Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance.

OBJECTIVES: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study. METHODS: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses. RESULTS: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection. CONCLUSIONS: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months. STUDY IDENTIFIER: NCT01932372.

Rheumatoid factor value for determining the first biologic agent to use for non-systemic juvenile idiopathic arthritis.

OBJECTIVES: Currently, no indicators on which biologic disease-modifying anti-rheumatic drugs (bDMARDs) should be used first for juvenile idiopathic arthritis (JIA) have been established. Thus, this study aimed to determine the useful biomarkers in JIA to enable the best selection of the first bDMARDs without primary failure. METHODS: This retrospective study used data of patients examined for JIA between 2015 and 2021 at Kagoshima University Hospital in Japan. RESULTS: Altogether, 67 cases of non-systemic JIA were analyzed, excluding cases that had been treated for <6 months. Of the 67 cases, 52 were treated with bDMARDs and all rheumatoid factor (RF)+ types (32 cases) were treated with bDMARDs. Eleven cases (31.4&) (all were RF+ types and used anti-tumor necrosis factor (TNF)α agents) switched to other bDMARDs because of primary failure, and nine cases had secondary failure (6;anti-TNF, 3;anti-Interleukin-6). A significant difference in pre-treatment RF values (177.9 vs 25.7 IU/ml, p = 0.002) and presence (Odds Ratio 1.952,p = 0.004) were observed between the primary failure group and effective group. CONCLUSIONS: RF+ JIA required bDMARDs with high probability. JIA with high titre of RF tends to be refractory to anti-TNFα agents. Tocilizumab or abatacept could be a first-choice bDMARD in such cases.

Long-term efficacy and safety of canakinumab in the treatment of systemic juvenile idiopathic arthritis in Japanese patients: Results from an open-label Phase III study.

OBJECTIVES: The objective of the study was to report the efficacy and safety of canakinumab treatment in Japanese patients with systemic juvenile idiopathic arthritis (sJIA) over a 48-week study period. METHODS: Patients were administered canakinumab 4 mg/kg (maximum dose 300 mg) every 4 weeks, with no dose adjustments. The key outcome measures included adapted American College of Rheumatology paediatric (aACR pedi) 30/50/70/90/100 response, proportion of patients with inactive disease, and corticosteroid (CS) tapering. RESULTS: In total, 16/19 (84.2%) patients received canakinumab for ≥96 weeks reaching end-of-study (EOS) visit without premature discontinuation. Regardless of the level of joint involvement at baseline, high aACR pedi responses were observed throughout the study; at the EOS, aACR pedi 90/100 response rates were 84.2%/63.2%, respectively. The proportion of patients who successfully tapered CSs at EOS was 66.7% (12/18), of which 10 patients were steroid-free. The most common adverse events were infections (238.3 events/100 patient-years). Serious adverse events were observed in 52.6%. The event (n=1) adjudicated as possible macrophage activation syndrome was preceded by sJIA flare. No deaths were reported. CONCLUSIONS: Canakinumab treatment resulted in a sustained treatment response in sJIA patients over 48 weeks and was associated with CS tapering in majority of patients. No new safety findings were reported.

Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases.

Interleukin (IL)-18 is a pleiotropic, pro-inflammatory cytokine involved in the regulation of innate and adaptive immune responses. IL-18 has attracted increasing attention as a key mediator in autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS) including systemic juvenile idiopathic arthritis and adult-onset Still's disease. In these diseases, dysregulation of inflammasome activity and overproduction of IL-18 might be associated with the development of MAS by inducing natural killer cell dysfunction. Serum IL-18 levels are high in patients with these diseases and therefore are useful for the diagnosis and monitoring of disease activity. In contrast, a recent study revealed the overproduction of IL-18 was present in cases of autoinflammation without susceptibility to MAS such as pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. The pathogenic and causative roles of IL-18 remain unclear in these autoinflammatory diseases. Further investigations are necessary to clarify the role of IL-18 and its importance as a therapeutic target in the pathogenesis of autoinflammatory diseases.

Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis.

Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.

Childhood Arthritis and Rheumatology Research for Dreams Come True Remission.

In recent years, newly developed therapeutic agents have brought clinical, structural, and functional remission to many pediatric patients with rheumatic diseases that were refractory to conventional therapy. However, achieving these remissions alone is insufficient as a treatment goal, especially for adolescent patients, because advanced therapies have not always encouraged their psychosocial stability and mental maturity. Consequently, various problems have arisen during the puberty and transition period from pediatrics to adult medical care. "Dreams come true remission" is a state of remission that allows patients to have clear dreams for the future in childhood and to increase the potential that their dreams will be realized in adulthood. This new treatment goal may empower children with chronic diseases such as PRDs to overcome the problems occurred during puberty and transition period.

Clinical practice guidance for childhood-onset systemic lupus erythematosus-secondary publication.

Childhood-onset systemic lupus erythematosus (cSLE) has been recognised as a more acute and severe autoimmune disease than adult-onset SLE. With the development of medications for the disease and supportive therapy, the mortality rate associated with cSLE has drastically improved; the 10-year survival rate among patients with cSLE between 1995 and 2006 in Japan was 98.3%. However, the 10-year survival rate without any permanent functional impairment remained low at 66.1%. Therefore, the current treatment goal for cSLE is to ensure that they can perform normal daily activities throughout their lives by preventing the occurrence and/or progression of organ damage. For this purpose, appropriate treatments and evaluations are required according to the severity and risk of organ damage; however, there are no established guidelines for cSLE. Therefore, the Pediatric Rheumatology Association of Japan and the Pediatric Rheumatology Subcommittee in the Japan College of Rheumatology developed a comprehensive guidance for clinical practice based on cSLE-related data collected from Japanese national surveys and relevant articles from both domestic and international sources. However, due to the lack of indications for defined and objective evidence quality levels, this guidance should be used on the basis of the judgement of the attending physicians for individual patients.

Anti-TNF treatment corrects IFN-γ-dependent proinflammatory signatures in Blau syndrome patient-derived macrophages.

BACKGROUND: Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear. OBJECTIVE: We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples. METHODS: Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison. RESULTS: Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ-dependent accelerated inflammatory responses. Comparisons of peripheral blood- and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature. CONCLUSIONS: IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB-driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS.

Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison.

OBJECTIVE: To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE). METHODS: We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III). RESULTS: SRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies. CONCLUSIONS: These analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE. TRIAL REGISTRATION NUMBERS: PLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. OBJECTIVES: This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. METHODS: Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. RESULTS: Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation. CONCLUSIONS: Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.

A case of cryopyrin-associated periodic fever syndrome during canakinumab administration complicated by inflammatory bowel disease.

Cryopyrin-associated periodic fever syndrome (CAPS) is a highly debilitating disorder, which is characterized by unregulated interleukin-1ß production driven by autosomal dominantly inherited mutations in the NLRP3 gene. Patients with CAPS often present with early-onset episodes of fever and rash. These patients also present with variable systemic signs and symptoms, such as arthritis, sensorineural hearing loss, chronic aseptic meningitis, and skeletal abnormalities, but minimal gastrointestinal symptoms. Recently, effective therapies for CAPS targeted against interleukin-1 have become available. We report a case of a young Japanese woman with CAPS who developed inflammatory bowel disease during canakinumab therapy. The patient had colostomy after intestinal perforation and changed canakinumab to infliximab. To the best of our knowledge, this is the first report of a case of inflammatory bowel disease secondary to CAPS complicated by gastrointestinal symptoms and arthritis which canakinumab could not control. Patients with CAPS who have symptoms that cannot be controlled by canakinumab should be considered for possible co-morbidities.

Safety and effectiveness of adalimumab in Japanese patients with juvenile idiopathic arthritis: Results from a real-world postmarketing study.

