Factors affecting discrepancies in disease activity evaluation between patients and physicians in systemic lupus erythematosus-The importance of symptoms such as fatigue.

OBJECTIVES: There are often discrepancies in the evaluation of disease activity between patients and physicians in systemic lupus erythematosus (SLE). In this study, we examined the factors that affect those evaluations. METHODS: Physician visual analogue scale (Ph-VAS), patient VAS (Pt-VAS), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k), glucocorticoid (GC) usage and dose, age, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and three patient-reported outcomes (SLE symptom checklist [SSC], short-form 36 questionnaire [SF-36], and LupusPRO) were obtained from a study performed in 2019 using 225 SLE outpatients of the Kyoto Lupus Cohort at Kyoto University Hospital. Correlations among Ph-VAS, Pt-VAS, or dif (Pt-VAS-Ph-VAS) (Pt-VAS minus Ph-VAS) and other factors were examined. RESULTS: We found a significant discrepancy between Pt-VAS (median 38.0 mm) and Ph-VAS (median 18.7 mm) scores (p < 0.001). SSC score showed a significant correlation with Pt-VAS and dif (Pt-VAS-Ph-VAS) (p < 0.001). Among SSC items, fatigue showed the most significant correlation with dif (Pt-VAS-Ph-VAS). We also showed that higher dif (Pt-VAS-Ph-VAS) was associated with lower quality of life (QOL) evaluated by SF-36 and LupusPRO. CONCLUSIONS: Pt-VAS scores tended to be higher than Ph-VAS scores, and the discrepancy was influenced mainly by fatigue. Higher dif (Pt-VAS-Ph-VAS) was associated with lower patient QOL.

Subjective symptoms are triggers for the detection of immune checkpoint inhibitor-induced interstitial lung disease and associate with disease severity: a single-center retrospective study.

BACKGROUND: Interstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody. METHODS: This was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The "Subjective symptoms" group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the "Routine examinations" group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined. RESULTS: Of 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the "Subjective symptoms" group. The "Subjective symptoms" group exhibited a significantly higher proportion of Grade 3-5 ICI-ILD cases than the "Routine examinations" group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms. CONCLUSION: Subjective symptoms triggered the suspicion of Grade 3-5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice.

A Case of Vesiculobullous Dermatomyositis with Anti-NXP-2 Antibody without Malignancy.

Vesiculobullous dermatomyositis (VD) is a rare manifestation of dermatomyositis (DM) and has been suggested to be associated with malignancy. Although the myositis-specific autoantibodies are associated with distinct clinical presentations of DM, those associated with VD remain unclear. Here, we present the case of a 54-year-old man with VD who tested positive for anti-nuclear matrix protein 2 (NXP-2) antibody, one of the DM-specific autoantibodies. Serological and histopathological findings did not support autoimmune blistering disease. Physical and histological findings suggested that the severe edema in combination with the interface dermatitis of DM contributed to blister formation. Although a systemic examination was performed, no evidence of malignancy was found. Following initiation of immunosuppressive therapy, the patient showed significant improvement in both skin lesions and myositis. This case represents the first report of anti-NXP-2-positive VD without malignancy or autoimmune blistering disease. Subcutaneous edema, a characteristic feature of anti-NXP-2-positive DM, could be related to the formation of VD.

Effects of IL-6, JAK, TNF inhibitors, and CTLA4-Ig on knee symptoms in patients with rheumatoid arthritis.

This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study.

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45-60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09-0.61), IL-6Ri: 0.34 (0.14-0.81), CTLA-4-Ig: 0.36 (0.15-0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Predictive factors and treatment outcomes associated with difficult-to-treat rheumatoid arthritis conditions: the ANSWER cohort study.

