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Tofacitinib (Xeljanz) in patients with rheumatoid arthritis (RA) stood out among several other biologic and targeted synthetic disease-modifying antirheumatic drugs (sDMARDs) when it came to the incidence of interstitial lung disease (ILD), a retrospective cohort study showed.

Among over 28,000 patients with RA, the crude incidence rate per 1,000 person-years for ILD was lowest with the Janus kinase (JAK) inhibitor tofacitinib, at 1.47 (95% CI 0.54-3.27), reported Matthew C. Baker, MD, MS, of Stanford University in Palo Alto, California, and co-authors in .

The crude incidence rates for the other drugs evaluated were:

• Adalimumab (Humira): 3.43 (95% CI 2.85-4.09)
• Abatacept (Orencia): 4.46 (95% CI 3.44-5.70)
• Tocilizumab (Actemra): 5.05 (95% CI 3.47-7.12)
• Rituximab (Rituxan): 6.15 (95% CI 4.76-7.84)

After multiple adjustments, patients treated with tofacitinib had a lower risk of ILD compared with patients treated with adalimumab (adjusted HR 0.31, 95% CI 0.12-0.78, P=0.009).

In a prevalent new-user cohort analysis, patients treated with tofacitinib (n=1,559) had a 68% reduced risk of ILD compared with the 4,677 treated with adalimumab (aHR 0.32, 95% CI 0.13-0.82, P<0.001).

"Clinicians must determine the best therapy to control a patient's joint disease, while at the same time minimize the potential risk of pulmonary toxic effects in these patients with already compromised lung function," Baker and team wrote. "Current data are lacking regarding the risk of biologic and targeted sDMARD use on the development of ILD in patients with RA."

Due to elevated risks for heart-related adverse events and cancer with JAK inhibitors, tofacitinib is indicated for RA patients that fail on tumor necrosis factor-α (TNF-α) inhibitors such as adalimumab.

Early reports had suggested that the use of TNF-α inhibitors in RA patients with ILD could worsen the underlying ILD, Baker's team noted, though later studies reported similar rates of ILD when compared with other classes of biologic DMARDs.

"Theoretically, biologic and targeted sDMARDs could induce or worsen ILD through idiosyncratic reactions, tissue injury, or susceptibility to infection, or they may provide a therapeutic effect given the likely harmful role that inflammatory cytokines play in ILD pathogenesis," they wrote. "Currently, the risks associated with TNF-α inhibitors in patients with RA-ILD are uncertain, and whether other biologic and targeted sDMARDs are safer also remains unclear."

"These results suggest that treatment with tofacitinib, and perhaps other Janus kinase inhibitors, may provide benefit in reducing the risk of developing RA-ILD. Future prospective studies of tofacitinib in patients with RA to prevent the development of ILD should be considered," Baker and colleagues.

For this study, the researchers used claims data from the Optum Clinformatics Data Mart from December 2003 to December 2019. They included 28,559 patients with RA; mean age was 55.6, and 78% were women. Of these patients, 13,326 were treated with adalimumab, 5,676 were taking abatacept, 5,444 were taking rituximab, 2,548 were taking tocilizumab, and 1,565 were taking tofacitinib.

Patients were excluded if they had a pre-existing diagnosis of ILD, according to one or more ICD-9 or ICD-10 codes, while those with restrictive lung disease but without ILD were included.

A total of 276 incident cases of ILD occurred during follow-up -- 119 in the adalimumab cohort, 60 in the abatacept cohort, 62 in the rituximab cohort, 30 in the tocilizumab cohort, and five in the tofacitinib cohort.

Baker and colleagues noted that there may be residual or unmeasured confounders in their study, due to its retrospective nature. There were also some missing data on certain variables, including autoantibodies, genetic risk alleles, and smoking, which can be associated with RA and ILD.

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