OBJECTIVES: This study was conducted to assess the real-world safety and effectiveness of adalimumab in patients with juvenile idiopathic arthritis (JIA). METHODS: In this all-case, postmarketing surveillance study (NCT01412021) conducted in Japan, patients receiving adalimumab for JIA affecting multiple joints were observed for 24 weeks. The safety (adverse drug reactions [ADRs]/serious ADRs) and effectiveness (4-variable Disease Activity Score in 28 joints using erythrocyte sedimentation rate [DAS28-4/ESR] remission rate) were assessed. RESULTS: In the safety population (n = 356), 90.3% (65/72; weight, ≥15-<30 kg) of patients received adalimumab 20 mg every 2 weeks (q2w) and 98.3% (236/240; weight ≥30 kg) received 40 mg q2w. Incidence of ADRs and serious ADRs was 29.8% (106/356) and 3.4% (12/356), respectively. Incidence of ADRs was significantly higher in patients aged <15 years vs. ≥15 years (34.6% vs. 21.1%, p = .0072), those with comorbidities vs. without (38.3% vs. 25.7%, p = .0155), and those receiving dose <40 mg q2w vs. ≥40 mg q2w (38.8% vs. 26.9%, p = .0418). DAS28-4/ESR remission rate improved from 21.7% (36/166) at baseline to 74.7% (112/150) at week 24. CONCLUSIONS: Adalimumab was well tolerated and had acceptable safety and effectiveness in patients with JIA in the real-world setting.

Efficacy and safety of canakinumab in systemic juvenile idiopathic arthritis: 48-week results from an open-label phase III study in Japanese patients.

OBJECTIVES: To assess the efficacy and safety of canakinumab in Japanese patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: This was an open-label, single-arm active treatment study. sJIA patients, aged ≥2 to <20 years, were administered canakinumab 4 mg/kg every 4 weeks for ≤48 weeks. The co-primary endpoints were the proportion of patients who achieved an adapted American College of Rheumatology pediatric (ACR pedi) 30 criteria at week 8, and the proportion of patients who successfully tapered corticosteroids at week 28. Herein, the efficacy and safety results up to 48 weeks are reported. RESULTS: Of the 19 patients enrolled, 15 (78.9%) had previously used tocilizumab. All patients achieved ACR pedi 30 at week 8 and 73.7% (14/19) successfully tapered corticosteroids at week 28. At week 48, ACR pedi 50/70/90/100 responses were achieved by 100.0%/100.0%/87.5%/68.8% of patients. The most common adverse events (AEs) were infections (271.6 patient-years), 42.1% (8/19) patients had serious AEs. Two potential cases of macrophage activation syndrome were identified. No deaths were reported. CONCLUSION: Canakinumab was efficacious in Japanese patients with sJIA and was associated with substantial corticosteroid dose reduction in the majority of patients. The safety profile of canakinumab was consistent with that observed from previous studies. CLINICALTRIALS.GOV (IDENTIFIER: NCT02396212).

Pediatric Dual-Energy X-Ray Absorptiometry in Japan: A Proposal for Shared Access to Equipment.

BACKGROUND: Regular assessment of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is essential for detecting glucocorticoid-induced osteoporosis in juvenile-onset autoimmune diseases. Z-score is used to standardize osteoporosis assessment in children and is evaluated with only one of three devices in Japan. The purpose of this study was to determine how many Japanese medical facilities for pediatric rheumatic diseases were unable to use Z-scores to evaluate osteoporosis. METHODS: Electronic questionnaires were distributed between 2017 and 2019 to hospitals belonging to the Pediatric Rheumatology Association of Japan and to university hospitals and public children's hospitals that provide medical care for pediatric rheumatic diseases. The questionnaire inquired about the location of DXA measurement, manufacturer (Hologic, GE healthcare, Hitachi), and measurement site, and the answers were collected using Google Forms. Statcel 4 was used for analysis. RESULTS: Overall, 120 facilities responded to the survey, of which 117 had DXA. In the remaining three facilities, DXA was not installed in two and was out of order in one. Bone loss in childhood was evaluated using a Z-score calculated from age-based reference values; however, 30% of hospitals without HOLOGIC DXA could not evaluate osteoporosis by Z-score in Japanese childhood. The characteristics of the hospitals enrolled in this study did not bias the selection of Hologic DXA. CONCLUSIONS: Neighboring institutions should consider sharing access to Hologic DXA equipment, to ensure use of uniform reference values. GE BMD reference values should be established for Japanese children.

Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Long-term efficacy and safety of tocilizumab in refractory Takayasu arteritis: final results of the randomized controlled phase 3 TAKT study.

OBJECTIVE: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. RESULTS: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported. CONCLUSION: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. TRIAL REGISTRATION: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Pre-conception status, obstetric outcome and use of medications during pregnancy of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) in Japan: Multi-center retrospective descriptive study.

Objective: To describe the pre-conception status, pregnancy outcomes, and medication prevalence in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease (CD), and ulcerative colitis (UC).Methods: E-mail-based questionnaire survey for the Japan Maternal Fetal Intensive Care Unit Network hospitals inquiring prevalence and clinical features of SLE, RA, CD and UC complicated pregnancies for 2 years.Results: The number of SLE, RA, CD and UC among 69,810 deliveries was 184, 139, 27 and 178, respectively. Less than half of pregnancies were planned. Assisted reproductive technology (ART) pregnancy rates were higher in SLE, RA and UC than in the general population (11.4, 23.0 and 7.4 vs 5.1%, p < .001 each). Preterm delivery, preeclampsia, and fetal growth restriction (FGR) were more frequent in SLE than in the general population (39.4 vs. 5.6% p < .001, 15.0 vs. 6.0% p < .001, 12.9 vs 4.2% p < .001). Prevalence of preterm delivery in RA and UC (27.5 vs. 5.6% p < .001, 11.3 vs. 5.6% p < .05) and FGR in CD (28.6 vs. 4.2% p < .001) was also higher than that in the general population.Conclusion: SLE, RA, CD, and UC complicated pregnancies were at high risks of obstetric adverse outcome. High ART rates necessitate pre-conception counseling in SLE, RA, and UC pregnancies.

Real-world Safety and Effectiveness of Infliximab in Pediatric Patients With Acute Kawasaki Disease: A Postmarketing Surveillance in Japan (SAKURA Study).

BACKGROUND: In 2015, infliximab was approved for the treatment of patients with intravenous immunoglobulin-refractory Kawasaki disease (KD) in Japan. However, limited real-world data exist on the usefulness of infliximab for acute KD patients. We conducted a postmarketing surveillance study in patients with acute KD refractory to conventional therapies to evaluate the safety (including any live vaccine-related infections) and the effectiveness of infliximab. METHODS: This was a multicenter, prospective, open-label, single-cohort, observational study in patients with acute KD refractory to conventional therapy who were prescribed a single 5 mg/kg dose of infliximab. Safety and effectiveness of infliximab were evaluated at 1 month, and live vaccine-related infections were further observed until 6 months from KD onset. Effectiveness assessments included fever resolution rate, the incidence of coronary artery lesions and change in coronary diameter Z scores. RESULTS: A total of 291 patients were enrolled, and all patients completed the study. Adverse drug reactions and serious adverse drug reactions were reported in 12.4% and 3.1% of patients, respectively. Live vaccine-related infections were not observed. In the 208 patients with effectiveness assessments, the fever resolution rate within 48 hours after infliximab infusion was 77.4% (95% confidence interval: 71.1-82.9). Median time until fever resolution was 16.6 hours. After infliximab administration, the incidence (at baseline: 10.9%; at the final observation point: 12.0%; maximum value: 14.6%) and severity of coronary artery lesions did not change notably. CONCLUSIONS: In this study, Infliximab for patients with acute KD refractory to conventional therapies was well tolerated and effective.

Intravenous abatacept in Japanese patients with polyarticular-course juvenile idiopathic arthritis: results from a phase III open-label study.