OBJECTIVES: To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biologic DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi). METHODS: Retrospective analysis was conducted on data from the ANSWER cohort comprising 3623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. RESULTS: Of the 3623 RA patients, 450 (12.4%) met the first two criteria of the EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared with those under 65, hazard ratio [HR] = 0.46; 95% CI: 0.31, 0.69), higher rheumatoid factor (RF) titres (HR = 1.005; 95% CI: 1.00, 1.01), higher clinical disease activity index (HR = 1.02; 95% CI: 1.01, 1.03), lower methotrexate dosage (HR = 0.97; 95% CI: 0.95, 0.99), and comorbidities like hypertension (HR = 1.53; 95% CI: 1.2, 1.95) and diabetes (HR = 1.37; 95% CI: 1.09, 1.73). Anti-IL-6 receptor antibodies (aIL-6R, HR = 0.53; 95% CI: 0.37, 0.75) and JAKi (HR = 0.64; 95% CI: 0.46, 0.90) were associated with fewer discontinuations due to ineffectiveness compared with TNF inhibitors. Oral glucocorticoid usage (HR = 1.65; 95% CI: 1.11, 2.47) was linked to increased discontinuation due to toxic adverse events. CONCLUSION: Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention.

Active Rheumatoid Arthritis and Scoliosis: A Mid-Term Cohort Study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To elucidate the factors related to progression of scoliosis in patients with rheumatoid arthritis (RA) using longitudinal cohort data. SUMMARY OF BACKGROUND DATA: Thirty percent of patients with RA have lumbar scoliosis. However, the effectiveness of current treatment methods in preventing the progression of scoliosis is not well-understood due to a lack of longitudinal studies. METHODS: We enrolled 180 patients with RA who were followed up for over two years, all of whom underwent standing spinal X-rays. These patients were categorized based on their disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR) into two groups: those in remission (n=76) and those in non-remission (n=104). We evaluated various radiographic measures, including C7 center sacral vertical line (C7-CSVL), pelvic obliquity, major Cobb angle, and curve location. RESULTS: Fifty-three (29.4%) patients presented progression of scoliosis during a mean follow-up period of 4.8 years. Patients in the non-remission showed larger Cobb angle at baseline and final follow-up, compared to those in remission. The annual progression rate of the curve was also greater in the non-remission group (1.04 degree /year), than in the remission group (0.59 degree /year, P=0.001). There was no difference in the incidence of new vertebral fractures. The presence of a baseline cobb angle of 10 degree or more (OR: 3.14; 95% CI: 1.38-7.13; P=0.006), glucocorticoid use (OR: 2.88; 95% CI: 1.18-7.06; P=0.021), and non-remission at baseline (OR: 2.83; 95% CI: 1.25-6.41; P=0.012) were significant risk factors for progression of scoliosis. CONCLUSION: RA disease activity is linked to progression of scoliosis in patients with RA. Patients with RA who present with an initial scoliosis of 10 degrees or greater, require glucocorticoids for treatment and are in non-remission at baseline may be at high risk for scoliosis progression.

Low Hounsfield unit values on computed tomography as a potential predictor of vertebral fracture in patients with rheumatoid arthritis: The KURAMA cohort study.

OBJECTIVE: Hounsfield units (HU) measured using computed tomography (CT) have gained considerable attention for the detection of osteoporosis. This study aimed to investigate whether opportunistic CT could predict vertebral fractures in patients with rheumatoid arthritis (RA). METHODS: A total of 233 patients with RA who underwent chest CT were included in this study. The HU values of the anterior 1/3 of the vertebral bodies based on the sagittal plane at T11-L2 after reconstruction were measured. The incidence of vertebral fractures was investigated with respect to the HU value. RESULTS: Vertebral fractures were identified in 32 patients during a mean follow-up period of 3.8 years. In patients who experienced vertebral fractures within 2 years of CT imaging, the HU values of the vertebral bodies (T11-L2) were lower than those in patients who did not experience fractures. Receiver operating characteristic curve analysis identified that a T11 HU value of <125 was a risk factor for vertebral fracture within 2 years. Multivariate analysis showed that a T11 HU value of <125 and the existence of prevalent vertebral fractures were significant risk factors for fracture. CONCLUSION: HU measurements of the anterior 1/3 of the vertebral body are a potential predictor for vertebral fractures in patients with RA.

Effect of high disease activity on spinal sagittal malalignment in patients with rheumatoid arthritis.

