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Objectives: The aim is to evaluate the treatment and prognosis of coronavirus disease 2019 (COVID-19) according to the time of onset and dominant strain in patients with rheumatic diseases., Methods: This study analysed a nationwide COVID-19 registry of Japanese patients with rheumatic diseases compiled between June 2020 and December 2022. The primary endpoints of the study were hypoxaemia incidence and mortality. Multivariate logistic regression analysis was performed to assess differences according to the period of onset., Results: A total of 760 patients were compared across four periods. Hypoxaemia rates were 34.9, 27.2, 13.8, and 6.1% and mortality rates were 5.6, 3.5, 1.8, and 0% until June 2021, between July and December 2021, January and June 2022, and July and December 2022, respectively. History of vaccination (odds ratio, 0.39; 95% confidence interval, 0.18-0.84) and onset during the July to December 2022 Omicron BA.5-dominant period (odds ratio, 0.17; 95% confidence interval, 0.07-0.41) were negatively associated with hypoxaemia in the multivariate model, adjusting for age, sex, obesity, glucocorticoid dose, and comorbidities. Over the Omicron-dominant period, antiviral treatment was administered in 30.5% of patients with a low probability of hypoxaemia., Conclusions: COVID-19 prognosis improved over time in patients with rheumatic diseases, especially in the Omicron BA.5-dominant period. In the future, treatment of mild cases should be optimised., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The incidence and prognosis of Coronavirus Disease 2019 (COVID-19) and rheumatic disease vary among ethnicities and regions. COVID-19 outcomes in rheumatic disease patients remain unclear, especially in the Asia-Pacific region. This study aimed to clarify the demographic and clinical factors that may influence COVID-19 prognosis in rheumatic disease patients., Methods: This was a case series of patients registered with the COVID-19 national registry of Japan College of Rheumatology between 3 June 2020 and 30 June 2021. Multivariable logistic regression was used to estimate the risk of hospitalization or death. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities, and rheumatic disease medications are taken immediately before infection was analysed., Results: A total of 220 patients from 55 institutions in Japan were included in the study, among whom 186 (84.5%) were hospitalized and 11 (5.0%) died. COVID-19 treatments were provided to 126 patients (57.3%) and mainly comprised glucocorticoids, favipiravir, remdesivir, and tocilizumab.In the multiple logistic regression model, older age and a history of hypertension were associated with hospitalization, while older age was associated with mortality. No specific treatment was correlated with mortality or hospitalization by the multivariate analysis., Conclusions: Older age and hypertension were associated with a poor prognosis in Japanese COVID-19 patients with connective tissue disease. Factors not directly related to connective tissue disease were closely associated with the prognosis., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Coronavirus disease 2019 (COVID-19) in children can be compounded by concurrent diseases and immunosuppressants. For the first time, we aimed to report the clinical features of concurrent COVID-19 and pediatric rheumatic disease (PRD) in Japan. Pediatric Rheumatology Association of Japan members were surveyed between 1 April 2020 and 31 August 2022. Outcome measurements included the clinical features of concurrent PRD and COVID-19. Questionnaire responses were obtained from 38 hospitals. Thirty-one hospitals (82%) had children with PRD and COVID-19. The female-to-male ratio in these children ( n = 156) was 7:3, with half aged 11-15 years. The highest proportion of children with PRD and COVID-19 was accounted for by juvenile idiopathic arthritis (52%), followed by systemic lupus erythematosus (24%), juvenile dermatomyositis (5%), scleroderma (4%), and Takayasu arteritis (3%). Of children with PRD, a significant majority (97%) were found to be asymptomatic (10%) or presented with mild symptoms (87%) of the COVID-19 infection. No severe cases or deaths were observed. Regarding the use of glucocorticoids, immunosuppressants, or biologics for PRD treatment before COVID-19, no significant difference was found between asymptomatic/mild and moderate COVID-19 in children with PRD. Therefore, COVID-19 is not a threat to children with PRD in Japan.

