High-dimensional analysis of T-cell profiling variations following belimumab treatment in systemic lupus erythematosus.

OBJECTIVE: This study sought to elucidate the molecular impacts of belimumab (BEL) treatment on T-cell immune profiling in SLE. METHODS: We used mass cytometry with 25 marker panels for T-cell immune profiling in peripheral blood T cells (CD3+) from 22 patients with BEL-treated SLE and 20 controls with non-BEL-treated SLE. An unsupervised machine-learning clustering, FlowSOM, was used to identify 39 T-cell clusters (TCLs; TCL01-TCL39). TCLs (% of CD3+) showing significant (p<0.05) associations with BEL treatment (BEL-TCL) were selected by a linear mixed-effects model for comparing groups of time-series data. Furthermore, we analysed the association between BEL treatment and variations in regulatory T-cell (Treg) phenotypes, and the ratio of other T-cell subsets to Treg as secondary analysis. RESULTS: Clinical outcomes: BEL treatment was associated with a decrease in daily prednisolone use (coef=-0.1769, p=0.00074), and an increase in serum CH50 (coef=0.4653, p=0.003), C3 (coef=1.1047, p=0.00001) and C4 (coef=0.2990, p=0.00157) levels. Molecular effects: five distinct BEL-TCLs (TCL 04, 07, 11, 12 and 27) were identified. Among these, BEL-treated patients exhibited increased proportions in the Treg-like cluster TCL11 (coef=0.404, p=0.037) and two naïve TCLs (TCL04 and TCL07). TCL27 showed increased levels (coef=0.222, p=0.037) inversely correlating with baseline C3 levels. Secondary analyses revealed associations between BEL treatment and an increase in Tregs (coef=1.749, p=0.0044), elevated proportions of the fraction of Tregs with inhibitory function (fTregs, coef=0.7294, p=0.0178) and changes in peripheral helper T cells/fTreg (coef=-4.475, p=0.0319) and T helper 17/fTreg ratios (coef=-6.7868, p=0.0327). Additionally, BEL was linked to variations in T-cell immunoglobulin and mucin domain-containing protein-3 expression (coef=0.2422, p=0.039). CONCLUSIONS: The study suggests an association between BEL treatment and variations in T cells, particularly Tregs, in SLE pathologies involving various immune cells.

Efficacy of denosumab on bisphosphonate-treated osteoporosis and osteopenia in systemic rheumatic disease patients receiving glucocorticoids.

INTRODUCTION: Evidence on second-line agents for osteoporosis and osteopenia associated with glucocorticoid use after first-line bisphosphonate therapy is limited. We, therefore, examine the efficacy of denosumab on bisphosphonate-treated osteoporosis and osteopenia in Japanese systemic rheumatic disease (SRD) patients receiving glucocorticoids. MATERIALS AND METHODS: Glucocorticoid-treated SRD patients with a pre-existing fragility fracture, either lumbar spine (LS) or femoral neck (FN) bone mineral density (BMD) T-score of ≤ -2.5 or of ≤ -1.5 without a significant increase in BMD in the past year despite oral bisphosphonate therapy were enrolled in this study. They were randomized to switch to 60 mg subcutaneous denosumab every six months (switching group) or to continue the bisphosphonate (continuing group). The primary endpoint was the percent change from baseline in BMD at the LS and FN at week 52. RESULTS: Of the 39 subjects, 19 were assigned to the switching group and 20 to the continuing group. The switching group showed significant increases in LS BMD (5.7% vs. 1.1%, p = 0.002) and FN BMD (4.2% vs. -0.3%, p = 0.008) at week 52 than the continuing group, with a significant decrease in serum tartrate-resistant acid phosphatase 5b (-28.1% vs. 7.0%, p < 0.001) and improved patient satisfaction. CONCLUSION: Switching to denosumab demonstrated greater efficacy than continuing bisphosphonates in increasing BMD, inhibiting osteoclast activation, and enhancing patient satisfaction in Japanese bisphosphonate-treated osteoporosis and osteopenia patients with concomitant SRD receiving glucocorticoids.

Impact of dysphagia and its severity on long-term survival and swallowing function outcomes in patients with idiopathic inflammatory myopathies other than inclusion body myositis.

