ObjectivesTo evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib.MethodsPhase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05).ResultsWe identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15–161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)).ConclusionsWithin the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.

The aim of this study was to investigate the role of IL‐12 in patients with RA. IL‐12 (p70) and its associated cytokines were measured in sera and synovial fluid (SF) using an enzyme‐linked immunosorbent method. Seven American College of Rheumatology (ACR) core set measures as well as IL‐12 levels were sequentially monitored at the commencement and 4 months after treatment with a low‐dose steroid and disease‐modifying anti‐rheumatic drugs (DMARDs). In sera, 64 (42.2%) of 152 RA patients had detectable concentrations of IL‐12 (p70), whereas one (1.4%) of 69 osteoarthritis (OA) patients and five (10%) of 50 healthy controls had detectable IL‐12 (P < 0.001). The median level of circulating IL‐12 was also higher in RA patients (P < 0.001). In SF, the number of patients with detectable IL‐12 and the median IL‐12 levels were significantly higher in RA patients (n = 53) than in OA patients (n = 22). In paired samples (n = 53) of sera and SF from RA patients, IL‐12 levels were higher in the SF than in sera (P < 0.001). Patients with detectable IL‐12 (n = 51) in sera had higher tender joint scores (P = 0.003), swollen joint scores (P < 0.001) and C‐reactive protein (CRP; P = 0.036), than those without (n = 55). Four months after treatment with DMARDs, the improved group showed a larger IL‐12 decrease than the non‐improved group (P = 0.017). The levels of IL‐12 correlated positively with those of IL‐2, interferon‐gamma, IL‐6, and tumour necrosis factor‐alpha, but were correlated inversely with those of IL‐10. Our results demonstrate that IL‐12 levels reflect RA disease activity and that IL‐12 is involved in the production of proinflammatory cytokines. An IL‐12 blockade could be useful for the treatment of RA.

Th17 cells that produce interleukin (IL)‐17 play a key role in the pathogenesis of autoimmune inflammation. Among the various cytokines that are involved in the IL‐17 pathway, members of the IL‐1β family, including IL‐18, have recently gained attention. In this study, we stimulated synovial fibroblasts with a combination of IL‐17 and IL‐18 and quantified their stromal cell–derived factor‐1 (SDF‐1) production by enzyme‐linked immunosorbent assay and their transcript levels by reverse transcription–polymerase chain reaction. Both IL‐17 and IL‐18 significantly increased the level of SDF‐1, not only individually but also synergistically (P < 0.05). The synergism was effectively suppressed by anti‐IL‐17 and ‐IL‐18 antibodies, and a PI3K inhibitor. To the best of our knowledge, this is the first report of PI3K‐dependent synergism between IL‐18 and IL‐17, and this work adds a novel perspective of the role of IL‐18 in immune regulation. The individual effects of these two cytokines, and their interactions, suggest an interrelationship between the IL‐1 family and IL‐17.