support the idea of a life-changing benefit from JAK inhibitor therapy. This is because the effects appear durable.

In the data she presented at the AAD, responders and mixed responders at 52 weeks were followed to 104 weeks. Mixed responders were defined as those without a SALT response of ≤ 20 at week 52 but who had achieved this degree of hair regrowth at some earlier point.

Of the responders, 90% maintained their response at 104 weeks. In addition, many of the mixed responders and patients with a partial response but who never achieved a SALT score ≤ 20% gained additional hair growth, including complete or near complete hair growth, when maintained on treatment over the 2 years of follow-up.

“The follow-up suggests that, if you keep patients on treatment, you can get many of them to a meaningful response,” she said.

Meanwhile, “there have been no new safety signals,” Dr. Senna said. She based this statement not only of the 104-week data but on follow-up of up to 3.6 years among patients who have remained on treatment after participating in previous studies.

According to Dr. Senna, the off-target events that have been reported previously in other diseases with other JAK inhibitors, such as major adverse cardiovascular events and thromboembolic events, have not so far been observed in the BRAVE-AA phase 3 program.

Baricitinib, much like all but one of the JAK inhibitors with dermatologic indications, carries a black box warning that lists multiple risks for drugs in this class, based on a rheumatoid arthritis study.

The Food and Drug Administration has granted deuruxolitinib Breakthrough Therapy designation for the treatment of adult patients with moderate to severe alopecia areata and Fast Track designation for the treatment of alopecia areata, according to its manufacturer Concert Pharmaceuticals.

Dr. King reports financial relationships with more than 15 pharmaceutical companies, including Concert Pharmaceuticals, which provided the funding for the THRIVE-AA trial program, and for Eli Lilly, which provided funding for the BRAVE-AA trial program. Dr. Senna reports financial relationships with Arena pharmaceuticals, Follica, and both Concert Pharmaceuticals and Eli Lilly.

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

NEW ORLEANS – The efficacy and safety of Janus kinase (JAK) inhibitors for hair regrowth in adults with alopecia areata were reinforced by new results from clinical trials of two drugs presented at a late-breaker research session at the annual meeting of the American Academy of Dermatology.

Based on phase 3 studies that document robust hair growth in about one third of patients, deuruxolitinib (CTP-543), an inhibitor of the JAK1 and JAK2 enzymes, has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received U.S. approval almost 1 year ago.

In his talk on THRIVE-AA2, a phase 3 trial of the investigational medicine deuruxolitinib, the principal investigator, Brett A. King, MD, PhD, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.”

THRIVE-AA2 was the second of two phase 3 studies of deuruxolitinib. King was a principal investigator for both pivotal trials, called THRIVE-AA1 and THRIVE AA-2. He characterized the results of the two THRIVE trials as “comparable.”

Dr. King also was a principal investigator for the trials with baricitinib, called BRAVE-AA1 and BRAVE AA-2, which were published last year in the New England Journal of Medicine. The trials for both drugs had similar designs and endpoints.
 

Deuruxolitinib and the THRIVE studies

In the THRIVE-AA2 trial, 517 adult patients were enrolled with moderate to severe alopecia areata, defined as a SALT (Severity of Alopecia Tool) score of ≥ 50%, which signifies a hair loss of at least 50%. Like THRIVE-AA1, patients participated at treatment centers in North America and Europe. About two-thirds were female. The mean age was 39 years. The majority of patients had complete or near complete hair loss at baseline.

“Many of these patients are the ones we have historically characterized as having alopecia totalis or universalis,” Dr. King said.

Participating patients were randomly assigned to 8 mg deuruxolitinib twice daily, 12 mg deuruxolitinib twice daily, or placebo. The primary endpoint was a SALT score of ≤ 20% at week 24.

At 24 weeks, almost no patients in the placebo group (1%) vs. 33% and 38% in the 8 mg and 12 mg twice-daily groups, respectively, met the primary endpoint. Each active treatment group was highly significant vs. placebo.

Of the responders, the majority achieved complete or near complete hair growth as defined by a SALT score of ≤ 10%, Dr. King reported.

Based on a graph that showed a relatively steep climb over the entire 24-week study period, deuruxolitinib “had a really fast onset of action,” Dr. King said. By week 8, which was the time of the first assessment, both doses of deuruxolitinib were superior to placebo.

The majority of patients had complete or significant loss of eyebrows and eye lashes at baseline, but more than two-thirds of these patients had regrowth by week 24, Dr. King said. Again, no significant regrowth was observed in the placebo arm.

On the Satisfaction of Hair Patient Reported Outcomes (SPRO), more than half of patients on both doses reported being satisfied or very satisfied with the improvement when evaluated at 24 weeks.

“The patient satisfaction overshot what one would expect by looking at the SALT scores, but a lot of subjects were at the precipice of the primary endpoint, sitting on SALT scores of 21, 25, or 30,” Dr. King said.
 

High participation in extension trial

More than 90% of the patients assigned to deuruxolitinib completed the trial and have entered an open-label extension (OLE). Dr. King credited the substantial rates of hair growth and the low rate of significant adverse events for the high rate of transition to OLE. Those who experienced the response were motivated to maintain it.  

“This is a devastating disease. Patients want to get better,” Dr. King said.

There were no serious treatment-emergent adverse events associated with deuruxolitinib, including no thromboembolic events or other off-target events that have been reported previously with other JAK inhibitors in other disease states, such as rheumatoid arthritis. Although some adverse events, such as nasopharyngitis, were observed more often in those taking deuruxolitinib than placebo, there were “very few” discontinuations because of an adverse event, he said.

The data of THRIVE-AA2 are wholly compatible with the previously reported 706-patient THRIVE-AA1, according to Dr. King. In THRIVE-AA1, the primary endpoint of SALT ≤ 20% was reached by 29.6%, 41.5%, and 0.8% of the 8 mg, 12 mg, and placebo groups, respectively. Patient satisfaction scores, safety, and tolerability were also similar, according to Dr. King.

The experience with deuruxolitinib in the THRIVE-AA phase 3 program is similar to the experience with baricitinib in the BRAVE-AA trials. Although they cannot be compared directly because of potential differences between study populations, the 4-mg dose of baricitinib also achieved SALT score ≤ 20 in about 35% of patients, he said. The proportion was lower in the 2-mg group but was also superior to the placebo group.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Responding to a question about payers reluctant to reimburse therapies for a “cosmetic” condition, Dr. King added that the effective treatments are “changing the landscape of how we think about this disease.” Dr. King believes these kinds of data show that “we are literally transforming lives forever.”
 

Baricitinib and the BRAVE studies

When baricitinib received regulatory approval for alopecia areata last year, it was not just the first JAK inhibitor approved for this disease, but the first systemic therapy of any kind, according to Maryanne Senna, MD, an assistant professor of dermatology at Harvard Medical School, Boston, and the director of the Lahey Hair Loss Center of Excellence, Burlington, Mass. Dr. Senna was a clinical investigator of BRAVE-AA1, as well as of THRIVE-AA2.

Providing an update on the BRAVE-AA program, Dr. Senna reported 104-week data that appear to support the idea of a life-changing benefit from JAK inhibitor therapy. This is because the effects appear durable.

In the data she presented at the AAD, responders and mixed responders at 52 weeks were followed to 104 weeks. Mixed responders were defined as those without a SALT response of ≤ 20 at week 52 but who had achieved this degree of hair regrowth at some earlier point.

Of the responders, 90% maintained their response at 104 weeks. In addition, many of the mixed responders and patients with a partial response but who never achieved a SALT score ≤ 20% gained additional hair growth, including complete or near complete hair growth, when maintained on treatment over the 2 years of follow-up.

“The follow-up suggests that, if you keep patients on treatment, you can get many of them to a meaningful response,” she said.

Meanwhile, “there have been no new safety signals,” Dr. Senna said. She based this statement not only of the 104-week data but on follow-up of up to 3.6 years among patients who have remained on treatment after participating in previous studies.

According to Dr. Senna, the off-target events that have been reported previously in other diseases with other JAK inhibitors, such as major adverse cardiovascular events and thromboembolic events, have not so far been observed in the BRAVE-AA phase 3 program.

Baricitinib, much like all but one of the JAK inhibitors with dermatologic indications, carries a black box warning that lists multiple risks for drugs in this class, based on a rheumatoid arthritis study.

The Food and Drug Administration has granted deuruxolitinib Breakthrough Therapy designation for the treatment of adult patients with moderate to severe alopecia areata and Fast Track designation for the treatment of alopecia areata, according to its manufacturer Concert Pharmaceuticals.

Dr. King reports financial relationships with more than 15 pharmaceutical companies, including Concert Pharmaceuticals, which provided the funding for the THRIVE-AA trial program, and for Eli Lilly, which provided funding for the BRAVE-AA trial program. Dr. Senna reports financial relationships with Arena pharmaceuticals, Follica, and both Concert Pharmaceuticals and Eli Lilly.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

More clinical guidance is needed for monitoring interstitial lung disease (ILD) in patients with rheumatoid arthritis, according to a new commentary.

Though ILD is a leading cause of death among patients with RA, these patients are not routinely screened for ILD, the authors say, and there are currently no guidelines on how to monitor ILD progression in patients with RA.

A.Prof Frank Gaillard, Radiopaedia.org

“ILD associated with rheumatoid arthritis is a disease for which there’s been very little research done, so it’s an area of rheumatology where there are many unknowns,” lead author Elizabeth R. Volkmann, MD, who codirects the connective tissue disease–related interstitial lung disease (CTD-ILD) program at University of California, Los Angeles, told this news organization.

The commentary was published in The Lancet Rheumatology.
 

Defining disease

One of the major unknowns is how to define the disease, she said. RA patients sometimes undergo imaging for other medical reasons, and interstitial lung abnormalities are incidentally detected. These patients can be classified as having “preclinical” or “subclinical” ILD, as they do not yet have symptoms; however, there is no consensus as to what these terms mean, the commentary authors write. “The other problem that we have with these terms is that it sometimes creates the perception that this is a nonworrisome feature of rheumatoid arthritis,” Dr. Volkmann said, although the condition should be followed closely.

“We know we can detect imaging features of ILD in people who may not yet have symptoms, and we need to know when to define a clinically important informality that requires follow-up or treatment,” added John M. Davis III, MD, a rheumatologist at the Mayo Clinic, Rochester, Minn. He was not involved with the work.

Mayo Clinic

Dr. Volkmann proposed eliminating the prefixes “pre” and “sub” when referring to ILD. “In other connective tissue diseases, like systemic sclerosis, for example, we can use the term ‘limited’ or ‘extensive’ ILD, based on the extent of involvement of the ILD on high-resolution computed tomography (HRCT) imaging,” she said. “This could potentially be something that is applied to how we classify patients with RA-ILD.”
 

Tracking ILD progression

Once ILD is identified, monitoring its progression poses challenges, as respiratory symptoms may be difficult to detect. RA patients may already be avoiding exercise because of joint pain, so they may not notice shortness of breath during physical activity, noted Jessica K. Gordon, MD, of the Hospital for Special Surgery, New York, in an interview with this news organization. She was not involved with the commentary. Cough is a potential symptom of ILD, but cough can also be the result of allergies, postnasal drip, or reflux, she said. Making the distinction between “preclinical” and symptomatic disease can be “complicated,” she added; “you may have to really dig.”

Hospital for Special Surgery

Additionally, there has been little research on the outcomes of patients with preclinical or subclinical ILD and clinical ILD, the commentary authors write. “It is therefore conceivable that some patients with rheumatoid arthritis diagnosed with preclinical or subclinical ILD could potentially have worse outcomes if both the rheumatoid arthritis and ILD are not monitored closely,” they note.

To better track RA-associated ILD for patients with and those without symptoms, the authors advocate for monitoring patients using pulmonary testing and CT scanning, as well as evaluating symptoms. How often these assessments should be conducted depends on the individual, they note. In her own practice, Dr. Volkmann sees patients every 3 months to evaluate their symptoms and conduct pulmonary function tests (PFTs). For patients early in the course of ILD, she orders HRCT imaging once per year.

For Dr. Davis, the frequency of follow-up depends on the severity of ILD. “For minimally symptomatic patients without compromised lung function, we would generally follow annually. For patients with symptomatic ILD on stable therapy, we may monitor every 6 months. For patients with active/progressive ILD, we would generally be following at least every 1-3 months,” he said.

Screening and future research

While there is no evidence to recommend screening patients for ILD using CT, there are certain risk factors for ILD in RA patients, including a history of smoking, male sex, and high RA disease activity despite antirheumatic treatment, Dr. Volkmann said. In both of their practices, Dr. Davis and Dr. Volkmann screen with RA via HRCT and PFTs for ILD for patients with known risk factors that predispose them to the lung condition and/or for patients who report respiratory symptoms.

National Jewish Health

“We still don’t have an algorithm [for screening patients], and that is a desperate need in this field,” added Joshua J. Solomon, MD, a pulmonologist at National Jewish Health, Denver, whose research focuses on RA-associated ILD. While recommendations state that all patients with scleroderma should be screened with CT, ILD incidence is lower among patients with RA, and thus these screening recommendations need to be narrowed, he said. But more research is needed to better fine tune recommendations, he said; “The only thing you can do is give some expert consensus until there are good data.”

Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and institutional support for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus. Dr. Gordon, Dr. Davis, and Dr. Solomon report no relevant financial relationships.

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

More clinical guidance is needed for monitoring interstitial lung disease (ILD) in patients with rheumatoid arthritis, according to a new commentary.

Though ILD is a leading cause of death among patients with RA, these patients are not routinely screened for ILD, the authors say, and there are currently no guidelines on how to monitor ILD progression in patients with RA.

A.Prof Frank Gaillard, Radiopaedia.org

“ILD associated with rheumatoid arthritis is a disease for which there’s been very little research done, so it’s an area of rheumatology where there are many unknowns,” lead author Elizabeth R. Volkmann, MD, who codirects the connective tissue disease–related interstitial lung disease (CTD-ILD) program at University of California, Los Angeles, told this news organization.

