Treatment of refractory adult onset Still’s disease with combination anakinra and baricitinib therapy

Janus kinase inhibitors may be a new way to treat refractory and cortico-dependent AOSD patients. Sir, Adult onset Still’s disease (AOSD) is a rare, multisystemic inflammatory disorder of unknown aetiology. AOSD is a diagnosis of exclusion that needs to rule out infections, autoimmune or malignant diseases [1]. Conventional therapies include non-steroidal anti-inflammatory drugs, corticosteroids, immunosuppressive drugs and biologics targeting in particular IL-1 or IL-6. A 43-year-old woman, without relevant medical history, was admitted in July 2010 to the department of infectious diseases after suddenly developing a 40°C fever, urticaria, arthritis, odynophagia and dyspnoea. Blood tests revealed a CRP at 149 mg/l and ferritinemia at 1541 µg/l, a 27% fraction glycosylated-ferritine, and an acute hepatitis but no leucocytosis. Further investigations of possible infectious, malignant and autoimmune diseases were negative, except mediastinal lymphadenitis at the chest scan confirmed by a PET scan. Biopsy of a mediastinal nodule was normal. The diagnosis of AOSD was retained. Clinical symptoms resolved progressively under a symptomatic treatment and nodules disappeared. A novel episode occurred 6 months later, requiring treatment of the patient with prednisone at 1 mg/kg/day with good clinical response. However, dependence on steroids was seen at the limiting dosage of 20 mg/day. Other treatments with hydroxychloroquine, methotrexate and sulfasalazine were also attempted, but ultimately withdrawn due to major disturbance. In March 2012, ciclosporin was introduced, leading temporarily to well-controlled disease and allowing progressive tapering of corticosteroids. In January 2013, the patient was seen for a chronic dry cough and dyspnoea associated to a retroclavicular nodule that had newly appeared at the PET scan. Biopsy of mediastinal lymphadenitis showed non-caseating granulomatous infiltrations. Sarcoidosis associated to a refractory AOSD was highly suspected. Treatment with an IL-1 inhibitor (anakinra) was proposed in February 2013. Anakinra allowed the disease to be controlled for one year with good tolerance and a corticosteroid -free regimen was achieved. Progressively, she relapsed with fever and arthritis. Corticosteroids were added at 1 mg/kg/day, but treatment failure occurred in August 2014. A switch to infliximab was decided upon; however, the patient developed a severe hypersensitivity reaction one week after first infusion. Tocilizumab and abatacept were consecutively introduced without additional benefit. Consequently, in May 2015, due to multiple drug resistance, physicians decided to retry anakinra once again, combined with methylprednisolone at 16 mg/day. This treatment regimen stabilized the patient, without real remission. In 2017, cortisonic impregnation signs were remarkable and the disease was not well controlled. Due to the high cost of canakinumab, this option was not retained. In December 2017, due to the persistent predominance of joint involvement and in accordance with clinical features resembling RA, we decided to combine baricitinib 4 mg/day with anakinra. Corticosteroids were withdrawn one month after baricitinib introduction. Elsewhere, she did not experience any adverse effects. Her blood tests were within normal ranges and no inflammatory syndrome was seen. Remission of AOSD was observed within 9 months of starting baricitinib, and a progressive spacing of anakinra is now underway. To the best of our knowledge, we report for the first time the efficiency of an inhibitor of the Janus kinase (JAK) family to treat AOSD in a corticosteroid-dependent patient and refractory to conventional treatments. The AOSD diagnosis was retained according to international classifications [2, 3]. In addition, the pulmonary sarcoidosis was probably unrelated to the AOSD. In the literature, we found no reports of an association between sarcoidosis and AOSD, or between drug-induced sarcoidosis (especially developing from ciclosporin, the last drug taken by the patient before she developed respiratory symptoms). Other causes of non-caseating granulomatous infiltration were ruled out. JAK inhibitors are an emerging therapeutic class, with efficacy in the treatment of inflammatory diseases such as RA, due to their broad effects on cytokine production [4]. Baricitinib is an oral, reversible inhibitor of JAK1 and JAK2. Interestingly, baricitinib inhibits IL-6 and IFN-γ, which are strongly implicated in the AOSD pathogenesis [1]. There is in fact evidence of a deregulated immune state playing a pivotal role in the pathogenesis of AOSD [1] and leading to abnormal response to antigens and cytokine overproduction [5]. IL-6 and IFN-γ are specifically correlated with disease activity markers due to the macrophage activation [1]. JAK is a family of signalling molecules implicated in the cell response after cytokine interaction with cell receptors [6]. To date, various JAK complexes are known to mediate distinct cytokine signalling pathways [7]. Targeting JAK pathways by blocking JAK1 decreases serum levels of IL-6, IL-11, IFN-α/β, IFN-γ and IL-10. JAK2 blockage inhibits IFN-γ as well as βc family cytokines [4]. The observed sustained clinical response in our patient after associating baricitinib to anakinra, and after tapering corticoids, enhances the role of JAK pathways in AOSD pathogenesis. Baricitinib allowed IL-6 and IFN-γ inhibition whereas anakinra allowed IL-1 inhibition, this combination possibly leading to a well-controlled disease. In our patient, targeting these cytokines, one by one, tuned out to be insufficient as evidenced by tocilizumab and anakinra’s failure. Moreover, some evidence suggests that patients with an RA-like phenotype are especially driven by TNF-α, INF-γ and IL-8 (as opposed to a systemic AOSD phenotype driven by IL-1 and IL-6) [1]. It may hence explain JAK inhibitors’ efficacy in this particular patient. In conclusion, further studies are surely needed to determine the role of JAK inhibitors in the treatment of AOSD as well as their long-term safety and efficacy. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest.