Rheumatology

Reducing the dose of tumor necrosis factor inhibitors by approximately one-third did not increase disease activity in adults with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) in a stable low–disease activity state, according to findings from two parallel controlled retrospective cohort studies.

Disease activity–guided dose optimization (DAGDO) can reduce drug exposure in patients with PsA or axSpA who have low disease activity, but its impact on increased disease activity has not been as well studied as full-dose continuation, Celia A.J. Michielsens, MD, of Sint Maartenskliniek, Nijmegen, the Netherlands, and colleagues wrote.

“DAGDO or discontinuation of bDMARDs [biologic disease-modifying antirheumatic drugs] as a standard of care in adults with stable axSpA is currently discouraged by” the American College of Rheumatology, the researchers said. However, guidelines from the European Alliance of Associations for Rheumatology allow for the slow tapering of bDMARDs in patients with sustained remission.

In a controlled, retrospective cohort study published in Rheumatology, the researchers analyzed data from their outpatient clinic, which initiated a specific TNF inhibitor DAGDO protocol in 2010 for patients with RA, PsA, and axSpA. Disease activity was measured using the Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) for patients with PsA and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for patients with axSpA.

The study population included 153 patients with PsA who had a mean DAS28-CRP of 6.5 and 171 with axSpA who had a similar mean number of disease activity measurements (6.5 with DAS28-CRP and 6.4 with BASDAI). Median follow-up time was several months short of 4 years in each group. Treatment was divided into three periods: continuation of full TNF inhibitor dose, TNF inhibitor DAGDO, and a period with stable TNF inhibitor dose after DAGDO.

Overall, no significant differences appeared in mean DAS28-CRP and BASDAI over the course of the study between the period of the full TNF inhibitor dose continuation and both the TNF inhibitor DAGDO period and the stable TNF inhibitor dose period. Among PsA patients, the mean DAS28-CRP was 1.94 for the full-dose period, 2.0 in the TNF inhibitor DAGDO period, and 1.97 in the stable TNF inhibitor dose after DAGDO period. For axSpA patients, the mean BASDAI was 3.44, 3.47, and 3.48, respectively, for the three periods. Older age, longer disease duration, and longer follow-up were significantly associated with higher DAS28-CRP scores in patients with PsA, and older age and female gender were significantly associated with higher BASDAI scores in patients with axSpA.

The mean percentage of daily defined dose (%DDD) for patients with PsA was 108% during the full dose period, 62% in the TNF inhibitor DAGDO period, and 78% with stable TNF inhibitor after DAGDO, and nearly the same for patients with axSPA at 108%, 62%, and 72%, respectively.

The %DDD represents “a modest degree of tapering,” compared with studies in RA patients, the researchers noted. “Explanations for this difference could be that the full dose-reduction potential was not met due to suboptimal execution of the local protocol, whereas in prospective intervention trials, protocol adherence is likely higher.”

The study findings were limited by several factors including the open-label design and potential for nocebo effects, possible incorrect attribution, and information bias, as well as the use of DAS28-CRP and BASDAI rather than more modern measurement tools, the researchers noted.

However, the results were strengthened by the large sample size and real-world clinical setting, frequent assessment of disease activity, long-term follow-up, and the performance of DAGDO by rheumatologists familiar with the measuring tools, they said. The results suggest that DAGDO is safe and effective for patients with low disease activity in either condition, but randomized, prospective studies can provide more definitive evidence.

The study received no outside funding. One author disclosed relationships with multiple pharmaceutical companies.

Reducing the dose of tumor necrosis factor inhibitors by approximately one-third did not increase disease activity in adults with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) in a stable low–disease activity state, according to findings from two parallel controlled retrospective cohort studies.

Disease activity–guided dose optimization (DAGDO) can reduce drug exposure in patients with PsA or axSpA who have low disease activity, but its impact on increased disease activity has not been as well studied as full-dose continuation, Celia A.J. Michielsens, MD, of Sint Maartenskliniek, Nijmegen, the Netherlands, and colleagues wrote.

“DAGDO or discontinuation of bDMARDs [biologic disease-modifying antirheumatic drugs] as a standard of care in adults with stable axSpA is currently discouraged by” the American College of Rheumatology, the researchers said. However, guidelines from the European Alliance of Associations for Rheumatology allow for the slow tapering of bDMARDs in patients with sustained remission.

In a controlled, retrospective cohort study published in Rheumatology, the researchers analyzed data from their outpatient clinic, which initiated a specific TNF inhibitor DAGDO protocol in 2010 for patients with RA, PsA, and axSpA. Disease activity was measured using the Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) for patients with PsA and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for patients with axSpA.

The study population included 153 patients with PsA who had a mean DAS28-CRP of 6.5 and 171 with axSpA who had a similar mean number of disease activity measurements (6.5 with DAS28-CRP and 6.4 with BASDAI). Median follow-up time was several months short of 4 years in each group. Treatment was divided into three periods: continuation of full TNF inhibitor dose, TNF inhibitor DAGDO, and a period with stable TNF inhibitor dose after DAGDO.

Overall, no significant differences appeared in mean DAS28-CRP and BASDAI over the course of the study between the period of the full TNF inhibitor dose continuation and both the TNF inhibitor DAGDO period and the stable TNF inhibitor dose period. Among PsA patients, the mean DAS28-CRP was 1.94 for the full-dose period, 2.0 in the TNF inhibitor DAGDO period, and 1.97 in the stable TNF inhibitor dose after DAGDO period. For axSpA patients, the mean BASDAI was 3.44, 3.47, and 3.48, respectively, for the three periods. Older age, longer disease duration, and longer follow-up were significantly associated with higher DAS28-CRP scores in patients with PsA, and older age and female gender were significantly associated with higher BASDAI scores in patients with axSpA.

The mean percentage of daily defined dose (%DDD) for patients with PsA was 108% during the full dose period, 62% in the TNF inhibitor DAGDO period, and 78% with stable TNF inhibitor after DAGDO, and nearly the same for patients with axSPA at 108%, 62%, and 72%, respectively.

The %DDD represents “a modest degree of tapering,” compared with studies in RA patients, the researchers noted. “Explanations for this difference could be that the full dose-reduction potential was not met due to suboptimal execution of the local protocol, whereas in prospective intervention trials, protocol adherence is likely higher.”

The study findings were limited by several factors including the open-label design and potential for nocebo effects, possible incorrect attribution, and information bias, as well as the use of DAS28-CRP and BASDAI rather than more modern measurement tools, the researchers noted.

However, the results were strengthened by the large sample size and real-world clinical setting, frequent assessment of disease activity, long-term follow-up, and the performance of DAGDO by rheumatologists familiar with the measuring tools, they said. The results suggest that DAGDO is safe and effective for patients with low disease activity in either condition, but randomized, prospective studies can provide more definitive evidence.

The study received no outside funding. One author disclosed relationships with multiple pharmaceutical companies.

Reducing the dose of tumor necrosis factor inhibitors by approximately one-third did not increase disease activity in adults with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) in a stable low–disease activity state, according to findings from two parallel controlled retrospective cohort studies.

Disease activity–guided dose optimization (DAGDO) can reduce drug exposure in patients with PsA or axSpA who have low disease activity, but its impact on increased disease activity has not been as well studied as full-dose continuation, Celia A.J. Michielsens, MD, of Sint Maartenskliniek, Nijmegen, the Netherlands, and colleagues wrote.

“DAGDO or discontinuation of bDMARDs [biologic disease-modifying antirheumatic drugs] as a standard of care in adults with stable axSpA is currently discouraged by” the American College of Rheumatology, the researchers said. However, guidelines from the European Alliance of Associations for Rheumatology allow for the slow tapering of bDMARDs in patients with sustained remission.

In a controlled, retrospective cohort study published in Rheumatology, the researchers analyzed data from their outpatient clinic, which initiated a specific TNF inhibitor DAGDO protocol in 2010 for patients with RA, PsA, and axSpA. Disease activity was measured using the Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) for patients with PsA and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for patients with axSpA.

The study population included 153 patients with PsA who had a mean DAS28-CRP of 6.5 and 171 with axSpA who had a similar mean number of disease activity measurements (6.5 with DAS28-CRP and 6.4 with BASDAI). Median follow-up time was several months short of 4 years in each group. Treatment was divided into three periods: continuation of full TNF inhibitor dose, TNF inhibitor DAGDO, and a period with stable TNF inhibitor dose after DAGDO.

Overall, no significant differences appeared in mean DAS28-CRP and BASDAI over the course of the study between the period of the full TNF inhibitor dose continuation and both the TNF inhibitor DAGDO period and the stable TNF inhibitor dose period. Among PsA patients, the mean DAS28-CRP was 1.94 for the full-dose period, 2.0 in the TNF inhibitor DAGDO period, and 1.97 in the stable TNF inhibitor dose after DAGDO period. For axSpA patients, the mean BASDAI was 3.44, 3.47, and 3.48, respectively, for the three periods. Older age, longer disease duration, and longer follow-up were significantly associated with higher DAS28-CRP scores in patients with PsA, and older age and female gender were significantly associated with higher BASDAI scores in patients with axSpA.

The mean percentage of daily defined dose (%DDD) for patients with PsA was 108% during the full dose period, 62% in the TNF inhibitor DAGDO period, and 78% with stable TNF inhibitor after DAGDO, and nearly the same for patients with axSPA at 108%, 62%, and 72%, respectively.

The %DDD represents “a modest degree of tapering,” compared with studies in RA patients, the researchers noted. “Explanations for this difference could be that the full dose-reduction potential was not met due to suboptimal execution of the local protocol, whereas in prospective intervention trials, protocol adherence is likely higher.”

The study findings were limited by several factors including the open-label design and potential for nocebo effects, possible incorrect attribution, and information bias, as well as the use of DAS28-CRP and BASDAI rather than more modern measurement tools, the researchers noted.

However, the results were strengthened by the large sample size and real-world clinical setting, frequent assessment of disease activity, long-term follow-up, and the performance of DAGDO by rheumatologists familiar with the measuring tools, they said. The results suggest that DAGDO is safe and effective for patients with low disease activity in either condition, but randomized, prospective studies can provide more definitive evidence.

The study received no outside funding. One author disclosed relationships with multiple pharmaceutical companies.

Patients with psoriatic arthritis (PsA) showed more improvement in symptoms at 6 months with risankizumab (Skyrizi) than with placebo in combined phase 3, randomized, controlled trials, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“Risankizumab was well tolerated and showed no new safety signals over those seen in the trial program for psoriasis,” reported Andrew Östör, MD, of Monash University and Cabrini Hospital, both in Melbourne. The results included pooled data that added KEEPsAKE 1 data to KEEPsAKE 2 results, which were presented at the 2021 congress of the European Alliance of Associations for Rheumatology.

Risankizumab received Food and Drug Administration approval in 2019 for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The humanized monoclonal antibody inhibits interleukin-23, which is believed to be involved in the development of PsA. The FDA updated its approval in August 2021 to make it available as a 150-mg single-dose injection instead of two 75-mg doses for psoriasis treatment, but it is not yet approved for PsA.