OBJECTIVE: Atlantoaxial subluxation is a well-known serious complication encountered in patients with rheumatoid arthritis (RA). However, it is unknown whether RA affects global spinal alignment. The aim of this study was to investigate whether high disease activity in patients with RA exacerbates spinal sagittal malalignment. METHODS: The authors included 197 patients with RA who were followed up for > 2 years; standing spinal radiographs were obtained in all patients. Patients were divided into persistent moderate disease activity/high disease activity (pMDA/HDA; n = 64) and non-pMDA/HDA (n = 133) groups based on the disease activity at follow-up visits. Radiographic parameters assessed included pelvic incidence, pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis (TK), and C7 sagittal vertical axis (SVA). RESULTS: Over an average 5-year follow-up, increases in SVA, PT, and TK and a decrease in LL were observed. The pMDA/HDA group had a larger increase in PT and a higher incidence of vertebral fractures than the non-pMDA/HDA group. After adjusting variables using propensity score matching, the authors still found a higher rate of increase in PT (0.79°/year vs 0.01°/year, p = 0.001) in the pMDA/HDA group than in the non-pMDA/HDA group. This trend remained consistent even when patients who developed vertebral fractures were excluded. CONCLUSIONS: Spinal sagittal alignment deteriorates over time in patients with RA. High disease activity in RA exacerbates spinal deformity.

Association of large joint involvement at the start of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors with disease activity and drug retention in patients with rheumatoid arthritis: The ANSWER cohort study.

AIM: To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease-modifying antirheumatic drug or Janus kinase inhibitor. METHODS: Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics. RESULTS: Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], p < .001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti-citrullinated peptide antibodies, and interleukin-6 receptor inhibitor (IL-6Ri) use. CONCLUSION: Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6Ri may be beneficial for patients with LJI.

Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort.

OBJECTIVES: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. METHODS: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy-ETN reference product (ETN-RP) or LBEC0101-between 2015 and 2021. Serum ETN levels were measured using liquid chromatography-tandem mass spectrometry. RESULTS: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. CONCLUSIONS: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

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

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

Monocyte-derived transcriptomes explain the ineffectiveness of abatacept in rheumatoid arthritis.

BACKGROUND: The biological mechanisms underlying the differential response to abatacept in patients with rheumatoid arthritis (RA) are unknown. Here, we aimed to identify cellular, transcriptomic, and proteomic features that predict resistance to abatacept in patients with RA. METHODS: Blood samples were collected from 22 RA patients treated with abatacept at baseline and after 3 months of treatment. Response to treatment was defined by the European League Against Rheumatism (EULAR) response criteria at 3 months, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels by RNA sequencing, 67 plasma protein levels, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry. In addition, three gene expression data sets, comprising a total of 27 responders and 50 non-responders, were used to replicate the results. RESULTS: Among the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment. Cell type enrichment analysis showed that differentially expressed genes (DEGs) between responders and non-responders were enriched in monocytes. Gene set enrichment analysis, together with single-cell analysis and deconvolution analysis, identified that Toll-like receptor 5 (TLR5) and interleukin-17 receptor A (IL17RA) pathway in monocytes was upregulated in non-responders. Hepatocyte growth factor (HGF) correlated with this signature showed higher concentrations in non-responders before treatment. The DEGs in the replication set were also enriched for the genes expressed in monocytes, not for the TLR5 and IL17RA pathway but for the oxidative phosphorylation (OXPHOS) pathway. CONCLUSIONS: Monocyte-derived transcriptomic features before treatment underlie the differences in abatacept efficacy in patients with RA. The pathway activated in monocytes was the TLR5 and IL17RA-HGF signature in the current study, while it was the OXPHOS pathway in the replication set. Elevated levels of HGF before treatment may serve as a potential biomarker for predicting poor responses to abatacept. These findings provide insights into the biological mechanisms of abatacept resistance, contributing valuable evidence for stratifying patients with RA.

Management and treatment outcomes of rheumatoid arthritis in the era of biologic and targeted synthetic therapies: evaluation of 10-year data from the KURAMA cohort.

