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Behçet’s syndrome (BS) is a chronic inflammatory disease characterised by recurrent oral and genital ulcers, frequently complicated with uveitis gastrointestinal, neurological, major vessel and cardiac involvement. For severe and (or) refractory BS, tumour necrosis factor alpha (TNF-α) inhibitors are indicated beyond glucocorticoids (GCs) and immunosuppressants,1 which are still responded inadequately in a small portion of refractory patients. Tofacitinib, a JAK1/3 inhibitor targeting T cell signalling, was approved for autoinflammatory diseases including rheumatoid arthritis, psoriatic arthritis and ulcerative colitis (UC).2 Given T cells are implicated in BS,3 tofacitinib could be a promising approach for BS.
In this study, we explored the efficacy and safety of tofacitinib in refractory BS. We enrolled seven male and six female patients with BS fulfilling the 2013 International Criteria for BS,4 presented with active vascular/cardiac (n=5), gastrointestinal (n=6) and articular (n=2) involvements between May 2018 and January 2020 (table 1), with a mean age of 42.2±15.5 years and a median disease duration of 102 (IQR 72–240) months. At enrolment, all patients had active disease (Behçet's Disease Current Activity Form (BDCAF) =5 (IQR 4–5)) despite receiving combination of GCs and multiple immunosuppressants (n=4 (IQR 3–4)) as well as biologics (n=6, TNF-α inhibitor=5, tocilizumab=1). Additionally, hepatitis B virus (HBV) infection, latent tuberculosis (TB) and previous pulmonary TB were presented in one patient each. All patients then received tofacitinib 5 mg two times a day along with background treatment of low-dose to medium-dose GCs and maintained or decreased immunosuppressants. The clinical response was defined as5: (1) improved: BS-related manifestations resolved and no newly onset imaging/endoscopic findings observed; (2) unchanged or worsened: BS-related manifestations or abnormal laboratory parameters persisted or worsened after following up for 12–24 weeks.
After a median follow-up of 8 (IQR 5.5–19) months, the overall BDCAF score improved significantly (5 (IQR 4–5) vs 0 (IQR 0–1.5), p<0.001; figure 1A). Specifically, patients with vascular/cardiac and articular involvement achieved remission both clinically and radiologically (figure 1B); erythrocyte sedimentation rate (21 (IQR 7–101) mm/hour vs 5 (IQR 1–11) mm/hour, p=0.0028) and C-reactive protein (21 (IQR 1.24–67) mg/L vs 0.5 (IQR 0.32–1.3) mg/L, p=0.019) level decreased significantly (figure 1C). For patients with gastrointestinal involvement, the intestinal ulceration was healed in one patient while persisted in the other five patients. The median GCs dosage of prednisone equivalent was tapered (baseline: 10 (IQR 10–17.5) mg/day vs last visit: 10 (IQR 5–12.5) mg/day, p=0.028), indicating a potential steroid-sparing effect. Cyclophosphamide was tapered and withdrew in five and one patients, respectively. One patient (no. 13) discontinued tofacitinib for disease progression. Two patients (nos. 10 and 12) withdrew tofacitinib due to herpes zoster (HZ) infection, which is consistent with previous studies that tofacitinib increased the risk of HZ infection.6 With prophylaxis of lamivudine (100 mg daily) for patient no. 4, and isoniazid and rifampin for patients nos. 4 and 8, no HBV or TB reactivation was observed.
Tofacitinib is a potential intervention for BS. Transcriptome analysis in patients with BS demonstrates that Th17-related genes and type I interferon-inducible genes were upregulated, and JAK/STAT signalling was activated through Th1/Th17 cytokines.7 Tofacitinib inhibited STAT1 and T-bet phosphorylation and suppressed Th1 and Th17 cell differentiation.8 As expected, our data showed that tofacitinib was effective for relieving the clinical manifestations and improving laboratory parameters in patients with BS. Surprisingly, patients with gastrointestinal-BS responded to tofacitinib poorly. Intriguingly, tofacitinib is effective for UC but not Crohn’s disease (CD).9 Therefore, patients with gastrointestinal-BS might have a similar response to tofacitinib with CD, as they share similar pathogenesis and genetic background.10
In summary, our study, to the best of our knowledge, is the first study on tofacitinib for refractory BS. Our data suggest that tofacitinib is well tolerated and might be effective for patients with BS with vascular and articular involvement. A prospective controlled study to confirm the therapeutic benefit of tofacitinib for patients with BS is warranted.
The authors thank all the patients who participated in this study.
Handling editor Josef S Smolen
Contributors All authors made substantial contributions to the conception and design of this study. LS, CL and LL acquired the data. JL and YH performed the data analysis and drafted the manuscript. YZ, XZ and FZ provided critical revisions to the manuscript. WZ designed the study, contributed to the discussion and edited the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the National Natural Science Foundation of China (grant number 81871299); CAMS Initiative for Innovative Medicine (grant numbers CIFMS2017-I2M-1-008 and CIFMS2016-I2M-1-013), National Key Research and Development Program: “Precise Medical Research” (grant number 2016YFC0906201).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval Institutional review board of Peking Union Medical College Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
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