Tocilizumab in VEXAS relapsing polychondritis: a single-center pilot study in Japan

Abstract

Recently, a rare severe autoinflammatory disease vacuoles, E1 enzyme, Xlinked, autoinflammatory, somatic (VEXAS) syndrome caused by somatic variants in the UBA1 gene was discovered. We reported the clinical features of eight relapsing polychondritis (RP) patients with UBA1 variants, six of which were accompanied by myelodysplastic syndrome (MDS). The clinical features of VEXAS syndrome are heterogeneous, including highgrade fever, polychondritis, large vessel vasculitis, skin eruptions, arthritis, thrombosis, scleritis and serositis, which require intensive immunosuppressive agents. Most of our patients before this study had received high doses of prednisolone (PSL) and cytotoxic immunosuppressants including methotrexate, cyclophosphamide and azathioprine. 2 However, even with concomitant immunosuppressant treatment, PSL tapering often led to a relapse of highgrade fever and skin rash in these patients; therefore, ≥20 mg oral PSL was required in most cases, resulting in frequent hospitalisation and death due to opportunistic infections. In addition, many cases of VEXAS syndrome already have MDS at the time of diagnosis, and cytotoxic immunosuppressive agents should be avoided or reduced in dose because they might cause further cytopenia. Tocilizumab (TCZ), an antiinterleukin (IL)-6 receptor antagonist approved for the treatment of inflammatory diseases, such as rheumatoid arthritis and giant cell arteritis, may be useful in managing severe inflammation in VEXAS–RP and preserving the cumulative dose of PSL, which causes organ damage. Previous papers reported high IL-6 transcriptome signatures not only in zebrafish but also in CD14 isolated monocytes from patients with VEXAS, suggesting IL-6 inhibition could be beneficial. Indeed, previous studies on VEXAS syndrome cases reported the use of TCZ. However, the clinical course after TCZ administration has not been reported in detail. Here, we report our experience with TCZ in patients with VEXAS–RP. Three cases of newly diagnosed VEXAS–RP (all male, median age 66.6 years) between August and December 2020 were included in the analysis. The details of their genetic and clinical characteristics were reported previously. The dosage of TCZ was 8 mg/kg intravenously every 2 weeks in RP13 and 162 mg subcutaneously every week in RP15 and RP16. The clinical courses before and after administration of TCZ are summarised in table 1. The observation period was 5–8 months. Two of the three patients showed afebrile status after TCZ treatment and had a reduced PSL dose. In RP16, rashes recurred after PSL was reduced to 17.5 mg and fever relapsed at 12.5 mg. After fever flareup, TCZ was changed to intravenous administration and PSL was increased to 30 mg. The serum cytokine profile of these patients showed that baseline serum IL-6 levels did not correlate with the efficacy of TCZ treatment, and high serum proinflammatory cytokine levels, such as IL-18, persisted more than 4 months after induction, even in patients who appeared to have responded to TCZ, suggesting that TCZ alone may not be able to suppress the underlying inflammation of VEXAS syndrome (table 1 and online supplemental table 1). Fractional abundance (equivalent to allele frequencies) of UBA1 mutation of RP16 who relapsed had the longest disease duration was highest with nearly 90% in the peripheral blood (table 1). Two patients had herpes zoster infection, one of whom required hospitalisation. However, after 1week treatment with antiviral therapy, both patients restarted TCZ. Our patients did not develop intestinal perforation as previously reported during the followup period. This report had several limitations. First, there was selection bias due to the small number of patients. Second, the Letter