Objectives: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases., Methods: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis., Results: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01)., Conclusions: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: To describe clinical characteristics of patients in Japan with coronavirus disease 19 (COVID-19) and pre-existing rheumatic disease and examine the possible risk factors associated with severe COVID-19., Methods: Adults with rheumatic disease and a COVID-19 diagnosis who were registered in the COVID-19 Global Rheumatology Alliance (C19-GRA) physician-reported registry from Japan between 15 May 2020 and 12 May 2021 were included. Multivariable logistic regression models were used to assess factors associated with severe COVID-19 progression, defined as death or requiring oxygen inhalation., Results: In total, 222 patients were included in the study. Rheumatoid arthritis (48.2%), gout (14.4%), and systemic lupus erythematosus (8.1%) were the most common types of rheumatic disease, 55.1% of patients were in remission and 66.2% had comorbid disease. Most patients were hospitalised (86.9%) for COVID-19, 43.3% received oxygen, and 9.0% died. Older age (≥ 65 years), corticosteroid use, comorbid diabetes, and lung diseases are associated with higher risk for severe COVID-19 progression (odds ratio (OR) 3.52 [95% confidence interval (CI) 1.69-7.33], OR 2.68 [95% CI 1.23-5.83], OR 3.56 [95% CI 1.42-8.88], and OR 2.59 [95% CI 1.10-6.09], respectively)., Conclusions: This study described clinical characteristics of COVID-19 patients with rheumatic diseases in Japan. Several possible risk factors for severe COVID-19 progression were suggested. Key points • Clinical characteristics of 222 adult patients in Japan with coronavirus disease 19 (COVID-19) and pre-existing rheumatic diseases were described. • Most patients were hospitalised (86.9%) for COVID-19 in Japan, 43.3% received oxygen, and 9.0% died. • The COVID-19 characteristics of patients with rheumatic diseases did not show any obvious different pattern from those of the general population in Japan. • In this study, older age (≥ 65 years), corticosteroid use, comorbid diabetes, and lung diseases are associated with higher risk for severe COVID-19 progression., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

We investigated serum total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain after BNT162b2 mRNA vaccination against coronavirus disease 2019 (COVID-19) in Japanese patients taking various immunosuppressive medications for rheumatic disease. In 212 outpatients with rheumatic diseases at Kagawa University Hospital and 43 healthy volunteers (controls), all of whom had received 2 doses of BNT162b2 vaccine, serum antibody titers of SARS-CoV-2 spike protein were analyzed at least 14 days after the second dose. Many of the patients were taking immunosuppressive agents to manage their rheumatic disease. The antibody titers against SARS-CoV-2 spike protein in these patients were significantly lower than those in controls. The analysis of therapeutic agents revealed that the antibody titers in patients treated with rituximab were much lower than those in controls. In patients treated with tacrolimus, baricitinib, azathioprine, mycophenolate mofetil, abatacept, tumor necrosis factor inhibitors, cyclosporine, interleukin-6 inhibitors, methotrexate, or glucocorticoids, antibody titers were moderately lower than those of controls. Interleukin-17 and interleukin-23 inhibitors did not impair the humoral response. In addition, the combination of methotrexate with various immunosuppressive agents reduced titers, although not significantly. In Japanese patients with rheumatic disease, many immunosuppressants impaired the immune response to the BNT162b2 vaccine. The degree of decline in antibody titers differed according to immunosuppressant. When used concomitantly with other immunosuppressants, methotrexate may impair the immune response to the BNT162b2 vaccine. However, immunomodulatory treatments such as interleukin-17 and -23 inhibitors may not attenuate this response in patients with rheumatic disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Glucocorticoid-induced osteoporosis and vertebral fracture are common complications in patients on glucocorticoid treatment for rheumatological diseases. The present study aimed to identify the risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis., Methods: This study included 225 Japanese women with glucocorticoid-induced osteoporosis and 72 patients with postmenopausal osteoporosis. All participants were treated with bisphosphonate or denosumab for osteoporosis with active form of vitamin D for at least 3 years. The differences of clinical parameters, including age, disease duration, body mass index (BMI), bone mineral density (BMD), and the dose and treatment duration of glucocorticoid were assessed between patients with and without vertebral fracture. Multivariate logistic regression analysis was also performed to evaluate the association of vertebral fracture with clinical parameters., Results: The significant differences related to age, BMD of the hip, disease duration, glucocorticoid treatment duration between patients with and without vertebral fractures were demonstrated. The present study indicated that disease duration, BMI, and the total hip BMD were independent risk factors for vertebral fractures in patients with glucocorticoid-induced osteoporosis., Conclusions: Prolonged disease duration, low BMI, and low total hip BMD could be risk factors of vertebral fracture in patients on glucocorticoid treatment for rheumatological diseases.