The trials included adults with active PsA, active plaque psoriasis or nail psoriasis, and at least five swollen joints and five tender joints. All the participants had an inadequate response or intolerance to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), and KEEPsAKE 2 included participants who had an inadequate response or intolerance to at least one biologic therapy.

The majority of patients in both groups were taking anti-inflammatory drugs (58.8% with risankizumab vs. 62.1% with placebo) and methotrexate (60% vs. 59.1%, respectively), but a minority were taking oral glucocorticoids (18.2% with risankizumab vs. 15.6% with placebo). A small proportion in both groups were also taking a csDMARD besides methotrexate (11.9% with risankizumab vs. 11.3% with placebo).

Participants were randomly assigned to receive either 150 mg of subcutaneous risankizumab or placebo at baseline, 4 weeks, and 16 weeks with a double-blind protocol. The proportion of patients with 20% improvement in ACR response criteria (ACR 20) at 24 weeks was the primary endpoint. The trial is currently continuing with all participants receiving open-label risankizumab.

The 1,407 patients initially enrolled included 707 receiving risankizumab and 700 receiving placebo across both trials, with similar baseline demographic and disease characteristics in both groups. A total of 1,354 participants completed the 24-week assessments, including 688 receiving risankizumab and 666 receiving placebo. In an intent-to-treat analysis, 55.5% of patients receiving risankizumab and 31.3% of those receiving placebo achieved ACR 20 at week 24 (P < .001). Participants who received risankizumab also had more improvement in secondary clinical and patient-reported outcomes than did those who received placebo. A quarter (25.2%) of risankizumab patients versus 10.6% of placebo patients showed minimal disease activity, and significantly more participants receiving risankizumab than placebo saw resolution of enthesitis, dactylitis, and fatigue.

Adverse events of any kind occurred in 45.5% of risankizumab and 43.9% of placebo participants, with similar numbers of serious adverse events (3% vs. 4.4%, respectively). One death caused by urosepsis in an 81-year-old participant with dementia occurred in the risankizumab group and was determined to be unrelated to the drug.

David Karp, MD, PhD, chief of division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas and ACR president, conducted a question-and-answer session with Dr. Östör following his presentation and asked whether a difference in responses was seen between patients who had failed biologic DMARDs. Dr. Östör said the response rates were similar independent of which previous therapies the participants had failed.

Regarding where risankizumab, as an IL-23 inhibitor, fits among the options for treating PsA, Dr. Östör said “the data speaks for itself” in terms of efficacy with arthritic, musculoskeletal manifestations and the patient-reported outcomes.

“One of the major benefits of these medications is their remarkable effect on skin with psoriasis,” Dr. Östör told Dr. Karp. Regarding axial response to the drug, Dr. Östör noted the statistically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index, appearing to show a clinical benefit with spinal inflammatory disease. Radiologic data, however, are not currently available for the trials.

Dr. Karp noted the recent findings of a phase 2a trial published in the New England Journal of Medicine regarding risankizumab’s poor performance in patients with severe asthma, who experienced worsening symptoms sooner and more rapidly than did those who received placebo. It’s unclear whether any patients in the KEEPsAKE 1 or 2 trials had an asthma diagnosis, but any people with unstable, severe asthma would have been excluded from participation, Dr. Östör said.

The research was funded by AbbVie. Dr. Östör and colleagues have a range of financial ties to numerous pharmaceutical companies.

Patients with psoriatic arthritis (PsA) showed more improvement in symptoms at 6 months with risankizumab (Skyrizi) than with placebo in combined phase 3, randomized, controlled trials, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“Risankizumab was well tolerated and showed no new safety signals over those seen in the trial program for psoriasis,” reported Andrew Östör, MD, of Monash University and Cabrini Hospital, both in Melbourne. The results included pooled data that added KEEPsAKE 1 data to KEEPsAKE 2 results, which were presented at the 2021 congress of the European Alliance of Associations for Rheumatology.

Risankizumab received Food and Drug Administration approval in 2019 for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The humanized monoclonal antibody inhibits interleukin-23, which is believed to be involved in the development of PsA. The FDA updated its approval in August 2021 to make it available as a 150-mg single-dose injection instead of two 75-mg doses for psoriasis treatment, but it is not yet approved for PsA.

The trials included adults with active PsA, active plaque psoriasis or nail psoriasis, and at least five swollen joints and five tender joints. All the participants had an inadequate response or intolerance to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), and KEEPsAKE 2 included participants who had an inadequate response or intolerance to at least one biologic therapy.

The majority of patients in both groups were taking anti-inflammatory drugs (58.8% with risankizumab vs. 62.1% with placebo) and methotrexate (60% vs. 59.1%, respectively), but a minority were taking oral glucocorticoids (18.2% with risankizumab vs. 15.6% with placebo). A small proportion in both groups were also taking a csDMARD besides methotrexate (11.9% with risankizumab vs. 11.3% with placebo).

Participants were randomly assigned to receive either 150 mg of subcutaneous risankizumab or placebo at baseline, 4 weeks, and 16 weeks with a double-blind protocol. The proportion of patients with 20% improvement in ACR response criteria (ACR 20) at 24 weeks was the primary endpoint. The trial is currently continuing with all participants receiving open-label risankizumab.

The 1,407 patients initially enrolled included 707 receiving risankizumab and 700 receiving placebo across both trials, with similar baseline demographic and disease characteristics in both groups. A total of 1,354 participants completed the 24-week assessments, including 688 receiving risankizumab and 666 receiving placebo. In an intent-to-treat analysis, 55.5% of patients receiving risankizumab and 31.3% of those receiving placebo achieved ACR 20 at week 24 (P < .001). Participants who received risankizumab also had more improvement in secondary clinical and patient-reported outcomes than did those who received placebo. A quarter (25.2%) of risankizumab patients versus 10.6% of placebo patients showed minimal disease activity, and significantly more participants receiving risankizumab than placebo saw resolution of enthesitis, dactylitis, and fatigue.

Adverse events of any kind occurred in 45.5% of risankizumab and 43.9% of placebo participants, with similar numbers of serious adverse events (3% vs. 4.4%, respectively). One death caused by urosepsis in an 81-year-old participant with dementia occurred in the risankizumab group and was determined to be unrelated to the drug.

David Karp, MD, PhD, chief of division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas and ACR president, conducted a question-and-answer session with Dr. Östör following his presentation and asked whether a difference in responses was seen between patients who had failed biologic DMARDs. Dr. Östör said the response rates were similar independent of which previous therapies the participants had failed.

Regarding where risankizumab, as an IL-23 inhibitor, fits among the options for treating PsA, Dr. Östör said “the data speaks for itself” in terms of efficacy with arthritic, musculoskeletal manifestations and the patient-reported outcomes.

“One of the major benefits of these medications is their remarkable effect on skin with psoriasis,” Dr. Östör told Dr. Karp. Regarding axial response to the drug, Dr. Östör noted the statistically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index, appearing to show a clinical benefit with spinal inflammatory disease. Radiologic data, however, are not currently available for the trials.

Dr. Karp noted the recent findings of a phase 2a trial published in the New England Journal of Medicine regarding risankizumab’s poor performance in patients with severe asthma, who experienced worsening symptoms sooner and more rapidly than did those who received placebo. It’s unclear whether any patients in the KEEPsAKE 1 or 2 trials had an asthma diagnosis, but any people with unstable, severe asthma would have been excluded from participation, Dr. Östör said.

The research was funded by AbbVie. Dr. Östör and colleagues have a range of financial ties to numerous pharmaceutical companies.

Patients with psoriatic arthritis (PsA) showed more improvement in symptoms at 6 months with risankizumab (Skyrizi) than with placebo in combined phase 3, randomized, controlled trials, according to data presented at the virtual annual meeting of the American College of Rheumatology.

“Risankizumab was well tolerated and showed no new safety signals over those seen in the trial program for psoriasis,” reported Andrew Östör, MD, of Monash University and Cabrini Hospital, both in Melbourne. The results included pooled data that added KEEPsAKE 1 data to KEEPsAKE 2 results, which were presented at the 2021 congress of the European Alliance of Associations for Rheumatology.

Risankizumab received Food and Drug Administration approval in 2019 for moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The humanized monoclonal antibody inhibits interleukin-23, which is believed to be involved in the development of PsA. The FDA updated its approval in August 2021 to make it available as a 150-mg single-dose injection instead of two 75-mg doses for psoriasis treatment, but it is not yet approved for PsA.

The trials included adults with active PsA, active plaque psoriasis or nail psoriasis, and at least five swollen joints and five tender joints. All the participants had an inadequate response or intolerance to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD), and KEEPsAKE 2 included participants who had an inadequate response or intolerance to at least one biologic therapy.

The majority of patients in both groups were taking anti-inflammatory drugs (58.8% with risankizumab vs. 62.1% with placebo) and methotrexate (60% vs. 59.1%, respectively), but a minority were taking oral glucocorticoids (18.2% with risankizumab vs. 15.6% with placebo). A small proportion in both groups were also taking a csDMARD besides methotrexate (11.9% with risankizumab vs. 11.3% with placebo).

Participants were randomly assigned to receive either 150 mg of subcutaneous risankizumab or placebo at baseline, 4 weeks, and 16 weeks with a double-blind protocol. The proportion of patients with 20% improvement in ACR response criteria (ACR 20) at 24 weeks was the primary endpoint. The trial is currently continuing with all participants receiving open-label risankizumab.

The 1,407 patients initially enrolled included 707 receiving risankizumab and 700 receiving placebo across both trials, with similar baseline demographic and disease characteristics in both groups. A total of 1,354 participants completed the 24-week assessments, including 688 receiving risankizumab and 666 receiving placebo. In an intent-to-treat analysis, 55.5% of patients receiving risankizumab and 31.3% of those receiving placebo achieved ACR 20 at week 24 (P < .001). Participants who received risankizumab also had more improvement in secondary clinical and patient-reported outcomes than did those who received placebo. A quarter (25.2%) of risankizumab patients versus 10.6% of placebo patients showed minimal disease activity, and significantly more participants receiving risankizumab than placebo saw resolution of enthesitis, dactylitis, and fatigue.

Adverse events of any kind occurred in 45.5% of risankizumab and 43.9% of placebo participants, with similar numbers of serious adverse events (3% vs. 4.4%, respectively). One death caused by urosepsis in an 81-year-old participant with dementia occurred in the risankizumab group and was determined to be unrelated to the drug.

David Karp, MD, PhD, chief of division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas and ACR president, conducted a question-and-answer session with Dr. Östör following his presentation and asked whether a difference in responses was seen between patients who had failed biologic DMARDs. Dr. Östör said the response rates were similar independent of which previous therapies the participants had failed.

Regarding where risankizumab, as an IL-23 inhibitor, fits among the options for treating PsA, Dr. Östör said “the data speaks for itself” in terms of efficacy with arthritic, musculoskeletal manifestations and the patient-reported outcomes.

