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, associated with tofacitinib treatment. subsequently decreased to 4 mg daily. blockade of these cytokines are Additional studies revealed normal effective for the treatment of However, her arthritis continued to serum lipid levels, liver function, and – sJIA.15 18 However, the challenge of progress in the next several months. renal function. However, because of using biologics requiring injection or Follow-up laboratory studies in a recent interruption of medication infusion for an extended length of November 2017 revealed worsening supply of tofacitinib for 3 weeks, the time, especially in young children, acute-phase reactants (ESR: 121 patient had a brief return of mild should not be underestimated. For mm/hour; CRP: 127.3 mg/L). Serum right elbow swelling, with an ESR of example, anakinra (recombinant IL-1 ferritin levels were elevated 25 mm/hour (normal CRP) and receptor antagonist) requires daily (1937.2 ng/mL; normal: ,274.7 a JADAS-10 of 1.5, all reflective of injection, whereas tocilizumab is ng/mL), but there was no cytopenia, mildly active disease (Fig 2 A and B). given intravenously every 2 weeks. coagulopathy, or other laboratory The patient has since resumed taking Availability of these biologics is also evidence to suggest MAS associated the appropriate dose of tofacitinib not universal, as illustrated by the with sJIA. Repeated MRI revealed new without further complaints. lack of IL-1 antagonists in mainland compression fractures at T5 and T7. Collectively, these observations China. Therefore, alternative Etanercept was discontinued given support the overall efficacy of treatment options are needed for the lack of efficacy in controlling her tofacitinib treatment of this case. patients with sJIA with refractory arthritis. Because anti-IL-1 agents are disease or logistic difficulties with not available in mainland China, DISCUSSION biologics therapy. tocilizumab (monoclonal anti-IL-6 receptor) was recommended, but the Despite recent advances in treatment JAK inhibitors are orally available family refused all parenteral therapy. options, sJIA remains one of the most small-molecule drugs that suppress Given the beneficial effect of JAK challenging pediatric rheumatologic inflammation by interfering with JAK- inhibitors in RA, we started the conditions. Distinct from other forms STAT (signal transducer and activator patient on oral tofacitinib (2.5 mg of childhood arthritis, sJIA has of transcription protein) signaling twice daily) while maintaining oral prominent clinical features of downstream of numerous methylprednisolone at 4 mg daily. She quotidian fever and systemic inflammatory cytokine receptors. was 13 years old at the time of this inflammation in addition to arthritis, Currently, 2 JAK inhibitors are treatment, and tofacitinib was titrated whereas autoantibodies are typically approved for the treatment of RA in to the dose of 5 mg twice daily after absent.3 Although genetic linkage in adults. Tofacitinib inhibits JAK-1/3, 2 weeks on the basis of available the HLA antigen cluster reveals a role whereas baricitinib is used to target pharmacokinetics data.8 of adaptive immunity in sJIA,10 the JAK-1/2. Several cytokines pertinent systemic manifestations of to arthritis, including IL-6, interleukin Remarkably, after experiencing inflammation are in line with 21, and granulocyte colony chronic joint inflammation for nearly aberrant activation of the innate stimulating factor, signal via JAK-1 2 years, her arthritis improved immune system characteristic of and/or JAK-3. Given the excess steadily over the next 2 months, as autoinflammatory syndromes.11 production of IL-6 in sJIA, tofacitinib reflected by the declining juvenile These distinctions in pathophysiology may function to inhibit IL-6 receptor arthritis disease activity score may help explain why a different signaling, but its exact target(s) (JADAS-10) (Fig 2A).9 The acute- approach is required for treatment of in vivo is difficult to determine. phase reactants decreased sJIA compared with other forms correspondingly (Fig 2B), and serum Although tofacitinib has been widely of JIA. ferritin levels were also within prescribed for adults with RA, data on normal limits (100.3 ng/mL). Effective management of sJIA JIA are limited. Authors of a case Complete remission was achieved requires establishing control of both report described successful treatment after 3 months of treatment by systemic features and joint of polyarticular JIA and collagenous

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 143, number 5, May 2019 3 FIGURE 2 Longitudinal follow-up of disease activity and acute-phase reactant levels with tofacitinib treatment. A, JADAS-10 before and after tofacitinib treatment. B, ESR and CRP levels before and after tofacitinib treatment.

Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 HUANG et al colitis by using tofacitinib in refractory sJIA with inadequate diseases in childhood: “lessons from a 58 year-old female patient response to nonsteroidal clinical trials of anti-cytokine diagnosed with JIA at age 10 years.19 antiinflammatory drugs, monoclonal antibodies for Kawasaki Results from a phase I trial in methotrexate, glucocorticoids, and disease, systemic onset juvenile children with polyarticular JIA etanercept. These data provide idiopathic arthritis, and cryopyrin- associated periodic fever syndrome”. revealed no adverse effects support to establish clinical trials to Mod Rheumatol. 2015;25(1):1–10 associated with short-term evaluate the efficacy and safety of administration of tofacitinib.8A phase tofacitinib in sJIA. 7. Hodge JA, Kawabata TT, Krishnaswami III trial to evaluate the efficacy of S, et al. The mechanism of action of tofacitinib in JIA is ongoing tofacitinib - an oral Janus kinase inhibitor for the treatment of (ClinicalTrials.gov Identifier: ABBREVIATIONS rheumatoid arthritis. Clin Exp NCT02592434) and another for sJIA CRP: C-reactive protein Rheumatol. 2016;34(2):318–328 is in the recruitment stage ESR: erythrocyte (NCT03000439). In the case of 8. Ruperto N, Brunner HI, Zuber Z, et al; sedimentation rate refractory sJIA presented here, Pediatric Rheumatology International IL-1: interleukin 1 Trials Organization (PRINTO); Pediatric tofacitinib resulted in resolution of IL-6: interleukin 6 Rheumatology Collaborative Study both systemic inflammation and JADAS-10: juvenile arthritis Group (PRCSG). Pharmacokinetic and arthritis after 3 months of therapy. disease activity score safety profile of tofacitinib in children We recognize that sJIA is a complex JAK: Janus-activated kinase with polyarticular course juvenile and heterogeneous disease and JIA: juvenile idiopathic arthritis idiopathic arthritis: results of a phase that not all patients respond similarly MAS: macrophage activation 1, open-label, multicenter study. Pediatr to the same agent. Our patient did not Rheumatol Online J. 2017;15(1):86 syndrome develop MAS, a life-threatening RA: rheumatoid arthritis 9. Consolaro A, Ruperto N, Bazso A, et al; complication of sJIA characterized by sJIA: systemic juvenile idiopathic Paediatric Rheumatology International coagulopathy, hemophagocytosis, arthritis Trials Organisation. 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