Objectives: We aimed to evaluate the obstetric complications and the risk factors for these events in pregnant women with rheumatic diseases (RDs)., Methods: A single-center retrospective study of women with RDs at Hokkaido University Hospital between 2007 and 2016 was conducted. Clinical features and maternal and fetal outcomes were retrospectively collected. The rate of pregnancy complications was compared with the general obstetric population (GOP) in Japan., Results: Overall, 132 pregnancies in 95 women with RDs were recorded. Underlying RDs were systemic erythematosus (SLE) ( n  = 57), antiphospholipid syndrome (APS) ( n  = 35), rheumatoid arthritis ( n  = 9), and other RDs ( n  = 31). Antiphospholipid antibodies (aPL) were detected in 44 pregnancies (32%). Glucocorticoid was used in 82 pregnancies (62%), and tacrolimus in 20 pregnancies (15%). There were 24 disease flares (18%), but no RD-related death was documented. We recorded 112 live births, 6 abortions, 8 miscarriages, and 6 stillbirths. Pregnancies with RDs appeared to have frequent, emergency cesarean sections and preterm deliveries compared with GOP (30% vs 15% and 21% vs 14%, respectively). The median [interquartile range] birthweight in SLE and APS was lower than GOP (2591 [2231-2958] g and 2600 [2276-2920] g vs 2950 [2650-3250] g, respectively). In pregnancies with SLE, low complement levels presented the risk of maternal complications (odds ratio [95% CI]; 3.9 [1.0-14.9], p  = 0.046) and anti-DNA antibody positivity was significantly correlated with the risk of fetal complications (3.5 [1.1-11.2], p  = 0.036). In pregnancies with APS, maternal age over 35 years and duration of disease longer than 9 years (7.4 [1.3-40.8], p  = 0.021, and 11.16 [1.1-118.8], p  = 0.046, respectively) were significantly correlated with the risk of fetal complications., Conclusion: Pregnancies with RDs were at increased risk of having both maternal complications and adverse neonatal outcomes, indicating these pregnancies should be closely monitored.

The randomized, clinical trial demonstrated that switching to monthly minodronate from weekly alendronate and risedronate provides greater increases in patients' satisfaction and bone mineral density and more substantial decreases in a bone resorption marker than continuing weekly alendronate and risedronate in patients with systemic rheumatic diseases on glucocorticoid therapy., Purpose: Osteoporosis and associated fractures are major concerns for patients with systemic rheumatic diseases on long-term glucocorticoid therapy. Bisphosphonates increase bone mineral density (BMD) and reduce the frequency of vertebral fractures, but they are associated with poor adherence. The effects of monthly oral minodronate on patients' satisfaction, BMD, and bone turnover markers were investigated in patients with systemic rheumatic diseases on glucocorticoids and weekly oral alendronate or risedronate., Methods: Study patients with systemic rheumatic diseases on oral glucocorticoids and weekly alendronate 35 mg or risedronate 17.5 mg were randomly assigned either to switch to minodronate 50 mg every 4 weeks or to continue the currently taking weekly bisphosphonate for 52 weeks after a 24-week run-in period.Patients were stratified by hospital site, sex, and menopausal status in women at enrollment. The primary endpoint was the difference between the proportions of patients who responded very satisfactory or satisfactory for the current bisphosphonate therapy at weeks 48 and 76 between the two groups. Secondary endpoints included percentage changes in lumbar spine BMD and bone turnover markers from the time of starting allocated treatment., Results: Monthly minodronate was superior to weekly alendronate or risedronate for patients' satisfaction, the increase of lumbar spine BMD, and suppression of serum tartrate-resistant acid phosphatase 5b at week 76., Conclusions: Monthly minodronate is more acceptable and may be more effective than weekly alendronate or risedronate for prevention and treatment of bone loss in patients with systemic rheumatic diseases on glucocorticoid therapy.

