Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood arthritis accompanied by persistent systemic inflammation. Patients with sJIA often exhibit poor response to conventional disease-modifying antirheumatic drugs, and chronic glucocorticoid use is associated with significant adverse effects. Although biologics used to target interleukin 1 and interleukin 6 are efficacious, the long-term commitment to frequent injections or infusions remains a challenge in young children. Janus-activated kinase (JAK) inhibitors block the signaling of numerous proinflammatory cytokines and are now used clinically for the treatment of rheumatoid arthritis in adults. Whether this new class of medication is effective for sJIA has not been reported. Here, we describe the case of a 13-year-old girl with recalcitrant sJIA characterized by polyarticular arthritis, fever, lymphadenopathy, and serological features of inflammation. She showed minimal response to nonsteroidal antiinflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs, and etanercept. She also developed osteoporosis and vertebral compression fracture as the result of chronic glucocorticoid therapy. Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient experienced steady improvement of both arthritis and systemic features. Complete remission was achieved after 3 months, and no evidence of disease activity or adverse effects was seen through 6 months of follow-up. Our experience reveals the effectiveness of JAK inhibition in a case of refractory sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for children with sJIA, and its efficacy and safety should be further assessed by clinical trial.
Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease in children and adolescents with a prevalence of ∼70 per 100 000 children.1 The International League of Associations for Rheumatology classification criteria divide JIA into 7 categories.2 Systemic juvenile idiopathic arthritis (sJIA) is a unique category characterized by variable arthritis and prominent systemic features that include quotidian fever, evanescent rash, generalized lymphadenopathy, hepatomegaly and/or splenomegaly, or serositis.3 sJIA accounts for 10% of JIA cases in North America and as high as 50% in Asian countries.4 Compared with other childhood arthritides, sJIA has the highest mortality because of numerous complications of persistent inflammation and chronic immunosuppression. These include macrophage activation syndrome (MAS), infections, pulmonary hypertension, and interstitial lung disease. Therefore, finding effective treatment for children with sJIA and controlling the disease early is a priority in pediatric rheumatology.
sJIA is traditionally treated with nonsteroidal antiinflammatory drugs, glucocorticoids, and/or conventional disease-modifying antirheumatic drugs in the prebiologics era. Unfortunately, approximately half of patients still suffer from active disease, whereas many experience the cumulative adverse effects of chronic glucocorticoid treatment.5 In recent years, biologics used to target interleukin 1 (IL-1) (anakinra, canakinumab, and rilonacept) and interleukin 6 (IL-6) (tocilizumab) have significantly improved outcomes in sJIA.6 These biologic agents, however, are not uniformly available, and frequent subcutaneous injections or intravenous infusion are also challenging for young children.
Janus-activated kinase (JAK) inhibitors, such as tofacitinib and baricitinib, have revealed favorable efficacy and safety data in adults with rheumatoid arthritis (RA).7 Because JAK signaling is critical for the signal transduction of multiple inflammatory cytokines, including IL-6, orally available JAK inhibitors may be an effective treatment of sJIA. In this report, we describe the treatment of refractory sJIA by using tofacitinib.
We present a patient who developed daily fever of 40°C and arthritis at the age of 11. The affected joints were the left knee, the left ankle, and both wrists. Abdominal computed tomography revealed multiple enlarged lymph nodes in the retroperitoneum, and an MRI confirmed synovitis of her left knee. With persistence of symptoms for weeks, the patient was diagnosed with sJIA and was started on a treatment regimen that comprised methylprednisolone (12 mg po daily), naproxen (250 mg po twice daily), and methotrexate (12.5 mg po weekly). Fever and arthritis partially improved on this regimen, but her disease promptly flared with attempts to wean her medications over the next 8 months.