The commentary was published in The Lancet Rheumatology.
 

Defining disease

One of the major unknowns is how to define the disease, she said. RA patients sometimes undergo imaging for other medical reasons, and interstitial lung abnormalities are incidentally detected. These patients can be classified as having “preclinical” or “subclinical” ILD, as they do not yet have symptoms; however, there is no consensus as to what these terms mean, the commentary authors write. “The other problem that we have with these terms is that it sometimes creates the perception that this is a nonworrisome feature of rheumatoid arthritis,” Dr. Volkmann said, although the condition should be followed closely.

“We know we can detect imaging features of ILD in people who may not yet have symptoms, and we need to know when to define a clinically important informality that requires follow-up or treatment,” added John M. Davis III, MD, a rheumatologist at the Mayo Clinic, Rochester, Minn. He was not involved with the work.

Mayo Clinic

Dr. Volkmann proposed eliminating the prefixes “pre” and “sub” when referring to ILD. “In other connective tissue diseases, like systemic sclerosis, for example, we can use the term ‘limited’ or ‘extensive’ ILD, based on the extent of involvement of the ILD on high-resolution computed tomography (HRCT) imaging,” she said. “This could potentially be something that is applied to how we classify patients with RA-ILD.”
 

Tracking ILD progression

Once ILD is identified, monitoring its progression poses challenges, as respiratory symptoms may be difficult to detect. RA patients may already be avoiding exercise because of joint pain, so they may not notice shortness of breath during physical activity, noted Jessica K. Gordon, MD, of the Hospital for Special Surgery, New York, in an interview with this news organization. She was not involved with the commentary. Cough is a potential symptom of ILD, but cough can also be the result of allergies, postnasal drip, or reflux, she said. Making the distinction between “preclinical” and symptomatic disease can be “complicated,” she added; “you may have to really dig.”

Hospital for Special Surgery

Additionally, there has been little research on the outcomes of patients with preclinical or subclinical ILD and clinical ILD, the commentary authors write. “It is therefore conceivable that some patients with rheumatoid arthritis diagnosed with preclinical or subclinical ILD could potentially have worse outcomes if both the rheumatoid arthritis and ILD are not monitored closely,” they note.

To better track RA-associated ILD for patients with and those without symptoms, the authors advocate for monitoring patients using pulmonary testing and CT scanning, as well as evaluating symptoms. How often these assessments should be conducted depends on the individual, they note. In her own practice, Dr. Volkmann sees patients every 3 months to evaluate their symptoms and conduct pulmonary function tests (PFTs). For patients early in the course of ILD, she orders HRCT imaging once per year.

For Dr. Davis, the frequency of follow-up depends on the severity of ILD. “For minimally symptomatic patients without compromised lung function, we would generally follow annually. For patients with symptomatic ILD on stable therapy, we may monitor every 6 months. For patients with active/progressive ILD, we would generally be following at least every 1-3 months,” he said.

Screening and future research

While there is no evidence to recommend screening patients for ILD using CT, there are certain risk factors for ILD in RA patients, including a history of smoking, male sex, and high RA disease activity despite antirheumatic treatment, Dr. Volkmann said. In both of their practices, Dr. Davis and Dr. Volkmann screen with RA via HRCT and PFTs for ILD for patients with known risk factors that predispose them to the lung condition and/or for patients who report respiratory symptoms.

National Jewish Health

“We still don’t have an algorithm [for screening patients], and that is a desperate need in this field,” added Joshua J. Solomon, MD, a pulmonologist at National Jewish Health, Denver, whose research focuses on RA-associated ILD. While recommendations state that all patients with scleroderma should be screened with CT, ILD incidence is lower among patients with RA, and thus these screening recommendations need to be narrowed, he said. But more research is needed to better fine tune recommendations, he said; “The only thing you can do is give some expert consensus until there are good data.”

Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and institutional support for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus. Dr. Gordon, Dr. Davis, and Dr. Solomon report no relevant financial relationships.

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

More clinical guidance is needed for monitoring interstitial lung disease (ILD) in patients with rheumatoid arthritis, according to a new commentary.

Though ILD is a leading cause of death among patients with RA, these patients are not routinely screened for ILD, the authors say, and there are currently no guidelines on how to monitor ILD progression in patients with RA.

A.Prof Frank Gaillard, Radiopaedia.org

“ILD associated with rheumatoid arthritis is a disease for which there’s been very little research done, so it’s an area of rheumatology where there are many unknowns,” lead author Elizabeth R. Volkmann, MD, who codirects the connective tissue disease–related interstitial lung disease (CTD-ILD) program at University of California, Los Angeles, told this news organization.

The commentary was published in The Lancet Rheumatology.
 

Defining disease

One of the major unknowns is how to define the disease, she said. RA patients sometimes undergo imaging for other medical reasons, and interstitial lung abnormalities are incidentally detected. These patients can be classified as having “preclinical” or “subclinical” ILD, as they do not yet have symptoms; however, there is no consensus as to what these terms mean, the commentary authors write. “The other problem that we have with these terms is that it sometimes creates the perception that this is a nonworrisome feature of rheumatoid arthritis,” Dr. Volkmann said, although the condition should be followed closely.

“We know we can detect imaging features of ILD in people who may not yet have symptoms, and we need to know when to define a clinically important informality that requires follow-up or treatment,” added John M. Davis III, MD, a rheumatologist at the Mayo Clinic, Rochester, Minn. He was not involved with the work.

Mayo Clinic

Dr. Volkmann proposed eliminating the prefixes “pre” and “sub” when referring to ILD. “In other connective tissue diseases, like systemic sclerosis, for example, we can use the term ‘limited’ or ‘extensive’ ILD, based on the extent of involvement of the ILD on high-resolution computed tomography (HRCT) imaging,” she said. “This could potentially be something that is applied to how we classify patients with RA-ILD.”
 

Tracking ILD progression

Once ILD is identified, monitoring its progression poses challenges, as respiratory symptoms may be difficult to detect. RA patients may already be avoiding exercise because of joint pain, so they may not notice shortness of breath during physical activity, noted Jessica K. Gordon, MD, of the Hospital for Special Surgery, New York, in an interview with this news organization. She was not involved with the commentary. Cough is a potential symptom of ILD, but cough can also be the result of allergies, postnasal drip, or reflux, she said. Making the distinction between “preclinical” and symptomatic disease can be “complicated,” she added; “you may have to really dig.”

Hospital for Special Surgery

Additionally, there has been little research on the outcomes of patients with preclinical or subclinical ILD and clinical ILD, the commentary authors write. “It is therefore conceivable that some patients with rheumatoid arthritis diagnosed with preclinical or subclinical ILD could potentially have worse outcomes if both the rheumatoid arthritis and ILD are not monitored closely,” they note.

To better track RA-associated ILD for patients with and those without symptoms, the authors advocate for monitoring patients using pulmonary testing and CT scanning, as well as evaluating symptoms. How often these assessments should be conducted depends on the individual, they note. In her own practice, Dr. Volkmann sees patients every 3 months to evaluate their symptoms and conduct pulmonary function tests (PFTs). For patients early in the course of ILD, she orders HRCT imaging once per year.

For Dr. Davis, the frequency of follow-up depends on the severity of ILD. “For minimally symptomatic patients without compromised lung function, we would generally follow annually. For patients with symptomatic ILD on stable therapy, we may monitor every 6 months. For patients with active/progressive ILD, we would generally be following at least every 1-3 months,” he said.

Screening and future research

While there is no evidence to recommend screening patients for ILD using CT, there are certain risk factors for ILD in RA patients, including a history of smoking, male sex, and high RA disease activity despite antirheumatic treatment, Dr. Volkmann said. In both of their practices, Dr. Davis and Dr. Volkmann screen with RA via HRCT and PFTs for ILD for patients with known risk factors that predispose them to the lung condition and/or for patients who report respiratory symptoms.

National Jewish Health

“We still don’t have an algorithm [for screening patients], and that is a desperate need in this field,” added Joshua J. Solomon, MD, a pulmonologist at National Jewish Health, Denver, whose research focuses on RA-associated ILD. While recommendations state that all patients with scleroderma should be screened with CT, ILD incidence is lower among patients with RA, and thus these screening recommendations need to be narrowed, he said. But more research is needed to better fine tune recommendations, he said; “The only thing you can do is give some expert consensus until there are good data.”

Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and institutional support for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus. Dr. Gordon, Dr. Davis, and Dr. Solomon report no relevant financial relationships.

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

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

Two recent studies examined interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Albrecht and colleagues examined the prevalence of ILD in German patients with RA using a nationwide claims database from 2007 to 2020. Using diagnosis codes for seropositive and seronegative RA (along with disease-modifying antirheumatic drug prescriptions) as well as ILD, they found the prevalence of ILD to be relatively stable from 1.6% to 2.2%, and that incidence was stable (reported as 0.13%-0.21% per year, rather than per patient-year) over the course of the study. There is likely some misclassification with the primary reliance on diagnosis codes (of the included patients with RA only 44% were seropositive). They also excluded drug-induced ILD by diagnosis code, which may not be sufficient. Overall, the prevalence of ILD seems on the low end of what might be expected and may reflect a need for earlier evaluation to detect subclinical ILD.

Kronzer and colleagues performed a case-control study of 84 patients with incident RA-ILD compared with 233 patients with RA without ILD to evaluate the risk associated with specific anticitrullinated protein antibodies (ACPA) for the development of ILD. Compared with the clinical risk factors of smoking, disease activity, obesity, and glucocorticoid use, six "fine-specificity" ACPA were better able to predict ILD risk, with immunoglobulin (Ig) A2 to citrullinated histone 4 associated with an odds ratio (OR) of 0.08, and the others (IgA2 to citrullinated histone 2A, IgA2 to native cyclic histone 2A, IgA2 to native histone 2A, IgG to cyclic citrullinated filaggrin, and IgG to native cyclic filaggrin) were associated with OR of 2.5-5.5 for ILD. In combination with clinical characteristics, the authors developed a risk score with 93% specificity for RA-ILD that should be validated in other populations.

Suh and colleagues examined the association of RA with another less well-studied organ complication, end-stage renal disease (ESRD), using a large national insurance database. Once again, the accuracy of diagnosis is not fully clear using International Classification of Diseases, Tenth Edition (ICD-10), codes for classification. Overall, people with RA had a higher risk for ESRD than did people without RA, regardless of sex or smoking status. Because no immediate mechanistic connection between RA and ESRD is evident, it is possible that part of the increased risk is due to medications used in RA treatment, such as nonsteroidal anti-inflammatory drugs, but this hypothesis remains to be tested.

Finally, a footnote to the success of the treat-to-target strategy (T2T) in RA comes in a study by Ramiro and colleagues of the RA-BIODAM cohort, which, along with other studies, has shown the success of T2T in achieving and maintaining long-term clinical remission in RA. The effect of T2T on radiographic progression, however, is less clear. In this study, over 500 patients were followed for 2 years and a comparison between the T2T strategy and radiographic damage was made. The T2T strategy consisted of intensification of treatment if the Disease Activity Score (DAS-44) did not achieve a goal of < 1.6. This was compared with the radiographic damage (based on the change in Sharp-van der Heijde score[SvdH]) over a 6-month period. Overall, the change in progression was not different among patients who were treated with a stricter adherence to T2T (ie, a higher proportion of T2T) compared with those who were not, suggesting that a looser application of T2T will not necessarily cause a worsening of radiographic progression. It is possible, given the intervals of assessment in this study, that a longer follow-up after T2T is necessary to detect progression, or, given that patients were not randomly assigned, patients who were more strictly treated with T2T were already at higher risk for radiographic progression. However, this study is also helpful in understanding how insights from controlled trials may play out in usual clinical practice.

The Food and Drug Administration approved sarilumab (Kevzara) on March 1 for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease. 

The FDA previously approved sarilumab, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate to severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.

Olivier Le Moal/Getty Images

The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid-resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.

After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). This news organization previously reported these trial results in November when they were presented at the 2022 annual meeting of the American College of Rheumatology.

The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection-site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.

“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PhD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”

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

The Food and Drug Administration approved sarilumab (Kevzara) on March 1 for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease. 

The FDA previously approved sarilumab, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate to severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.

Olivier Le Moal/Getty Images

The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid-resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.

After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). This news organization previously reported these trial results in November when they were presented at the 2022 annual meeting of the American College of Rheumatology.

The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection-site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.

“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PhD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”

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

The Food and Drug Administration approved sarilumab (Kevzara) on March 1 for the treatment of polymyalgia rheumatica (PMR) in adults who have had an inadequate response to corticosteroids or could not tolerate a corticosteroid taper, joint developers Sanofi and Regeneron announced. The drug is the first and only FDA-approved biologic treatment for this inflammatory rheumatic disease. 

The FDA previously approved sarilumab, an interleukin-6 receptor antagonist, in May 2017 for the treatment of moderate to severe active rheumatoid arthritis in adults who do not respond well or have an intolerance to disease-modifying antirheumatic drugs (DMARDs), like methotrexate.

Olivier Le Moal/Getty Images

The FDA approval for this new indication was based on results from the multicenter, phase 3 SAPHYR trial in patients with corticosteroid-resistant, active PMR. In the randomized, double-blind, placebo-controlled study, 59 participants received 200 mg of sarilumab plus a 14-week taper of corticosteroid treatment and 58 participants received placebo every 2 weeks along with a 52-week taper of corticosteroid treatment.

After 1 year, 28% of sarilumab patients achieved sustained remission, compared with 10% of the placebo group (P = .0193). This news organization previously reported these trial results in November when they were presented at the 2022 annual meeting of the American College of Rheumatology.

The most common adverse events in the sarilumab group were neutropenia (15%), leukopenia (7%), constipation (7%), pruritic rash (5%), myalgia (7%), fatigue (5%), and injection-site pruritus (5%). Two patients had serious adverse reactions of neutropenia, which resolved after discontinuing treatment.

