Be careful out there if you are being treated with Enbrel (etanercept) by
Dr. Edward Tobinick.
TNF Inhibitor Use for Rheumatic Diseases Tied to Incident Neuroinflammatory Events
-Risk only seen in patients with psoriatic arthritis and ankylosing spondylitis
Study Authors: Tine Iskov Kopp, Bénédicte Delcoigne, et al.
Target Audience and Goal Statement: Rheumatologists
The goal of this study was to determine if use of tumor necrosis factor (TNF) inhibitors was associated with an increased risk of neuroinflammatory events among patients with rheumatic diseases.
Question Addressed:
TNF inhibitors are among the most effective agents for reducing inflammation associated with several rheumatic diseases. The availability of such effective therapeutic options enables rheumatologists to use a multifaceted approach to achieve disease control. According to Jain and Singh, this includes starting aggressive treatment early in the course of inflammatory arthritides, tailoring therapies to disease response that slows radiographic damage to joints and minimizes structural joint damage and disability, providing better symptom control and quality of life to patients, and switching therapy when the response is not adequate.
However,
small studies have suggested that treatment with TNF inhibitors may be
associated with risk of neuroinflammatory disorders, including multiple
sclerosis (MS), inflammatory neuropathies, and optic neuritis. For
example, TNF may play an important role in the pathogenesis of MS.
Randomized clinical trials involving TNF inhibitor-treated patients with
MS have also shown unfavorable results, such as disease exacerbations.
Psoriatic arthritis (PsA) patients have been reported to be at elevated risk for MS, even without treatment with TNF inhibitors, while an inverse correlation has been suggested for rheumatoid arthritis (RA) and MS. There was clearly a need to assess whether MS-related disorders may be adverse events following treatment with TNF inhibitors for arthritic diseases.
According to a large prospective cohort study conducted in Denmark and Sweden, patients with PsA or ankylosing spondylitis (AS) who were exposed to TNF inhibitors had a 50% greater risk for any neuroinflammatory event compared with unexposed patients (hazard ratio [HR] 1.50, 95% CI 1.07-2.11). And among Danish patients with AS or PsA who used TNF inhibitors, the risk increased 3.4-fold (HR 3.41, 95% CI 1.30-8.96), said Tine Iskov Kopp, PhD, of the department of neurology at Rigshospitalet Glostrup in Denmark, and colleagues.
However, there was no significantly increased risk for patients with RA, with hazard ratios of 0.97 (95% CI 0.72-1.33) in Sweden and 1.45 (95% CI 0.74-2.81) in Denmark, they reported in Annals of the Rheumatic Diseases.
"This information will be important for risk communication and evaluation in clinical practice, even though the absolute risk is low," they noted.
Of the 175,520 patients with RA, PsA, or AS identified from national registers in Denmark (Danish DANBIO register) and Sweden (Swedish Rheumatology Quality Register) from 2000 to 2017, 43,909 were treated with TNF inhibitors at any time during follow-up.
Median follow-up time varied from 2.7 years for non-exposed PsA and AS patients in DANBIO to 7.4 years among RA patients exposed to TNF inhibitors in both cohorts. The most commonly used TNF inhibitors were adalimumab, infliximab, etanercept, golimumab, and certolizumab pegol.
Neuroinflammatory events were classified as MS, other demyelinating diseases such as optic neuritis, or polyneuropathy events. Adjusted models included age, gender, and year of inclusion in the cohorts.
For AS and PsA, crude incidence rates of all neuroinflammatory events in each country (per 1,000 person-years) were 0.59 (Sweden) and 0.87 (Denmark) in TNF inhibitor-exposed patients versus 0.40 (Sweden) and 0.19 (Denmark) in unexposed patients.
Time to any event among exposed patients was 3.8 years in the Swedish group and 3.1 years in the Danish group, and patient ages at the time of the event were 43 and 46 years, respectively.
Compared with unexposed patients, risks for neuroinflammatory events in exposed patients were the greatest for demyelinating diseases of the central nervous system and optic neuritis: a 1.65-fold and a threefold increase in the Swedish and Danish cohorts, respectively. The Swedish cohort had a significant 1.65-fold increased risk for MS. There was only a 1.13-fold increase in risk for inflammatory polyneuropathies.
"The risk estimates obtained from the 'on-drug' analysis among PsA and AS patients were lower than in the main analysis which may suggest that demyelinating events develop after longer exposure time, and even after the treatment has been discontinued," the researchers wrote.
Nevertheless, they added the caveat that "the time to event varied across cohorts, thus making it difficult to confirm the nature of any temporal association between exposure and outcome."
Other study limitations included confounding by indication.
Source Reference: Annals of the Rheumatic Diseases 2020; DOI: 10.1136/annrheumdis-2019-216693
Study Highlights and Explanation of Findings:
Some of the study strengths listed by the authors included the use of high-quality population-based rheumatic disease registers with long follow-up times, increased statistical power gained by using data from two countries, and the agreement between results from the two countries (despite slightly different definitions of TNF inhibitor-naive comparative cohorts in the two countries).
Both Etminan et al. and Bernatsky et al. used U.S. health claims databases and a nested case-control design to also assess the risk of different neuroinflammatory events after treatment with TNF inhibitors for arthritis patients. Etminan et al. found a more than twofold increased risk of peripheral neuropathy among arthritis patients (RA, PsA, and AS) with a past use of TNF inhibitors compared with arthritis patients not exposed to this treatment, while Bernatsky et al. found a non-significant 31% increased risk of demyelinating events following TNF inhibitor exposure among RA patients compared with non-exposed RA patients.
However, Kopp and team stated that "both studies had relatively short mean follow-up times (1.9 and 2.3 person-years, respectively) and the claims-based databases used were unrepresentative (based on unemployed and older individuals)."