With recurrence of fever and arthritis, she was admitted to our rheumatology service for initial evaluation in February 2017. The patient exhibited poor growth, with height and weight both under the first percentile for age (height: 130 cm; weight: 24.5 kg). On physical examination, her left knee, left ankle, and wrists were warm, swollen, and tender to palpation. She reported right hip pain with movement, and the result of a Patrick’s test was positive. Laboratory investigations revealed leukocytosis (20.2 × 109/L) with neutrophil predominance (75.0%), a normal platelet count (320 × 109/L), an erythrocyte sedimentation rate (ESR) of 102 mm/hour (normal: <15 mm/hour), and a C-reactive protein (CRP) level of 86.0 mg/L (normal: <8.0 mg/L). Serum creatinine levels, transaminase levels, lipid profile, and procalcitonin levels were within normal limits, whereas results for rheumatoid factor, antinuclear antibody, anti–cyclic-citrullinated peptide antibodies, and HLA antigen B27 tests were negative. An ultrasound examination revealed axillary lymph node enlargement. A bone marrow biopsy and MRI of the sacroiliac joint were unremarkable. The diagnostic workup supported the diagnosis of sJIA, and treatment was resumed by using methylprednisolone (8 mg po daily), diclofenac (25 mg po twice daily), and methotrexate (12.5 mg po weekly), with the addition of etanercept (25 mg subcutaneously weekly) to better capture her arthritis and inflammation.
Although her fever resolved, minimal improvement of arthritis was seen. In addition, the patient was readmitted 1 month later with epigastric pain. An endoscopy revealed mild chronic superficial gastritis. Surprisingly, a chest radiograph revealed suspicion of a T6 vertebral compression fracture (Fig 1A). A thoracic MRI confirmed the fracture and revealed bone edema in the T6 vertebral body (Fig 1B). Dual radiograph absorptiometry of the L1 to L4 vertebral body and left femoral neck revealed z scores of −2.8 and −3.2, respectively, suggesting osteoporosis as the likely cause of her vertebral compression fracture. A salcatonin injection was given, and the dose of methylprednisolone was subsequently decreased to 4 mg daily.
However, her arthritis continued to progress in the next several months. Follow-up laboratory studies in November 2017 revealed worsening acute-phase reactants (ESR: 121 mm/hour; CRP: 127.3 mg/L). Serum ferritin levels were elevated (1937.2 ng/mL; normal: <274.7 ng/mL), but there was no cytopenia, coagulopathy, or other laboratory evidence to suggest MAS associated with sJIA. Repeated MRI revealed new compression fractures at T5 and T7. Etanercept was discontinued given the lack of efficacy in controlling her arthritis. Because anti-IL-1 agents are not available in mainland China, tocilizumab (monoclonal anti-IL-6 receptor) was recommended, but the family refused all parenteral therapy. Given the beneficial effect of JAK inhibitors in RA, we started the patient on oral tofacitinib (2.5 mg twice daily) while maintaining oral methylprednisolone at 4 mg daily. She was 13 years old at the time of this treatment, and tofacitinib was titrated to the dose of 5 mg twice daily after 2 weeks on the basis of available pharmacokinetics data.8
Remarkably, after experiencing chronic joint inflammation for nearly 2 years, her arthritis improved steadily over the next 2 months, as reflected by the declining juvenile arthritis disease activity score (JADAS-10) (Fig 2A).9 The acute-phase reactants decreased correspondingly (Fig 2B), and serum ferritin levels were also within normal limits (100.3 ng/mL). Complete remission was achieved after 3 months of treatment by clinical examination and disease activity score.
After 6 months of tofacitinib therapy, the patient was able to discontinue corticosteroid treatment for the first time since her initial diagnosis and remained well without arthritis or fever. She did not experience any infection or other adverse effects associated with tofacitinib treatment. Additional studies revealed normal serum lipid levels, liver function, and renal function. However, because of a recent interruption of medication supply of tofacitinib for 3 weeks, the patient had a brief return of mild right elbow swelling, with an ESR of 25 mm/hour (normal CRP) and a JADAS-10 of 1.5, all reflective of mildly active disease (Fig 2 A and B). The patient has since resumed taking the appropriate dose of tofacitinib without further complaints. Collectively, these observations support the overall efficacy of tofacitinib treatment of this case.
Despite recent advances in treatment options, sJIA remains one of the most challenging pediatric rheumatologic conditions. Distinct from other forms of childhood arthritis, sJIA has prominent clinical features of quotidian fever and systemic inflammation in addition to arthritis, whereas autoantibodies are typically absent.3 Although genetic linkage in the HLA antigen cluster reveals a role of adaptive immunity in sJIA,10 the systemic manifestations of inflammation are in line with aberrant activation of the innate immune system characteristic of autoinflammatory syndromes.11 These distinctions in pathophysiology may help explain why a different approach is required for treatment of sJIA compared with other forms of JIA.