“Polymyalgia rheumatica can be an incapacitating disease, causing painful disease flares in multiple parts of the bodies that leave people fatigued and unable to fully perform everyday activities. Corticosteroids have been the primary treatment to date, but many patients do not adequately respond to steroids or cannot be tapered off steroids, which puts such patients at risk of complications from long-term steroid therapy,” George D. Yancopolous, MD, PhD, president and chief scientific officer at Regeneron, said in the announcement. “With the approval of Kevzara for polymyalgia rheumatica, patients now have an FDA-approved treatment to help offer relief from the disabling symptoms of this disease and long-term dependence on steroids.”

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

Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”
 

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.
 

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”
 

Experts welcome the results

“It is well established that oral health impacts overall health. In particular, the link between periodontal disease and chronic systemic diseases has been explored in many robust studies,” Chi T. Viet, MD, DDS, PhD, oral and maxillofacial surgeon and associate professor at the Loma Linda (Calif.) University School of Dentistry, told this news organization.

“The study ... highlights the importance of early treatment and prevention of oral health issues, as they can have devastating systemic sequelae,” added Dr. Viet, who was not involved in the study.

Devon Charlton, MD, MPH, director of rheumatology at the University of Pittsburgh Medical Center Regional Orthopedics in New Castle, Pa., advised patients and providers to team up to manage RA and PD.

“If the patient and provider aggressively treat periodontal disease and dental health in general, the patient decreases their risk of infection and inflammation, decreases the potential development of RA, and increases their future quality of life,” said Dr. Charlton, also not involved in the study.

However, findings from the study population may be difficult to generalize to other populations, he added.

Dr. Orange and her colleagues suggest further related research, including studies on whether treating PD makes RA easier to treat and whether the treatment of PD in patients whose RA is in clinical remission raises the likelihood of being able to discontinue therapy safely.

The study was supported through grant funding from the National Institutes of Health, the National Science Foundation, the Robertson Foundation, Rockefeller University, the Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and the Rheumatology Research Foundation. Dr. Orange reports no relevant financial relationships. Several coauthors report financial relationships with the pharmaceutical industry. Dr. Viet and Dr. Charlton report no relevant financial relationships. All experts commented by email.

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

Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”
 

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.
 

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”
 

Experts welcome the results

“It is well established that oral health impacts overall health. In particular, the link between periodontal disease and chronic systemic diseases has been explored in many robust studies,” Chi T. Viet, MD, DDS, PhD, oral and maxillofacial surgeon and associate professor at the Loma Linda (Calif.) University School of Dentistry, told this news organization.

“The study ... highlights the importance of early treatment and prevention of oral health issues, as they can have devastating systemic sequelae,” added Dr. Viet, who was not involved in the study.

Devon Charlton, MD, MPH, director of rheumatology at the University of Pittsburgh Medical Center Regional Orthopedics in New Castle, Pa., advised patients and providers to team up to manage RA and PD.

“If the patient and provider aggressively treat periodontal disease and dental health in general, the patient decreases their risk of infection and inflammation, decreases the potential development of RA, and increases their future quality of life,” said Dr. Charlton, also not involved in the study.

However, findings from the study population may be difficult to generalize to other populations, he added.

Dr. Orange and her colleagues suggest further related research, including studies on whether treating PD makes RA easier to treat and whether the treatment of PD in patients whose RA is in clinical remission raises the likelihood of being able to discontinue therapy safely.

The study was supported through grant funding from the National Institutes of Health, the National Science Foundation, the Robertson Foundation, Rockefeller University, the Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and the Rheumatology Research Foundation. Dr. Orange reports no relevant financial relationships. Several coauthors report financial relationships with the pharmaceutical industry. Dr. Viet and Dr. Charlton report no relevant financial relationships. All experts commented by email.

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

Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”
 

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.
 

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”
 

Experts welcome the results

“It is well established that oral health impacts overall health. In particular, the link between periodontal disease and chronic systemic diseases has been explored in many robust studies,” Chi T. Viet, MD, DDS, PhD, oral and maxillofacial surgeon and associate professor at the Loma Linda (Calif.) University School of Dentistry, told this news organization.

“The study ... highlights the importance of early treatment and prevention of oral health issues, as they can have devastating systemic sequelae,” added Dr. Viet, who was not involved in the study.

Devon Charlton, MD, MPH, director of rheumatology at the University of Pittsburgh Medical Center Regional Orthopedics in New Castle, Pa., advised patients and providers to team up to manage RA and PD.

“If the patient and provider aggressively treat periodontal disease and dental health in general, the patient decreases their risk of infection and inflammation, decreases the potential development of RA, and increases their future quality of life,” said Dr. Charlton, also not involved in the study.

However, findings from the study population may be difficult to generalize to other populations, he added.

Dr. Orange and her colleagues suggest further related research, including studies on whether treating PD makes RA easier to treat and whether the treatment of PD in patients whose RA is in clinical remission raises the likelihood of being able to discontinue therapy safely.

The study was supported through grant funding from the National Institutes of Health, the National Science Foundation, the Robertson Foundation, Rockefeller University, the Bernard and Irene Schwartz Foundation, the Iris and Junming Le Foundation, and the Rheumatology Research Foundation. Dr. Orange reports no relevant financial relationships. Several coauthors report financial relationships with the pharmaceutical industry. Dr. Viet and Dr. Charlton report no relevant financial relationships. All experts commented by email.

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

While most providers think that biosimilars will positively impact care, few feel that the economic benefits of biosimilars to date are enough to motivate switching.

Fuse/Thinkstock

In a new survey of over 350 dermatologists, gastroenterologists, ophthalmologists, and rheumatologists, clinicians shared their opinions on the rapidly evolving landscape of biosimilars, detailing top concerns about prescribing these medications and how they presently use biosimilars in clinical practice. Across all specialties, providers said they would be most likely to prescribe biosimilars to new patients or if a patient’s health plan mandated the switch. Most providers listed concerns about biosimilar efficacy and lack of economic benefit as the main barriers to adoption of biosimilars in clinical practice.

Cardinal Health, a health care services company based in Dublin, Ohio, conducted the surveys from July through October 2022.
 

Rheumatologists want cost-savings for patients

2023 is gearing up to be a big year for biosimilars for inflammatory diseases, with at least eight adalimumab biosimilars entering the market in the United States. Amjevita, manufactured by Amgen, was the first to become commercially available on Jan. 31. Out of 103 surveyed rheumatologists, 62% said they were very comfortable prescribing biosimilars to patients, and 32% said they were somewhat comfortable. Providers said they would be most likely to prescribe a biosimilar to new patients (40%) or if biosimilars were mandated by a patient’s health plan (41%). Nearly one-third (31%) of rheumatologists said that a discount of 21%-30% from a reference product would be necessary to consider switching a patient to a biosimilar.

There are several reasons why a rheumatologist might be wary of switching patients to biosimilars, said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “Rheumatologists will always express concern about changing medications that work well for their patients. It is not ideal to ‘force switch’ to a different product, even if it is almost identical,” he told this news organization in an email. “Also, we must remember that a patient on a biologic has failed traditional medications, which speaks to the struggle a patient must endure to get their disease under control. Fail-first situations can cause a rheumatologist to be initially resistant or hesitant to any changes.”

The top concerns among rheumatologists about prescribing biosimilars were medication efficacy (36%), lack of economic benefit (24%), and evaluating when to prescribe a biosimilar versus a reference product (17%). For adalimumab biosimilars, rheumatologists said that interchangeability – a regulatory designation where a biosimilar can be automatically substituted for its reference product at the pharmacy – and citrate-free formulation were the most important product attributes. Sixty-four percent of providers also noted that patient out-of-pocket cost would be key when deciding to prescribe an adalimumab biosimilar.

“There needs to be a true reduction in price, to change providers’ opinions on the economic benefits of biosimilars – in the system generally and for the patient,” Dr. Snow said. “Things will get there eventually, but it is not there yet, based on the list prices we see for some biosimilars.”
 

Gastroenterologists emphasize patient education

Gastroenterology is another specialty to be affected by the influx of adalimumab biosimilars. Out of 72 surveyed gastroenterologists, 86% said they were very comfortable prescribing biosimilars. About half (49%) said they would be most likely to prescribe a biosimilar to patients with health plans mandating a biosimilar. More than 60% of surveyed gastroenterologists said that biosimilars would positively impact care; providers were divided on the current economic benefits of biosimilars, with 36% saying that the current discounts on biosimilars versus reference products were not favorable enough to motivate switching, and 35% stating that they were. A total of 40% of surveyed providers said that savings of 21%-30%, compared with savings of a reference product, would motivate them to switch patients to a biosimilar, with all other clinical factors being equal.

Gastroenterologists said that, along with the efficacy and cost savings of biosimilars, providing patient education (18%) was a top concern when prescribing biosimilars. Eighty-four percent of respondents said that educating patients about biosimilars as safe and effective treatment options was at least somewhat important. Nearly all participants (99%) cited device ease-of-use as at least somewhat important when considering prescribing adalimumab biosimilars, in addition to interchangeability (97%) and citrate-free formulation (93%).

“Despite general acceptance of biosimilars, there remains some uncertainty regarding their place in the current gastroenterology landscape,” wrote Vivek Kaul, MD, a professor of medicine at the University of Rochester (N.Y.) Medical Center, in the report. “This is likely because only half of the survey respondents believed that biosimilars will positively impact gastroenterology care, further highlighting the ongoing need for real-world data and incorporation of biosimilar use and interchangeability into clinical guidelines.”

Few dermatologists currently prescribe biosimilars

Eight out of ten dermatologists reported being at least somewhat comfortable prescribing biosimilars to patients, though fewer than 20% said they had prescribed a biosimilar in the past year. This indicates limited adoption of infliximab biosimilars, which were the only biosimilars with a dermatologic indication available in 2022, Alex Gross, MD, a dermatologist in Cumming, Ga., noted in his featured commentary in the report. Just 15% of respondents disagreed that biosimilars would have a positive impact on care, and 41% said they were excited about new biosimilars becoming available.

About half (47%) of dermatologists thought the economic benefits of biosimilars were not strong enough to motivate switching patients from reference products. Twenty-nine percent of respondents said that discounts of 21%-30% from a reference product would motivate them to switch patients to a biosimilar, with all other clinical factors being equal, while 20% said they were not likely to prescribe a biosimilar regardless of savings.

Dermatologists may be concerned that these cost savings may not be passed onto patients, said Alison Ehrlich, MD, a dermatologist in Washington, in an email to this news organization. Patient out-of-pocket cost savings would need to be “both significant and transparent” to begin to change providers’ minds, she noted.

Biosimilar efficacy was a top concern for 48% of dermatologists, while 13% said their main concern around prescribing biosimilars was lack of payer adoption. At least 95% of providers said that device ease-of-use and interchangeability were the most important attributes when considering adalimumab biosimilars. Nearly two-thirds (65%) reported that patient out-of-pocket cost would be key when deciding to prescribe an adalimumab biosimilar.

If both patients and providers are informed on biosimilar use and there are cost benefits, dermatologists’ opinions may become more favorable toward biosimilars, but that will take time, Dr. Ehrlich said. “We are very early in the game for biosimilar use in dermatology,” she added.
 

Ophthalmologists remain wary

Biosimilars have been relatively new to ophthalmology, with the first ranibizumab biosimilar becoming commercially available in July 2022. In the survey, 64 retina specialists were asked different questions than participants from other specialties to gauge ophthalmologists› familiarity with the biosimilars approval process and their overall comfort prescribing these medications. The primary concerns with prescribing biosimilars among respondents was payer coverage (52%), being uncomfortable with biosimilars from a clinical standpoint (48%), and administrative barriers (45%), such as prior authorization. Despite this lack of comfort with biosimilars, two-thirds of participants thought the U.S. Food and Drug Administration approval process for these medications was sufficient to evaluate their efficacy and safety. Still, fewer than half (48%) of providers said they do or would prescribe biosimilars.

George Williams, MD, a spokesperson for the American Academy of Ophthalmology, noted that the FDA approval process for biosimilars was not as rigorous as for the respective reference product, and fewer patients are followed over a shorter time period. “Since anti–[vascular endothelial growth factor (VEGF)] therapy for indications such as neovascular age-related macular degeneration continues indefinitely over years, ophthalmologists may have concerns about the long-term efficacy and safety when applied to larger real-world populations. Ophthalmologists are well aware of safety issues with VEGF inhibitors arising after FDA approval,” he told this news organization in an email.

When asked about the likelihood of using either aflibercept or ranibizumab biosimilars in their clinical practice once commercially available, 70% of ophthalmologists said they would be at least somewhat likely to prescribe aflibercept biosimilars, and 64% said they would be at least somewhat likely to prescribe ranibizumab biosimilars. About half of respondents said they would not likely switch a currently stable patient on either aflibercept or ranibizumab to the corresponding biosimilar. More than half of ophthalmologists (56%) said they would prescribe a biosimilar only if it had an interchangeability designation.

Out of all four specialties, ophthalmologists more frequently reported that higher discounts from a reference product would be necessary to consider switching a patient to a biosimilar. Currently, many ophthalmologists are comfortable with the off-label use of bevacizumab (Avastin) for treating wet age-related macular degeneration, which also offers more cost savings than any currently available biosimilar on the market, Dr. Williams said.

While the limited number of respondents makes it difficult to draw concrete conclusions, Dr. Williams emphasized that the AAO supported the use of biosimilars. “We believe that with clinical experience ophthalmic biosimilars will become useful therapeutic agents,” he noted.

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

While most providers think that biosimilars will positively impact care, few feel that the economic benefits of biosimilars to date are enough to motivate switching.

Fuse/Thinkstock

In a new survey of over 350 dermatologists, gastroenterologists, ophthalmologists, and rheumatologists, clinicians shared their opinions on the rapidly evolving landscape of biosimilars, detailing top concerns about prescribing these medications and how they presently use biosimilars in clinical practice. Across all specialties, providers said they would be most likely to prescribe biosimilars to new patients or if a patient’s health plan mandated the switch. Most providers listed concerns about biosimilar efficacy and lack of economic benefit as the main barriers to adoption of biosimilars in clinical practice.

Cardinal Health, a health care services company based in Dublin, Ohio, conducted the surveys from July through October 2022.
 

