Background Tofacitinib is a novel inhibitor of Janus kinase (JAK) 3 and JAK1 . The JAK inhibitors are in the focus of research in myriad of other inflammatory diseases as it seems the JAK- (signal transducer and activator of transcription) STAT pathway has a central role in cytokines' signal transduction. We herein describe a case of refractory polyarteritis nodosa (PAN) successfully treated with tofacitinib.Preliminary evidence for the role of JAK-STAT pathway in vasculitis has been recently published .
A 28 years-old man had been diagnosed with PAN at the age of 14. He presented with livedo reticularis, arthritis and skin nodules with fibrinoid necrosis, as confirmed by biopsy. Immunologic panel at the time of diagnosis was negative for ANCA, ANA, SSA, SSB, RF, and complement levels were normal. He was treated with azathioprine and methotrexate for several years and was in complete remission. Three years prior the initiation of tofacitinib his disease flared and he began suffering from necrotizing vasculitis of the scrotum and calves, abdominal pain and polyarthritis with high CRP levels (160–300 mg/l) for which he received recurrent intravenous solumedrol pulses and oral prednisone therapy of 40–60 mg daily in between pulses. Numerous treatments including, infliximab, adalimumab, rituximab, etanercept, tocilizumab, potassium iodide and cyclophosphamide intravenous and oral failed to achieve remission. Subsequently, he was hospitalized for reevaluation and was treated by plasma exchange for 3 weeks with partial remission, but had to discontinue the treatment due to central line sepsis. At this point he was in severe long standing inflammatory state for 3 years with high CRP levels low albumin (3 mg/dl) and ongoing leukocytosis.
Objectives To evaluate the activity of the JAK-STAT pathway guiding the treatment with tofacitinib.
Methods We have profiled his peripheral blood cells using mass cytometry (CyTOF), a single cell proteomics platform capable of simultaneously measuring the expression up to 45 proteins on each cell and on millions of cells. This provided a high-dimensional immune cell type profile of his immune system, both in cell abundance as well as the activity of the JAK1 and 3 along with STAT 3 pathways in response to stimulation with interleukin 6, specifically in CD4+ and CD8+ T cells subsets (figure 1).
Results We initiated treatment with tofacitinib 10 mg BID that resulted in prompt normalization of his CRP, albumin and leukocyte count, resolution of skin ulcers and relief of pain. Prednisone therapy was soon tapered from 60 mg to 10 mg daily. Reevaluating the response of the JAK-STAT pathway to IL-6 stimulation after treatment confirmed attenuated response of the CD8+T and CD4+T cell (figure 1). After one year of follow-up the patient remained in complete remission.
Conclusions In conclusion, this is the first report in the literature of treatment of refractory PAN vasculitis with tofacitinib. Using high resolution mass cytometry technology we were able to tailor and monitor therapy.
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Hartmann B, et al. The STAT1 Signaling Pathway In Giant Cell Arteritis. 2013 ACR/ARHP Annual Meeting, Plenary Session II, abstract number: 1691.
Disclosure of Interest None declared