Tumor Necrosis Factor Inhibitors May Increase Extra-articular RA Risk

Severe extra-articular rheumatoid arthritis (ExRA) is an important contributor to morbidity and premature mortality in RA; however, data on the effect of tumor necrosis factor (TNF) inhibitors on ExRA are limited and contradictory. The relationship between TNF inhibitor treatment and the risk for severe ExRA in patients with RA was investigated using an extension of a previous cohort study.

The risk of developing ExRA was 0.71 per 100 PY during TNF inhibitor therapy among patients exposed to anti-TNF treatment and 0.67 per 100 PY among patients not treated with TNF inhibitors.

Predictors for developing ExRA included older age (HR, 1.14 per 10 years), longer duration of RA (HR, 1.23 per 10 years), male sex (HR, 2.16), positive rheumatoid factor at baseline (HR, 1.90), and greater disability (HR, 1.16 per standard deviation).

Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors may slightly raise the risk for severe extra-articular manifestations of RA (ExRA), according to a study published in the Journal of Rheumatology.

Severe ExRA is an important contributor to morbidity and premature mortality in RA, and the risk factors for ExRA, such as smoking and positive rheumatoid factor, are similar to those for severe RA. Early and aggressive treatment of RA is expected to lower the incidence of severe RA, but whether the frequency of ExRA will be affected is still unclear.

TNF inhibitors have been demonstrated to slow down RA disease progression and reduce structural joint damage, but data on the effect of TNF inhibitors on ExRA are limited and contradictory. Furthermore, randomized controlled trials did not include patients with active ExRA and did not measure the incidence of ExRA manifestations as a study outcome.

Researchers, led by Lisa Theander, MD, a PhD student, and Carl Turesson, MD, PhD, from Lund University in Sweden, examined the relationship between TNF inhibitor treatment and the risk for severe ExRA, as well as predictors of ExRA, in patients with RA in an extension of a previous cohort study.

Of 1977 patients with RA, 27% were men and 73% were women. Approximately one-quarter of patients received a TNF inhibitor as their first biologic disease-modifying anti-rheumatic drug during the study. TNF inhibitor treatment was associated with younger age and higher rates of methotrexate and glucocorticoid therapy.

The incidence of new-onset ExRA was 6.3% in the study population, or 0.67 per 100 person-years (PY). The most common ExRA manifestations were major cutaneous vasculitis and pleuritis.

The risk of developing ExRA was 0.71 per 100 PY during TNF inhibitor therapy among patients exposed to anti-TNF treatment and 0.67 per 100 PY among patients not treated with TNF inhibitors. The adjusted risk for ExRA was slightly higher with TNF inhibitor therapy (with a hazard ratio [HR], 1.21).

Predictors for developing ExRA included older age (HR, 1.14 per 10 years), longer duration of RA (HR, 1.23 per 10 years), male sex (HR, 2.16), and positive rheumatoid factor at baseline (HR, 1.90). Greater disability at baseline, as measured by the Health Assessment Questionnaire, was another risk factor for ExRA in the age- and sex-adjusted analysis (HR, 1.16 per standard deviation).

Summary and Applicability

Although early aggressive treatment of RA will likely reduce the rates of severe RA, the effect of TNF inhibitors on ExRA manifestations was unclear until recently. Researchers evaluated the risk of developing ExRA with TNF inhibitor treatment in a retrospective cohort study.

“Severe extra-articular manifestations occur mainly in patients with seropositive, longstanding, severe RA. The risk of severe ExRA was slightly increased in patients treated with TNF inhibitors. This may be due to confounding by indication,” Dr Turesson told Rheumatology Advisor.

“The study results do not support a major role for TNF inhibitors in the induction of interstitial lung disease in patients with RA. The risk of vasculitis and pericarditis was reduced in patients treated with TNF inhibitors, whereas ophthalmologic manifestations were more frequent in this group,” he added.

Limitations and Disclosures

Patients treated with TNF inhibitors were more likely to receive methotrexate or glucocorticoid therapy, which may indicate that the anti-TNF group had higher disease activity than the group not treated with TNF inhibitors. This may have contributed to the finding that TNF inhibitor use was associated with a higher risk for ExRA.

The researchers report no relevant disclosures.

Reference

Theander L, Nyhäll-Wåhlin BM, Nilsson JÅ, et al. Severe extraarticular manifestations in a community-based cohort of patients with rheumatoid arthritis: risk factors and incidence in relation to treatment with tumor necrosis factor inhibitors. J Rheumatol. 2017;44(7): 981-987. doi: 10.3899/jrheum.161103