BACKGROUND: Advances in rheumatoid arthritis (RA) treatment, highlighted by biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), have altered the paradigm of RA treatment in the last decade. Therefore, real-world clinical evidence is needed to understand how treatment strategies and outcomes have changed. METHODS: Using an observational cohort of RA from 2012 to 2021, we collected cross-sectional data of RA patients annually to analyze a trend in RA management. For patients who initiated b/tsDMRDs, we evaluated treatment outcomes between b/tsDMARDs. Mixed-effect models were applied to examine the statistical implications of changes over time in treatment outcomes with a background adjustment. RESULTS: We analyzed annual cross-sectional data from 5070 patients and longitudinal data from 1816 patients in whom b/tsDMARDs were initiated between 2012 and 2021. b/tsDMARD use increased, whereas glucocorticoid use decreased from 2012 to 2021. Disease activity and functional disability measures improved over time. The percentage of tsDMARD prescriptions considerably increased. All b/tsDMARDs showed clinical improvements in disease activity and functional disability. Statistically, TNFi showed better short-term improvements in b/tsDMARD-naïve patients, while IL6Ri demonstrated significant long-term benefits. IL6Ri had better retention rates in switched patients. After adjustment for patient characteristics, the annual change of RA disease activity and functional disability fared significantly better from 2012 to 2021. CONCLUSIONS: With the development of new RA therapeutics, overall treatment outcomes advanced in the past decade.

Predictive value of baseline concomitant glucocorticoid for abatacept-mediated long-term inhibition of radiographic progression: insights from the KURAMA cohort.

Abatacept (ABT) is a biological disease-modifying antirheumatic drug (bDMARDs) for rheumatoid arthritis (RA) when conventional synthetic DMARDs are ineffective. We aimed to evaluate the long-term effects of ABT on joint destruction in patients treated for over 2 years. Radiographic progression was evaluated using the van der Heijde-modified Total Sharp Score (mTSS) by two rheumatologists at ABT initiation and after 2 years. Multivariate logistic regression analysis was used to identify factors associated with structural remission, defined as the mean annual change in mTSS ≤0.5. Among the 111 patients included, 48 discontinued, and 63 continued ABT treatment until radiographic evaluation was performed. The rate of patients who achieved estimated TSS REM (yearly progression of van der Heijde modified total Sharp scores ≤0.5) was significantly lower in ABT-dropouts than in the ABT-continued group (69% vs. 48%, p = .0336 by Fisher's exact test). Among the continued ABT cases, concomitant glucocorticoid treatment at ABT initiation was the strongest negative predictive factor of estimated TSS REM in univariate and multivariate logistic regression analyses. Radiographic progression after ABT administration should be evaluated separately for dropout and non-dropout cases. Glucocorticoids at the initiation of ABT may serve as a predictive factor for joint destruction in long-term ABT use.

Pathogenicity of IgG-Fc desialylation and its association with Th17 cells in an animal model of systemic lupus erythematosus.

OBJECTIVES: Decreased sialylation of IgG-Fc glycans has been reported in autoimmune diseases, but its role in systemic lupus erythematosus (SLE) is not fully understood. In this study, we examined the pathogenicity of IgG desialylation and its association with Th17 in SLE using an animal model. METHODS: B6SKG mice, which develop lupus-like systemic autoimmunity due to the ZAP70 mutation, were used to investigate the pathogenicity of IgG desialylation. The proportion of sialylated IgG was compared between B6SKG and wild-type mice with or without ß-glucan treatment-induced Th17 expansion. Anti-interleukin (IL)-23 and anti-IL-17 antibodies were used to examine the role of Th17 cells in IgG glycosylation. Activation-induced cytidine deaminase-specific St6gal1 conditionally knockout (cKO) mice were generated to examine the direct effect of IgG desialylation. RESULTS: The proportions of sialylated IgG were similar between B6SKG and wild-type mice in the steady state. However, IgG desialylation was observed after ß-glucan-induced Th17 expansion, and nephropathy also worsened in B6SKG mice. Anti-IL-23/17 treatment suppressed IgG desialylation and nephropathy. Glomerular atrophy was observed in the cKO mice, suggesting that IgG desialylation is directly involved in disease exacerbation. CONCLUSIONS: IgG desialylation contributes to the progression of nephropathy, which is ameliorated by blocking IL-17A or IL-23 in an SLE mouse model.

IL-6 inhibitors and JAK inhibitors as favourable treatment options for patients with anaemia and rheumatoid arthritis: ANSWER cohort study.