Effective management of sJIA requires establishing control of both systemic features and joint inflammation. The systemic features are thought to be driven by proinflammatory cytokines IL-1 and IL-6.12,13 A “window of opportunity” may exist in the early systemic phase of disease before the inflammatory milieu primes the development of autoreactive T cells, leading to chronic arthritis.14 Consistent with the importance of IL-1 and IL-6, blockade of these cytokines are effective for the treatment of sJIA.15,–18 However, the challenge of using biologics requiring injection or infusion for an extended length of time, especially in young children, should not be underestimated. For example, anakinra (recombinant IL-1 receptor antagonist) requires daily injection, whereas tocilizumab is given intravenously every 2 weeks. Availability of these biologics is also not universal, as illustrated by the lack of IL-1 antagonists in mainland China. Therefore, alternative treatment options are needed for patients with sJIA with refractory disease or logistic difficulties with biologics therapy.
JAK inhibitors are orally available small-molecule drugs that suppress inflammation by interfering with JAK-STAT (signal transducer and activator of transcription protein) signaling downstream of numerous inflammatory cytokine receptors. Currently, 2 JAK inhibitors are approved for the treatment of RA in adults. Tofacitinib inhibits JAK-1/3, whereas baricitinib is used to target JAK-1/2. Several cytokines pertinent to arthritis, including IL-6, interleukin 21, and granulocyte colony stimulating factor, signal via JAK-1 and/or JAK-3. Given the excess production of IL-6 in sJIA, tofacitinib may function to inhibit IL-6 receptor signaling, but its exact target(s) in vivo is difficult to determine.
Although tofacitinib has been widely prescribed for adults with RA, data on JIA are limited. Authors of a case report described successful treatment of polyarticular JIA and collagenous colitis by using tofacitinib in a 58 year-old female patient diagnosed with JIA at age 10 years.19 Results from a phase I trial in children with polyarticular JIA revealed no adverse effects associated with short-term administration of tofacitinib.8A phase III trial to evaluate the efficacy of tofacitinib in JIA is ongoing (ClinicalTrials.gov Identifier: NCT02592434) and another for sJIA is in the recruitment stage (NCT03000439). In the case of refractory sJIA presented here, tofacitinib resulted in resolution of both systemic inflammation and arthritis after 3 months of therapy. We recognize that sJIA is a complex and heterogeneous disease and that not all patients respond similarly to the same agent. Our patient did not develop MAS, a life-threatening complication of sJIA characterized by coagulopathy, hemophagocytosis, cytopenia, and multi‐organ dysfunction. Whether JAK inhibitors have beneficial effects for the treatment of MAS by modulating cytokine signaling is an intriguing question.
Common adverse effects of tofacitinib in adults include increased low-density lipoprotein levels, neutropenia, and transaminase elevation.20 Serious infections are rare but have been reported, including cases of herpesvirus reactivation.21 In trials for RA, the infection risk for tofacitinib was similar to that of other biologics.22,23 The risk of infection may be partly mitigated if treatment allows for the reduction of corticosteroid use. Although the patient presented here did not experience any notable adverse effects, the safety profile of long-term tofacitinib therapy in children is an important topic that warrants further study.
We demonstrated the effectiveness of tofacitinib treatment in a case of refractory sJIA with inadequate response to nonsteroidal antiinflammatory drugs, methotrexate, glucocorticoids, and etanercept. These data provide support to establish clinical trials to evaluate the efficacy and safety of tofacitinib in sJIA.
Dr Huang supervised data collection and drafted the manuscript; Dr Lee designed the study and revised the manuscript; Dr Yao analyzed the data and drafted part of the manuscript; Dr Zheng collected the patient’s data and reviewed the manuscript; Dr Li designed the study, assigned the treatment protocol, and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
erythrocyte sedimentation rate
juvenile arthritis disease activity score
juvenile idiopathic arthritis
macrophage activation syndrome
systemic juvenile idiopathic arthritis
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.