Two Cases of Painful Thyroiditis With Subsequent Hypothyroidism Following Cord Blood Transplant.

We report two rare cases of painful thyroiditis approximately 100 days after unrelated cord blood transplantation (CBT), which progressed to hypothyroidism. Patient one, a 45-year-old woman, developed goiter, tenderness, and thyrotoxicity on day 100 after CBT for relapsed acute lymphocytic leukemia. Scintigraphy suggested destructive thyroiditis; symptoms improved with one-month beta-blocker and prednisolone treatment. Two months later, hypothyroidism developed which required supplementation-based treatment. Patient two, a 49-year-old man, developed goiter, tenderness, and thyrotoxicosis on day 96 after CBT for acute myelogenous leukemia. Hypothyroidism developed after nonsteroidal anti-inflammatory drug treatment. Thyroiditis and hypothyroidism should be considered in patients who develop neck pain after CBT.

Vitamin D efficacy in type 1 and type 2 diabetes.

It is well known that vitamin D has a profound effect on calcium and bone metabolism, but its influence on other organs (extraskeletal effect) has been proposed. Consistently, vitamin D deficiency is associated with an increased incidence of various diseases, including type 1 and type 2 diabetes, as reported by many observational studies. However, there has been no consensus on whether vitamin D deficiency is a causative factor in the incidence of diabetes mellitus. There have been no randomized controlled trials (RCTs) aimed at preventing the onset of type 1 diabetes with vitamin D intake. In addition, the results of RCTs evaluating the preventive effect of vitamin D supplementation on type 2 diabetes development have been inconsistent. The recent observational studies, randomized controlled trials, and meta-analyses are confirming that vitamin D or active vitamin D administration is effective in preventing the incident of type 1 and type 2 diabetes.

A Machine Learning Approach for Prediction of CDAI Remission with TNF Inhibitors: A Concept of Precision Medicine from the FIRST Registry.

INTRODUCTION: This study aimed to develop low-cost models using machine learning approaches predicting the achievement of Clinical Disease Activity Index (CDAI) remission 6 months after initiation of tumor necrosis factor inhibitors (TNFi) as primary biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatoid arthritis (RA). METHODS: Data of patients with RA initiating TNFi as first b/tsDMARD after unsuccessful methotrexate treatment were collected from the FIRST registry (August 2003 to October 2022). Baseline characteristics and 6-month CDAI were collected. The analysis used various machine learning approaches including logistic regression with stepwise variable selection, decision tree, support vector machine, and lasso logistic regression (Lasso), with 48 factors accessible in routine clinical practice for the prediction model. Robustness was ensured by k-fold cross validation. RESULTS: Among the approaches tested, Lasso showed the advantages in predicting CDAI remission: with a mean area under the curve 0.704, sensitivity 61.7%, and specificity 69.9%. Predicted TNFi responders achieved CDAI remission at an average rate of 53.2%, while only 26.4% of predicted TNFi non-responders achieved remission. Encouragingly, the models generated relied solely on patient-reported outcomes and quantitative parameters, excluding subjective physician input. CONCLUSIONS: While external cohort validation is warranted for broader applicability, this study highlights the potential for a low-cost predictive model to predict CDAI remission following TNFi treatment. The approach of the study using only baseline data and 6-month CDAI measures, suggests the feasibility of establishing regional cohorts to generate low-cost models tailored to specific regions or institutions. This may facilitate the application of regional/in-house precision medicine strategies in RA management.

This study aims to enhance the management of rheumatoid arthritis by predicting the likelihood of achieving the treatment target­Clinical Disease Activity Index remission within 6 months of initiating tumor necrosis factor inhibitors. In rheumatoid arthritis, the goal is often Clinical Disease Activity Index remission, and the standard approach involves using medications like methotrexate and biologic/targeted synthetic disease-modifying antirheumatic drugs. However, not all patients respond to these treatments, leading to a trial-and-error process of changing medications. Tumor necrosis factor inhibitors are commonly used as the initial biologic/targeted synthetic disease-modifying antirheumatic drugs for patients who do not respond adequately to methotrexate; however, tumor necrosis factor inhibitor treatment may not achieve effective outcomes for all patients. The study, using a cohort of patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor, has developed a model predicting Clinical Disease Activity Index remission with tumor necrosis factor inhibitors. The models use only standard clinical parameters, therefore no special examination or additional cost is required for the predictions. This approach holds the potential to improve rheumatoid arthritis management by reducing the need for trial-and-error approaches and facilitating more personalized and effective treatment strategies. While further validation is necessary, the study also suggests that creating cost-effective models tailored to specific regions or institutions is possible.