Rheumatologists want cost-savings for patients

2023 is gearing up to be a big year for biosimilars for inflammatory diseases, with at least eight adalimumab biosimilars entering the market in the United States. Amjevita, manufactured by Amgen, was the first to become commercially available on Jan. 31. Out of 103 surveyed rheumatologists, 62% said they were very comfortable prescribing biosimilars to patients, and 32% said they were somewhat comfortable. Providers said they would be most likely to prescribe a biosimilar to new patients (40%) or if biosimilars were mandated by a patient’s health plan (41%). Nearly one-third (31%) of rheumatologists said that a discount of 21%-30% from a reference product would be necessary to consider switching a patient to a biosimilar.

There are several reasons why a rheumatologist might be wary of switching patients to biosimilars, said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “Rheumatologists will always express concern about changing medications that work well for their patients. It is not ideal to ‘force switch’ to a different product, even if it is almost identical,” he told this news organization in an email. “Also, we must remember that a patient on a biologic has failed traditional medications, which speaks to the struggle a patient must endure to get their disease under control. Fail-first situations can cause a rheumatologist to be initially resistant or hesitant to any changes.”

The top concerns among rheumatologists about prescribing biosimilars were medication efficacy (36%), lack of economic benefit (24%), and evaluating when to prescribe a biosimilar versus a reference product (17%). For adalimumab biosimilars, rheumatologists said that interchangeability – a regulatory designation where a biosimilar can be automatically substituted for its reference product at the pharmacy – and citrate-free formulation were the most important product attributes. Sixty-four percent of providers also noted that patient out-of-pocket cost would be key when deciding to prescribe an adalimumab biosimilar.

“There needs to be a true reduction in price, to change providers’ opinions on the economic benefits of biosimilars – in the system generally and for the patient,” Dr. Snow said. “Things will get there eventually, but it is not there yet, based on the list prices we see for some biosimilars.”
 

Gastroenterologists emphasize patient education

Gastroenterology is another specialty to be affected by the influx of adalimumab biosimilars. Out of 72 surveyed gastroenterologists, 86% said they were very comfortable prescribing biosimilars. About half (49%) said they would be most likely to prescribe a biosimilar to patients with health plans mandating a biosimilar. More than 60% of surveyed gastroenterologists said that biosimilars would positively impact care; providers were divided on the current economic benefits of biosimilars, with 36% saying that the current discounts on biosimilars versus reference products were not favorable enough to motivate switching, and 35% stating that they were. A total of 40% of surveyed providers said that savings of 21%-30%, compared with savings of a reference product, would motivate them to switch patients to a biosimilar, with all other clinical factors being equal.

Gastroenterologists said that, along with the efficacy and cost savings of biosimilars, providing patient education (18%) was a top concern when prescribing biosimilars. Eighty-four percent of respondents said that educating patients about biosimilars as safe and effective treatment options was at least somewhat important. Nearly all participants (99%) cited device ease-of-use as at least somewhat important when considering prescribing adalimumab biosimilars, in addition to interchangeability (97%) and citrate-free formulation (93%).

“Despite general acceptance of biosimilars, there remains some uncertainty regarding their place in the current gastroenterology landscape,” wrote Vivek Kaul, MD, a professor of medicine at the University of Rochester (N.Y.) Medical Center, in the report. “This is likely because only half of the survey respondents believed that biosimilars will positively impact gastroenterology care, further highlighting the ongoing need for real-world data and incorporation of biosimilar use and interchangeability into clinical guidelines.”

Few dermatologists currently prescribe biosimilars

Eight out of ten dermatologists reported being at least somewhat comfortable prescribing biosimilars to patients, though fewer than 20% said they had prescribed a biosimilar in the past year. This indicates limited adoption of infliximab biosimilars, which were the only biosimilars with a dermatologic indication available in 2022, Alex Gross, MD, a dermatologist in Cumming, Ga., noted in his featured commentary in the report. Just 15% of respondents disagreed that biosimilars would have a positive impact on care, and 41% said they were excited about new biosimilars becoming available.

About half (47%) of dermatologists thought the economic benefits of biosimilars were not strong enough to motivate switching patients from reference products. Twenty-nine percent of respondents said that discounts of 21%-30% from a reference product would motivate them to switch patients to a biosimilar, with all other clinical factors being equal, while 20% said they were not likely to prescribe a biosimilar regardless of savings.

Dermatologists may be concerned that these cost savings may not be passed onto patients, said Alison Ehrlich, MD, a dermatologist in Washington, in an email to this news organization. Patient out-of-pocket cost savings would need to be “both significant and transparent” to begin to change providers’ minds, she noted.

Biosimilar efficacy was a top concern for 48% of dermatologists, while 13% said their main concern around prescribing biosimilars was lack of payer adoption. At least 95% of providers said that device ease-of-use and interchangeability were the most important attributes when considering adalimumab biosimilars. Nearly two-thirds (65%) reported that patient out-of-pocket cost would be key when deciding to prescribe an adalimumab biosimilar.

If both patients and providers are informed on biosimilar use and there are cost benefits, dermatologists’ opinions may become more favorable toward biosimilars, but that will take time, Dr. Ehrlich said. “We are very early in the game for biosimilar use in dermatology,” she added.
 

Ophthalmologists remain wary

Biosimilars have been relatively new to ophthalmology, with the first ranibizumab biosimilar becoming commercially available in July 2022. In the survey, 64 retina specialists were asked different questions than participants from other specialties to gauge ophthalmologists› familiarity with the biosimilars approval process and their overall comfort prescribing these medications. The primary concerns with prescribing biosimilars among respondents was payer coverage (52%), being uncomfortable with biosimilars from a clinical standpoint (48%), and administrative barriers (45%), such as prior authorization. Despite this lack of comfort with biosimilars, two-thirds of participants thought the U.S. Food and Drug Administration approval process for these medications was sufficient to evaluate their efficacy and safety. Still, fewer than half (48%) of providers said they do or would prescribe biosimilars.

George Williams, MD, a spokesperson for the American Academy of Ophthalmology, noted that the FDA approval process for biosimilars was not as rigorous as for the respective reference product, and fewer patients are followed over a shorter time period. “Since anti–[vascular endothelial growth factor (VEGF)] therapy for indications such as neovascular age-related macular degeneration continues indefinitely over years, ophthalmologists may have concerns about the long-term efficacy and safety when applied to larger real-world populations. Ophthalmologists are well aware of safety issues with VEGF inhibitors arising after FDA approval,” he told this news organization in an email.

When asked about the likelihood of using either aflibercept or ranibizumab biosimilars in their clinical practice once commercially available, 70% of ophthalmologists said they would be at least somewhat likely to prescribe aflibercept biosimilars, and 64% said they would be at least somewhat likely to prescribe ranibizumab biosimilars. About half of respondents said they would not likely switch a currently stable patient on either aflibercept or ranibizumab to the corresponding biosimilar. More than half of ophthalmologists (56%) said they would prescribe a biosimilar only if it had an interchangeability designation.

Out of all four specialties, ophthalmologists more frequently reported that higher discounts from a reference product would be necessary to consider switching a patient to a biosimilar. Currently, many ophthalmologists are comfortable with the off-label use of bevacizumab (Avastin) for treating wet age-related macular degeneration, which also offers more cost savings than any currently available biosimilar on the market, Dr. Williams said.

While the limited number of respondents makes it difficult to draw concrete conclusions, Dr. Williams emphasized that the AAO supported the use of biosimilars. “We believe that with clinical experience ophthalmic biosimilars will become useful therapeutic agents,” he noted.

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

While most providers think that biosimilars will positively impact care, few feel that the economic benefits of biosimilars to date are enough to motivate switching.

Fuse/Thinkstock

In a new survey of over 350 dermatologists, gastroenterologists, ophthalmologists, and rheumatologists, clinicians shared their opinions on the rapidly evolving landscape of biosimilars, detailing top concerns about prescribing these medications and how they presently use biosimilars in clinical practice. Across all specialties, providers said they would be most likely to prescribe biosimilars to new patients or if a patient’s health plan mandated the switch. Most providers listed concerns about biosimilar efficacy and lack of economic benefit as the main barriers to adoption of biosimilars in clinical practice.

Cardinal Health, a health care services company based in Dublin, Ohio, conducted the surveys from July through October 2022.
 

Rheumatologists want cost-savings for patients

2023 is gearing up to be a big year for biosimilars for inflammatory diseases, with at least eight adalimumab biosimilars entering the market in the United States. Amjevita, manufactured by Amgen, was the first to become commercially available on Jan. 31. Out of 103 surveyed rheumatologists, 62% said they were very comfortable prescribing biosimilars to patients, and 32% said they were somewhat comfortable. Providers said they would be most likely to prescribe a biosimilar to new patients (40%) or if biosimilars were mandated by a patient’s health plan (41%). Nearly one-third (31%) of rheumatologists said that a discount of 21%-30% from a reference product would be necessary to consider switching a patient to a biosimilar.

There are several reasons why a rheumatologist might be wary of switching patients to biosimilars, said Marcus Snow, MD, chair of the American College of Rheumatology’s Committee on Rheumatologic Care. “Rheumatologists will always express concern about changing medications that work well for their patients. It is not ideal to ‘force switch’ to a different product, even if it is almost identical,” he told this news organization in an email. “Also, we must remember that a patient on a biologic has failed traditional medications, which speaks to the struggle a patient must endure to get their disease under control. Fail-first situations can cause a rheumatologist to be initially resistant or hesitant to any changes.”

The top concerns among rheumatologists about prescribing biosimilars were medication efficacy (36%), lack of economic benefit (24%), and evaluating when to prescribe a biosimilar versus a reference product (17%). For adalimumab biosimilars, rheumatologists said that interchangeability – a regulatory designation where a biosimilar can be automatically substituted for its reference product at the pharmacy – and citrate-free formulation were the most important product attributes. Sixty-four percent of providers also noted that patient out-of-pocket cost would be key when deciding to prescribe an adalimumab biosimilar.

“There needs to be a true reduction in price, to change providers’ opinions on the economic benefits of biosimilars – in the system generally and for the patient,” Dr. Snow said. “Things will get there eventually, but it is not there yet, based on the list prices we see for some biosimilars.”
 

Gastroenterologists emphasize patient education

Gastroenterology is another specialty to be affected by the influx of adalimumab biosimilars. Out of 72 surveyed gastroenterologists, 86% said they were very comfortable prescribing biosimilars. About half (49%) said they would be most likely to prescribe a biosimilar to patients with health plans mandating a biosimilar. More than 60% of surveyed gastroenterologists said that biosimilars would positively impact care; providers were divided on the current economic benefits of biosimilars, with 36% saying that the current discounts on biosimilars versus reference products were not favorable enough to motivate switching, and 35% stating that they were. A total of 40% of surveyed providers said that savings of 21%-30%, compared with savings of a reference product, would motivate them to switch patients to a biosimilar, with all other clinical factors being equal.

Gastroenterologists said that, along with the efficacy and cost savings of biosimilars, providing patient education (18%) was a top concern when prescribing biosimilars. Eighty-four percent of respondents said that educating patients about biosimilars as safe and effective treatment options was at least somewhat important. Nearly all participants (99%) cited device ease-of-use as at least somewhat important when considering prescribing adalimumab biosimilars, in addition to interchangeability (97%) and citrate-free formulation (93%).

“Despite general acceptance of biosimilars, there remains some uncertainty regarding their place in the current gastroenterology landscape,” wrote Vivek Kaul, MD, a professor of medicine at the University of Rochester (N.Y.) Medical Center, in the report. “This is likely because only half of the survey respondents believed that biosimilars will positively impact gastroenterology care, further highlighting the ongoing need for real-world data and incorporation of biosimilar use and interchangeability into clinical guidelines.”

Few dermatologists currently prescribe biosimilars

Eight out of ten dermatologists reported being at least somewhat comfortable prescribing biosimilars to patients, though fewer than 20% said they had prescribed a biosimilar in the past year. This indicates limited adoption of infliximab biosimilars, which were the only biosimilars with a dermatologic indication available in 2022, Alex Gross, MD, a dermatologist in Cumming, Ga., noted in his featured commentary in the report. Just 15% of respondents disagreed that biosimilars would have a positive impact on care, and 41% said they were excited about new biosimilars becoming available.

About half (47%) of dermatologists thought the economic benefits of biosimilars were not strong enough to motivate switching patients from reference products. Twenty-nine percent of respondents said that discounts of 21%-30% from a reference product would motivate them to switch patients to a biosimilar, with all other clinical factors being equal, while 20% said they were not likely to prescribe a biosimilar regardless of savings.

Dermatologists may be concerned that these cost savings may not be passed onto patients, said Alison Ehrlich, MD, a dermatologist in Washington, in an email to this news organization. Patient out-of-pocket cost savings would need to be “both significant and transparent” to begin to change providers’ minds, she noted.

Biosimilar efficacy was a top concern for 48% of dermatologists, while 13% said their main concern around prescribing biosimilars was lack of payer adoption. At least 95% of providers said that device ease-of-use and interchangeability were the most important attributes when considering adalimumab biosimilars. Nearly two-thirds (65%) reported that patient out-of-pocket cost would be key when deciding to prescribe an adalimumab biosimilar.

If both patients and providers are informed on biosimilar use and there are cost benefits, dermatologists’ opinions may become more favorable toward biosimilars, but that will take time, Dr. Ehrlich said. “We are very early in the game for biosimilar use in dermatology,” she added.
 

Ophthalmologists remain wary

Biosimilars have been relatively new to ophthalmology, with the first ranibizumab biosimilar becoming commercially available in July 2022. In the survey, 64 retina specialists were asked different questions than participants from other specialties to gauge ophthalmologists› familiarity with the biosimilars approval process and their overall comfort prescribing these medications. The primary concerns with prescribing biosimilars among respondents was payer coverage (52%), being uncomfortable with biosimilars from a clinical standpoint (48%), and administrative barriers (45%), such as prior authorization. Despite this lack of comfort with biosimilars, two-thirds of participants thought the U.S. Food and Drug Administration approval process for these medications was sufficient to evaluate their efficacy and safety. Still, fewer than half (48%) of providers said they do or would prescribe biosimilars.