“One of the major benefits of these medications is their remarkable effect on skin with psoriasis,” Dr. Östör told Dr. Karp. Regarding axial response to the drug, Dr. Östör noted the statistically significant improvement in Bath Ankylosing Spondylitis Disease Activity Index, appearing to show a clinical benefit with spinal inflammatory disease. Radiologic data, however, are not currently available for the trials.

Dr. Karp noted the recent findings of a phase 2a trial published in the New England Journal of Medicine regarding risankizumab’s poor performance in patients with severe asthma, who experienced worsening symptoms sooner and more rapidly than did those who received placebo. It’s unclear whether any patients in the KEEPsAKE 1 or 2 trials had an asthma diagnosis, but any people with unstable, severe asthma would have been excluded from participation, Dr. Östör said.

The research was funded by AbbVie. Dr. Östör and colleagues have a range of financial ties to numerous pharmaceutical companies.

Early intervention with the immunomodulator abatacept (Orencia) may enable people at risk for rheumatoid arthritis but who don’t yet manifest symptomatic inflammation to either avoid or delay the onset of full-blown, symptomatic rheumatoid arthritis, early results of a European clinical trial have shown.

Early results of the ARIAA study, presented at the virtual annual meeting of the American College of Rheumatology, showed that among patients considered at-risk for RA and having arthralgia and subclinical inflammation – considered symptomatic but not having full-blown RA – 61% of those who received a 6-month course of abatacept versus 31% of the placebo group had an improvement in MRI inflammation score (P = .0043), said Juergen Rech, MD, a rheumatologist at Friedrich-Alexander University of Erlangen-Nuremberg (Germany) and University Clinic Erlangen.

“When we actually talk about early treatment, this may be not early enough or at least could be improved,” Dr. Rech said in an interview when asked what the findings add to the evidence for treating at-risk RA patients before disease onset. “It seems as if we were in the situation of delaying the development of disease or possibly even preventing it in some patients, and in our trial this approach was safe with abatacept.”

ARIAA randomized 100 patients to abatacept or placebo at 14 study sites between November 2014 and December 2019. The goal is to treat at-risk patients for 6 months with abatacept, then follow them for 12 months to determine their progression to RA. Dr. Rech noted that 8% of patients in the treatment group and 35% in the placebo group developed arthritis (P = .0025).

He noted that the safety profile of abatacept in this patient population was similar to previous trials. “No safety issues emerged,” Dr. Rech said.

The investigators used MRI to determine the patients’ status for arthralgia and subclinical inflammation before enrollment. They had no history of clinically obvious inflammation fulfilling the criteria for RA and no previous treatment with glucocorticoids or disease-modifying antirheumatic drugs.

The results showed that abatacept is superior to placebo in improving subclinical inflammation and in inhibiting the progression to RA in at-risk patients at 6 months, Dr. Rech said, but early clinical results of patients in the study who’ve had 18 months of follow-up, which were not part of the dataset he presented, revealed that time-limited treatment with the immunomodulator has a significant sustained effect on progression to RA. That “means 6 months of treatment with abatacept will delay the development of RA after 18 months,” he said.

After the complete 18-month dataset is analyzed, the next step for investigators will be to re-evaluate the ARIAA population, perhaps for genetic markers, Dr. Rech said. What would then follow, he said, could be to conduct a larger phase 3 trial, determine the risk factors that drive RA autoimmunity, see if disease progression varies among ethnic groups and people in different geographic regions, and perhaps start a head-to-head trial with rituximab (Rituxan) or an evaluation of combined time-limited abatacept and rituximab in at-risk patients.

“We should think about new strategies, new life-quality questionnaires, new biomarkers and tools for covering and understanding these RA patients at-risk in a better way,” Dr. Rech said, noting that a European Alliance of Associations for Rheumatology task force has already addressed this topic.

John D. Isaacs, MBBS, PhD, professor of rheumatology at Newcastle (England) University, said in an interview that ARIAA is the first readout from a number of studies evaluating preemptive treatment to prevent or delay RA onset. “You have to ask a question: Is this just suppressing what’s going on?” Dr. Isaacs said. “In other words, now that the treatment has been stopped, there’s great interest in what happens over the next 12 months of this study. Have we delayed the onset of rheumatoid arthritis or have we actually prevented it? I think that’s the $10 billion dollar question of this and similar studies.”

Answering that question may be difficult without a known blood biomarker. “That’s not a criticism of the trial; we just don’t have that scientifically at the moment,” Dr. Isaacs said. “Until then, it will be difficult to say we have delayed or we have prevented rheumatoid arthritis. My feeling is, even if we delay it 6 months or even a year with safe treatment, that would be worth it.”

Bristol-Myers Squibb sponsored the trial. Dr. Rech and Dr. Isaacs disclosed having financial relationships with Bristol-Myers Squibb and other pharmaceutical companies.

Early intervention with the immunomodulator abatacept (Orencia) may enable people at risk for rheumatoid arthritis but who don’t yet manifest symptomatic inflammation to either avoid or delay the onset of full-blown, symptomatic rheumatoid arthritis, early results of a European clinical trial have shown.

Early results of the ARIAA study, presented at the virtual annual meeting of the American College of Rheumatology, showed that among patients considered at-risk for RA and having arthralgia and subclinical inflammation – considered symptomatic but not having full-blown RA – 61% of those who received a 6-month course of abatacept versus 31% of the placebo group had an improvement in MRI inflammation score (P = .0043), said Juergen Rech, MD, a rheumatologist at Friedrich-Alexander University of Erlangen-Nuremberg (Germany) and University Clinic Erlangen.

“When we actually talk about early treatment, this may be not early enough or at least could be improved,” Dr. Rech said in an interview when asked what the findings add to the evidence for treating at-risk RA patients before disease onset. “It seems as if we were in the situation of delaying the development of disease or possibly even preventing it in some patients, and in our trial this approach was safe with abatacept.”

ARIAA randomized 100 patients to abatacept or placebo at 14 study sites between November 2014 and December 2019. The goal is to treat at-risk patients for 6 months with abatacept, then follow them for 12 months to determine their progression to RA. Dr. Rech noted that 8% of patients in the treatment group and 35% in the placebo group developed arthritis (P = .0025).

He noted that the safety profile of abatacept in this patient population was similar to previous trials. “No safety issues emerged,” Dr. Rech said.

The investigators used MRI to determine the patients’ status for arthralgia and subclinical inflammation before enrollment. They had no history of clinically obvious inflammation fulfilling the criteria for RA and no previous treatment with glucocorticoids or disease-modifying antirheumatic drugs.

The results showed that abatacept is superior to placebo in improving subclinical inflammation and in inhibiting the progression to RA in at-risk patients at 6 months, Dr. Rech said, but early clinical results of patients in the study who’ve had 18 months of follow-up, which were not part of the dataset he presented, revealed that time-limited treatment with the immunomodulator has a significant sustained effect on progression to RA. That “means 6 months of treatment with abatacept will delay the development of RA after 18 months,” he said.

After the complete 18-month dataset is analyzed, the next step for investigators will be to re-evaluate the ARIAA population, perhaps for genetic markers, Dr. Rech said. What would then follow, he said, could be to conduct a larger phase 3 trial, determine the risk factors that drive RA autoimmunity, see if disease progression varies among ethnic groups and people in different geographic regions, and perhaps start a head-to-head trial with rituximab (Rituxan) or an evaluation of combined time-limited abatacept and rituximab in at-risk patients.

“We should think about new strategies, new life-quality questionnaires, new biomarkers and tools for covering and understanding these RA patients at-risk in a better way,” Dr. Rech said, noting that a European Alliance of Associations for Rheumatology task force has already addressed this topic.

John D. Isaacs, MBBS, PhD, professor of rheumatology at Newcastle (England) University, said in an interview that ARIAA is the first readout from a number of studies evaluating preemptive treatment to prevent or delay RA onset. “You have to ask a question: Is this just suppressing what’s going on?” Dr. Isaacs said. “In other words, now that the treatment has been stopped, there’s great interest in what happens over the next 12 months of this study. Have we delayed the onset of rheumatoid arthritis or have we actually prevented it? I think that’s the $10 billion dollar question of this and similar studies.”

Answering that question may be difficult without a known blood biomarker. “That’s not a criticism of the trial; we just don’t have that scientifically at the moment,” Dr. Isaacs said. “Until then, it will be difficult to say we have delayed or we have prevented rheumatoid arthritis. My feeling is, even if we delay it 6 months or even a year with safe treatment, that would be worth it.”

Bristol-Myers Squibb sponsored the trial. Dr. Rech and Dr. Isaacs disclosed having financial relationships with Bristol-Myers Squibb and other pharmaceutical companies.

Early intervention with the immunomodulator abatacept (Orencia) may enable people at risk for rheumatoid arthritis but who don’t yet manifest symptomatic inflammation to either avoid or delay the onset of full-blown, symptomatic rheumatoid arthritis, early results of a European clinical trial have shown.

Early results of the ARIAA study, presented at the virtual annual meeting of the American College of Rheumatology, showed that among patients considered at-risk for RA and having arthralgia and subclinical inflammation – considered symptomatic but not having full-blown RA – 61% of those who received a 6-month course of abatacept versus 31% of the placebo group had an improvement in MRI inflammation score (P = .0043), said Juergen Rech, MD, a rheumatologist at Friedrich-Alexander University of Erlangen-Nuremberg (Germany) and University Clinic Erlangen.

“When we actually talk about early treatment, this may be not early enough or at least could be improved,” Dr. Rech said in an interview when asked what the findings add to the evidence for treating at-risk RA patients before disease onset. “It seems as if we were in the situation of delaying the development of disease or possibly even preventing it in some patients, and in our trial this approach was safe with abatacept.”

ARIAA randomized 100 patients to abatacept or placebo at 14 study sites between November 2014 and December 2019. The goal is to treat at-risk patients for 6 months with abatacept, then follow them for 12 months to determine their progression to RA. Dr. Rech noted that 8% of patients in the treatment group and 35% in the placebo group developed arthritis (P = .0025).

He noted that the safety profile of abatacept in this patient population was similar to previous trials. “No safety issues emerged,” Dr. Rech said.

The investigators used MRI to determine the patients’ status for arthralgia and subclinical inflammation before enrollment. They had no history of clinically obvious inflammation fulfilling the criteria for RA and no previous treatment with glucocorticoids or disease-modifying antirheumatic drugs.

The results showed that abatacept is superior to placebo in improving subclinical inflammation and in inhibiting the progression to RA in at-risk patients at 6 months, Dr. Rech said, but early clinical results of patients in the study who’ve had 18 months of follow-up, which were not part of the dataset he presented, revealed that time-limited treatment with the immunomodulator has a significant sustained effect on progression to RA. That “means 6 months of treatment with abatacept will delay the development of RA after 18 months,” he said.

After the complete 18-month dataset is analyzed, the next step for investigators will be to re-evaluate the ARIAA population, perhaps for genetic markers, Dr. Rech said. What would then follow, he said, could be to conduct a larger phase 3 trial, determine the risk factors that drive RA autoimmunity, see if disease progression varies among ethnic groups and people in different geographic regions, and perhaps start a head-to-head trial with rituximab (Rituxan) or an evaluation of combined time-limited abatacept and rituximab in at-risk patients.