Objectives: The purpose of this study was to clarify the incidence of (CS)-associated osteonecrosis among different underlying diseases and to evaluate the risk factors for steroid-associated osteonecrosis in a prospective MRI study., Methods: We prospectively used MRI to study 337 eligible underlying disease patients requiring CS therapy and succeeded in examining 1199 joints (hips and knees) in 302 patients with MRI for at least 1 year starting immediately after the onset of CS therapy (1-year follow-up rate of 90%). The underlying diseases included SLE in 687 joints (173 patients) and a variety of other rheumatological disorders in 512 joints (129 patients)., Results: The incidence of osteonecrosis was significantly higher in SLE patients than in non-SLE patients (37 vs 21%, P = 0.001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk of osteonecrosis compared with paediatric patients [odds ratio (OR) = 13.2], that high daily CS dosage (>40 mg/day) entailed a significantly higher risk of osteonecrosis compared with the dosage of <40 mg/day (OR = 4.2), that SLE patients had a significantly higher risk of osteonecrosis compared with non-SLE patients (OR = 2.6) and that male patients had a significantly higher risk of osteonecrosis compared with female patients (OR = 1.6)., Conclusion: These findings suggest that the incidence of CS-associated osteonecrosis varies among different underlying diseases.

We created the final bill of "Intravenous cyclophosphamide (IVCY) for the treatment of rheumatic disease of children in general" in order to get approval for the off-label use of IVCY from the Study Group on Pediatric Drug Therapy. As a result, this study group approved IVCY's off-label use in children via public applications. We could create IVCY regimen specific for Japanese children independently of the efficacy, dosage, and administration applied in Germany, which at the time of application was the only country in Europe and the USA where IVCY was approved. Later, its use in adults was given approval through public applications after being fully reviewed by the Study Group on Unapproved and Off-label Drugs of High Medical Need. Consequently, IVCY is now available for the treatment of both childhood and adult rheumatic diseases in general.

The incidence of tuberculosis among patients with systemic rheumatic diseases is much higher than in the general population (the risk is multiplied by 5 to 15 in patients with systemic lupus erythematosus). Reactivation of a latent tuberculosis is frequent, as assessed by the short delay of occurrence after a systemic rheumatic disease has been diagnosed. Besides immunosuppression induced by the underlying disease, the role of glucocorticoids and of immunosuppressive therapy including biotherapies using TNF antagonists must be underlined. Tuberculosis in such patients frequently presents as extrapulmonary or disseminated disease. A screening of tuberculosis is recommended before anti-TNF therapy, and includes previous history questioning, chest X ray, tuberculin skin test with 5 international units of tuberculin. Immunological methods of tuberculosis detection are under evaluation in these patients. If a latent tuberculosis infection is diagnosed, a specific tuberculosis chemoprophylaxis, started at least 3 weeks before initiation of TNF antagonists, has allowed to reduce the occurrence of anti-TNF-associated tuberculosis in patients living in Europe and North America. The screening strategies for tuberculosis should probably be extended in all patients with systemic rheumatic diseases receiving glucocorticoids and/or immunosuppressive therapy.