OBJECTIVE: To investigate the impact of dysphagia on long-term survival and swallowing function outcomes in patients with idiopathic inflammatory myopathy other than inclusion body myositis. METHODS: We retrospectively evaluated consecutive patients with idiopathic inflammatory myopathy other than inclusion body myositis to investigate the impact of dysphagia and its severity assessed using the Food Intake LEVEL Scale on survival and swallowing function outcomes. Time-to-event analyses were used, including Kaplan-Meier curves with log-rank (trend) test, cumulative incidence with Gray's test, and Cox proportional hazards models. RESULTS: Of the 254 patients, 26 were dysphagic, including eight severe (Food Intake LEVEL Scale [FILS] score 2, 3) and six most severe (FILS score 1) cases; 210 were non-dysphagic, and 18 were indeterminate cases. During the 5 years after myositis diagnosis, 15 (57.7%) dysphagic and 31 (14.8%) non-dysphagic patients died, and dysphagic patients had significantly shorter survival. However, multivariate analysis showed that shorter survival was significantly associated with baseline age-adjusted Charlson Comorbidity Index (hazard ratio [HR] 1.57, 95% confidence interval [CI] 1.36-1.82]), but not with dysphagia (HR 1.46, 95% CI 0.69-3.10). Dysphagia severity was significantly associated with delayed recovery of dysphagia. In 20 non-severe or severe dysphagic cases, 19 restored swallowing function within 1 year. The most severe cases had a significantly higher cumulative probability of death before recovery from dysphagia than severe cases. CONCLUSION: The poor survival of dysphagic myositis patients was largely confounded by advanced age and comorbid malignancies. However, patients with the most severe dysphagia had a significantly worse swallowing function and survival prognosis than those with milder dysphagia.

Baseline clinical features predicting macrophage activation syndrome in patients with systemic adult-onset Still's disease receiving interleukin-6 inhibitor treatment.

AIM: Macrophage activation syndrome (MAS), a severe complication of systemic adult-onset Still's disease (AOSD), has been reported to occur during interleukin-6 (IL-6) inhibitor treatment. However, predictors for MAS development are unknown. Therefore, this study investigated predictive features for MAS development after starting IL-6 inhibitor treatment in systemic AOSD patients. METHOD: In a single-center retrospective study involving systemic AOSD patients who were refractory to high-dose glucocorticoids with immunosuppressants and started IL-6 inhibitor treatment between April 2008 and March 2020, we compared the baseline clinical features between patients who developed AOSD flare with MAS features (MAS group) and those who did not (non-MAS group) during IL-6 inhibitor treatment. RESULTS: Only tocilizumab was used as an IL-6 inhibitor. Six of 14 refractory systemic AOSD patients developed AOSD flares with MAS features during tocilizumab treatment, including 4 who developed them shortly after initiation. The MAS group had significantly lower neutrophil counts, fibrinogen, and higher IL-18/C-reactive protein (CRP) ratio at starting tocilizumab (baseline) than the non-MAS group. Before starting tocilizumab, neutrophil counts were trending downward and upward in the MAS and non-MAS groups, respectively, with significant differences in changes. Receiver operating characteristic analysis showed that baseline neutrophil counts and fibrinogen and their changes before tocilizumab treatment and baseline IL-18/CRP ratio had significant discriminatory abilities for subsequent MAS development. CONCLUSION: We identified baseline laboratory features associated with MAS development after initiating an IL-6 inhibitor in refractory systemic AOSD patients. These features may reflect the suppression of IL-6 signaling, and further suppression of IL-6 signaling might trigger early-onset MAS.

Improvement of Chronic Rhinosinusitis and Reduction of the Myeloperoxidase-Antineutrophil Cytoplasmic Antibody Titer in a Patient with Eosinophilic Granulomatosis with Polyangiitis by Additional Mepolizumab.

A case of eosinophilic granulomatosis with polyangiitis (EGPA) in which chronic rhinosinusitis (CRS) was improved with a reduction in the myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) titer after the addition of mepolizumab is reported. A 55-year-old woman with EGPA receiving prednisolone 5 mg/day developed CRS with increases in the eosinophil count and the MPO-ANCA titer. Although it improved with prednisolone 15 mg/day in addition to mizoribine 150 mg/day, because azathioprine could not be taken orally due to side effects, it relapsed after prednisolone was tapered to 5 mg/day. There was no exacerbation of other vasculitis symptoms such as mononeuropathy multiplex. The patient was treated with additional mepolizumab 300 mg every 4 weeks, which resulted in the improvement of CRS and marked reductions of the eosinophil count and MPO-ANCA titer, and the reduction of prednisolone to 2 mg/day. Furthermore, even after tapering mepolizumab to 200 mg every 4 weeks, her condition remained stable without relapse of EGPA and without increases in the eosinophil count and MPO-ANCA titer. The clinical course of mepolizumab treatment in this patient suggests that the IL5-dependent inflammatory cascade is one of the factors contributing to the increase in MPO-ANCA in EGPA.