“We should think about new strategies, new life-quality questionnaires, new biomarkers and tools for covering and understanding these RA patients at-risk in a better way,” Dr. Rech said, noting that a European Alliance of Associations for Rheumatology task force has already addressed this topic.

John D. Isaacs, MBBS, PhD, professor of rheumatology at Newcastle (England) University, said in an interview that ARIAA is the first readout from a number of studies evaluating preemptive treatment to prevent or delay RA onset. “You have to ask a question: Is this just suppressing what’s going on?” Dr. Isaacs said. “In other words, now that the treatment has been stopped, there’s great interest in what happens over the next 12 months of this study. Have we delayed the onset of rheumatoid arthritis or have we actually prevented it? I think that’s the $10 billion dollar question of this and similar studies.”

Answering that question may be difficult without a known blood biomarker. “That’s not a criticism of the trial; we just don’t have that scientifically at the moment,” Dr. Isaacs said. “Until then, it will be difficult to say we have delayed or we have prevented rheumatoid arthritis. My feeling is, even if we delay it 6 months or even a year with safe treatment, that would be worth it.”

Bristol-Myers Squibb sponsored the trial. Dr. Rech and Dr. Isaacs disclosed having financial relationships with Bristol-Myers Squibb and other pharmaceutical companies.

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



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

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



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

For those of us who cannot sit in the sun and fish all day, the next best thing for preventing autoimmune diseases may be supplementation with vitamin D and fish oil-derived omega-3 fatty acids, results of a large prospective randomized trial suggest.

Ziga Plahutar

Among nearly 26,000 adults enrolled in a randomized trial designed primarily to study the effects of vitamin D and omega-3 supplementation on incident cancer and cardiovascular disease, 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of omega-3 fatty acid supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases, reported Karen H. Costenbader, MD, MPH, of Brigham & Women’s Hospital in Boston.

“The clinical importance of these results is very high, given that these are nontoxic, well-tolerated supplements, and that there are no other known effective therapies to reduce the incidence of autoimmune diseases,” she said during the virtual annual meeting of the American College of Rheumatology.

“People do have to take the supplements a long time to start to see the reduction in risk, especially for vitamin D, but they make biological sense, and autoimmune diseases develop slowly over time, so taking it today isn’t going to reduce risk of developing something tomorrow,” Dr. Costenbader said in an interview.

“These supplements have other health benefits. Obviously, fish oil is anti-inflammatory, and vitamin D is good for osteoporosis prevention, especially in our patients who take glucocorticoids. People who are otherwise healthy and have a family history of autoimmune disease might also consider starting to take these supplements,” she said.

After watching her presentation, session co-moderator Gregg Silverman, MD, from the NYU Langone School of Medicine in New York, who was not involved in the study, commented “I’m going to [nutrition store] GNC to get some vitamins.”

When asked for comment, the other session moderator, Tracy Frech, MD, of Vanderbilt University, Nashville, said, “I think Dr. Costenbader’s work is very important and her presentation excellent. My current practice is replacement of vitamin D in all autoimmune disease patients with low levels and per bone health guidelines. Additionally, I discuss omega-3 supplementation with Sjögren’s [syndrome] patients as a consideration.”

Evidence base

Dr. Costenbader noted that in a 2013 observational study from France, vitamin D derived through ultraviolet (UV) light exposure was associated with a lower risk for incident Crohn’s disease but not ulcerative colitis, and in two analyses of data in 2014 from the Nurses’ Health Study, both high plasma levels of 25-OH vitamin D and geographic residence in areas of high UV exposure were associated with a decreased incidence of rheumatoid arthritis (RA).

Other observational studies have supported omega-3 fatty acids for their anti-inflammatory properties, including a 2005 Danish prospective cohort study showing a lower risk for RA in participants who reported higher levels of fatty fish intake. In a separate study conducted in 2017, healthy volunteers with higher omega-3 fatty acid/total lipid proportions in red blood cell membranes had a lower prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor and a lower incidence of progression to inflammatory arthritis, she said.

Ancillary study

Despite the evidence, however, there have been no prospective randomized trials to test the effects of either vitamin D or omega-3 fatty acid supplementation on the incidence of autoimmune disease over time.

To rectify this, Dr. Costenbader and colleagues piggybacked an ancillary study onto the Vitamin D and Omega-3 Trial (VITAL), which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older, and 13,085 women aged 55 and older.

The study had a 2 x 2 factorial design, with patients randomly assigned to vitamin D 2,000 IU/day or placebo, and then further randomized to either 1 g/day omega-3 fatty acids or placebo in both the vitamin D and placebo primary randomization arms.

At baseline 16,956 participants were assayed for 25-OH vitamin D and plasma omega 3 index, the ratio of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to total fatty acids. Participants self-reported baseline and all incident autoimmune diseases annually, with the reports confirmed by medical record review and disease criteria whenever possible.

Results

At 5 years of follow-up, confirmed incident autoimmune diseases had occurred in 123 patients in the active vitamin D group, compared with 155 in the placebo vitamin D group, translating into a hazard ratio (HR) for vitamin D of 0.78 (P = .045).

In the active omega-3 arm, 130 participants developed an autoimmune disease, compared with 148 in the placebo omega-3 arm, which translated into a nonsignificant HR of 0.85.

There was no statistical interaction between the two supplements. The investigators did observe an interaction between vitamin D and body mass index, with the effect stronger among participants with low BMI (P = .02). There also was an interaction between omega-3 fatty acids with a family history of autoimmune disease (P = .03).

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with an HR for incident autoimmune disease of 0.68 (P = .02), omega-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03).

Dr. Costenbader and colleagues acknowledged that the study was limited by the lack of a high-risk or nutritionally-deficient population, where the effects of supplementation might be larger; the restriction of the sample to older adults; and to the difficulty of confirming incident autoimmune thyroid disease from patient reports.

Cheryl Koehn, an arthritis patient advocate from Vancouver, Canada, who was not involved in the study, commented in the “chat” section of the presentation that her rheumatologist “has recommended vitamin D for years now. Says basically everyone north of Boston is vitamin D deficient. I take 1,000 IU per day. Been taking it for years.” Ms. Koehn is the founder and president of Arthritis Consumer Experts, a website that provides education to those with arthritis.

“Agreed. I tell every patient to take vitamin D supplement,” commented Fatma Dedeoglu, MD, a rheumatologist at Boston Children’s Hospital.



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

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

A new study has found that physical therapy may lead to a reduced risk of long-term opioid use in patients who have undergone total knee replacement (TKR).

ChooChin/Getty Images

“Greater number of PT intervention sessions and earlier initiation of outpatient PT care after TKR were associated with lower odds of long-term opioid use,” authors from Boston University wrote in their report on the study, which was published online Oct. 27 in JAMA Network Open.

“In previous large studies, we’ve seen that physical therapy can reduce pain in people with knee osteoarthritis, which is usually the primary indication for TKR,” study coauthor Deepak Kumar, PT, PhD, said in an interview. “But the association of physical therapy with opioid use in people with knee replacement has not yet been explored.

“The reason we focused on opioid use in these patients is because the number of knee replacement surgeries is going up exponentially,” Dr. Kumar said. “And, depending on which data you look at, from one-third to up to half of people who undergo knee replacement and have used opioids before end up becoming long-term users. Even in people who have not used them before, 5%-8% become long-term users after the surgery.

“Given how many surgeries are happening – and that number is expected to keep going up – the number of people who are becoming long-term opioid users is not trivial,” he said.
 

Study details

To assess the value of PT in reducing opioid use in this subset of patients, the authors reviewed records from the OptumLabs Data Warehouse insurance claims database to identify 67,322 eligible participants aged 40 or older who underwent TKR from Jan. 1, 2001, to Dec. 31, 2016. Of those patients, 38,408 were opioid naive and 28,914 had taken opioids before. The authors evaluated long-term opioid use – defined as 90 days or more of filled prescriptions – during a 12-month outcome assessment period that varied depending on differences in post-TKR PT start date and duration.

The researchers found a significantly lower likelihood of long-term opioid use associated with receipt of any PT before TKR among patients who had not taken opioids before (adjusted odds ratio [aOR], 0.75; 95% confidence interval, 0.60-0.95) and those who had taken opioids in the past (aOR, 0.75; 95% CI, 0.70-0.80).

Investigators found that 2.2% of participants in the opioid-naive group and 32.5% of those in the opioid-experienced group used opioids long-term after TKR. Approximately 76% of participants overall received outpatient PT within the 90 days after surgery, and the receipt of post-TKR PT at any point was associated with lower odds of long-term opioid use in the opioid-experienced group (aOR, 0.75; 95% CI, 0.70-0.79).

Among the opioid-experienced group, receiving between 6 and 12 PT sessions (aOR, 0.82; 95% CI, 0.75-0.90) or ≥ 13 sessions (aOR, 0.71; 95% CI, 0.65-0.77) were both associated with lower odds of long-term opioid use, compared with those who received 1-5 sessions. Beginning PT 31-60 days or 61-90 days after surgery was associated with greater odds of long-term opioid use across both cohorts, compared with those who initiated therapy within 30 days of TKR.
 

Physical therapy: Underexplored option for pain in knee replacement

One finding caught the researchers slightly off guard: There was no association between active physical therapy and reduced odds of long-term opioid use. “From prior studies, at least in people with knee osteoarthritis, we know that active interventions were more useful than passive interventions,” Dr. Kumar said.

That said, he added that there is still some professional uncertainty regarding “the right type or the right components of physical therapy for managing pain in this population.” Regardless, he believes their study emphasizes the benefits of PT as a pain alleviator in these patients, especially those who have previously used opioids.

“Pharmaceuticals have side effects. Injections are not super effective,” he said. “The idea behind focusing on physical therapy interventions is that it’s widely available, it does you no harm, and it could potentially be lower cost to both the payers and the providers.”

The authors acknowledged their study’s limitations, including not adjusting for opioid use within the 90 days after surgery as well as the different outcome assessment periods for pre-TKR and post-TKR PT exposures. In addition, they admitted that some of the patients who received PT could have been among those less likely to be treated with opioids, and vice versa. “A randomized clinical trial,” they wrote, “would be required to disentangle these issues.”

The study was supported by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kumar reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Pfizer for unrelated projects outside the submitted work. The full list of author disclosures can be found with the original article.

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

A new study has found that physical therapy may lead to a reduced risk of long-term opioid use in patients who have undergone total knee replacement (TKR).

ChooChin/Getty Images

“Greater number of PT intervention sessions and earlier initiation of outpatient PT care after TKR were associated with lower odds of long-term opioid use,” authors from Boston University wrote in their report on the study, which was published online Oct. 27 in JAMA Network Open.

“In previous large studies, we’ve seen that physical therapy can reduce pain in people with knee osteoarthritis, which is usually the primary indication for TKR,” study coauthor Deepak Kumar, PT, PhD, said in an interview. “But the association of physical therapy with opioid use in people with knee replacement has not yet been explored.