Objective: To survey and elucidate the clinical characteristics of CMV infection in rheumatic disease patients., Methods: A detailed questionnaire survey on CMV infection was carried out against rheumatic disease patients hospitalized in member hospitals, and the obtained clinical and/or laboratory data were analysed., Results: Out of 7377 patients, 151 were diagnosed as having CMV infection. The underlying diseases ranged broadly, but SLE, microscopic polyangiitis, and dermatomyositis were the most common. Four were diagnosed histopathologically, and the others via positive CMV antigenaemia. In addition to oral corticosteroid for all but one patient, 81 were treated with pulsed methylprednisolone (MPSL), 64 with cyclophosphamide (CYC) and 36 with other immunosuppressants. Forty-four had a fatal outcome, for which presence of clinical symptoms, other infectious complications, lymphopenia, an older age (>59.3 yrs) and the use of pulsed MPSL were significant risk factors (P < 0.05) by univariate analysis. Multivariate analysis retained the first three (P < 0.05). The CMV antigenaemia count was significantly higher for the symptomatic than asymptomatic [10.1 (0.0-2998.0) vs 4.0 (1.3-1144.4)/10(5) PMNs, respectively, P < 0.05; threshold count: 5.6/10(5) PMNs]. No treatment benefit by anti-viral agent was observed as for survival., Conclusion: CMV infection was mostly diagnosed by antigenaemia, and occurred among patients under strong immunosuppressive therapy using pulsed MPSL and/or immunosuppressants. Lymphopenia, presence of symptoms and other infections are significant risk factors for a poor outcome and pulsed MPSL and an older age may predict it. Patients were prone to be symptomatic with anti-genaemia count over 5.6/10(5) PMNs.

Objective: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including Azathioprine (AZA). It has been reported that the level of AZA toxicity is dependent on the TPMT genotypes in Caucasian individuals; we thus investigated this relationship in Japanese., Methods: The TPMT genotype was determined using peripheral blood cell DNA obtained from 36 Japanese patients with rheumatic diseases who were treated with AZA, by polymerase chain reaction (PCR) technique. Duration of AZA administration, white blood cell counts before and after AZA administration, and side effects were investigated in each subject, and were compared between the patients with or without TPMT mutation., Results: The TPMT allelotype was TPMT*1/TPMT*1 in 33 (91.7%) and TPMT*1/TPMT*3C in 3 (8.3%) individuals. All 3 patients (100%) with the mutant TPMT allele (TPMT*3C) discontinued AZA treatment due to leucopenia while only 4 patients (12%) without mutant TPMT alleles showed leucopenia (p=0.0049, Fisher's exact test). However, leucopenia developed relatively late in patients with mutant TPMT., Conclusion: The TPMT mutant allele, TPMT*3C, also exists in Japanese individuals, and the bone marrow toxicity of AZA is likely stronger in patients with this mutant allele.

The root and stem decoctions of Sinomenium acutum Rehd. et Wils. (formerly Sinomenium diversifolius Diels, one type of Fang-chi (Chinese)) have been used as a folk remedy for neuralgia and rheumatoid arthritis in many areas of the Far East. In Japan and China various viny plants have been identified as Fang-chi (Boi in Japanese) since antiquity. This uncertain nomenclature has made it difficult to evaluate the efficacy of the Fang-chi described in the classic literature. Among traditional Fang-chi plants only Sinomeniumacutum has been demonstrated to contain the alkaloid sinomenine, which is now known to be effective in neuralgia and rheumatic diseases. Sinomenine is a unique plant alkaloid, as it potently releases histamine in association with degranulation of tissue mast cells in mammalian tissues. This action occurs preferentially in the skin and joint capsules. The released histamine is responsible for the dominant pharmacological actions of sinomenine, such as vasodilatation, increased vascular permeability, acceleration of the thoracic and peripheral lymph flow, contraction of plain muscles, increased peristalsis of the intestines, and stimulation of gastric acid secretion. At toxic doses of sinomenine, convulsive central excitation was observed in most laboratory animals. Clinical side effects encountered with high doses of injected sinomenine or of decocted Sinomenium acutum were: injection site flare, pruritus in the head and upper part of the body, edema around the lips and eyelids, and temporary cephalalgia. Most of these side effects were reduced by classical antihistamines (H1-receptor antagonists). Daily subcutaneous injections of sinomenine for more than one week produced an analgesic effect in mice. Granulation tissue growth and adjuvant arthritis induced in rats were both inhibited by daily injections of a small dose of sinomenine hydrochloride or histamine dihydrochloride. These inhibitory effects were mediated through histamine H2-receptors probably on fibroblasts (for granulation tissue growth) and on T-cells (for adjuvant arthritis), since these effects were clearly inhibited by the H2-antagonist burimamide but not by the H1-antagonist mepyramine. The anti-rheumatic effect on Sinomenium acutum are probably genuine and can probably be attributed to the histamine-releasing properties of sinomenine.