Coalition for Health and Gender Equity (CHANGE)-a protocol for a global cross-sectional survey of health and gender equity in rheumatology.

Objectives: The primary aim of the CHANGE survey is to determine the current state of gender equity within rheumatology, and secondarily, to review the physician perspective on bullying, harassment and equipoise of opportunities within rheumatology. Methods: The CHANGE e-survey is a cross-sectional self-reported questionnaire adapted from EULAR's gender equity in academic rheumatology task force. The survey was launched in January 2023; it is available in six languages and distributed widely via rheumatology organizations and social media. Eligible participants include rheumatologist physicians and rheumatology health-care professionals. Survey responses will undergo descriptive analysis and inter-group comparison aiming to explore gender-based discrimination using logistic regression, with subgroup analyses for country/continent variations. Conclusion: This e-survey represents a comprehensive global initiative led by an international consortium, aimed at exploring and investigating the gender-related disparities and obstacles encountered by rheumatologists and rheumatology health-care professionals across diverse communities and health-care environments. By pursuing this initiative, we aim to take the broader rheumatology community a step closer to understanding the underlying origins of inequities and their determinants. Such insights are pivotal in identifying viable interventions and strategies to foster gender equity within the field. Ultimately, our collective objective is to ensure equitable access to opportunities for every individual, irrespective of gender, thereby promoting inclusivity and fairness across the entire spectrum of professional practice and career development.

Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials.

INTRODUCTION: This integrated analysis of the phase 2/3 and phase 3 SELECT trials describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, for up to 5 years of exposure across psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) (including pooled axial spondyloarthritis [axSpA]). METHODS: Safety data from five trials of upadacitinib in PsA (2 trials), AS (2 trials), and nr-axSpA (1 trial) were analyzed up to a data cut-off of August 15, 2022. One PsA study included adalimumab as an active comparator. Treatment-emergent adverse events (TEAEs) were summarized for PsA (pooled upadacitinib 15 mg once daily and adalimumab 40 mg biweekly), AS (pooled upadacitinib 15 mg), nr-axSpA (upadacitinib 15 mg), and pooled axSpA (pooled upadacitinib 15 mg from axSpA trials). TEAEs were reported as exposure-adjusted event rates per 100 patient-years (E/100 PY). RESULTS: A total of 1789 patients (PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15 mg for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Overall TEAEs and serious TEAEs were highest in PsA and numerically higher with upadacitinib versus adalimumab; rates were similar between AS and nr-axSpA. In PsA, higher rates of serious infection, herpes zoster (HZ), lymphopenia, and nonmelanoma skin cancer (NMSC) were observed with upadacitinib versus adalimumab. Rates of malignancy excluding NMSC, adjudicated major adverse cardiovascular events, and adjudicated venous thromboembolic events were comparable between upadacitinib and adalimumab in PsA and were similar across diseases. CONCLUSION: Higher rates of serious infection, HZ, lymphopenia, and NMSC were observed with upadacitinib versus adalimumab in PsA; slightly elevated rates for most of these TEAEs were seen with upadacitinib in PsA versus axSpA. Upadacitinib 15 mg demonstrated a generally consistent safety profile across disease states with no new safety signals identified. TRIAL REGISTRATION: SELECT-AXIS 1: NCT03178487; SELECT-AXIS 2: NCT04169373; SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis are a group of diseases that cause pain and inflammation of the joints and/or spine. Safety data were combined from five studies: two in psoriatic arthritis, two in ankylosing spondylitis, and one in non-radiographic axial spondyloarthritis. Patients were treated with upadacitinib or adalimumab for up to 5 years. Adalimumab was only used for patients participating in one of the two psoriatic arthritis studies. Side effects from treatment were more common in patients with psoriatic arthritis than those with ankylosing spondylitis and non-radiographic axial spondyloarthritis; more patients with psoriatic arthritis had side effects with upadacitinib than adalimumab. A similar number of patients across treatment groups and diseases had side effects that made them stop treatment. The number of cancer cases (except cancer of the upper layer of the skin), cardiovascular issues, and blood clots were similar between the upadacitinib and adalimumab groups in psoriatic arthritis and across diseases. Serious infections, painful rashes that cause blisters (herpes zoster, also commonly referred to as shingles), low levels of white blood cells, and cancer of the upper layer of the skin were more common with upadacitinib than adalimumab in patients with psoriatic arthritis; overall, these events occurred more often with upadacitinib in patients with psoriatic arthritis than with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Our results showed that the safety of upadacitinib was generally similar across diseases, and patients could tolerate it well for up to 5 years. No new safety risks were found with upadacitinib treatment.