By contrast, their study had a longer follow-up time and demonstrated that the pattern of risks for developing a
Target Audience and Goal Statement: Rheumatologists
The goal of this study was to determine if use of tumor necrosis factor (TNF) inhibitors was associated with an increased risk of neuroinflammatory events among patients with rheumatic diseases.
Question Addressed:
- Did patients with rheumatic diseases experience a higher risk of neuroinflammatory events when treated with TNF inhibitors?
TNF inhibitors are among the most effective agents for reducing inflammation associated with several rheumatic diseases. The availability of such effective therapeutic options enables rheumatologists to use a multifaceted approach to achieve disease control. According to Jain and Singh, this includes starting aggressive treatment early in the course of inflammatory arthritides, tailoring therapies to disease response that slows radiographic damage to joints and minimizes structural joint damage and disability, providing better symptom control and quality of life to patients, and switching therapy when the response is not adequate.
Action Points
- Patients with psoriatic arthritis and ankylosing spondylitis -- but not rheumatoid arthritis -- who were treated with tumor necrosis factor (TNF) inhibitors were at increased risk for developing neuroinflammatory events, according to a large prospective Danish and Swedish cohort study.
- Understand that the underlying biological mechanism needs to be further explored to characterize the mechanism of action and to enable identification of susceptible patients.
Psoriatic arthritis (PsA) patients have been reported to be at elevated risk for MS, even without treatment with TNF inhibitors, while an inverse correlation has been suggested for rheumatoid arthritis (RA) and MS. There was clearly a need to assess whether MS-related disorders may be adverse events following treatment with TNF inhibitors for arthritic diseases.
According to a large prospective cohort study conducted in Denmark and Sweden, patients with PsA or ankylosing spondylitis (AS) who were exposed to TNF inhibitors had a 50% greater risk for any neuroinflammatory event compared with unexposed patients (hazard ratio [HR] 1.50, 95% CI 1.07-2.11). And among Danish patients with AS or PsA who used TNF inhibitors, the risk increased 3.4-fold (HR 3.41, 95% CI 1.30-8.96), said Tine Iskov Kopp, PhD, of the department of neurology at Rigshospitalet Glostrup in Denmark, and colleagues.
However, there was no significantly increased risk for patients with RA, with hazard ratios of 0.97 (95% CI 0.72-1.33) in Sweden and 1.45 (95% CI 0.74-2.81) in Denmark, they reported in Annals of the Rheumatic Diseases.
"This information will be important for risk communication and evaluation in clinical practice, even though the absolute risk is low," they noted.
Of the 175,520 patients with RA, PsA, or AS identified from national registers in Denmark (Danish DANBIO register) and Sweden (Swedish Rheumatology Quality Register) from 2000 to 2017, 43,909 were treated with TNF inhibitors at any time during follow-up.
Median follow-up time varied from 2.7 years for non-exposed PsA and AS patients in DANBIO to 7.4 years among RA patients exposed to TNF inhibitors in both cohorts. The most commonly used TNF inhibitors were adalimumab, infliximab, etanercept, golimumab, and certolizumab pegol.
Neuroinflammatory events were classified as MS, other demyelinating diseases such as optic neuritis, or polyneuropathy events. Adjusted models included age, gender, and year of inclusion in the cohorts.
For AS and PsA, crude incidence rates of all neuroinflammatory events in each country (per 1,000 person-years) were 0.59 (Sweden) and 0.87 (Denmark) in TNF inhibitor-exposed patients versus 0.40 (Sweden) and 0.19 (Denmark) in unexposed patients.
Time to any event among exposed patients was 3.8 years in the Swedish group and 3.1 years in the Danish group, and patient ages at the time of the event were 43 and 46 years, respectively.
Compared with unexposed patients, risks for neuroinflammatory events in exposed patients were the greatest for demyelinating diseases of the central nervous system and optic neuritis: a 1.65-fold and a threefold increase in the Swedish and Danish cohorts, respectively. The Swedish cohort had a significant 1.65-fold increased risk for MS. There was only a 1.13-fold increase in risk for inflammatory polyneuropathies.
"The risk estimates obtained from the 'on-drug' analysis among PsA and AS patients were lower than in the main analysis which may suggest that demyelinating events develop after longer exposure time, and even after the treatment has been discontinued," the researchers wrote.
Nevertheless, they added the caveat that "the time to event varied across cohorts, thus making it difficult to confirm the nature of any temporal association between exposure and outcome."
Other study limitations included confounding by indication.
Source Reference: Annals of the Rheumatic Diseases 2020; DOI: 10.1136/annrheumdis-2019-216693
Study Highlights and Explanation of Findings:
Some of the study strengths listed by the authors included the use of high-quality population-based rheumatic disease registers with long follow-up times, increased statistical power gained by using data from two countries, and the agreement between results from the two countries (despite slightly different definitions of TNF inhibitor-naive comparative cohorts in the two countries).
Both Etminan et al. and Bernatsky et al. used U.S. health claims databases and a nested case-control design to also assess the risk of different neuroinflammatory events after treatment with TNF inhibitors for arthritis patients. Etminan et al. found a more than twofold increased risk of peripheral neuropathy among arthritis patients (RA, PsA, and AS) with a past use of TNF inhibitors compared with arthritis patients not exposed to this treatment, while Bernatsky et al. found a non-significant 31% increased risk of demyelinating events following TNF inhibitor exposure among RA patients compared with non-exposed RA patients.
However, Kopp and team stated that "both studies had relatively short mean follow-up times (1.9 and 2.3 person-years, respectively) and the claims-based databases used were unrepresentative (based on unemployed and older individuals)."
By contrast, their study had a longer follow-up time and demonstrated that the pattern of risks for developing a
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