Tofacitinib Treatment of Refractory Systemic Juvenile Idiopathic Arthritis Zhixiang Huang, MD,a Pui Y. Lee, MD, PhD,b Xiaoyan Yao, MD,a Shaoling Zheng, MD,a Tianwang Li, MD, PhDa Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood abstract 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 aDepartment of Rheumatology and Immunology, Guangdong by polyarticular arthritis, fever, lymphadenopathy, and serological features Second Provincial General Hospital, Guangzhou, China; and bDivision of Allergy, Immunology and Rheumatology, Boston of inflammation. She showed minimal response to nonsteroidal Children’s Hospital, Boston, Massachusetts antiinflammatory drugs, glucocorticoids, conventional disease-modifying Dr Huang supervised data collection and drafted the antirheumatic drugs, and etanercept. She also developed osteoporosis and manuscript; Dr Lee designed the study and revised vertebral compression fracture as the result of chronic glucocorticoid therapy. the manuscript; Dr Yao analyzed the data and Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient drafted part of the manuscript; Dr Zheng collected the patient’s data and reviewed the manuscript; Dr Li experienced steady improvement of both arthritis and systemic features. designed the study, assigned the treatment protocol, Complete remission was achieved after 3 months, and no evidence of disease and revised the manuscript; and all authors activity or adverse effects was seen through 6 months of follow-up. Our approved the final manuscript as submitted and agree to be accountable for all aspects of the work. experience reveals the effectiveness of JAK inhibition in a case of refractory DOI: sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for https://doi.org/10.1542/peds.2018-2845 children with sJIA, and its efficacy and safety should be further assessed by Accepted for publication Dec 5, 2018 clinical trial. Address correspondence to Tianwang Li, MD, PhD, Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, 466 Xingangzhong Rd, Guangzhou 510317, China. E-mail: [email protected] 4 Juvenile idiopathic arthritis (JIA) is 50% in Asian countries. Compared PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, a chronic rheumatic disease in children with other childhood arthritides, sJIA 1098-4275). and adolescents with a prevalence of has the highest mortality because of Copyright © 2019 by the American Academy of ∼70 per 100 000 children.1 The numerous complications of persistent Pediatrics International League of Associations for inflammation and chronic FINANCIAL DISCLOSURE: The authors have indicated Rheumatology classification criteria immunosuppression. These include they have no financial relationships relevant to this divide JIA into 7 categories.2 Systemic macrophage activation syndrome article to disclose. juvenile idiopathic arthritis (sJIA) is (MAS), infections, pulmonary FUNDING: No external funding. a unique category characterized by hypertension, and interstitial lung POTENTIAL CONFLICT OF INTEREST: The authors have variable arthritis and prominent disease. Therefore, finding effective indicated they have no potential conflicts of interest systemic features that include treatment for children with sJIA and to disclose. quotidian fever, evanescent rash, controlling the disease early is generalized lymphadenopathy, a priority in pediatric rheumatology. To cite: Huang Z, Lee PY, Yao X, et al. Tofacitinib hepatomegaly and/or splenomegaly, or Treatment of Refractory Systemic Juvenile serositis.3 sJIA accounts for 10% of JIA sJIA is traditionally treated with Idiopathic Arthritis. Pediatrics. 2019;143(5): e20182845 cases in North America and as high as nonsteroidal antiinflammatory drugs, Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 143, number 5, May 2019:e20182845 CASE REPORT 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 7 rheumatoid arthritis (RA). Because FIGURE 1 JAK signaling is critical for the signal Compression fracture of the T6 vertebral body likely secondary to osteoporosis. A, Radiograph transduction of multiple demonstration of the affected vertebral body. B, MRI (T2-weighted image with hyperintense signal in inflammatory cytokines, including IL- short-t inversion recovery) demonstration of the affected vertebral body. 6, orally available JAK inhibitors may be an effective treatment of sJIA. In With recurrence of fever and arthritis, anti–cyclic-citrullinated peptide this report, we describe the treatment she was admitted to our antibodies, and HLA antigen B27 tests of refractory sJIA by using tofacitinib. rheumatology service for initial were negative. An ultrasound evaluation in February 2017. The examination revealed axillary lymph patient exhibited poor growth, with node enlargement. A bone marrow CASE REPORT height and weight both under the first biopsy and MRI of the sacroiliac joint We present a patient who developed percentile for age (height: 130 cm; were unremarkable. The diagnostic daily fever of 40°C and arthritis at weight: 24.5 kg). On physical workup supported the diagnosis of the age of 11. The affected joints were examination, her left knee, left ankle, sJIA, and treatment was resumed by the left knee, the left ankle, and and wrists were warm, swollen, and using methylprednisolone (8 mg po both wrists. Abdominal computed tender to palpation. She reported daily), diclofenac (25 mg po twice tomography revealed multiple right hip pain with movement, and daily), and methotrexate (12.5 mg po enlarged lymph nodes in the the result of a Patrick’s test was weekly), with the addition of retroperitoneum, and an MRI positive. Laboratory investigations etanercept (25 mg subcutaneously confirmed synovitis of her left knee. revealed leukocytosis (20.2 3 109/L) weekly) to better capture her arthritis With persistence of symptoms for with neutrophil predominance and inflammation. weeks, the patient was diagnosed (75.0%), a normal platelet count with sJIA and was started on (320 3 109/L), an erythrocyte Although her fever resolved, minimal a treatment regimen that comprised sedimentation rate (ESR) of 102 improvement of arthritis was seen. In methylprednisolone (12 mg po daily), mm/hour (normal: ,15 mm/hour), addition, the patient was readmitted naproxen (250 mg po twice daily), and a C-reactive protein (CRP) level 1 month later with epigastric pain. An and methotrexate (12.5 mg po of 86.0 mg/L (normal: ,8.0 mg/L). endoscopy revealed mild chronic weekly). Fever and arthritis partially Serum creatinine levels, transaminase superficial gastritis. Surprisingly, improved on this regimen, but her levels, lipid profile, and procalcitonin a chest radiograph revealed suspicion disease promptly flared with levels were within normal limits, of a T6 vertebral compression attempts to wean her medications whereas results for rheumatoid fracture (Fig 1A). A thoracic MRI over the next 8 months. factor, antinuclear antibody, confirmed the fracture and revealed Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 HUANG et al bone edema in the T6 vertebral body clinical examination and disease inflammation. The systemic features (Fig 1B). Dual radiograph activity score. are thought to be driven by absorptiometry of the L1 to L4 proinflammatory cytokines IL-1 and After 6 months of tofacitinib therapy, vertebral body and left femoral neck IL-6.12,13 A “window of opportunity” the patient was able to discontinue revealed z scores of 22.8 and 23.2, may exist in the early systemic phase corticosteroid treatment for the first respectively, suggesting osteoporosis of disease before the inflammatory time since her initial diagnosis and as the likely cause of her vertebral milieu primes the development of remained well without arthritis or compression fracture. A salcatonin autoreactive T cells, leading to fever. She did not experience any injection was given, and the dose of chronic arthritis.14 Consistent with infection or other adverse effects methylprednisolone was the importance of IL-1 and IL-6,