“The reason we focused on opioid use in these patients is because the number of knee replacement surgeries is going up exponentially,” Dr. Kumar said. “And, depending on which data you look at, from one-third to up to half of people who undergo knee replacement and have used opioids before end up becoming long-term users. Even in people who have not used them before, 5%-8% become long-term users after the surgery.

“Given how many surgeries are happening – and that number is expected to keep going up – the number of people who are becoming long-term opioid users is not trivial,” he said.
 

Study details

To assess the value of PT in reducing opioid use in this subset of patients, the authors reviewed records from the OptumLabs Data Warehouse insurance claims database to identify 67,322 eligible participants aged 40 or older who underwent TKR from Jan. 1, 2001, to Dec. 31, 2016. Of those patients, 38,408 were opioid naive and 28,914 had taken opioids before. The authors evaluated long-term opioid use – defined as 90 days or more of filled prescriptions – during a 12-month outcome assessment period that varied depending on differences in post-TKR PT start date and duration.

The researchers found a significantly lower likelihood of long-term opioid use associated with receipt of any PT before TKR among patients who had not taken opioids before (adjusted odds ratio [aOR], 0.75; 95% confidence interval, 0.60-0.95) and those who had taken opioids in the past (aOR, 0.75; 95% CI, 0.70-0.80).

Investigators found that 2.2% of participants in the opioid-naive group and 32.5% of those in the opioid-experienced group used opioids long-term after TKR. Approximately 76% of participants overall received outpatient PT within the 90 days after surgery, and the receipt of post-TKR PT at any point was associated with lower odds of long-term opioid use in the opioid-experienced group (aOR, 0.75; 95% CI, 0.70-0.79).

Among the opioid-experienced group, receiving between 6 and 12 PT sessions (aOR, 0.82; 95% CI, 0.75-0.90) or ≥ 13 sessions (aOR, 0.71; 95% CI, 0.65-0.77) were both associated with lower odds of long-term opioid use, compared with those who received 1-5 sessions. Beginning PT 31-60 days or 61-90 days after surgery was associated with greater odds of long-term opioid use across both cohorts, compared with those who initiated therapy within 30 days of TKR.
 

Physical therapy: Underexplored option for pain in knee replacement

One finding caught the researchers slightly off guard: There was no association between active physical therapy and reduced odds of long-term opioid use. “From prior studies, at least in people with knee osteoarthritis, we know that active interventions were more useful than passive interventions,” Dr. Kumar said.

That said, he added that there is still some professional uncertainty regarding “the right type or the right components of physical therapy for managing pain in this population.” Regardless, he believes their study emphasizes the benefits of PT as a pain alleviator in these patients, especially those who have previously used opioids.

“Pharmaceuticals have side effects. Injections are not super effective,” he said. “The idea behind focusing on physical therapy interventions is that it’s widely available, it does you no harm, and it could potentially be lower cost to both the payers and the providers.”

The authors acknowledged their study’s limitations, including not adjusting for opioid use within the 90 days after surgery as well as the different outcome assessment periods for pre-TKR and post-TKR PT exposures. In addition, they admitted that some of the patients who received PT could have been among those less likely to be treated with opioids, and vice versa. “A randomized clinical trial,” they wrote, “would be required to disentangle these issues.”

The study was supported by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kumar reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Pfizer for unrelated projects outside the submitted work. The full list of author disclosures can be found with the original article.

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

A new study has found that physical therapy may lead to a reduced risk of long-term opioid use in patients who have undergone total knee replacement (TKR).

ChooChin/Getty Images

“Greater number of PT intervention sessions and earlier initiation of outpatient PT care after TKR were associated with lower odds of long-term opioid use,” authors from Boston University wrote in their report on the study, which was published online Oct. 27 in JAMA Network Open.

“In previous large studies, we’ve seen that physical therapy can reduce pain in people with knee osteoarthritis, which is usually the primary indication for TKR,” study coauthor Deepak Kumar, PT, PhD, said in an interview. “But the association of physical therapy with opioid use in people with knee replacement has not yet been explored.

“The reason we focused on opioid use in these patients is because the number of knee replacement surgeries is going up exponentially,” Dr. Kumar said. “And, depending on which data you look at, from one-third to up to half of people who undergo knee replacement and have used opioids before end up becoming long-term users. Even in people who have not used them before, 5%-8% become long-term users after the surgery.

“Given how many surgeries are happening – and that number is expected to keep going up – the number of people who are becoming long-term opioid users is not trivial,” he said.
 

Study details

To assess the value of PT in reducing opioid use in this subset of patients, the authors reviewed records from the OptumLabs Data Warehouse insurance claims database to identify 67,322 eligible participants aged 40 or older who underwent TKR from Jan. 1, 2001, to Dec. 31, 2016. Of those patients, 38,408 were opioid naive and 28,914 had taken opioids before. The authors evaluated long-term opioid use – defined as 90 days or more of filled prescriptions – during a 12-month outcome assessment period that varied depending on differences in post-TKR PT start date and duration.

The researchers found a significantly lower likelihood of long-term opioid use associated with receipt of any PT before TKR among patients who had not taken opioids before (adjusted odds ratio [aOR], 0.75; 95% confidence interval, 0.60-0.95) and those who had taken opioids in the past (aOR, 0.75; 95% CI, 0.70-0.80).

Investigators found that 2.2% of participants in the opioid-naive group and 32.5% of those in the opioid-experienced group used opioids long-term after TKR. Approximately 76% of participants overall received outpatient PT within the 90 days after surgery, and the receipt of post-TKR PT at any point was associated with lower odds of long-term opioid use in the opioid-experienced group (aOR, 0.75; 95% CI, 0.70-0.79).

Among the opioid-experienced group, receiving between 6 and 12 PT sessions (aOR, 0.82; 95% CI, 0.75-0.90) or ≥ 13 sessions (aOR, 0.71; 95% CI, 0.65-0.77) were both associated with lower odds of long-term opioid use, compared with those who received 1-5 sessions. Beginning PT 31-60 days or 61-90 days after surgery was associated with greater odds of long-term opioid use across both cohorts, compared with those who initiated therapy within 30 days of TKR.
 

Physical therapy: Underexplored option for pain in knee replacement

One finding caught the researchers slightly off guard: There was no association between active physical therapy and reduced odds of long-term opioid use. “From prior studies, at least in people with knee osteoarthritis, we know that active interventions were more useful than passive interventions,” Dr. Kumar said.

That said, he added that there is still some professional uncertainty regarding “the right type or the right components of physical therapy for managing pain in this population.” Regardless, he believes their study emphasizes the benefits of PT as a pain alleviator in these patients, especially those who have previously used opioids.

“Pharmaceuticals have side effects. Injections are not super effective,” he said. “The idea behind focusing on physical therapy interventions is that it’s widely available, it does you no harm, and it could potentially be lower cost to both the payers and the providers.”

The authors acknowledged their study’s limitations, including not adjusting for opioid use within the 90 days after surgery as well as the different outcome assessment periods for pre-TKR and post-TKR PT exposures. In addition, they admitted that some of the patients who received PT could have been among those less likely to be treated with opioids, and vice versa. “A randomized clinical trial,” they wrote, “would be required to disentangle these issues.”

The study was supported by grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kumar reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Pfizer for unrelated projects outside the submitted work. The full list of author disclosures can be found with the original article.

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

Disease-modifying antirheumatic drugs (DMARDs) such as biologics may carry an increased risk for preterm birth or cesarean delivery for pregnant women with psoriatic arthritis (PsA), according to a recent study published in Arthritis & Rheumatology.

zoranm/Getty Images

The risk was particularly high for women with PsA who received biologic disease-modifying antirheumatic drugs (bDMARDs), according to Katarina Remaeus, PhD, of the Karolinska Institute in Stockholm and colleagues.

“The results may indicate that a more severe or active PsA disease that requires antirheumatic treatment during pregnancy, especially bDMARDs, is associated with increased risks of adverse pregnancy outcomes compared to non-PsA pregnancies,” Dr. Remaeus and colleagues write in their study. “The risk of preterm birth in PsA pregnancies is further influenced by parity with the most increased risks observed in first pregnancies.”

In a nationwide, register-based cohort study, the researchers evaluated 921 pregnancies of women with PsA between 2007 and 2017, comparing them to the pregnancies of 9,210 women without PsA over the same time frame. The pregnancies for women with PsA were further categorized based on whether the women had not received antirheumatic treatment in the year prior to and/or during pregnancy (495 pregnancies) or had received antirheumatic treatment at any point in the year before and/or during pregnancy (426 pregnancies).

Of the women in the PsA group who were treated in the year prior to pregnancy (170 women), 39.4% received monotherapy with a conventional synthetic DMARD (csDMARD) such as an antimalarial, methotrexate, or sulfasalazine; 24.1% received oral corticosteroids, and 15.9% received a tumor necrosis factor inhibitor (TNFi), whereas about 20% of women received two or more antirheumatic drugs.

In the group of women treated during pregnancy (256 women), 153 did not receive bDMARDs; of these, 41.8% had monotherapy with either a csDMARD or corticosteroids, whereas the group treated with bDMARDs received TNFi monotherapy (43.7%) or TNFi with corticosteroids (35.9%), TNFi with csDMARD (9.7%), or TNFi with csDMARD plus corticosteroids (9.7%).

A majority of women in both groups (70.1%) were between ages 30 and 34 years (37.1%) or older than age 35 years (33%) and had delivered more than one child (63.2%). Women in the PsA group were more likely to be born in a Nordic country (91.8% vs. 82.8%), to have a body mass index between 30.0 and 60.0 kg/m² (19.9% vs. 12.6%), to be a smoker (9.2% vs. 5.3%), to have hypertension (1.4% vs. 0.8%) or diabetes (1.3% vs. 0.5%) prior to pregnancy, and to have a higher level of education (>12 years; 50.1% vs. 43.3%), compared with women in the non-PsA group.

The results showed women in the PsA group were more likely to experience preterm birth (adjusted odds ratio, 1.69; 95% confidence interval, 1.27-2.24) and undergo an elective (aOR, 1.77; 95% CI, 1.43-2.20) or emergency C-section (aOR, 1.42; 95% CI, 1.10-1.84). The group at highest risk for preterm birth with regard to parity was women with PsA having their first child (aOR, 3.95; 95% CI, 1.43-10.95).

Women who received antirheumatic treatment were at greater risk for experiencing preterm birth (aOR, 2.30; 95% CI, 1.49-3.56), and this risk was even higher for treatment with bDMARDs, compared with women without PsA (aOR, 4.49; 95% CI, 2.60-7.79). Use of bDMARDs also was associated with higher risks for spontaneous preterm birth (aOR, 4.73; 95% CI, 2.53-8.87), preterm birth between 32 and 36 weeks’ gestation (aOR, 5.06; 95% CI, 2.91-8.79), elective C-section (aOR, 2.72; 95% CI, 1.61-4.59), emergency C-section (aOR, 2.06; 95% CI, 1.04-4.07), and preeclampsia (aOR, 2.88, 95% CI, 1.35-6.17).