BACKGROUND: To investigate efficacy and safety of intravenous abatacept in Japanese patients with active polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: In this phase III, open-label, multicenter, single-arm study, patients with pJIA aged 4-17 years who failed ≥1 biologic or methotrexate received weight-tiered (< 75 kg: 10 mg/kg; 75-100 kg: 750 mg; > 100 kg: 1000 mg) intravenous abatacept at Weeks 0, 2, 4, and every 4 weeks thereafter. The study comprised a short-term period (16 weeks) and ongoing long-term period. Primary endpoint: Week 16 JIA-American College of Rheumatology criteria 30 (JIA-ACR30) response rate. Secondary endpoints/outcomes included Week 16 JIA-ACR50/70/90 response and inactive disease rates, Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), pharmacokinetics, safety, and immunogenicity. Proportions of patients achieving Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP) remission (score < 1) and minimal disease activity (MDA; score < 3.8), were among exploratory endpoints. RESULTS: All 20 patients who received study medication completed the short-term period. During the long-term period, two patients discontinued due to insufficient efficacy or patient decision. Median age and disease duration at baseline were 10.5 and 0.75 years, respectively. Week 16 JIA-ACR30 response rate (primary endpoint) was 90.0% (18/20). JIA-ACR50/70/90 response and inactive disease rates at Week 16 were 75.0% (15/20), 70.0% (14/20), 35.0% (7/20), and 25.0% (5/20), respectively. At Week 52, JIA-ACR30/50/70/90 response and inactive disease rates were observed by 88.9% (16/18), 88.9% (16/18), 83.3% (15/18), 66.7% (12/18) and 44.4% (8/18), respectively. CHAQ-DI improved after Week 12. JADAS27-CRP remission and MDA were achieved by 15.0% (3/20) and 45.0% (9/20) of patients at Week 16, and by 50.0% (9/18) and 78.0% (14/18) of patients at Week 52, respectively. The mean abatacept pre-dose serum concentration was above the target therapeutic exposure (10 µg/ml) from Week 8 through Week 16. All adverse events were of mild/moderate intensity, except for one case of severe gastroenteritis. No deaths, malignancies, or autoimmune disorders were observed. No antidrug antibodies were detected through Week 16; one patient had a positive immunogenic response during the cumulative period. CONCLUSION: Intravenous abatacept was efficacious and well tolerated in Japanese patients with active pJIA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01835470 . Date of registration: April 19, 2013.

A low-birth-weight risk assessment scale: development and validation through a questionnaire-based survey.

BACKGROUND: Birth weight is continuously decreasing in Japan since food satiation has become a problem in recent years. The present study aimed to develop and examine the reliability and validity of a scale for the assessment of risk factors for low birth weight in infants born at term. METHODS: A self-administered postal questionnaire survey comprising a low birth weight risk assessment scale was conducted on mothers with children of nursery school or kindergarten age. After item analysis (scale), factor structure was confirmed by an exploratory factor analysis using the main factor method promax rotation. The reliability of this scale was confirmed by Cronbach's α coefficient and Item-Total correlation. The validity was confirmed by known-groups validity and internal validity. RESULTS: The responses of 630 mothers (valid response rate, 18.5%) were analyzed. Factor analysis (principal factor analysis and promax rotation) obtained an optimal scale comprising 25 items in the following nine factors: "guidance at each checkup," "adequate rest," "support from husband," "effects on the fetus," "support from society," "support from family," "effects of minor troubles," "good lifestyle habits," and "fall risk and lifestyle changes." The overall Cronbach's α coefficient for the scale was 0.701. Known-groups validity examination revealed significant differences in scale scores of birth weight, birth history, and maternal smoking status. CONCLUSION: The scale demonstrated internal consistency, construct validity, and known-groups validity, indicating that it can be used as an indicator of low birth weight risk. In the future, this scale may be included in medical questionnaires as part of health guidance for pregnant women at a risk of delivering low birth weight children.