Circulating Th17.1 cells as candidate for the prediction of therapeutic response to abatacept in patients with rheumatoid arthritis: An exploratory research.

T-helper (Th)17.1 cells exhibit high pathogenicity in inflammatory diseases. This study aimed to identify the changes in the proportions of Th subsets, including Th17.1, which are associated with abatacept treatment response in Japanese patients with rheumatoid arthritis. On the basis of the results, we assessed whether Th17.1 is a potential cellular biomarker. Multicolor flow cytometry was used to determine the circulating Th subsets among CD4+ T lymphocytes in 40 patients with rheumatoid arthritis before abatacept treatment. All the patients received abatacept treatment for 24 weeks; changes in disease activity score, including 28-joint count C-reactive protein, and responsiveness indicated by other indices to abatacept treatment were evaluated according the European League Against Rheumatism criteria (good and moderate responders and nonresponders). The correlation between the abatacept responses and the proportions of Th subsets (baseline) was analyzed. Logistic regression analysis with inverse probability weighting method was performed to calculate the odds ratio adjusted for patient characteristics. The proportion of baseline Th17.1 cells was significantly lower in patients categorized as good responders than in those categorized as non-good responders (moderate responders and nonresponders; p = 0.0064). The decrease in 28-joint count C-reactive protein after 24 weeks of abatacept therapy showed a significant negative correlation with the proportion of Th17.1 cells. The adjusted odds ratio for achieving good response in patients with baseline Th17.1 levels below the median value was 14.6 (95% confidence interval, 2.9-72.3; p = 0.0021) relative to that in the remaining patients. The proportion of Th17.1 cells at baseline is a good candidate for predicting abatacept treatment response in Japanese patients. These novel findings may represent a significant step in the pursuit of precision medicine.

Effectiveness and safety of lower dose sulfamethoxazole/trimethoprim therapy for Pneumocystis jirovecii pneumonia in patients with systemic rheumatic diseases: A retrospective multicenter study.

OBJECTIVES: To evaluate the effectiveness and safety of lower-dose sulfamethoxazole/trimethoprim therapy (SMX/TMP) for Pneumocystis jirovecii pneumonia (PCP) in patients with systemic rheumatic diseases. METHODS: In this multicenter retrospective study, we compared effectiveness and safety of SMX/TMP for the treatment of PCP among patients divided into three groups according to the initial dosage of SMX/TMP: the low, ≤10 mg/kg/day; the intermediate, 10-15 mg/kg/day; and the high and conventional, 15-20 mg/kg/day for TMP dose. RESULTS: Eighty-one patients, including 22, 30, and 29 patients in the low-, the intermediate- and the high-dose group could be analyzed and the 30-day survival rate were 100%, 93.3%, and 96.7%, respectively (P = 0.28). There were significant dose-dependent increasing trends of severe adverse drug reactions (ADRs) for SMX/TMP that were graded as ≥3 according to the Common Terminology Criteria for Adverse Events. When stratified by presence of severe hypoxemia defined by alveolar-arterial O2 gradient ≥45 mmHg, the 30-day survival and treatment modification rate were similar among the three groups, but frequency of severe ADRs were significantly decreased in the low-dose group. The low-dose group was independently and negatively associated with treatment modification within 14 days and severe ADRs. CONCLUSIONS: Lower dose SMX/TMP therapy with ≤10 mg/kg/day for TMP was as effective as higher dose therapy for the treatment of PCP and associated with lower rates of treatment modification and severe ADRs in patients with systemic rheumatic diseases.

Patient satisfaction and efficacy of switching from weekly bisphosphonates to monthly minodronate for treatment and prevention of glucocorticoid-induced osteoporosis in Japanese patients with systemic rheumatic diseases: a randomized, clinical trial.

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.