The researchers note that women with PsA should be evaluated for preterm birth particularly if they are having their first child, and “from a clinical point of view, all women with PsA, regardless of antirheumatic treatment, should be counseled about pregnancy outcomes and receive individualized monitoring during pregnancy.”

Are adverse outcomes linked to disease activity or treatment?

Patients in the study had a higher risk of adverse outcomes when they had a PsA diagnosis, and when they received antirheumatic treatment – but were the adverse outcomes associated with a patient’s high disease activity or need for antirheumatic treatment?

“Our interpretation is that a PsA disease that requires continued antirheumatic treatment during pregnancy is more severe than PsA that does not require treatment,” Dr. Remaeus and colleagues write. “Thus, the increased risk of adverse outcomes in pregnancies with maternal antirheumatic treatment is probably attributed to disease severity rather than an effect of the medication itself.”

Anja Strangfeld, MD, PhD, of the German Rheumatism Research Centre in Berlin, told this news organization that the results of the study are important because it is one of the first to report differences in risk in pregnancy outcomes for women with and without PsA.

“The information is relevant to guide rheumatologists in advising patients with PsA when planning the first or subsequent pregnancies,” she said. “The results are reassuring in reporting that the elevated risk for PsA patients for adverse pregnancy outcomes is low in patients not in need of antirheumatic medication, presumably in low-disease activity.”

However, the study is still unclear on whether the association with adverse pregnancy outcomes in patients is the result of higher disease activity or the need for antirheumatic treatment, she explained.

“It was only hypothesized that those patients under bDMARD treatment are/were in high disease activity. There [is] no information on disease activity in the data sources, which limits the results,” she said. “The investigation still does not solve the important question – if adverse pregnancy outcomes are rather related to high disease activity or the medication to treat this situation.”

There was no specific funding for this study. The study authors and Dr. Strangfeld have disclosed no relevant financial relationships.

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

Disease-modifying antirheumatic drugs (DMARDs) such as biologics may carry an increased risk for preterm birth or cesarean delivery for pregnant women with psoriatic arthritis (PsA), according to a recent study published in Arthritis & Rheumatology.

zoranm/Getty Images

The risk was particularly high for women with PsA who received biologic disease-modifying antirheumatic drugs (bDMARDs), according to Katarina Remaeus, PhD, of the Karolinska Institute in Stockholm and colleagues.

“The results may indicate that a more severe or active PsA disease that requires antirheumatic treatment during pregnancy, especially bDMARDs, is associated with increased risks of adverse pregnancy outcomes compared to non-PsA pregnancies,” Dr. Remaeus and colleagues write in their study. “The risk of preterm birth in PsA pregnancies is further influenced by parity with the most increased risks observed in first pregnancies.”

In a nationwide, register-based cohort study, the researchers evaluated 921 pregnancies of women with PsA between 2007 and 2017, comparing them to the pregnancies of 9,210 women without PsA over the same time frame. The pregnancies for women with PsA were further categorized based on whether the women had not received antirheumatic treatment in the year prior to and/or during pregnancy (495 pregnancies) or had received antirheumatic treatment at any point in the year before and/or during pregnancy (426 pregnancies).

Of the women in the PsA group who were treated in the year prior to pregnancy (170 women), 39.4% received monotherapy with a conventional synthetic DMARD (csDMARD) such as an antimalarial, methotrexate, or sulfasalazine; 24.1% received oral corticosteroids, and 15.9% received a tumor necrosis factor inhibitor (TNFi), whereas about 20% of women received two or more antirheumatic drugs.

In the group of women treated during pregnancy (256 women), 153 did not receive bDMARDs; of these, 41.8% had monotherapy with either a csDMARD or corticosteroids, whereas the group treated with bDMARDs received TNFi monotherapy (43.7%) or TNFi with corticosteroids (35.9%), TNFi with csDMARD (9.7%), or TNFi with csDMARD plus corticosteroids (9.7%).

A majority of women in both groups (70.1%) were between ages 30 and 34 years (37.1%) or older than age 35 years (33%) and had delivered more than one child (63.2%). Women in the PsA group were more likely to be born in a Nordic country (91.8% vs. 82.8%), to have a body mass index between 30.0 and 60.0 kg/m² (19.9% vs. 12.6%), to be a smoker (9.2% vs. 5.3%), to have hypertension (1.4% vs. 0.8%) or diabetes (1.3% vs. 0.5%) prior to pregnancy, and to have a higher level of education (>12 years; 50.1% vs. 43.3%), compared with women in the non-PsA group.

The results showed women in the PsA group were more likely to experience preterm birth (adjusted odds ratio, 1.69; 95% confidence interval, 1.27-2.24) and undergo an elective (aOR, 1.77; 95% CI, 1.43-2.20) or emergency C-section (aOR, 1.42; 95% CI, 1.10-1.84). The group at highest risk for preterm birth with regard to parity was women with PsA having their first child (aOR, 3.95; 95% CI, 1.43-10.95).

Women who received antirheumatic treatment were at greater risk for experiencing preterm birth (aOR, 2.30; 95% CI, 1.49-3.56), and this risk was even higher for treatment with bDMARDs, compared with women without PsA (aOR, 4.49; 95% CI, 2.60-7.79). Use of bDMARDs also was associated with higher risks for spontaneous preterm birth (aOR, 4.73; 95% CI, 2.53-8.87), preterm birth between 32 and 36 weeks’ gestation (aOR, 5.06; 95% CI, 2.91-8.79), elective C-section (aOR, 2.72; 95% CI, 1.61-4.59), emergency C-section (aOR, 2.06; 95% CI, 1.04-4.07), and preeclampsia (aOR, 2.88, 95% CI, 1.35-6.17).

The researchers note that women with PsA should be evaluated for preterm birth particularly if they are having their first child, and “from a clinical point of view, all women with PsA, regardless of antirheumatic treatment, should be counseled about pregnancy outcomes and receive individualized monitoring during pregnancy.”

Are adverse outcomes linked to disease activity or treatment?

Patients in the study had a higher risk of adverse outcomes when they had a PsA diagnosis, and when they received antirheumatic treatment – but were the adverse outcomes associated with a patient’s high disease activity or need for antirheumatic treatment?

“Our interpretation is that a PsA disease that requires continued antirheumatic treatment during pregnancy is more severe than PsA that does not require treatment,” Dr. Remaeus and colleagues write. “Thus, the increased risk of adverse outcomes in pregnancies with maternal antirheumatic treatment is probably attributed to disease severity rather than an effect of the medication itself.”

Anja Strangfeld, MD, PhD, of the German Rheumatism Research Centre in Berlin, told this news organization that the results of the study are important because it is one of the first to report differences in risk in pregnancy outcomes for women with and without PsA.

“The information is relevant to guide rheumatologists in advising patients with PsA when planning the first or subsequent pregnancies,” she said. “The results are reassuring in reporting that the elevated risk for PsA patients for adverse pregnancy outcomes is low in patients not in need of antirheumatic medication, presumably in low-disease activity.”

However, the study is still unclear on whether the association with adverse pregnancy outcomes in patients is the result of higher disease activity or the need for antirheumatic treatment, she explained.

“It was only hypothesized that those patients under bDMARD treatment are/were in high disease activity. There [is] no information on disease activity in the data sources, which limits the results,” she said. “The investigation still does not solve the important question – if adverse pregnancy outcomes are rather related to high disease activity or the medication to treat this situation.”

There was no specific funding for this study. The study authors and Dr. Strangfeld have disclosed no relevant financial relationships.

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

Disease-modifying antirheumatic drugs (DMARDs) such as biologics may carry an increased risk for preterm birth or cesarean delivery for pregnant women with psoriatic arthritis (PsA), according to a recent study published in Arthritis & Rheumatology.

zoranm/Getty Images

The risk was particularly high for women with PsA who received biologic disease-modifying antirheumatic drugs (bDMARDs), according to Katarina Remaeus, PhD, of the Karolinska Institute in Stockholm and colleagues.

“The results may indicate that a more severe or active PsA disease that requires antirheumatic treatment during pregnancy, especially bDMARDs, is associated with increased risks of adverse pregnancy outcomes compared to non-PsA pregnancies,” Dr. Remaeus and colleagues write in their study. “The risk of preterm birth in PsA pregnancies is further influenced by parity with the most increased risks observed in first pregnancies.”

In a nationwide, register-based cohort study, the researchers evaluated 921 pregnancies of women with PsA between 2007 and 2017, comparing them to the pregnancies of 9,210 women without PsA over the same time frame. The pregnancies for women with PsA were further categorized based on whether the women had not received antirheumatic treatment in the year prior to and/or during pregnancy (495 pregnancies) or had received antirheumatic treatment at any point in the year before and/or during pregnancy (426 pregnancies).

Of the women in the PsA group who were treated in the year prior to pregnancy (170 women), 39.4% received monotherapy with a conventional synthetic DMARD (csDMARD) such as an antimalarial, methotrexate, or sulfasalazine; 24.1% received oral corticosteroids, and 15.9% received a tumor necrosis factor inhibitor (TNFi), whereas about 20% of women received two or more antirheumatic drugs.

In the group of women treated during pregnancy (256 women), 153 did not receive bDMARDs; of these, 41.8% had monotherapy with either a csDMARD or corticosteroids, whereas the group treated with bDMARDs received TNFi monotherapy (43.7%) or TNFi with corticosteroids (35.9%), TNFi with csDMARD (9.7%), or TNFi with csDMARD plus corticosteroids (9.7%).

A majority of women in both groups (70.1%) were between ages 30 and 34 years (37.1%) or older than age 35 years (33%) and had delivered more than one child (63.2%). Women in the PsA group were more likely to be born in a Nordic country (91.8% vs. 82.8%), to have a body mass index between 30.0 and 60.0 kg/m² (19.9% vs. 12.6%), to be a smoker (9.2% vs. 5.3%), to have hypertension (1.4% vs. 0.8%) or diabetes (1.3% vs. 0.5%) prior to pregnancy, and to have a higher level of education (>12 years; 50.1% vs. 43.3%), compared with women in the non-PsA group.

The results showed women in the PsA group were more likely to experience preterm birth (adjusted odds ratio, 1.69; 95% confidence interval, 1.27-2.24) and undergo an elective (aOR, 1.77; 95% CI, 1.43-2.20) or emergency C-section (aOR, 1.42; 95% CI, 1.10-1.84). The group at highest risk for preterm birth with regard to parity was women with PsA having their first child (aOR, 3.95; 95% CI, 1.43-10.95).

Women who received antirheumatic treatment were at greater risk for experiencing preterm birth (aOR, 2.30; 95% CI, 1.49-3.56), and this risk was even higher for treatment with bDMARDs, compared with women without PsA (aOR, 4.49; 95% CI, 2.60-7.79). Use of bDMARDs also was associated with higher risks for spontaneous preterm birth (aOR, 4.73; 95% CI, 2.53-8.87), preterm birth between 32 and 36 weeks’ gestation (aOR, 5.06; 95% CI, 2.91-8.79), elective C-section (aOR, 2.72; 95% CI, 1.61-4.59), emergency C-section (aOR, 2.06; 95% CI, 1.04-4.07), and preeclampsia (aOR, 2.88, 95% CI, 1.35-6.17).