George Williams, MD, a spokesperson for the American Academy of Ophthalmology, noted that the FDA approval process for biosimilars was not as rigorous as for the respective reference product, and fewer patients are followed over a shorter time period. “Since anti–[vascular endothelial growth factor (VEGF)] therapy for indications such as neovascular age-related macular degeneration continues indefinitely over years, ophthalmologists may have concerns about the long-term efficacy and safety when applied to larger real-world populations. Ophthalmologists are well aware of safety issues with VEGF inhibitors arising after FDA approval,” he told this news organization in an email.

When asked about the likelihood of using either aflibercept or ranibizumab biosimilars in their clinical practice once commercially available, 70% of ophthalmologists said they would be at least somewhat likely to prescribe aflibercept biosimilars, and 64% said they would be at least somewhat likely to prescribe ranibizumab biosimilars. About half of respondents said they would not likely switch a currently stable patient on either aflibercept or ranibizumab to the corresponding biosimilar. More than half of ophthalmologists (56%) said they would prescribe a biosimilar only if it had an interchangeability designation.

Out of all four specialties, ophthalmologists more frequently reported that higher discounts from a reference product would be necessary to consider switching a patient to a biosimilar. Currently, many ophthalmologists are comfortable with the off-label use of bevacizumab (Avastin) for treating wet age-related macular degeneration, which also offers more cost savings than any currently available biosimilar on the market, Dr. Williams said.

While the limited number of respondents makes it difficult to draw concrete conclusions, Dr. Williams emphasized that the AAO supported the use of biosimilars. “We believe that with clinical experience ophthalmic biosimilars will become useful therapeutic agents,” he noted.

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

The latest guideline for perioperative management of antirheumatic medication in patients undergoing total hip (THA) and total knee arthroplasty (TKA) offers recommendations based on the latest evidence, but many of those recommendations are based on a low level of evidence, according to a speaker at the 2023 Rheumatology Winter Clinical Symposium.

Martin Bergman, MD, clinical professor of medicine at Drexel University, Philadelphia, said the development of the American College of Rheumatology/American Association of Hip and Knee Surgeons guideline was necessary because there was a lack of consensus on when to stop treatments prior to patients with rheumatologic disease undergoing THA and TKA, and when it was appropriate to restart those treatments.

“We all were having the same problem, and I think everybody recognized that just stopping medicines forever didn’t make sense, but maybe continuing medicines also didn’t make sense,” Dr. Bergman said.

While the 2017 ACR/AAHKS perioperative management guideline contained good recommendations, the “explosion” of new medications in rheumatology made it necessary to update the guideline with the latest data on new medications such as immunosuppressants.
 

2022 guideline recommendations

In the 2022 guideline, which covers disease-modifying treatments taken by patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis, the authors reaffirmed their recommendations to continue methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and apremilast through total joint arthroplasty.

Where the 2022 guideline differs from the 2017 guideline is in which biologics are covered and under what circumstances they should be withheld and restarted around surgery. The 2022 guideline includes recommendations for abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, rituximab, secukinumab, tocilizumab, and ustekinumab. Each biologic has its own recommended stop and restart times based around the dosing interval and respective method of administration. Dr. Bergman said a general rule with biologics under the new guideline is that the timing of surgery should occur approximately 1 week after the first missed dose of the medication. The only biologic that does not follow this pattern is rituximab, where surgery should be planned for 1 month after the last missed dose.

Dr. Bergman noted that how the guidelines handle interval dosing with infliximab may present a problem. The guideline provides recommendations for patients receiving infliximab every 4 weeks, every 6 weeks, and every 8 weeks. However, Dr. Bergman said this can create a scenario where a patient receiving infliximab at a dose of 3 mg/kg every 8 weeks has surgery at 9 weeks, a patient receiving 5 mg/kg every 6 weeks has surgery at 7 weeks, and a patient receiving 10 mg/kg every 4 weeks has surgery at 5 weeks. “There is some intellectual problem with it,” he said.

Another change from the 2017 guideline is how long to wait for surgery after stopping Janus kinase inhibitors. While the 2017 guideline recommended withholding JAK inhibitors 7 days before surgery, the 2022 guideline lowered that waiting period to 3 days, Dr. Bergman explained.

Concerning use of steroids around THA and TKA surgery, “the days of stress steroid dosing are done,” Dr. Bergman said. “You don’t have to stress dose them. You just follow them, and you keep them on their steroid dose.”

The new guideline recommends restarting therapy once the wound is healed and there is no physical evidence of infection at approximately 2 weeks. “There’s no data to support this,” he said, and his concern is that patients who have stopped a tumor necrosis factor inhibitor may flare if they don’t restart their medication.

While the guideline also covered recommendations for systemic lupus erythematosus, they are “very similar” to the recommendations for inflammatory arthritis, Dr. Bergman noted. “If you have somebody who is not very sick, you stop the medications,” he said, “but try to stop anything else about a week before the surgery. If they’re sick, you basically have to keep them on their medications.”
 

Caveats in guideline

The recommendations in the 2022 guideline come with a number of caveats, Dr. Bergman noted. For instance, the authors acknowledged limitations in the guideline regarding providing recommendations for only THA and TKA, the “paucity of evidence” around direct infection risk resulting from medications in the perioperative period for THA and TKA, the nonseparation of biologics when assessing infection risk, and the use of dosing interval as a metric for stopping the drug without considering the drug’s half-life.

A “crucial caveat,” Dr. Bergman said, was that the guideline focused on infection risk based on a statement from a panel of patients prior to the development of the 2017 guideline, which “stated very clearly any risk of infection, while rare, was more significant to them than the possibility of postoperative flares, despite flares being reported in over 60% of patients after surgery.

“For the patients, the paramount question was infection, infection, infection, infection. That’s all they cared about, and that is the basis behind a lot of the decision-making here,” Dr. Bergman said.

Another caveat came from a communication Dr. Bergman received from one of the panel members. The panel member noted there were no conclusions or recommendations provided in the guideline for how to manage perioperative flares, such as restarting a corticosteroid or biologic agent. “There was a lot of discussion about what to do with steroids if patients flare, or what to do with [other] medications if they flare, and they just couldn’t come to a consensus,” Dr. Bergman said. “It’s just not discussed.”

Dr. Bergman said he is “somewhat critical” of the ACR/AAHKS guideline, but noted it is an “ambitious project” given the lack of evidence for the recommendations. “The alternative was stop the medications forever and having people really flare, or at least try to get some semblance of rationality behind what we’re going to do,” he said.
 

Response from attendees

Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, took issue with the new recommendations surrounding stopping infliximab. When giving a patient infliximab every 8 weeks at 3 mg/kg, “you’re giving [it] at the nadir of the drug,” he said.

Rather than drug half-life, “it’s about inflammation,” he emphasized. “Inflammation is dominant in causing infection. It drives risk more than anything. The worst thing you can do is wash someone out.

“If you’re going beyond 8 weeks on infliximab, you’re getting closer to washing them out,” he pointed out. “I think it’s a really bad idea.”

Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at Hospital for Special Surgery, both in New York, explained that the guideline is not standard of care, which would be subject to malpractice if not implemented properly.

“When you have guidelines, you follow them unless there are clinical situations which would necessitate another approach to the patient,” he said. “Professional institutions and associations will never put forth rules, they will put forth guidelines so you have the opportunity to deviate from them when the appropriate clinical situation dictates.”

Dr. Bergman reported being a speaker and consultant for AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, and Regeneron; he holds stock in Johnson & Johnson and Merck.

The latest guideline for perioperative management of antirheumatic medication in patients undergoing total hip (THA) and total knee arthroplasty (TKA) offers recommendations based on the latest evidence, but many of those recommendations are based on a low level of evidence, according to a speaker at the 2023 Rheumatology Winter Clinical Symposium.

Martin Bergman, MD, clinical professor of medicine at Drexel University, Philadelphia, said the development of the American College of Rheumatology/American Association of Hip and Knee Surgeons guideline was necessary because there was a lack of consensus on when to stop treatments prior to patients with rheumatologic disease undergoing THA and TKA, and when it was appropriate to restart those treatments.

“We all were having the same problem, and I think everybody recognized that just stopping medicines forever didn’t make sense, but maybe continuing medicines also didn’t make sense,” Dr. Bergman said.

While the 2017 ACR/AAHKS perioperative management guideline contained good recommendations, the “explosion” of new medications in rheumatology made it necessary to update the guideline with the latest data on new medications such as immunosuppressants.
 

2022 guideline recommendations

In the 2022 guideline, which covers disease-modifying treatments taken by patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis, the authors reaffirmed their recommendations to continue methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and apremilast through total joint arthroplasty.

Where the 2022 guideline differs from the 2017 guideline is in which biologics are covered and under what circumstances they should be withheld and restarted around surgery. The 2022 guideline includes recommendations for abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, rituximab, secukinumab, tocilizumab, and ustekinumab. Each biologic has its own recommended stop and restart times based around the dosing interval and respective method of administration. Dr. Bergman said a general rule with biologics under the new guideline is that the timing of surgery should occur approximately 1 week after the first missed dose of the medication. The only biologic that does not follow this pattern is rituximab, where surgery should be planned for 1 month after the last missed dose.

Dr. Bergman noted that how the guidelines handle interval dosing with infliximab may present a problem. The guideline provides recommendations for patients receiving infliximab every 4 weeks, every 6 weeks, and every 8 weeks. However, Dr. Bergman said this can create a scenario where a patient receiving infliximab at a dose of 3 mg/kg every 8 weeks has surgery at 9 weeks, a patient receiving 5 mg/kg every 6 weeks has surgery at 7 weeks, and a patient receiving 10 mg/kg every 4 weeks has surgery at 5 weeks. “There is some intellectual problem with it,” he said.

Another change from the 2017 guideline is how long to wait for surgery after stopping Janus kinase inhibitors. While the 2017 guideline recommended withholding JAK inhibitors 7 days before surgery, the 2022 guideline lowered that waiting period to 3 days, Dr. Bergman explained.

Concerning use of steroids around THA and TKA surgery, “the days of stress steroid dosing are done,” Dr. Bergman said. “You don’t have to stress dose them. You just follow them, and you keep them on their steroid dose.”

The new guideline recommends restarting therapy once the wound is healed and there is no physical evidence of infection at approximately 2 weeks. “There’s no data to support this,” he said, and his concern is that patients who have stopped a tumor necrosis factor inhibitor may flare if they don’t restart their medication.

While the guideline also covered recommendations for systemic lupus erythematosus, they are “very similar” to the recommendations for inflammatory arthritis, Dr. Bergman noted. “If you have somebody who is not very sick, you stop the medications,” he said, “but try to stop anything else about a week before the surgery. If they’re sick, you basically have to keep them on their medications.”
 

Caveats in guideline

The recommendations in the 2022 guideline come with a number of caveats, Dr. Bergman noted. For instance, the authors acknowledged limitations in the guideline regarding providing recommendations for only THA and TKA, the “paucity of evidence” around direct infection risk resulting from medications in the perioperative period for THA and TKA, the nonseparation of biologics when assessing infection risk, and the use of dosing interval as a metric for stopping the drug without considering the drug’s half-life.

A “crucial caveat,” Dr. Bergman said, was that the guideline focused on infection risk based on a statement from a panel of patients prior to the development of the 2017 guideline, which “stated very clearly any risk of infection, while rare, was more significant to them than the possibility of postoperative flares, despite flares being reported in over 60% of patients after surgery.

“For the patients, the paramount question was infection, infection, infection, infection. That’s all they cared about, and that is the basis behind a lot of the decision-making here,” Dr. Bergman said.

Another caveat came from a communication Dr. Bergman received from one of the panel members. The panel member noted there were no conclusions or recommendations provided in the guideline for how to manage perioperative flares, such as restarting a corticosteroid or biologic agent. “There was a lot of discussion about what to do with steroids if patients flare, or what to do with [other] medications if they flare, and they just couldn’t come to a consensus,” Dr. Bergman said. “It’s just not discussed.”

Dr. Bergman said he is “somewhat critical” of the ACR/AAHKS guideline, but noted it is an “ambitious project” given the lack of evidence for the recommendations. “The alternative was stop the medications forever and having people really flare, or at least try to get some semblance of rationality behind what we’re going to do,” he said.
 

Response from attendees

Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, took issue with the new recommendations surrounding stopping infliximab. When giving a patient infliximab every 8 weeks at 3 mg/kg, “you’re giving [it] at the nadir of the drug,” he said.

Rather than drug half-life, “it’s about inflammation,” he emphasized. “Inflammation is dominant in causing infection. It drives risk more than anything. The worst thing you can do is wash someone out.

“If you’re going beyond 8 weeks on infliximab, you’re getting closer to washing them out,” he pointed out. “I think it’s a really bad idea.”

Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at Hospital for Special Surgery, both in New York, explained that the guideline is not standard of care, which would be subject to malpractice if not implemented properly.

“When you have guidelines, you follow them unless there are clinical situations which would necessitate another approach to the patient,” he said. “Professional institutions and associations will never put forth rules, they will put forth guidelines so you have the opportunity to deviate from them when the appropriate clinical situation dictates.”

Dr. Bergman reported being a speaker and consultant for AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, and Regeneron; he holds stock in Johnson & Johnson and Merck.

The latest guideline for perioperative management of antirheumatic medication in patients undergoing total hip (THA) and total knee arthroplasty (TKA) offers recommendations based on the latest evidence, but many of those recommendations are based on a low level of evidence, according to a speaker at the 2023 Rheumatology Winter Clinical Symposium.

Martin Bergman, MD, clinical professor of medicine at Drexel University, Philadelphia, said the development of the American College of Rheumatology/American Association of Hip and Knee Surgeons guideline was necessary because there was a lack of consensus on when to stop treatments prior to patients with rheumatologic disease undergoing THA and TKA, and when it was appropriate to restart those treatments.