Inflammatory Cytokines and Chemokines Are Synergistically Induced in a ROS-Dependent Manner by a Co-Culture of Corneal Epithelial Cells and Neutrophil-like Cells in the Presence of Particulate Matter.

Ocular exposure to particulate matter (PM) causes local inflammation; however, the influence of neutrophils on PM-induced ocular inflammation is still not fully understood. In this study, we constructed a system to investigate the role of PM in ocular inflammation using a co-culture of human corneal epithelial cells (HCE-T) and differentiation-induced neutrophils (dHL-60). To investigate whether HCE-T directly endocytosed PM, we performed a holographic analysis, which showed the endocytosis of PM in HCE-T. The cytokines and chemokines produced by HCE-T were measured using an ELISA. HCE-T treated with PM produced IL-6 and IL-8, which were inhibited by N-Acetyl-L-cysteine (NAC), suggesting the involvement of ROS. Their co-culture with dHL-60 enhanced their production of IL-6, IL-8, and MCP-1. This suggests an inflammatory loop involving intraocular corneal epithelial cells and neutrophils. These cytokines and chemokines are mainly regulated by NF-κB. Therefore, this co-culture system was examined in the presence of an IKK inhibitor known to downregulate NF-κB activity. The IKK inhibitor dramatically suppressed the production of these factors in co-culture supernatants. The results suggest that the inflammatory loop observed in the co-culture is mediated through ROS and the transcription factor NF-κB. Thus, the co-culture system is considered a valuable tool for analyzing complex inflammations.

Development of quality indicators for pregnancy and childbirth in patients with systemic lupus erythematosus.

OBJECTIVES: A quality indicator for the treatment of systemic lupus erythematosus during pregnancy and childbirth that is useful for sharing standard treatment policies has not yet been developed. This study aimed to develop a quality indicator for systemic lupus erythematosus associated with pregnancy and childbirth. METHODS: To identify candidate quality indicators, we conducted a systematic literature review on the development of quality indicators for systemic lupus erythematosus related to pregnancy and childbirth and on clinical practice guidelines. Candidate quality indicator items were extracted from the final selected articles, and a first evaluation, panel meeting, and second evaluation were conducted to determine whether the candidate items were appropriate as quality indicators. Items for which all panel members reached a consensus were designated pregnancy and childbirth-related systemic lupus erythematosus quality indicators. RESULTS: Four articles on systemic lupus erythematosus-quality indicator development and 28 practice guidelines were listed through abstract/text screening. Based on these studies, 52 candidate quality indicators were extracted that were limited to items related to pregnancy and childbirth, and 41 items were selected on which all panel members agreed. CONCLUSION: We developed pregnancy-related systemic lupus erythematosus quality indicators using the RAND/UCLA method and selected 41 items, which could be used clinically.

Evolution of diagnostic criteria and new insights into clinical testing in mixed connective tissue disease; anti-survival motor neuron complex antibody as a novel marker of severity of the disease.