The researchers note that women with PsA should be evaluated for preterm birth particularly if they are having their first child, and “from a clinical point of view, all women with PsA, regardless of antirheumatic treatment, should be counseled about pregnancy outcomes and receive individualized monitoring during pregnancy.”

Are adverse outcomes linked to disease activity or treatment?

Patients in the study had a higher risk of adverse outcomes when they had a PsA diagnosis, and when they received antirheumatic treatment – but were the adverse outcomes associated with a patient’s high disease activity or need for antirheumatic treatment?

“Our interpretation is that a PsA disease that requires continued antirheumatic treatment during pregnancy is more severe than PsA that does not require treatment,” Dr. Remaeus and colleagues write. “Thus, the increased risk of adverse outcomes in pregnancies with maternal antirheumatic treatment is probably attributed to disease severity rather than an effect of the medication itself.”

Anja Strangfeld, MD, PhD, of the German Rheumatism Research Centre in Berlin, told this news organization that the results of the study are important because it is one of the first to report differences in risk in pregnancy outcomes for women with and without PsA.

“The information is relevant to guide rheumatologists in advising patients with PsA when planning the first or subsequent pregnancies,” she said. “The results are reassuring in reporting that the elevated risk for PsA patients for adverse pregnancy outcomes is low in patients not in need of antirheumatic medication, presumably in low-disease activity.”

However, the study is still unclear on whether the association with adverse pregnancy outcomes in patients is the result of higher disease activity or the need for antirheumatic treatment, she explained.

“It was only hypothesized that those patients under bDMARD treatment are/were in high disease activity. There [is] no information on disease activity in the data sources, which limits the results,” she said. “The investigation still does not solve the important question – if adverse pregnancy outcomes are rather related to high disease activity or the medication to treat this situation.”

There was no specific funding for this study. The study authors and Dr. Strangfeld have disclosed no relevant financial relationships.

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

Platelet-rich plasma (PRP) injections did not significantly improve pain or function when compared with placebo injections in patients with ankle osteoarthritis (OA), a new study has found.

“Previous evidence for PRP injections in ankle osteoarthritis was limited to 4 small case series with methodological flaws,” wrote Liam D. A. Paget, MD, of the University of Amsterdam, and coauthors. The study was published online Oct. 26 in JAMA.

To assess the value of PRP injections as a treatment for ankle OA, the researchers launched a double-blind, randomized clinical trial of Dutch patients with notable ankle pain and tibiotalar joint space narrowing. From six sites in the Netherlands, 100 patients (45% women, mean age 56 years) were split into two groups: one that received two intra-articular injections of PRP 6 weeks apart (n = 48) and one that received two injections of saline placebo (n = 52).

At baseline, mean American Orthopaedic Foot and Ankle Society (AOFAS) scores were 63 in the PRP group and 64 in the placebo group (range 0-100, with higher scores indicating less pain and more function). At 26-week follow-up, the mean AOFAS score improved by 10 points in the PRP group (95% confidence interval, 6-14; P < .001) and by 11 points in the placebo group (95% CI, 7-15; P < .001). The adjusted between-group difference for AOFAS improvement over 26 weeks was –1 point (95% CI, –6 to 3; P = .56).

There was one serious adverse event in the placebo group – a transient ischemic attack 3 weeks after the first injection – but it was deemed unrelated.
 

Searching for answers regarding PRP and osteoarthritis

“From my standpoint, this study is a great step forward to where the field needs to be, which is honing in on longer-term studies that are standardizing PRP and teasing out its effects,” Prathap Jayaram, MD, director of regenerative sports medicine at the Baylor College of Medicine in Houston, said in an interview.

He highlighted the authors’ acknowledgment of previous studies in which PRP injections appeared effective in treating knee OA, including their statement that the “results reported here for ankle osteoarthritis were not consistent with these potentially beneficial effects in knee osteoarthritis.”

“They’re acknowledging that this does have some benefit in knees,” he said. “Could that translate toward the ankle?”

“PRP did lead to an improvement,” he added. “There just wasn’t a big enough difference to say one was superior to the other.”

Citing his team’s recent preclinical study that was published in Osteoarthritis and Cartilage, Dr. Jayaram emphasized the possibility that PRP could have much-needed disease-modifying effects in osteoarthritis. More work is needed to pin down the details.

“We need more mechanistic studies to be done so we can actually identify the therapeutic properties in PRP and leverage them to track reproducible outcomes,” he said, adding that “simply put, your blood and my blood might be different. There is going to be heterogeneity there. The analogy I give my patients is, when they take an antibiotic, we have a specific dose, a specific drug, and a specific duration. It’s very standardized. We’re just not there yet with PRP.”

The authors acknowledged their study’s limitations, including a likely inability to generalize their results to other platelet-rich blood products as well as a lack of composition analysis of the PRP they used. That said, they added that this particular PRP has been “analyzed previously” for another trial and noted that such analysis is not typically performed in a clinical setting.

The study was supported by a grant from the Dutch Arthritis Society. Its authors reported several potential conflicts of interest, including receiving their own grants from the Dutch Arthritis Society and other organizations, as well as accepting loaned Hettich centrifuges from a medical device company for the study.

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

Platelet-rich plasma (PRP) injections did not significantly improve pain or function when compared with placebo injections in patients with ankle osteoarthritis (OA), a new study has found.

“Previous evidence for PRP injections in ankle osteoarthritis was limited to 4 small case series with methodological flaws,” wrote Liam D. A. Paget, MD, of the University of Amsterdam, and coauthors. The study was published online Oct. 26 in JAMA.

To assess the value of PRP injections as a treatment for ankle OA, the researchers launched a double-blind, randomized clinical trial of Dutch patients with notable ankle pain and tibiotalar joint space narrowing. From six sites in the Netherlands, 100 patients (45% women, mean age 56 years) were split into two groups: one that received two intra-articular injections of PRP 6 weeks apart (n = 48) and one that received two injections of saline placebo (n = 52).

At baseline, mean American Orthopaedic Foot and Ankle Society (AOFAS) scores were 63 in the PRP group and 64 in the placebo group (range 0-100, with higher scores indicating less pain and more function). At 26-week follow-up, the mean AOFAS score improved by 10 points in the PRP group (95% confidence interval, 6-14; P < .001) and by 11 points in the placebo group (95% CI, 7-15; P < .001). The adjusted between-group difference for AOFAS improvement over 26 weeks was –1 point (95% CI, –6 to 3; P = .56).

There was one serious adverse event in the placebo group – a transient ischemic attack 3 weeks after the first injection – but it was deemed unrelated.
 

Searching for answers regarding PRP and osteoarthritis

“From my standpoint, this study is a great step forward to where the field needs to be, which is honing in on longer-term studies that are standardizing PRP and teasing out its effects,” Prathap Jayaram, MD, director of regenerative sports medicine at the Baylor College of Medicine in Houston, said in an interview.

He highlighted the authors’ acknowledgment of previous studies in which PRP injections appeared effective in treating knee OA, including their statement that the “results reported here for ankle osteoarthritis were not consistent with these potentially beneficial effects in knee osteoarthritis.”

“They’re acknowledging that this does have some benefit in knees,” he said. “Could that translate toward the ankle?”

“PRP did lead to an improvement,” he added. “There just wasn’t a big enough difference to say one was superior to the other.”

Citing his team’s recent preclinical study that was published in Osteoarthritis and Cartilage, Dr. Jayaram emphasized the possibility that PRP could have much-needed disease-modifying effects in osteoarthritis. More work is needed to pin down the details.

“We need more mechanistic studies to be done so we can actually identify the therapeutic properties in PRP and leverage them to track reproducible outcomes,” he said, adding that “simply put, your blood and my blood might be different. There is going to be heterogeneity there. The analogy I give my patients is, when they take an antibiotic, we have a specific dose, a specific drug, and a specific duration. It’s very standardized. We’re just not there yet with PRP.”

The authors acknowledged their study’s limitations, including a likely inability to generalize their results to other platelet-rich blood products as well as a lack of composition analysis of the PRP they used. That said, they added that this particular PRP has been “analyzed previously” for another trial and noted that such analysis is not typically performed in a clinical setting.

The study was supported by a grant from the Dutch Arthritis Society. Its authors reported several potential conflicts of interest, including receiving their own grants from the Dutch Arthritis Society and other organizations, as well as accepting loaned Hettich centrifuges from a medical device company for the study.

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

Platelet-rich plasma (PRP) injections did not significantly improve pain or function when compared with placebo injections in patients with ankle osteoarthritis (OA), a new study has found.

“Previous evidence for PRP injections in ankle osteoarthritis was limited to 4 small case series with methodological flaws,” wrote Liam D. A. Paget, MD, of the University of Amsterdam, and coauthors. The study was published online Oct. 26 in JAMA.

To assess the value of PRP injections as a treatment for ankle OA, the researchers launched a double-blind, randomized clinical trial of Dutch patients with notable ankle pain and tibiotalar joint space narrowing. From six sites in the Netherlands, 100 patients (45% women, mean age 56 years) were split into two groups: one that received two intra-articular injections of PRP 6 weeks apart (n = 48) and one that received two injections of saline placebo (n = 52).

At baseline, mean American Orthopaedic Foot and Ankle Society (AOFAS) scores were 63 in the PRP group and 64 in the placebo group (range 0-100, with higher scores indicating less pain and more function). At 26-week follow-up, the mean AOFAS score improved by 10 points in the PRP group (95% confidence interval, 6-14; P < .001) and by 11 points in the placebo group (95% CI, 7-15; P < .001). The adjusted between-group difference for AOFAS improvement over 26 weeks was –1 point (95% CI, –6 to 3; P = .56).

There was one serious adverse event in the placebo group – a transient ischemic attack 3 weeks after the first injection – but it was deemed unrelated.
 

Searching for answers regarding PRP and osteoarthritis

“From my standpoint, this study is a great step forward to where the field needs to be, which is honing in on longer-term studies that are standardizing PRP and teasing out its effects,” Prathap Jayaram, MD, director of regenerative sports medicine at the Baylor College of Medicine in Houston, said in an interview.

He highlighted the authors’ acknowledgment of previous studies in which PRP injections appeared effective in treating knee OA, including their statement that the “results reported here for ankle osteoarthritis were not consistent with these potentially beneficial effects in knee osteoarthritis.”

“They’re acknowledging that this does have some benefit in knees,” he said. “Could that translate toward the ankle?”

“PRP did lead to an improvement,” he added. “There just wasn’t a big enough difference to say one was superior to the other.”

Citing his team’s recent preclinical study that was published in Osteoarthritis and Cartilage, Dr. Jayaram emphasized the possibility that PRP could have much-needed disease-modifying effects in osteoarthritis. More work is needed to pin down the details.