“We all were having the same problem, and I think everybody recognized that just stopping medicines forever didn’t make sense, but maybe continuing medicines also didn’t make sense,” Dr. Bergman said.

While the 2017 ACR/AAHKS perioperative management guideline contained good recommendations, the “explosion” of new medications in rheumatology made it necessary to update the guideline with the latest data on new medications such as immunosuppressants.
 

2022 guideline recommendations

In the 2022 guideline, which covers disease-modifying treatments taken by patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis, the authors reaffirmed their recommendations to continue methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and apremilast through total joint arthroplasty.

Where the 2022 guideline differs from the 2017 guideline is in which biologics are covered and under what circumstances they should be withheld and restarted around surgery. The 2022 guideline includes recommendations for abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, rituximab, secukinumab, tocilizumab, and ustekinumab. Each biologic has its own recommended stop and restart times based around the dosing interval and respective method of administration. Dr. Bergman said a general rule with biologics under the new guideline is that the timing of surgery should occur approximately 1 week after the first missed dose of the medication. The only biologic that does not follow this pattern is rituximab, where surgery should be planned for 1 month after the last missed dose.

Dr. Bergman noted that how the guidelines handle interval dosing with infliximab may present a problem. The guideline provides recommendations for patients receiving infliximab every 4 weeks, every 6 weeks, and every 8 weeks. However, Dr. Bergman said this can create a scenario where a patient receiving infliximab at a dose of 3 mg/kg every 8 weeks has surgery at 9 weeks, a patient receiving 5 mg/kg every 6 weeks has surgery at 7 weeks, and a patient receiving 10 mg/kg every 4 weeks has surgery at 5 weeks. “There is some intellectual problem with it,” he said.

Another change from the 2017 guideline is how long to wait for surgery after stopping Janus kinase inhibitors. While the 2017 guideline recommended withholding JAK inhibitors 7 days before surgery, the 2022 guideline lowered that waiting period to 3 days, Dr. Bergman explained.

Concerning use of steroids around THA and TKA surgery, “the days of stress steroid dosing are done,” Dr. Bergman said. “You don’t have to stress dose them. You just follow them, and you keep them on their steroid dose.”

The new guideline recommends restarting therapy once the wound is healed and there is no physical evidence of infection at approximately 2 weeks. “There’s no data to support this,” he said, and his concern is that patients who have stopped a tumor necrosis factor inhibitor may flare if they don’t restart their medication.

While the guideline also covered recommendations for systemic lupus erythematosus, they are “very similar” to the recommendations for inflammatory arthritis, Dr. Bergman noted. “If you have somebody who is not very sick, you stop the medications,” he said, “but try to stop anything else about a week before the surgery. If they’re sick, you basically have to keep them on their medications.”
 

Caveats in guideline

The recommendations in the 2022 guideline come with a number of caveats, Dr. Bergman noted. For instance, the authors acknowledged limitations in the guideline regarding providing recommendations for only THA and TKA, the “paucity of evidence” around direct infection risk resulting from medications in the perioperative period for THA and TKA, the nonseparation of biologics when assessing infection risk, and the use of dosing interval as a metric for stopping the drug without considering the drug’s half-life.

A “crucial caveat,” Dr. Bergman said, was that the guideline focused on infection risk based on a statement from a panel of patients prior to the development of the 2017 guideline, which “stated very clearly any risk of infection, while rare, was more significant to them than the possibility of postoperative flares, despite flares being reported in over 60% of patients after surgery.

“For the patients, the paramount question was infection, infection, infection, infection. That’s all they cared about, and that is the basis behind a lot of the decision-making here,” Dr. Bergman said.

Another caveat came from a communication Dr. Bergman received from one of the panel members. The panel member noted there were no conclusions or recommendations provided in the guideline for how to manage perioperative flares, such as restarting a corticosteroid or biologic agent. “There was a lot of discussion about what to do with steroids if patients flare, or what to do with [other] medications if they flare, and they just couldn’t come to a consensus,” Dr. Bergman said. “It’s just not discussed.”

Dr. Bergman said he is “somewhat critical” of the ACR/AAHKS guideline, but noted it is an “ambitious project” given the lack of evidence for the recommendations. “The alternative was stop the medications forever and having people really flare, or at least try to get some semblance of rationality behind what we’re going to do,” he said.
 

Response from attendees

Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, took issue with the new recommendations surrounding stopping infliximab. When giving a patient infliximab every 8 weeks at 3 mg/kg, “you’re giving [it] at the nadir of the drug,” he said.

Rather than drug half-life, “it’s about inflammation,” he emphasized. “Inflammation is dominant in causing infection. It drives risk more than anything. The worst thing you can do is wash someone out.

“If you’re going beyond 8 weeks on infliximab, you’re getting closer to washing them out,” he pointed out. “I think it’s a really bad idea.”

Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at Hospital for Special Surgery, both in New York, explained that the guideline is not standard of care, which would be subject to malpractice if not implemented properly.

“When you have guidelines, you follow them unless there are clinical situations which would necessitate another approach to the patient,” he said. “Professional institutions and associations will never put forth rules, they will put forth guidelines so you have the opportunity to deviate from them when the appropriate clinical situation dictates.”

Dr. Bergman reported being a speaker and consultant for AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer, and Regeneron; he holds stock in Johnson & Johnson and Merck.

Gastroenterologists in 2023 will have more tools in their arsenal to treat patients with Crohn’s disease or ulcerative colitis. As many as 8-10 adalimumab biosimilars are anticipated to come on the market this year, giving mainstay drug Humira some vigorous competition.

Three scenarios will drive adalimumab biosimilar initiation: Insurance preference for the initial treatment of a newly diagnosed condition, a change in a patient’s insurance plan, or an insurance-mandated switch, said Edward C. Oldfield IV, MD, assistant professor at Eastern Virginia Medical School’s division of gastroenterology in Norfolk.

Even with more drugs to choose from, some gastroenterologists may be hesitant to make a switch. “Outside of these scenarios, I would encourage patients to remain on their current biologic so long as cost and accessibility remain stable,” said Dr. Oldfield.

Many factors will contribute to the success of biosimilars. Will physicians be prescribing them? How are biosimilars placed on formularies and will they be given preferred status?  How will manufacturers price their biosimilars? “We have to wait and see to get the answers to these questions,” said Steven Newmark, JD, MPA, chief legal officer and director of policy, Global Healthy Living Foundation/CreakyJoints, a nonprofit advocacy organization based in New York.

Prescribing biosimilars is no different than prescribing originator biologics, so providers should know how to use them, said Mr. Newmark. “Most important will be the availability of patient-friendly resources that providers can share with their patients to provide education about and confidence in using biosimilars,” he added.

Overall, biosimilars are a good thing, said Dr. Oldfield. “In the long run they should bring down costs and increase access to medications for our patients.”

Others are skeptical that the adalimumab biosimilars will save patients much money.

Biosimilar laws were created to lower costs. However, if a patient with insurance pays only $5 a month out of pocket for Humira – a drug that normally costs $7,000 without coverage – it’s unlikely they would want to switch unless there’s comparable savings from the biosimilar, said Stephen B. Hanauer, MD, medical director of the Digestive Health Center and professor of medicine at Northwestern Medicine, Northwestern University, Evanston, Ill.

Like generics, Humira biosimilars may face some initial backlash, said Dr. Hanauer.
 

2023 broadens scope of adalimumab treatments

The American Gastroenterological Association describes a biosimilar as something that’s “highly similar to, but not an exact copy of, a biologic reference product already approved” by the Food and Drug Administration. Congress under the 2010 Affordable Care Act created a special, abbreviated pathway to approval for biosimilars.

AbbVie’s Humira, the global revenue for which exceeded $20 billion in 2021, has long dominated the U.S. market on injectable treatments for autoimmune diseases. The popular drug faces some competition in 2023, however, following a series of legal settlements that allowed AbbVie competitors to release their own adalimumab biosimilars.

“So far, we haven’t seen biosimilars live up to their potential in the U.S. in the inflammatory space,” said Mr. Newmark. This may change, however. Previously, biosimilars have required infusion, which demanded more time, commitment, and travel from patients. “The new set of forthcoming Humira biosimilars are injectables, an administration method preferred by patients,” he said.

The FDA will approve a biosimilar if it determines that the biological product is highly similar to the reference product, and that there are no clinically meaningful differences between the biological and reference product in terms of the safety, purity, and potency of the product. 

The agency to date has approved 8 adalimumab biosimilars. These include: Idacio (adalimumab-aacf, Fresenius Kabi); Amjevita (adalimumab-atto, Amgen); Hadlima (adalimumab-bwwd, Organon); Cyltezo (adalimumab-adbm, Boehringer Ingelheim); Yusimry (adalimumab-aqvh from Coherus BioSciences); Hulio (adalimumab-fkjp; Mylan/Fujifilm Kyowa Kirin Biologics); Hyrimoz (adalimumab-adaz, Sandoz), and Abrilada (adalimumab-afzb, Pfizer).

“While FDA doesn’t formally track when products come to market, we know based on published reports that application holders for many of the currently FDA-approved biosimilars plan to market this year, starting with Amjevita being the first adalimumab biosimilar launched” in January, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the agency.

At press time, two other companies (Celltrion and Alvotech/Teva) were awaiting FDA approval for their adalimumab biosimilar drugs.

Among the eight approved drugs, Cyltezo is the only one that has a designation for interchangeability with Humira.

An interchangeable biosimilar may be substituted at the pharmacy without the intervention of the prescriber – much like generics are substituted, depending on state laws, said Dr. Yim. “However, in terms of safety and effectiveness, FDA’s standards for approval mean that biosimilar or interchangeable biosimilar products can be used in place of the reference product they were compared to.”

FDA-approved biosimilars undergo a rigorous evaluation for safety, effectiveness, and quality for their approved conditions of use, she continued. “Therefore, patients and health care providers can rely on a biosimilar to be as safe and effective for its approved uses as the original biological product.”
 

Remicade as a yard stick

Gastroenterologists dealt with this situation once before, when Remicade (infliximab) biosimilars came on the market in 2016, noted Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic.

Remicade and Humira are both tumor necrosis factor inhibitors with the same mechanism of action and many of the same indications. “We already had that experience with Remicade and biosimilar switch 2 or 3 years ago. Now we’re talking about Humira,” said Dr. Regueiro.

Most GI doctors have prescribed one of the more common infliximab biosimilars (Inflectra or Renflexis), noted Dr. Oldfield.

Cardinal Health, which recently surveyed 300 gastroenterologists, rheumatologists, and dermatologists about adalimumab biosimilars, found that gastroenterologists had the highest comfort level in prescribing them. Their top concern, however, was changing a patient from adalimumab to an adalimumab biosimilar.

For most patients, Dr. Oldfield sees the Humira reference biologic and biosimilar as equivalent.

However, he said he would change a patient’s drug only if there were a good reason or if his hand was forced by insurance. He would not make the change for a patient who recently began induction with the reference biologic or a patient with highly active clinical disease.

“While there is limited data to support this, I would also have some qualms about changing a patient from reference biologic to a biosimilar if they previously had immune-mediated pharmacokinetic failure due to antibody development with a biologic and were currently doing well on their new biologic,” he said.

Those with a new ulcerative colitis or Crohn’s diagnosis who are initiating a biologic for the first time might consider a biosimilar. If a patient is transitioning from a reference biologic to a biosimilar, “I would want to make that change during a time of stable remission and with the recognition that the switch is not a temporary switch, but a long-term switch,” he continued.

A paper that reviewed 23 observational studies of adalimumab and other biosimilars found that switching biosimilars was safe and effective. But if possible, patients should minimize the number of switches until more robust long-term data are available, added Dr. Oldfield.

If a patient is apprehensive about switching to a new therapy, “one may need to be cognizant of the ‘nocebo’ effect in which there is an unexplained or unfavorable therapeutic effect after switching,” he said.

Other gastroenterologists voiced similar reservations about switching. “I won’t use an adalimumab biosimilar unless the patient requests it, the insurance requires it, or there is a cost advantage for the patient such that they prefer it,” said Doug Wolf, MD, an Atlanta gastroenterologist.

“There is no medical treatment advantage to a biosimilar, especially if switching from Humira,” added Dr. Wolf.

Insurance will guide treatment

Once a drug is approved for use by the FDA, that drug will be available in all 50 states. “Different private insurance formularies, as well as state Medicaid formularies, might affect the actual ability of patients to receive such drugs,” said Mr. Newmark.

Patients should consult with their providers and insurance companies to see what therapies are available, he advised.

Dr. Hanauer anticipates some headaches arising for patients and doctors alike when negotiating for a specific drug.

Cyltezo may be the only biosimilar interchangeable with Humira, but the third-party pharmacy benefit manager (PBM) could negotiate for one of the noninterchangeable ones. “On a yearly basis they could switch their preference,” said Dr. Hanauer.

In the Cardinal Health survey, more than 60% of respondents said they would feel comfortable prescribing an adalimumab biosimilar only with an interchangeability designation.

A PBM may offer a patient Cyltezo if it’s cheaper than Humira. If the patient insists on staying on Humira, then they’ll have to pay more for that drug on their payer’s formulary, said Dr. Hanauer. In a worst-case scenario, a physician may have to appeal on a patient’s behalf to get Humira if the insurer offers only the biosimilar.

Taking that step to appeal is a major hassle for the physician, and leads to extra back door costs as well, said Dr. Hanauer.

Humira manufacturer AbbVie, in turn, may offer discounts and rebates to the PBMs to put Humira on their formulary. “That’s the AbbVie negotiating power. It’s not that the cost is going to be that much different. It’s going to be that there are rebates and discounts that are going to make the cost different,” he added.

As a community physician, Dr. Oldfield has specific concerns about accessibility.

The ever-increasing burden of insurance documentation and prior authorization means it can take weeks or months to get these medications approved. “The addition of new biosimilars is a welcome entrance if it can get patients the medications they need when they need it,” he said.

When it comes to prescribing biologics, many physicians rely on ancillary staff for assistance. It’s a team effort to sift through all the paperwork, observed Dr. Oldfield.

