Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey.

OBJECTIVE: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. METHODS: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. RESULTS: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)-unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti-tumor necrosis factor-α agents was effective for IBD- and CAPS-associated symptoms not resolved by canakinumab monotherapy. CONCLUSION: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment.

Treatment for macrophage activation syndrome associated with systemic juvenile idiopathic arthritis in Japan.

OBJECTIVES: To clarify how pediatric rheumatologists treat systemic juvenile idiopathic arthritis (s-JIA) associated macrophage activation syndrome (MAS) in the real world and to assess the efficacy and safety of dexamethasone palmitate (DEX-P) in the treatment of s-JIA-associated MAS. METHODS: This multicenter, retrospective study was conducted at 13 pediatric rheumatology institutes in Japan. This study included 28 patients with s-JIA-associated MAS. Clinical findings, such as treatment details and adverse events, were evaluated. RESULTS: Methylprednisolone (mPSL) pulse therapy was selected as the first-line treatment in more than half of the patients with MAS. Cyclosporine A (CsA) was used as first-line therapy in combination with corticosteroids in half of the patients with MAS. DEX-P and/or CsA were selected as the second-line therapy in 63% of patients with corticosteroid-resistant MAS. Plasma exchange was selected as the third-line therapy for DEX-P and CsA-resistant MAS. All patients improved and there were no characteristically severe adverse events associated with DEX-P. CONCLUSIONS: The first-line treatment for MAS in Japan is mPSL pulse therapy and/or CyA. DEX-P could be an effective and safe therapeutic option for patients with corticosteroid-resistant MAS.

Clinical Significance of Serum Soluble TNF Receptor I/II Ratio for the Differential Diagnosis of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome From Other Autoinflammatory Diseases.

Objectives: Genetic analysis of TNFRSF1A can confirm the diagnosis of tumor necrosis factor receptor-associated periodic syndrome (TRAPS), but interpretation of the pathogenesis of variants of unknown significance is sometimes required. The aim of this study was to evaluate the clinical significance of serum soluble tumor necrosis factor receptor type I (sTNFR-I)/II ratio to differentiate TRAPS from other autoinflammatory diseases. Methods: Serum sTNFR-I and sTNFR-II levels were measured using an enzyme-linked immunosorbent assay in patients with TRAPS (n = 5), familial Mediterranean fever (FMF) (n = 14), systemic juvenile idiopathic arthritis (s-JIA) (n = 90), and Kawasaki disease (KD) (n = 37) in the active and inactive phase, along with healthy controls (HCs) (n = 18). Results: In the active phase, the serum sTNFR-I/II ratio in patients with s-JIA, KD, and FMF was significantly elevated compared with that in HCs, whereas it was not elevated in patients with TRAPS. In the inactive phase, the serum sTNFR-I/II ratio in patients with s-JIA and FMF was significantly higher compared with that in HCs, and the ratio was lower in TRAPS patients than in patients with s-JIA and FMF. Conclusions: Low serum sTNFR-I/II ratio in the active and inactive phase might be useful for the differential diagnosis of TRAPS and other autoinflammatory diseases.

Tocilizumab modifies clinical and laboratory features of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

BACKGROUND: This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. METHODS: A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. RESULTS: Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIA-associated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p < 0.01). This is ascribed to the absence of fever or insufficient ferritin elevation, compared with the untreated patients. CONCLUSION: TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

Clinical features and characteristics of uveitis associated with juvenile idiopathic arthritis in Japan: first report of the pediatric rheumatology association of Japan (PRAJ).

BACKGROUND: Although there are many reports on Juvenile Idiopathic arthritis-associated uveitis (JIA-U) from various countries, especially from Europe and North America, there are few reports from Asia. Our aim was to investigate the epidemiology, characteristics and predictors of JIA-U in Japan. METHODS: Data were retrospectively collected on 726 patients with JIA from medical records as of April 2016 at 15 medical centers specialized in pediatric rheumatic diseases. Of these, patients with uveitis were further investigated for the specific characteristics of this manifestation. RESULTS: The prevalence of uveitis was 6.1% in the 726 JIA patients examined. Incidence of uveitis was significantly higher in patients with an earlier arthritis onset (2.6-vs.-5.8 years, P < 0.0001), oligoarthritis (16.1%-vs.-1.6%, P < 0.001), or anti-nuclear antibodies. On the contrary, it was significantly less common in patients with rheumatoid factor or anti-cyclic citrullinated peptide antibodies. A history of using methotrexate (MTX), infliximab or adalimumab was also associated with uveitis occurrence. The median age at uveitis diagnosis was 5 years, and the median time from arthritis onset to uveitis diagnosis was 2 years. The occurrence of anterior and bilateral uveitis was 79.3 and 53.7%, respectively. There were no symptoms at uveitis diagnosis in 58.5% of cases. Complications arising between the time of uveitis diagnosis and the last observation increased from 31.7 to 56.1%; in particular, cataract was increased 3-fold. While no patients lost their vision, 61.9% did not recover normal vision (≥ 1.0), and in many cases active uveitis persisted, especially in males. In addition to steroid eye drops (97.6%) and MTX (15.4%), biological agents were used for treating the uveitis in 41.5% of patients. CONCLUSIONS: The epidemiology, characteristics and predictors of JIA-U in Japan are described here for the first time. Although the prevalence of JIA-U in Japan is lower than in predominantly Caucasian cohorts, as reported from North America and Europe, the epidemiology, characteristics and predictors were found to be similar.