“We need more mechanistic studies to be done so we can actually identify the therapeutic properties in PRP and leverage them to track reproducible outcomes,” he said, adding that “simply put, your blood and my blood might be different. There is going to be heterogeneity there. The analogy I give my patients is, when they take an antibiotic, we have a specific dose, a specific drug, and a specific duration. It’s very standardized. We’re just not there yet with PRP.”

The authors acknowledged their study’s limitations, including a likely inability to generalize their results to other platelet-rich blood products as well as a lack of composition analysis of the PRP they used. That said, they added that this particular PRP has been “analyzed previously” for another trial and noted that such analysis is not typically performed in a clinical setting.

The study was supported by a grant from the Dutch Arthritis Society. Its authors reported several potential conflicts of interest, including receiving their own grants from the Dutch Arthritis Society and other organizations, as well as accepting loaned Hettich centrifuges from a medical device company for the study.

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

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published in JAMA Network Open The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

“These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes,” write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. “Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine,” they write.
 

Findings mirror those seen in other settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia.

“In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors,” Dr. Gelfand, who was not involved in the study, told this news organization. “This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease.”

Dr. Gelfand emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

“I typically recommend this third dose be taken 6 months after the second dose,” Dr. Gelfand said. “The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines.”
 

Study details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and Feb. 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6,077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one-third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn’s disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

“Therefore, blocking TNF could inhibit this detrimental immune response,” the authors write. “Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion.”

Another possibility relates to the effects of taking non–TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body’s ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. “This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence,” the authors write.

 

Caution needed in interpreting uncontrolled, registry-based data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who was not involved in the research.

Northwestern University

“We’ve been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups,” Dr. Hanauer told this news organization. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, antiadhesion therapies, or anti–IL12/23 inhibitors, compared with the general population not taking these therapies.

The study’s size and the diversity of patients strengthen its findings. However, the registries’ use of convenience sampling increases the potential for reporting bias, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

“These are databases that rely on reporting from investigators and are not comprehensive prospective studies,” Dr. Hanauer noted as another study limitation.

Dr. Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a “collection of spontaneous reports” that should be viewed as hypothesis-generating rather than testing.

“Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments,” Dr. Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, in an accompanying commentary.

On the basis of the findings of this study, “which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial,” Dr. Velloso writes. “The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients.”

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the United Kingdom’s National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Dr. Velloso has disclosed no relevant financial relationships. Dr. Hanauer has served as a consultant to companies that market TNF inhibitors. Dr. Gelfand has consulted for and received research grants from companies that market TNF inhibitors.

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

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published in JAMA Network Open The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

“These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes,” write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. “Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine,” they write.
 

Findings mirror those seen in other settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia.

“In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors,” Dr. Gelfand, who was not involved in the study, told this news organization. “This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease.”

Dr. Gelfand emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

“I typically recommend this third dose be taken 6 months after the second dose,” Dr. Gelfand said. “The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines.”
 

Study details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and Feb. 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6,077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one-third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn’s disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

“Therefore, blocking TNF could inhibit this detrimental immune response,” the authors write. “Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion.”

Another possibility relates to the effects of taking non–TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body’s ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. “This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence,” the authors write.

 

Caution needed in interpreting uncontrolled, registry-based data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who was not involved in the research.

Northwestern University

“We’ve been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups,” Dr. Hanauer told this news organization. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, antiadhesion therapies, or anti–IL12/23 inhibitors, compared with the general population not taking these therapies.

The study’s size and the diversity of patients strengthen its findings. However, the registries’ use of convenience sampling increases the potential for reporting bias, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

“These are databases that rely on reporting from investigators and are not comprehensive prospective studies,” Dr. Hanauer noted as another study limitation.

Dr. Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a “collection of spontaneous reports” that should be viewed as hypothesis-generating rather than testing.

“Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments,” Dr. Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, in an accompanying commentary.

On the basis of the findings of this study, “which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial,” Dr. Velloso writes. “The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients.”

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the United Kingdom’s National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Dr. Velloso has disclosed no relevant financial relationships. Dr. Hanauer has served as a consultant to companies that market TNF inhibitors. Dr. Gelfand has consulted for and received research grants from companies that market TNF inhibitors.

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

Among patients with immune-mediated inflammatory diseases (IMIDs) who get COVID-19, the risk for hospitalization and death is lower if they are receiving tumor necrosis factor (TNF) inhibitor monotherapy, compared with receiving most other common drugs for these conditions, with or without TNF inhibitors, according to a study published in JAMA Network Open The only combination not associated with an increased risk for hospitalization or death was TNF inhibitor therapy with methotrexate.

“These findings support the continued use of TNF inhibitor monotherapy during the pandemic and warrant further research investigating the association of other biologic therapies with COVID-19 outcomes,” write Zara Izadi, MPharm, of the University of California, San Francisco, and her colleagues. “Treatment with TNF inhibitor combination therapy was associated with a more favorable safety profile when methotrexate rather than azathioprine/6-mercaptopurine was used, suggesting that clinicians would benefit from weighing the risks versus benefits of deescalating treatment or changing medications when a patient is receiving concomitant TNF inhibitors and azathioprine/6-mercaptopurine,” they write.
 

Findings mirror those seen in other settings

These findings are in line with what has been found in other settings, according to Joel M. Gelfand, MD, director of the psoriasis and phototherapy treatment center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, Philadelphia.

“In the beginning of the pandemic, there was concern about use of immune-modulating treatments, and many patients self-discontinued treatments like TNF inhibitors,” Dr. Gelfand, who was not involved in the study, told this news organization. “This has ultimately proved unnecessary and unfortunately resulted in harm to many patients due to flaring of their underlying disease.”

Dr. Gelfand emphasized the importance of vaccinating patients against COVID-19 as soon as possible and of getting a third dose for those who are already fully vaccinated with the Pfizer or Moderna shots, as recommended by the Centers for Disease Control and Prevention.

“I typically recommend this third dose be taken 6 months after the second dose,” Dr. Gelfand said. “The good news is that TNF inhibitors do not seem to meaningfully impact response to mRNA vaccines.”
 

Study details

The researchers analyzed data from three international registries of adults with rheumatic diseases, inflammatory bowel disease, and psoriasis who had COVID-19 between March 12, 2020, and Feb. 1, 2021. The registries included the Secure Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), and the physician-reported registry from the Global Rheumatology Alliance (GRA).

The population included 6,077 patients from 74 countries. About half of the cohort (52.9%) were from Europe; more than half were women (58.6%). The average age was 48 years. A little over one-third of the patients (35.3%) had rheumatoid arthritis, 25.3% had Crohn’s disease, 12.5% had ulcerative colitis, 10.3% had spondyloarthritis, and 9.3% had psoriatic arthritis. Smaller percentages had psoriasis (4.9%), another type of arthritis or multiple types (1.7%), or another inflammatory bowel disease (0.6%).

One in five patients (21.3%) were hospitalized, and 3.1% died. The researchers compared outcomes for those who were receiving TNF inhibitor therapy alone to outcomes for those who were taking azathioprine/6-mercaptopurine therapy (alone or with a TNF inhibitor), methotrexate (alone or with a TNF inhibitor), and Janus kinase (JAK) inhibitors. They adjusted their analysis to account for active disease and common comorbidities, as well as geography and the period during the pandemic in which the person was admitted, because treatment regimens and hospitalization indications have varied over time.

All of the therapies except the combination of TNF inhibitors and methotrexate were associated with higher odds of hospitalization and death than TNF inhibitor monotherapy.

The researchers explored several possible explanations for the findings, including the possibility that high serum TNF concentrations may have been associated with more organ damage at the time of COVID-19 admission, owing to interaction with SARS-CoV-2–associated hyperinflammation.

“Therefore, blocking TNF could inhibit this detrimental immune response,” the authors write. “Multiple case series reporting favorable outcomes among patients receiving TNF inhibitor therapy support this assertion.”

Another possibility relates to the effects of taking non–TNF inhibitor medications for immunosuppression. The authors note that thiopurine medications are linked to a greater risk for opportunistic viral infections and that JAK inhibitors may reduce the body’s ability to clear the virus because of its suppression of innate immune response.

The authors also postulate that methotrexate may lower the likelihood of cytokine storm linked to COVID-19, even though methotrexate monotherapy was associated with poorer outcomes. “This association could mean that TNF inhibitor therapy is exerting a protective benefit or that methotrexate therapy is exerting a harmful consequence,” the authors write.

 

Caution needed in interpreting uncontrolled, registry-based data

The findings were not surprising to Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern University, Chicago, who was not involved in the research.

Northwestern University

“We’ve been monitoring IBD [inflammatory bowel disease] patients through the Secure registry similar to the rheumatologic and dermatologic societies and have not identified a signal of harm from any international groups,” Dr. Hanauer told this news organization. He noted that these registries also have not shown an increased risk for COVID-19 complications among patients receiving TNF inhibitors, antiadhesion therapies, or anti–IL12/23 inhibitors, compared with the general population not taking these therapies.

The study’s size and the diversity of patients strengthen its findings. However, the registries’ use of convenience sampling increases the potential for reporting bias, although the results remained similar after a sensitivity analysis. The study also lacked a control group, and the registries did not collect data uniformly.

“These are databases that rely on reporting from investigators and are not comprehensive prospective studies,” Dr. Hanauer noted as another study limitation.

Dr. Gelfand similarly advised caution in interpreting these findings, inasmuch as the study is a “collection of spontaneous reports” that should be viewed as hypothesis-generating rather than testing.

“Fortunately, more rigorous studies have been conducted, typically in large medical record systems, and have confirmed the hypothesis that TNF inhibitors are associated with a lower risk of poor COVID-19 outcomes, compared to other treatments,” Dr. Gelfand said.

Previous smaller studies similarly found better outcomes among patients taking TNF inhibitors, compared with other therapies, but their participants were predominantly from North America and Europe, noted Licio A. Velloso, MD, PhD, of the University of Campinas, in São Paulo, in an accompanying commentary.

On the basis of the findings of this study, “which included a much larger sample comprising distinct diseases and patients with a multitude of genetic backgrounds, the evidence in favor of the continued use of TNF inhibitor monotherapy for patients with IMIDs during the COVID-19 pandemic has become more substantial,” Dr. Velloso writes. “The finding that maintenance of TNF inhibitor monotherapy is associated with reductions in the risk of severe COVID-19 among patients with IMIDs offers new perspective that may guide health care professionals in the difficult decisions regarding therapeutic approaches among this specific group of patients.”

The research was funded by the American College of Rheumatology, the European Alliance of Associations for Rheumatology, the United Kingdom’s National Institute for Health Research Biomedical Research Center, and the Psoriasis Association. Many authors reported receiving grants and/or personal fees from a variety of pharmaceutical companies. Dr. Velloso has disclosed no relevant financial relationships. Dr. Hanauer has served as a consultant to companies that market TNF inhibitors. Dr. Gelfand has consulted for and received research grants from companies that market TNF inhibitors.

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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