A case with systemic juvenile idiopathic arthritis treated with tofacitinib and rapamycin

Rheumatology key message.

• The combination of tofacitinib and rapamycin may provide an alternative treatment regimen for resistant sJIAs.

Dear Editor, Despite the increasingly successful use of biological therapies, remission is still not achieved in a significant proportion of patients with systemic juvenile idiopathic arthritis (sJIA) and patients continue to experience steroid side effects [1, 2]. Here, we report a refractory sJIA in which clinically inactive disease was achieved with the combination of rapamycin and tofacitinib.

The patient was diagnosed with sJIA in 2015 at the age of five, presenting with symptoms of fever, rash, lymphadenopathy and joint swelling. Initial treatment started with steroids and methotrexate. Throughout the course of the disease, the patient was treated with anakinra, followed by canakinumab and then tocilizumab. When the patient was admitted to our hospital in 2018, She was on tocilizumab and prednisolone 0.5 mg/kg/day. During this visit, the patient was diagnosed with an episode of macrophage activation syndrome (MAS) and pulmonary hypertension and was treated with anakinra, high-dose prednisolone, ciclosporin and plasmapheresis. However, upon reduction of prednisolone, the MAS attack recurred, and another round of plasmapheresis was required. From 2018 to 2023, the patient experienced six further disease flares triggered by steroid taper. Clinical inactive disease was achieved with 200 mg anakinra (6 mg/kg) and 0.3 mg/kg/day prednisolone. Due to the intense side effects of steroids and persistently elevated sedimentation rate and CRP despite clinical remission, tofacitinib treatment was planned in February 2023. Unfortunately, another episode of MAS occurred in the first month of follow-up. Treatment with 200 mg (5 mg/kg) anakinra and prednisolone was continued, and ciclosporin was added. In December 2023, with the approval of the relevant committee of the Ministry of Health, rapamycin treatment was started concurrently with tofacitinib and anakinra was continued for two weeks. Clinical and laboratory inactive disease was achieved in the third month (Fig. 1). Clinically inactive disease continues in the eighth month, and she has been on prednisolone 2 mg/day (<0.1 mg/kg/day) for the last two months.

Figure 1.

Treatment response of the patient

Refractory sJIA-MAS is defined as MAS associated with sJIA that requires long-term additional treatment with glucocorticoids or MAS associated with recurrent (two episodes of) sJIA [3]. To our knowledge, there is only one case in the literature in which rapamycin was used successfully in sJIA [4]. As in that case, no side effects were observed in our case. Because our patient had pulmonary hypertension, we used tofacitinib together with rapamycin treatment. Macrophage activation syndrome is associated with high expression of numerous proinflammatory cytokines. Additionally, IL-15 expression induced by type 1 IFNs is postulated to have a potential role in the pathogenesis of MAS [5]. Consequently, JAK inhibition may be a viable option for the treatment of refractory sJIA. Huang et al. reported that the mTOR pathway was active in a mouse model and its inhibition alleviated disease severity [6]. Our case is a clinical reflection of this study. Although clinical inactivation was occasionally achieved with previous treatments, the glucocorticoid requirement was reduced to 0.1 mg/kg/day for the first time. The combination of tofacitinib and rapamycin may provide an alternative treatment regimen for resistant sJIAs. Nevertheless, in respect of the limited follow-up period, further experience and clinical trials are necessary to ascertain the safety and efficacy of the treatment.

Informed consent was obtained from the patient for publication of the case report with all accompanying visual elements.

Data availability

The de-identified data of the case report are available on request from the corresponding author.

Funding

No specific funding has been received from any organization in the public, commercial or non-profit sectors for the ingredients and medicines used in this case report.

Disclosure statement: All authors declare no conflicts of interest.