“While many community GI practices have specialized staff to deal with prior authorizations, they are still a far cry from the IBD [inflammatory bowel disease] academic centers where there are often pharmacists, nursing specialists, and home-monitoring programs to check in on patients,” he explained.

Landscape on cost is uncertain

At present, little is known about the cost of the biosimilars and impact on future drug pricing, said Dr. Oldfield.

At least for Medicare, Humira biosimilars will be considered Medicare Part D drugs if used for a medically accepted indication, said a spokesperson for the Centers for Medicare and Medicaid Services.

Part D sponsors (pharmacy and therapeutic committees) “will make the determination as to whether Amjevita and other products will be added to their formularies,” said the spokesperson.

Patients never saw a significant cost savings with Remicade biosimilars. “I imagine the same would be true with biosimilars for Humira,” said Dr. Regueiro. Patients may see greater access to these drugs, however, because the insurance plan or the pharmacy plan will make them more readily available, he added.

The hope is that, as biosimilars are introduced, the price of the originator biologic will go down, said Mr. Newmark. “Therefore, we can expect Humira to be offered at a lower price as it faces competition. Where it will sit in comparison to the forthcoming biosimilars will depend on how much biosimilar companies drop their price and how much pressure will be on PBMs and insurers to cover the lowest list price drug,” he said.

AbbVie did not respond to several requests for comment.

Charitable patient assistance programs for biosimilars or biologics can help offset the price of copayments, Mr. Newmark offered.

Ideally, insurers will offer designated biosimilars at a reduced or even no out-of-pocket expense on their formularies. This should lead to a decreased administrative burden for approval with streamlined (or even removal) of prior authorizations for certain medications, said Dr. Oldfield.

Without insurance or medication assistance programs, the cost of biosimilars is prohibitively expensive, he added.

“Biosimilars have higher research, development, and manufacturing costs than what people conventionally think of [for] a generic medication.”

Educating, advising patients

Dr. Oldfield advised that gastroenterologists refer to biologics by the generic name rather than branded name when initiating therapy unless there is a very specific reason not to. “This approach should make the process more streamlined and less subjected to quick denials for brand-only requests as biosimilars start to assume a larger market share,” he said.

Uptake of the Humira biosimilars also will depend on proper education of physicians and patients and their comfort level with the biosimilars, said Dr. Regueiro. Cleveland Clinic uses a team approach to educate on this topic, relying on pharmacists, clinicians, and nurses to explain that there’s no real difference between the reference drug and its biosimilars, based on efficacy and safety data.

Physicians can also direct patients to patient-friendly resources, said Mr. Newmark. “By starting the conversation early, it ensures that when/if the time comes that your patient is switched to or chooses a biosimilar they will feel more confident because they have the knowledge to make decisions about their care.”

The Global Healthy Living Foundation’s podcast, Breaking Down Biosimilars , is a free resource for patients, he added.

It’s important that doctors also understand these products so they can explain to their patients what to expect, said the FDA’s Dr. Yim. The FDA provides educational materials on its website, including a comprehensive curriculum toolkit.

Dr. Hanauer has served as a consultant for AbbVie, Amgen, American College of Gastroenterology, GlaxoSmithKline, American Gastroenterological Association, Pfizer, and a host of other companies . Dr. Regueiro has served on advisory boards and as a consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, TARGET Pharma Solutions,Trellis, and Boehringer Ingelheim Pharmaceuticals. Dr. Wolf, Dr. Yim, Dr. Oldfield, and Mr. Newmark have no financial conflicts of interest.

Gastroenterologists in 2023 will have more tools in their arsenal to treat patients with Crohn’s disease or ulcerative colitis. As many as 8-10 adalimumab biosimilars are anticipated to come on the market this year, giving mainstay drug Humira some vigorous competition.

Three scenarios will drive adalimumab biosimilar initiation: Insurance preference for the initial treatment of a newly diagnosed condition, a change in a patient’s insurance plan, or an insurance-mandated switch, said Edward C. Oldfield IV, MD, assistant professor at Eastern Virginia Medical School’s division of gastroenterology in Norfolk.

Even with more drugs to choose from, some gastroenterologists may be hesitant to make a switch. “Outside of these scenarios, I would encourage patients to remain on their current biologic so long as cost and accessibility remain stable,” said Dr. Oldfield.

Many factors will contribute to the success of biosimilars. Will physicians be prescribing them? How are biosimilars placed on formularies and will they be given preferred status?  How will manufacturers price their biosimilars? “We have to wait and see to get the answers to these questions,” said Steven Newmark, JD, MPA, chief legal officer and director of policy, Global Healthy Living Foundation/CreakyJoints, a nonprofit advocacy organization based in New York.

Prescribing biosimilars is no different than prescribing originator biologics, so providers should know how to use them, said Mr. Newmark. “Most important will be the availability of patient-friendly resources that providers can share with their patients to provide education about and confidence in using biosimilars,” he added.

Overall, biosimilars are a good thing, said Dr. Oldfield. “In the long run they should bring down costs and increase access to medications for our patients.”

Others are skeptical that the adalimumab biosimilars will save patients much money.

Biosimilar laws were created to lower costs. However, if a patient with insurance pays only $5 a month out of pocket for Humira – a drug that normally costs $7,000 without coverage – it’s unlikely they would want to switch unless there’s comparable savings from the biosimilar, said Stephen B. Hanauer, MD, medical director of the Digestive Health Center and professor of medicine at Northwestern Medicine, Northwestern University, Evanston, Ill.

Like generics, Humira biosimilars may face some initial backlash, said Dr. Hanauer.
 

2023 broadens scope of adalimumab treatments

The American Gastroenterological Association describes a biosimilar as something that’s “highly similar to, but not an exact copy of, a biologic reference product already approved” by the Food and Drug Administration. Congress under the 2010 Affordable Care Act created a special, abbreviated pathway to approval for biosimilars.

AbbVie’s Humira, the global revenue for which exceeded $20 billion in 2021, has long dominated the U.S. market on injectable treatments for autoimmune diseases. The popular drug faces some competition in 2023, however, following a series of legal settlements that allowed AbbVie competitors to release their own adalimumab biosimilars.

“So far, we haven’t seen biosimilars live up to their potential in the U.S. in the inflammatory space,” said Mr. Newmark. This may change, however. Previously, biosimilars have required infusion, which demanded more time, commitment, and travel from patients. “The new set of forthcoming Humira biosimilars are injectables, an administration method preferred by patients,” he said.

The FDA will approve a biosimilar if it determines that the biological product is highly similar to the reference product, and that there are no clinically meaningful differences between the biological and reference product in terms of the safety, purity, and potency of the product. 

The agency to date has approved 8 adalimumab biosimilars. These include: Idacio (adalimumab-aacf, Fresenius Kabi); Amjevita (adalimumab-atto, Amgen); Hadlima (adalimumab-bwwd, Organon); Cyltezo (adalimumab-adbm, Boehringer Ingelheim); Yusimry (adalimumab-aqvh from Coherus BioSciences); Hulio (adalimumab-fkjp; Mylan/Fujifilm Kyowa Kirin Biologics); Hyrimoz (adalimumab-adaz, Sandoz), and Abrilada (adalimumab-afzb, Pfizer).

“While FDA doesn’t formally track when products come to market, we know based on published reports that application holders for many of the currently FDA-approved biosimilars plan to market this year, starting with Amjevita being the first adalimumab biosimilar launched” in January, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the agency.

At press time, two other companies (Celltrion and Alvotech/Teva) were awaiting FDA approval for their adalimumab biosimilar drugs.

Among the eight approved drugs, Cyltezo is the only one that has a designation for interchangeability with Humira.

An interchangeable biosimilar may be substituted at the pharmacy without the intervention of the prescriber – much like generics are substituted, depending on state laws, said Dr. Yim. “However, in terms of safety and effectiveness, FDA’s standards for approval mean that biosimilar or interchangeable biosimilar products can be used in place of the reference product they were compared to.”

FDA-approved biosimilars undergo a rigorous evaluation for safety, effectiveness, and quality for their approved conditions of use, she continued. “Therefore, patients and health care providers can rely on a biosimilar to be as safe and effective for its approved uses as the original biological product.”
 

Remicade as a yard stick

Gastroenterologists dealt with this situation once before, when Remicade (infliximab) biosimilars came on the market in 2016, noted Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic.

Remicade and Humira are both tumor necrosis factor inhibitors with the same mechanism of action and many of the same indications. “We already had that experience with Remicade and biosimilar switch 2 or 3 years ago. Now we’re talking about Humira,” said Dr. Regueiro.

Most GI doctors have prescribed one of the more common infliximab biosimilars (Inflectra or Renflexis), noted Dr. Oldfield.

Cardinal Health, which recently surveyed 300 gastroenterologists, rheumatologists, and dermatologists about adalimumab biosimilars, found that gastroenterologists had the highest comfort level in prescribing them. Their top concern, however, was changing a patient from adalimumab to an adalimumab biosimilar.

For most patients, Dr. Oldfield sees the Humira reference biologic and biosimilar as equivalent.

However, he said he would change a patient’s drug only if there were a good reason or if his hand was forced by insurance. He would not make the change for a patient who recently began induction with the reference biologic or a patient with highly active clinical disease.

“While there is limited data to support this, I would also have some qualms about changing a patient from reference biologic to a biosimilar if they previously had immune-mediated pharmacokinetic failure due to antibody development with a biologic and were currently doing well on their new biologic,” he said.

Those with a new ulcerative colitis or Crohn’s diagnosis who are initiating a biologic for the first time might consider a biosimilar. If a patient is transitioning from a reference biologic to a biosimilar, “I would want to make that change during a time of stable remission and with the recognition that the switch is not a temporary switch, but a long-term switch,” he continued.

A paper that reviewed 23 observational studies of adalimumab and other biosimilars found that switching biosimilars was safe and effective. But if possible, patients should minimize the number of switches until more robust long-term data are available, added Dr. Oldfield.

If a patient is apprehensive about switching to a new therapy, “one may need to be cognizant of the ‘nocebo’ effect in which there is an unexplained or unfavorable therapeutic effect after switching,” he said.

Other gastroenterologists voiced similar reservations about switching. “I won’t use an adalimumab biosimilar unless the patient requests it, the insurance requires it, or there is a cost advantage for the patient such that they prefer it,” said Doug Wolf, MD, an Atlanta gastroenterologist.

“There is no medical treatment advantage to a biosimilar, especially if switching from Humira,” added Dr. Wolf.

Insurance will guide treatment

Once a drug is approved for use by the FDA, that drug will be available in all 50 states. “Different private insurance formularies, as well as state Medicaid formularies, might affect the actual ability of patients to receive such drugs,” said Mr. Newmark.

Patients should consult with their providers and insurance companies to see what therapies are available, he advised.

Dr. Hanauer anticipates some headaches arising for patients and doctors alike when negotiating for a specific drug.

Cyltezo may be the only biosimilar interchangeable with Humira, but the third-party pharmacy benefit manager (PBM) could negotiate for one of the noninterchangeable ones. “On a yearly basis they could switch their preference,” said Dr. Hanauer.

In the Cardinal Health survey, more than 60% of respondents said they would feel comfortable prescribing an adalimumab biosimilar only with an interchangeability designation.

A PBM may offer a patient Cyltezo if it’s cheaper than Humira. If the patient insists on staying on Humira, then they’ll have to pay more for that drug on their payer’s formulary, said Dr. Hanauer. In a worst-case scenario, a physician may have to appeal on a patient’s behalf to get Humira if the insurer offers only the biosimilar.

Taking that step to appeal is a major hassle for the physician, and leads to extra back door costs as well, said Dr. Hanauer.

Humira manufacturer AbbVie, in turn, may offer discounts and rebates to the PBMs to put Humira on their formulary. “That’s the AbbVie negotiating power. It’s not that the cost is going to be that much different. It’s going to be that there are rebates and discounts that are going to make the cost different,” he added.

As a community physician, Dr. Oldfield has specific concerns about accessibility.

The ever-increasing burden of insurance documentation and prior authorization means it can take weeks or months to get these medications approved. “The addition of new biosimilars is a welcome entrance if it can get patients the medications they need when they need it,” he said.

When it comes to prescribing biologics, many physicians rely on ancillary staff for assistance. It’s a team effort to sift through all the paperwork, observed Dr. Oldfield.

“While many community GI practices have specialized staff to deal with prior authorizations, they are still a far cry from the IBD [inflammatory bowel disease] academic centers where there are often pharmacists, nursing specialists, and home-monitoring programs to check in on patients,” he explained.

Landscape on cost is uncertain

At present, little is known about the cost of the biosimilars and impact on future drug pricing, said Dr. Oldfield.

At least for Medicare, Humira biosimilars will be considered Medicare Part D drugs if used for a medically accepted indication, said a spokesperson for the Centers for Medicare and Medicaid Services.

Part D sponsors (pharmacy and therapeutic committees) “will make the determination as to whether Amjevita and other products will be added to their formularies,” said the spokesperson.

Patients never saw a significant cost savings with Remicade biosimilars. “I imagine the same would be true with biosimilars for Humira,” said Dr. Regueiro. Patients may see greater access to these drugs, however, because the insurance plan or the pharmacy plan will make them more readily available, he added.

The hope is that, as biosimilars are introduced, the price of the originator biologic will go down, said Mr. Newmark. “Therefore, we can expect Humira to be offered at a lower price as it faces competition. Where it will sit in comparison to the forthcoming biosimilars will depend on how much biosimilar companies drop their price and how much pressure will be on PBMs and insurers to cover the lowest list price drug,” he said.

AbbVie did not respond to several requests for comment.

Charitable patient assistance programs for biosimilars or biologics can help offset the price of copayments, Mr. Newmark offered.

Ideally, insurers will offer designated biosimilars at a reduced or even no out-of-pocket expense on their formularies. This should lead to a decreased administrative burden for approval with streamlined (or even removal) of prior authorizations for certain medications, said Dr. Oldfield.

Without insurance or medication assistance programs, the cost of biosimilars is prohibitively expensive, he added.