OBJECTIVES: Anaemia, a common comorbidity of RA, is related to high disease activity and poor prognosis. It is unknown which biologic/targeted synthetic (b/ts)-DMARDs are optimal for patients with anaemia and RA in regulating anaemia and controlling disease activity. METHODS: We investigated the change in haemoglobin (Hb) levels, drug retention rates and disease activities after the administration of b/ts-DMARDs with different modes of action [TNF inhibitors (TNFis), immunoglobulin fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis)] in patients with RA stratified by baseline Hb levels using the multicentre observational registry for patients with RA in Japan (ANSWER cohort). RESULTS: A total of 2093 patients with RA were classified into three groups based on tertiles of the baseline Hb levels (Hblow, anaemic; Hbint, intermediate; Hbhigh, non-anaemic). IL-6Ri increased Hb levels in all groups (the mean change at 12 months in Hblow was +1.5 g/dl, Hbint +0.7 g/dl and Hbhigh +0.1 g/dl). JAKis increased the Hb level in patients with anaemia and RA and retained or decreased the Hb level in non-anaemic patients (the mean change at 12 months in Hblow was +0.6 g/dl, Hbint 0 g/dl and Hbhigh -0.3 g/dl). In patients with anaemia and RA, overall adjusted 3-year drug retention rates were higher in JAKi followed by IL-6Ri, CTLA4-Ig and TNFi (78.6%, 67.9%, 61.8% and 50.8%, respectively). Change of disease activity at 12 months was not different among different b/ts-DMARDs treatments. CONCLUSION: IL-6Ri and JAKi can effectively treat patients with anaemia and RA in a real-world setting.

A case of atypical IgG4-related disease presenting hypereosinophilia, polyneuropathy, and liver dysfunction.

Ig (immunoglobulin) G4-related disease (Ig4-RD) affects several organs, including salivary glands, lacrimal glands, pancreas, biliary ducts, and retroperitoneum. A 72-year-old woman was examined for hypereosinophilia, high levels of IgG4, polyneuropathy, liver dysfunction, enlargement of lymph nodes and lacrimal glands, and beaded dilation of the bile ducts. We diagnosed Ig4-RD based on biopsies of the lymph nodes, liver, and submandibular gland. The symptoms of the patient improved after glucocorticoid treatment. This was a novel and atypical case of Ig4-RD that was difficult to differentiate from other diseases, including eosinophilic granulomatosis with polyangiitis, idiopathic hypereosinophilic syndrome, and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes syndrome. This case report highlights the importance of biopsies in differentiating Ig4-RD.

Impact of methotrexate on humoral and cellular immune responses to SARS-CoV-2 mRNA vaccine in patients with rheumatoid arthritis.

The aim of this study was to longitudinally evaluate the undetermined impact of methotrexate (MTX) on the cumulative immunogenicity elicited by three doses of SARS-CoV-2 mRNA vaccination in patients with rheumatoid arthritis (RA). We prospectively evaluated vaccine-induced immune responses following the first dose, 1 and 6 months after the second dose, and 1 month after the third dose of BNT162b2 or mRNA-1273 in 144 SARS-CoV-2 naïve participants (70 patients with RA, 29 disease controls without immunosuppressive conditions, and 45 healthy controls). Humoral immune responses were assessed by quantifying anti-spike IgG antibody titers and the capacity of circulating antibodies to neutralize the ancestral SARS-CoV-2 strain and the Alpha, Delta, and Omicron variants. Vaccine-induced T-cell responses were measured using an interferon-gamma release assay. At 1 and 6 months after the second dose, anti-spike titers were highest in healthy controls, followed by disease controls and patients with RA. Multivariate analyses revealed that MTX treatment was significantly associated with a decrease in anti-spike titers, neutralizing activity, and SARS-CoV-2-specific interferon-gamma levels. Furthermore, MTX dose per body weight was negatively correlated with these two indices of humoral immune response. The third vaccine dose boosted anti-spike titers, especially in patients receiving MTX, while sera from these patients neutralized the Omicron variant far less robustly than those from healthy controls. In conclusion, MTX attenuated immunogenicity following two doses of SARS-CoV-2 mRNA vaccine in patients with RA, particularly resulting in dose-dependent suppression of the humoral immune response. Furthermore, MTX deteriorated the neutralizing activity against the Omicron variant, even after the third immunization.