Not All RA Drug Classes Are Created Equal Save

Clear differences were apparent among the three major types of targeted medications for rheumatoid arthritis (RA) in a large European registry study.

For one, patients using inhibitors of the Janus-associated kinase (JAK) pathway were more likely to stop them because of adverse effects compared with those on tumor necrosis factor (TNF) inhibitors, according to a group led by Kim Lauper, MD, of Geneva University Hospitals in Switzerland.

But JAK inhibitor users were also less likely to discontinue treatment because of inefficacy relative to TNF inhibitors, the researchers reported in Annals of the Rheumatic Diseases.

Inhibitors of interleukin (IL)-6 showed the same pattern in comparison with TNF inhibitors, while there were fewer differences in outcomes between TNF inhibitors and the unique agent abatacept (Orencia), the group noted.

These findings emerged from data on nearly 32,000 treatment courses administered to RA patients participating in 19 European registries, analyzed in a collaboration called "JAK-pot." Included were 17,522 courses of TNF inhibitors, 3,863 involving IL-6 inhibitors, 7,686 with JAK inhibitors, and 2,775 with abatacept.

TNF inhibitors have become established as the principal go-to treatment for RA in patients for whom old-line drugs such as methotrexate are no longer adequate; the first such agent, infliximab (Remicade), won approval in 1999. But they are not effective or well-tolerated in all patients. Hence, other drug types were developed with different biological targets, which also allowed oral administration in the case of JAK inhibitors.

That, of course, has raised questions about whether any of these drug classes should be preferred in particular clinical situations. Since head-to-head randomized trials are rare -- and when they are conducted, it's usually in carefully selected patients lacking comorbidities or other complicating factors -- researchers have turned to registries to shed light on how these targeted drugs perform in the real world.

Overall, patients included in the current JAK-pot analyses appeared representative of the general RA population who receive targeted therapies: mean age was about 57, three-quarters were women, and disease duration was 10-11 years. Also reflective of standard practice, about 60% of those on TNF inhibitors were receiving them as their first targeted therapy, whereas two-thirds of those using JAK and IL-6 inhibitors and abatacept had already used another such agent. Of note, roughly half in each group had at least one comorbidity.

Outcomes assessed in the analysis included achievement of low disease activity (Clinical Disease Activity Index [CDAI] ≤10) or remission (CDAI ≤2.8) and discontinuations, both overall and for specific reasons (i.e., adverse effects or inefficacy).

Differences were not huge for effectiveness. For low disease activity, 1-year rates ranged from 50.2% for abatacept to 55.8% for JAK inhibitors, and these disparities were not statistically significant despite the substantial numbers of patients. One clear difference emerged for achievement of remission: abatacept was clearly inferior to TNF inhibitors (11.6% vs 15.9%, P<0.05), while rates for JAK and IL-6 inhibitors were very similar to those for TNF inhibitors.

Rates of discontinuation (after adjustment for confounders) were similar overall among the four drug types, but not when analyzed by reason. Relative to TNF inhibitors, patients on JAK and IL-6 inhibitors were significantly less likely to stop treatment for ineffectiveness:

• JAK inhibitors: adjusted HR 0.75 (95% CI 0.67-0.83)
• IL-6 inhibitors: adjusted HR 0.76 (95% CI 0.67-0.85)

But JAK inhibitors were also more likely than TNF blockers to be stopped for adverse effects (adjusted HR 1.16, 95% CI 1.03-1.33), and a strong trend in that direction was also seen for IL-6 inhibitors. Lauper and colleagues found no significant differences in these outcomes for abatacept.

The researchers asserted that their study, "conducted on a large sample of patients seen in daily clinical practice, enables [us] to better appraise the persistence of therapy, a composite endpoint incorporating clinical effectiveness and safety" for the major drug classes in RA, in comparison to manufacturer-sponsored trial data.

On the other hand, the study also revealed substantial variation among the 19 countries' individual registries in terms of discontinuations, which Lauper and colleagues suggested probably stem from the similar wide variation in national affluence.

Addressing the higher discontinuation rate for JAK inhibitors on account of adverse effects, the researchers were hesitant to ascribe it to genuinely poorer safety, although questions have certainly been raised. "It is possible that less experience in the treatment with JAK [inhibitors] and differences in the perceived or factual utility and safety ... in particular considering the warnings of medicine agencies, could contribute to this finding," they wrote. "To what extent this phenomenon mirrored a real 'biological' behavior of JAK [inhibitors] remains to be further investigated."

Source Reference: Lauper K, et al "Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration" Ann Rheum Dis 2022; DOI: 10.1136/annrheumdis-2022-222586.