“Biosimilars have higher research, development, and manufacturing costs than what people conventionally think of [for] a generic medication.”

Educating, advising patients

Dr. Oldfield advised that gastroenterologists refer to biologics by the generic name rather than branded name when initiating therapy unless there is a very specific reason not to. “This approach should make the process more streamlined and less subjected to quick denials for brand-only requests as biosimilars start to assume a larger market share,” he said.

Uptake of the Humira biosimilars also will depend on proper education of physicians and patients and their comfort level with the biosimilars, said Dr. Regueiro. Cleveland Clinic uses a team approach to educate on this topic, relying on pharmacists, clinicians, and nurses to explain that there’s no real difference between the reference drug and its biosimilars, based on efficacy and safety data.

Physicians can also direct patients to patient-friendly resources, said Mr. Newmark. “By starting the conversation early, it ensures that when/if the time comes that your patient is switched to or chooses a biosimilar they will feel more confident because they have the knowledge to make decisions about their care.”

The Global Healthy Living Foundation’s podcast, Breaking Down Biosimilars , is a free resource for patients, he added.

It’s important that doctors also understand these products so they can explain to their patients what to expect, said the FDA’s Dr. Yim. The FDA provides educational materials on its website, including a comprehensive curriculum toolkit.

Dr. Hanauer has served as a consultant for AbbVie, Amgen, American College of Gastroenterology, GlaxoSmithKline, American Gastroenterological Association, Pfizer, and a host of other companies . Dr. Regueiro has served on advisory boards and as a consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, TARGET Pharma Solutions,Trellis, and Boehringer Ingelheim Pharmaceuticals. Dr. Wolf, Dr. Yim, Dr. Oldfield, and Mr. Newmark have no financial conflicts of interest.

Gastroenterologists in 2023 will have more tools in their arsenal to treat patients with Crohn’s disease or ulcerative colitis. As many as 8-10 adalimumab biosimilars are anticipated to come on the market this year, giving mainstay drug Humira some vigorous competition.

Three scenarios will drive adalimumab biosimilar initiation: Insurance preference for the initial treatment of a newly diagnosed condition, a change in a patient’s insurance plan, or an insurance-mandated switch, said Edward C. Oldfield IV, MD, assistant professor at Eastern Virginia Medical School’s division of gastroenterology in Norfolk.

Even with more drugs to choose from, some gastroenterologists may be hesitant to make a switch. “Outside of these scenarios, I would encourage patients to remain on their current biologic so long as cost and accessibility remain stable,” said Dr. Oldfield.

Many factors will contribute to the success of biosimilars. Will physicians be prescribing them? How are biosimilars placed on formularies and will they be given preferred status?  How will manufacturers price their biosimilars? “We have to wait and see to get the answers to these questions,” said Steven Newmark, JD, MPA, chief legal officer and director of policy, Global Healthy Living Foundation/CreakyJoints, a nonprofit advocacy organization based in New York.

Prescribing biosimilars is no different than prescribing originator biologics, so providers should know how to use them, said Mr. Newmark. “Most important will be the availability of patient-friendly resources that providers can share with their patients to provide education about and confidence in using biosimilars,” he added.

Overall, biosimilars are a good thing, said Dr. Oldfield. “In the long run they should bring down costs and increase access to medications for our patients.”

Others are skeptical that the adalimumab biosimilars will save patients much money.

Biosimilar laws were created to lower costs. However, if a patient with insurance pays only $5 a month out of pocket for Humira – a drug that normally costs $7,000 without coverage – it’s unlikely they would want to switch unless there’s comparable savings from the biosimilar, said Stephen B. Hanauer, MD, medical director of the Digestive Health Center and professor of medicine at Northwestern Medicine, Northwestern University, Evanston, Ill.

Like generics, Humira biosimilars may face some initial backlash, said Dr. Hanauer.
 

2023 broadens scope of adalimumab treatments

The American Gastroenterological Association describes a biosimilar as something that’s “highly similar to, but not an exact copy of, a biologic reference product already approved” by the Food and Drug Administration. Congress under the 2010 Affordable Care Act created a special, abbreviated pathway to approval for biosimilars.

AbbVie’s Humira, the global revenue for which exceeded $20 billion in 2021, has long dominated the U.S. market on injectable treatments for autoimmune diseases. The popular drug faces some competition in 2023, however, following a series of legal settlements that allowed AbbVie competitors to release their own adalimumab biosimilars.

“So far, we haven’t seen biosimilars live up to their potential in the U.S. in the inflammatory space,” said Mr. Newmark. This may change, however. Previously, biosimilars have required infusion, which demanded more time, commitment, and travel from patients. “The new set of forthcoming Humira biosimilars are injectables, an administration method preferred by patients,” he said.

The FDA will approve a biosimilar if it determines that the biological product is highly similar to the reference product, and that there are no clinically meaningful differences between the biological and reference product in terms of the safety, purity, and potency of the product. 

The agency to date has approved 8 adalimumab biosimilars. These include: Idacio (adalimumab-aacf, Fresenius Kabi); Amjevita (adalimumab-atto, Amgen); Hadlima (adalimumab-bwwd, Organon); Cyltezo (adalimumab-adbm, Boehringer Ingelheim); Yusimry (adalimumab-aqvh from Coherus BioSciences); Hulio (adalimumab-fkjp; Mylan/Fujifilm Kyowa Kirin Biologics); Hyrimoz (adalimumab-adaz, Sandoz), and Abrilada (adalimumab-afzb, Pfizer).

“While FDA doesn’t formally track when products come to market, we know based on published reports that application holders for many of the currently FDA-approved biosimilars plan to market this year, starting with Amjevita being the first adalimumab biosimilar launched” in January, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the agency.

At press time, two other companies (Celltrion and Alvotech/Teva) were awaiting FDA approval for their adalimumab biosimilar drugs.

Among the eight approved drugs, Cyltezo is the only one that has a designation for interchangeability with Humira.

An interchangeable biosimilar may be substituted at the pharmacy without the intervention of the prescriber – much like generics are substituted, depending on state laws, said Dr. Yim. “However, in terms of safety and effectiveness, FDA’s standards for approval mean that biosimilar or interchangeable biosimilar products can be used in place of the reference product they were compared to.”

FDA-approved biosimilars undergo a rigorous evaluation for safety, effectiveness, and quality for their approved conditions of use, she continued. “Therefore, patients and health care providers can rely on a biosimilar to be as safe and effective for its approved uses as the original biological product.”
 

Remicade as a yard stick

Gastroenterologists dealt with this situation once before, when Remicade (infliximab) biosimilars came on the market in 2016, noted Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute at the Cleveland Clinic.

Remicade and Humira are both tumor necrosis factor inhibitors with the same mechanism of action and many of the same indications. “We already had that experience with Remicade and biosimilar switch 2 or 3 years ago. Now we’re talking about Humira,” said Dr. Regueiro.

Most GI doctors have prescribed one of the more common infliximab biosimilars (Inflectra or Renflexis), noted Dr. Oldfield.

Cardinal Health, which recently surveyed 300 gastroenterologists, rheumatologists, and dermatologists about adalimumab biosimilars, found that gastroenterologists had the highest comfort level in prescribing them. Their top concern, however, was changing a patient from adalimumab to an adalimumab biosimilar.

For most patients, Dr. Oldfield sees the Humira reference biologic and biosimilar as equivalent.

However, he said he would change a patient’s drug only if there were a good reason or if his hand was forced by insurance. He would not make the change for a patient who recently began induction with the reference biologic or a patient with highly active clinical disease.

“While there is limited data to support this, I would also have some qualms about changing a patient from reference biologic to a biosimilar if they previously had immune-mediated pharmacokinetic failure due to antibody development with a biologic and were currently doing well on their new biologic,” he said.

Those with a new ulcerative colitis or Crohn’s diagnosis who are initiating a biologic for the first time might consider a biosimilar. If a patient is transitioning from a reference biologic to a biosimilar, “I would want to make that change during a time of stable remission and with the recognition that the switch is not a temporary switch, but a long-term switch,” he continued.

A paper that reviewed 23 observational studies of adalimumab and other biosimilars found that switching biosimilars was safe and effective. But if possible, patients should minimize the number of switches until more robust long-term data are available, added Dr. Oldfield.

If a patient is apprehensive about switching to a new therapy, “one may need to be cognizant of the ‘nocebo’ effect in which there is an unexplained or unfavorable therapeutic effect after switching,” he said.

Other gastroenterologists voiced similar reservations about switching. “I won’t use an adalimumab biosimilar unless the patient requests it, the insurance requires it, or there is a cost advantage for the patient such that they prefer it,” said Doug Wolf, MD, an Atlanta gastroenterologist.

“There is no medical treatment advantage to a biosimilar, especially if switching from Humira,” added Dr. Wolf.

Insurance will guide treatment

Once a drug is approved for use by the FDA, that drug will be available in all 50 states. “Different private insurance formularies, as well as state Medicaid formularies, might affect the actual ability of patients to receive such drugs,” said Mr. Newmark.

Patients should consult with their providers and insurance companies to see what therapies are available, he advised.

Dr. Hanauer anticipates some headaches arising for patients and doctors alike when negotiating for a specific drug.

Cyltezo may be the only biosimilar interchangeable with Humira, but the third-party pharmacy benefit manager (PBM) could negotiate for one of the noninterchangeable ones. “On a yearly basis they could switch their preference,” said Dr. Hanauer.

In the Cardinal Health survey, more than 60% of respondents said they would feel comfortable prescribing an adalimumab biosimilar only with an interchangeability designation.

A PBM may offer a patient Cyltezo if it’s cheaper than Humira. If the patient insists on staying on Humira, then they’ll have to pay more for that drug on their payer’s formulary, said Dr. Hanauer. In a worst-case scenario, a physician may have to appeal on a patient’s behalf to get Humira if the insurer offers only the biosimilar.

Taking that step to appeal is a major hassle for the physician, and leads to extra back door costs as well, said Dr. Hanauer.

Humira manufacturer AbbVie, in turn, may offer discounts and rebates to the PBMs to put Humira on their formulary. “That’s the AbbVie negotiating power. It’s not that the cost is going to be that much different. It’s going to be that there are rebates and discounts that are going to make the cost different,” he added.

As a community physician, Dr. Oldfield has specific concerns about accessibility.

The ever-increasing burden of insurance documentation and prior authorization means it can take weeks or months to get these medications approved. “The addition of new biosimilars is a welcome entrance if it can get patients the medications they need when they need it,” he said.

When it comes to prescribing biologics, many physicians rely on ancillary staff for assistance. It’s a team effort to sift through all the paperwork, observed Dr. Oldfield.

“While many community GI practices have specialized staff to deal with prior authorizations, they are still a far cry from the IBD [inflammatory bowel disease] academic centers where there are often pharmacists, nursing specialists, and home-monitoring programs to check in on patients,” he explained.

Landscape on cost is uncertain

At present, little is known about the cost of the biosimilars and impact on future drug pricing, said Dr. Oldfield.

At least for Medicare, Humira biosimilars will be considered Medicare Part D drugs if used for a medically accepted indication, said a spokesperson for the Centers for Medicare and Medicaid Services.

Part D sponsors (pharmacy and therapeutic committees) “will make the determination as to whether Amjevita and other products will be added to their formularies,” said the spokesperson.

Patients never saw a significant cost savings with Remicade biosimilars. “I imagine the same would be true with biosimilars for Humira,” said Dr. Regueiro. Patients may see greater access to these drugs, however, because the insurance plan or the pharmacy plan will make them more readily available, he added.

The hope is that, as biosimilars are introduced, the price of the originator biologic will go down, said Mr. Newmark. “Therefore, we can expect Humira to be offered at a lower price as it faces competition. Where it will sit in comparison to the forthcoming biosimilars will depend on how much biosimilar companies drop their price and how much pressure will be on PBMs and insurers to cover the lowest list price drug,” he said.

AbbVie did not respond to several requests for comment.

Charitable patient assistance programs for biosimilars or biologics can help offset the price of copayments, Mr. Newmark offered.

Ideally, insurers will offer designated biosimilars at a reduced or even no out-of-pocket expense on their formularies. This should lead to a decreased administrative burden for approval with streamlined (or even removal) of prior authorizations for certain medications, said Dr. Oldfield.

Without insurance or medication assistance programs, the cost of biosimilars is prohibitively expensive, he added.

“Biosimilars have higher research, development, and manufacturing costs than what people conventionally think of [for] a generic medication.”

Educating, advising patients

Dr. Oldfield advised that gastroenterologists refer to biologics by the generic name rather than branded name when initiating therapy unless there is a very specific reason not to. “This approach should make the process more streamlined and less subjected to quick denials for brand-only requests as biosimilars start to assume a larger market share,” he said.

Uptake of the Humira biosimilars also will depend on proper education of physicians and patients and their comfort level with the biosimilars, said Dr. Regueiro. Cleveland Clinic uses a team approach to educate on this topic, relying on pharmacists, clinicians, and nurses to explain that there’s no real difference between the reference drug and its biosimilars, based on efficacy and safety data.

Physicians can also direct patients to patient-friendly resources, said Mr. Newmark. “By starting the conversation early, it ensures that when/if the time comes that your patient is switched to or chooses a biosimilar they will feel more confident because they have the knowledge to make decisions about their care.”

The Global Healthy Living Foundation’s podcast, Breaking Down Biosimilars , is a free resource for patients, he added.

It’s important that doctors also understand these products so they can explain to their patients what to expect, said the FDA’s Dr. Yim. The FDA provides educational materials on its website, including a comprehensive curriculum toolkit.

Dr. Hanauer has served as a consultant for AbbVie, Amgen, American College of Gastroenterology, GlaxoSmithKline, American Gastroenterological Association, Pfizer, and a host of other companies . Dr. Regueiro has served on advisory boards and as a consultant for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, TARGET Pharma Solutions,Trellis, and Boehringer Ingelheim Pharmaceuticals. Dr. Wolf, Dr. Yim, Dr. Oldfield, and Mr. Newmark have no financial conflicts of interest.