Clinical practice guidance for juvenile idiopathic arthritis (JIA) 2018.

Juvenile idiopathic arthritis (JIA) is the most common disease in pediatric rheumatism. There is no specific symptom or examination finding for JIA, and the diagnosis is made by exclusion and differentiation. Because non-pediatric rheumatologists are sometimes involved in medical care, 'proposal for JIA guidance on diagnosis and treatment for primary care pediatricians and non-pediatric rheumatologists' was first published in 2007. In these 10 years, a number of new findings on pathophysiology and treatment of JIA have been published; therefore, we propose this guidance of 2018th edition aiming at updating and standardization of JIA medical care in Japan. This edition included the management of uveitis, macrophage activation syndrome, infectious diseases before and during treatment. Moreover, details of biologics are also described. Although this guidance is tailored to adaptation of examinations and drugs, we do not purpose to limit the physicians' discretion in clinical practice. This guidance should be viewed as recommendations and be individualized according to the condition of the patient. We hope that medical care for JIA will advance and more patients will get benefit based on this guidance. Then, further revisions are needed due to changes in future conditions.

Early prediction for over two years efficacy of the first biologic agent for polyarticular juvenile idiopathic arthritis: A multi-institutional study in Japan.

OBJECTIVE: To estimate target of treatment for long-term efficacy of the first biologic agent used to treat polyarticular juvenile idiopathic arthritis (pJIA). METHODS: A retrospective cohort of patients with pJIA treated at six medical institutions in Japan between 1 March 2005 and 31 October 2014 was identified. The patients were divided by 2-year treatment periods with the first biologic agent into continuous treatment group and switching group. Three markers were examined: matrix metalloproteinase-3 (MMP-3), erythrocyte sedimentation rate (ESR), and disease activity score (DAS) 28-ESR. RESULTS: Thirty-two pJIA patients (8 boys, 24 girls) from 43 recruited patients were included in this study. The treatment periods with the first biologic agent in continuous treatment group (24 patients, 75%) was 40 months (median, range 24-119) and switching group (8 patients; 25%) was 9.5 months (median, 6-18). Markers [odds ratio (95% confidence interval)] at 3 months were MMP-3 [1.02 (0.99-1.05), p = .219], ESR [1.00 (0.78-1.30), p = .998], and DAS28-ESR [13.9 (2.08-409.82), p = .035]. The cut-off point for DAS28-ESR at 3 months to distinguish the two groups was 2.49 (sensitivity, 87.5%; specificity, 87.5%). CONCLUSION: DAS28-ESR of 2.49 at 3 months after initiating the first biologic agent can be a target of sustained treatment in pJIA patients.

Validation of Classification Criteria of Macrophage Activation Syndrome in Japanese Patients With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world. METHODS: A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. A total of 65 profiles comprised 18 patients with systemic JIA-associated MAS and 47 patients with active systemic JIA without evidence of MAS. From these profiles, 10 patient data points for full-blown MAS, 11 patient data points for MAS onset, and 47 patient data points for acute systemic JIA without MAS were evaluated. RESULTS: Evaluation of the classification criteria to discriminate full-blown MAS from acute systemic JIA without MAS showed a sensitivity of 1.000 and specificity of 1.000 at the time of full-blown MAS. Sensitivity was 0.636 and specificity was 1.000 at the time of MAS onset. The number of measurement items that fulfilled the criteria increased in full-blown MAS compared to that at MAS onset. At MAS onset, the positive rates of patients who met the criteria for platelet counts and triglycerides were low, whereas those for aspartate aminotransferase were relatively high. At full-blown MAS, the number of patients who met the criteria for each measurement item increased. CONCLUSION: The classification criteria for MAS complicating systemic JIA had a very high diagnostic performance. However, the diagnostic sensitivity for MAS onset was relatively low. For the early diagnosis of MAS in systemic JIA, the dynamics of laboratory values during the course of MAS should be further investigated.

A 2-year-old Japanese girl with TNF receptor-associated periodic syndrome: A case report of the youngest diagnosed proband in Japan.

We report a 2-year-old girl with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) who is the youngest proband diagnosed in Japan. Recurrent fever had started at her 6 months of age, and she had the familial history of recurrent fever, suggesting underlying genetic disorder, in her father and grandfather. Careful clinical observation of characteristics of fever with disease course and the familial history of recurrent fever may lead to diagnosis of TRAPS in early infancy.