Mixed connective tissue disease (MCTD) is an autoimmune disorder characterized by a combination of clinical features from systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease, along with the presence of positive anti-U1-ribonucleoprotein (U1-RNP) antibodies. The exact etiology of the disease remains unclear, but it is believed to involve vascular damage within the context of heightened autoimmune responses. Consequently, Raynaud's phenomenon and pulmonary arterial hypertension are observed in patients with MCTD. While specific biomarkers for MCTD have not yet been identified, the recent study of the utility of anti-survival motor neuron complex (SMN) antibodies in MCTD suggests a promising avenue for further research and the accumulation of additional evidence.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Occupational Medicine, Go Above and Beyond.

The population of people in Japan over 65 years old is expected to exceed 30% by 2025. As the society ages, there are not only healthy workers and employers, but also an increasing number of diseased or injured workers. Falls, the most common occupational hazard, increase in incidence with age. The management of osteoporosis and prevention of bone fractures from falls are emerging in elderly female workers, to reduce the loss of work productivity. Rheumatoid arthritis is a representative musculoskeletal disease that causes functional decline because of joint damage mainly in working women, but appropriate treatment improves disease activity and work productivity in workers with rheumatoid arthritis. It is also important not only to digitize subjective information by converting it into digital form (digitization), but also to digitalize the physiological information related to health, labor and disease (digitalization). In the future, artificial intelligence (AI) will be able to analyze vast amounts of physiological information (big data) obtained from workers and patients via the Internet of things (IoT), which will improve the information value linked to health promotion and optimal treatment practices, and contribute to the Digital transformation (DX).

Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial.

BACKGROUND: Observational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 µg per day]) can reduce the development of sarcopenia among adults with prediabetes. METHODS: This randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394. FINDINGS: A total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8-3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups. INTERPRETATION: We found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls. FUNDING: Kitakyushu Medical Association. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

TYK2: an emerging therapeutic target in rheumatic disease.

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Phase II trials of deucravacitinib have also reported positive results in the treatment of psoriatic arthritis and systemic lupus erythematosus, with a preliminary safety profile that seems to differ from that of the JAK1, JAK2 and JAK3 inhibitors. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State In Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

Bimekizumab treatment in patients with active psoriatic arthritis and prior inadequate response to tumour necrosis factor inhibitors: 52-week safety and efficacy from the phase III BE COMPLETE study and its open-label extension BE VITAL.

OBJECTIVES: To assess 52-week safety and efficacy of bimekizumab in patients with active psoriatic arthritis (PsA) and prior inadequate response/intolerance to tumour necrosis factor inhibitors. METHODS: Patients completing the 16-week phase III double-blind, placebo-controlled BE COMPLETE (NCT03896581) study entered the open-label extension, BE VITAL (NCT04009499). All patients in BE VITAL received 160 mg bimekizumab every 4 weeks. Safety and efficacy are reported to week 52. RESULTS: A total of 347/400 (86.8%) patients completed week 52. To week 52, the exposure-adjusted incidence rate/100 patient-years for ≥1 treatment-emergent adverse event (TEAE) was 126.0, and was 7.0 for serious TEAEs. The most frequent TEAEs were SARS-CoV-2 (COVID-19), oral candidiasis, nasopharyngitis and urinary tract infection. All fungal infections were mild or moderate in severity and localised; two patients discontinued the study due to oral candidiasis. No cases of active tuberculosis, uveitis or inflammatory bowel disease were reported. One sudden death occurred. Sustained efficacy was observed with bimekizumab from week 16 to |52 across clinical and patient-reported outcomes. At week 52, 51.7% bimekizumab-randomised and 40.6% placebo/bimekizumab patients (receiving bimekizumab from week 16 to 52) had ≥50% improvement in the American College of Rheumatology criteria. Complete skin clearance (Psoriasis Area and Severity Index 100) was achieved by 65.9% bimekizumab and 60.2% placebo/bimekizumab patients at week 52. Minimal disease activity was achieved by 47.2% bimekizumab and 33.1% placebo/bimekizumab patients at week 52. CONCLUSIONS: Bimekizumab demonstrated a safety profile consistent with previous reports; no new safety signals were identified. Sustained efficacy was observed from week 16 to 52.

Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

Why does malaise/fatigue occur? Underlying mechanisms and potential relevance to treatments in rheumatoid arthritis.

INTRODUCTION: Fatigue and malaise are commonly associated with a wide range of medical conditions, including rheumatoid arthritis (RA). Evidence suggests that fatigue and malaise can be overwhelming for patients, yet these symptoms remain inadequately-managed, largely due to an incomplete elucidation of the underlying causes. AREAS COVERED: In this assessment of the published literature relating to the pathogenesis of fatigue or malaise in chronic conditions, four key mechanistic themes were identified. Each theme (inflammation, hypothalamic-pituitary-adrenal axis, dysautonomia, and monoamines) is discussed, as well as the complex network of interconnections between themes which suggests a key role for inflammatory cytokines in the development and persistence of fatigue. EXPERT OPINION: Fatigue is multifaceted, poorly defined, and imperfectly comprehended. Moreover, the cause and severity of fatigue may change over time, as a consequence of the natural disease course or pharmacologic treatment. This detailed synthesis of available evidence permits us to identify avenues for current treatment optimization and future research, to improve the management of fatigue and malaise in RA. Within the development pipeline, several new anti-inflammatory therapies are currently under investigation, and we anticipate that the next five years will herald much-needed progress to reduce the debilitating nature of fatigue in patients with RA.

A delayed diagnosis of fascioliasis: The importance of appropriate fecal diagnostic method.

Fascioliasis, a zoonotic helminthiasis, occurs sporadically in Japan. In this report, we describe a case of fascioliasis that was initially difficult to diagnose because the fecal examination method was negative for the Fasciola sp. eggs. A 64-year-old man living in Shimonoseki City, Japan, presented with fatigue and anorexia. Laboratory tests showed hepatic dysfunction and eosinophilia. Abdominal dynamic contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested intrahepatic biliary cysts. Thereafter, fever and night sweats persisted, and positron emission tomography and biopsy of the porta hepatis lymph node were performed on suspicion of malignancy. However, histopathological diagnosis found non-specific inflammation. As fascioliasis was suspected due to eosinophilia and the multiple hepatic masses, fecal egg examination was performed by an external private laboratory, which adopted the flotation method and reported the absence of parasite eggs. However, fecal examination was retried in our laboratory using the formalin-ether concentration method, and we detected Fasciola sp. eggs. This case suggests that misdiagnosis may occur depending on the fecal examination method; thus, it is necessary to choose a suitable method for certain parasite species.

Safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatments: An interim analysis of a post-marketing surveillance.

OBJECTIVES: An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment. METHODS: The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety. RESULTS: In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections. CONCLUSIONS: Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal.

Physician approval for pregnancy in patients with systemic lupus erythematosus showing only serological activity: A vignette survey study.

OBJECTIVE: The European League Against Rheumatism recommends that the disease activity of systemic lupus erythematosus should be stable before pregnancy because complications and disease flares increase if pregnancy occurs while disease activity is high. However, some patients have ongoing serological activity even after treatment. Herein, we investigated how physicians decide on the acceptability of pregnancy in patients showing only serological activity. METHODS: A questionnaire was administered from December 2020 to January 2021. It included the characteristics of physicians, facilities, and the allowance for pregnancies of patients using vignette scenarios. RESULTS: The questionnaire was distributed to 4946 physicians, and 9.4% responded. The median age of respondents was 46 years, and 85% were rheumatologists. Pregnancy allowance was significantly affected by the duration of the stable period and status of serological activity [duration: proportion difference 11.8 percentage points (p.p.), P < .001; mild activity: proportion difference -25.8 p.p., P < .001; high activity: proportion difference -65.6 p.p., P < .001]. For patients with high-level serological activity, 20.5% of physicians allowed pregnancy if there were no clinical symptoms for 6 months. CONCLUSIONS: Serological activity had a significant effect on the acceptability of pregnancy. However, some physicians allowed patients with serological activity alone to become pregnant. Further observational studies are required to clarify such prognoses.