Clinical and experimental rheumatology最新文献

Objectives: Anti-MDA5 autoantibodies are strongly associated with interstitial lung disease (ILD) and rapidly progressive ILD (RP-ILD) in Asian patients with dermatomyositis (DM) or amyopathic DM (ADM). However, this association has not yet been established in Brazilian patients with anti-MDA5(+) DM/ADM. This study aimed to investigate the phenotypic differences between Brazilian and Japanese patients with anti-MDA5(+) DM/ADM, with a particular focus on ILD.

Methods: This was an international, tricentric, retrospective cohort study conducted in one Brazilian and two Japanese tertiary centres. Patients diagnosed with anti-MDA5(+) DM/ADM at the three centres were enrolled. Clinical characteristics and outcomes were collected using a pre-standardised protocol and compared between Brazilian and Japanese patients.

Results: Thirty-four Brazilian and 65 Japanese patients were analysed. Brazilian patients were younger at the time of diagnosis than Japanese patients. The prevalence of muscle weakness, myalgia, dysphagia, heliotrope rash, V-sign, calcinosis, Raynaud's phenomenon, and digital ulcers was higher in Brazilian patients, whereas mechanic's hands were more prevalent in Japanese patients. The prevalence of ILD was significantly lower in Brazilian patients than in Japanese patients (50.0% vs. 98.5%, p<0.001). RP-ILD was observed in 34 (52.3%) Japanese patients and in only one (3.3%) Brazilian patient (p<0.001). Outcomes including overall survival and the frequency of relapses and complications, such as severe infection and malignancy, were comparable between the two populations.

Conclusions: Brazilian patients with anti-MDA5(+) DM/ADM had a higher prevalence of skin and muscle involvement, whereas the prevalence of ILD and RP-ILD was significantly lower than in Japanese patients.

Objectives: To investigate the intramuscular effects of arimoclomol using quantitative magnetic resonance imaging (qMRI) of the thighs in a subset of inclusion body myositis (IBM) participants from a multicentre, randomised, double-blind, placebo-controlled trial, and to further evaluate the utility of qMRI assessments as outcome measures.

Methods: Eighteen participants (10 placebo, 8 arimoclomol-treated) were recruited to undergo an MRI at baseline, 12 and 20 months. Spearman correlations between baseline clinical measures and qMRI measurements [fat fraction (FF), remaining muscle area (RMA), magnetisation transfer ratio (MTR), muscle water T2 (T2m) and fat fraction apparent (FFa)] were used to evaluate construct validity. A mixed model repeated measures (MMRM) strategy was employed to estimate mean changes, in order to determine treatment effects on qMRI biomarkers and evaluate responsiveness to disease progression over time. Longitudinal analyses examined Spearman correlations between changes in qMRI and changes in clinical assessments at the last available follow-up.

Results: Baseline FF, RMA, MTR and FFa of the thigh and quadriceps demonstrated strong construct validity. No significant treatment effects on the qMRI measures were detected. FF, RMA and FFa demonstrated strong responsiveness to disease progression (standardised response means>0.8, p<0.05) at 20 months. Longitudinal changes in thigh T2m were strongly correlated with changes in myometry and modified timed up and go velocity.

Conclusions: Arimoclomol had no significant effects on the qMRI measurements evaluated, consistent with clinical outcomes from the main trial. The qMRI measurements demonstrated both validity and responsiveness, further supporting their potential utility as biomarkers in IBM.

Myositis-specific autoantibodies (MSAs) are hallmarks of idiopathic inflammatory myopathies (IIMs) and have become increasing valuable in disease diagnosis, phenotyping, and classification. In addition to their clinical utility, emerging data, including findings from several animal studies, suggest that MSAs and autoreactive T cells substantially contribute to the etiopathogenesis of IIMs. This review aims to provide an updated perspective on myositis autoantibodies by focusing on relevant clinical and translational studies.

Objectives: This study aimed to evaluate the clinical significance of the coexistence of 2 or more myositis-specific antibodies (multiple MSAs) in adult patients with idiopathic inflammatory myopathies (IIM).

Methods: We assessed a cohort of 202 consecutive patients with IIM. Clinical features and survival rates were compared between patients with and without multiple MSAs.

Results: Of those 202 patients, 44 (21.8%) were found to have multiple MSAs. 63.6% of the 44 patients tested positive for anti-aminoacyl-tRNA synthetase antibodies (anti-ARS+) and 52.3% positive for anti-melanoma differentiation-associated protein-5 antibody (anti-MDA5+). The presence of multiple MSAs was associated with less rapidly progressive interstitial lung disease (RP-ILD), fever, rash, periungual erythema, more muscle involvement and dysphagia, higher albumin level, and higher positive rate of ANA antibody in anti-MDA5+ population. In anti-ARS+ population with multiple MSAs, there were more V-neck sign, skin ulcers, dysphagia and peripheral edema. No differences in survival rates were observed between patients with or without multiple MSAs in the overall and anti-ARS+ populations. However, the survival rate in anti-MDA5+ population with multiple MSAs was significantly higher than those without multiple MSAs (p = 0.003). Moreover, multiple MSAs remained an independent protective factor against mortality in multivariable Cox regression analysis of anti-MDA5+ population [HR 0.108 (95% CI 0.013, 0.908), p=0.041].

Conclusions: Multiple MSAs coexist in some IIM patients and their existence indicates mixed features from concomitant MSAs in anti-MDA5+ population and anti-ARS+ population. Identifying multiple MSAs could help to discover a more favourable disease phenotype with decreased mortality in anti-MDA5+ population.

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

Objectives: Inclusion body myositis (IBM) is a rare neuromuscular disease that confers significant functional disability. Understanding the priorities of IBM patients and carers is critical to directing care interventions where resources are limited. This Australian patient-led study aimed to identify current challenges for IBM patients and carers; prioritisation of these challenges; and self-reported ability to cope.

Methods: This phased study used a mixed methods approach. An initial qualitative 'discovery' phase, involving a small cohort of patients and carers (n=23), determined key challenges (themes). A subsequent quantification phase, involving 149 Australian IBM patients and carers, utilised an online survey to prioritise themes and determine current level of coping.

Results: The study identified 10 inter-related themes, and their relative importance was then determined. Ninety-five percent of total importance came from 7 themes: (1) Uncertain future; (2) Coping with daily frustrations; (3) Lack of cure, treatment and understanding; (4) Impact on carer's capabilities and own needs; (5) Change of roles and relationships; (6) Getting information, education and support; and (7) Significant impact on mental health. Other themes identified were: (8) Financial impact; (9) Issues with government-provided care provision; and (10) Concerns around access to voluntary euthanasia. Participants reported low mean 'coping scores' across all themes.

Conclusions: This study identified gaps in care, education and support. The highest priority themes focussed on practical challenges of living with IBM in addition to significant impact on mental health. Understanding the priorities of IBM patients and carers is critical in directing resources and providing person-centered care and support.

Objectives: The ubiquitin proteasome system is the main mediator of inflammation-induced muscle atrophy through the expression of TRIM63 and Atrogin-1. The aim of this study was to address the expression of these ubiquitin ligases and their relationship with inflammatory and atrophy parameters of patients with idiopathic inflammatory myopathies (IIM).

Methods: We recruited 37 adult IIM patients, and 10 age and sex-matched healthy donors. We assessed the proportion of different peripheral blood mononuclear cells (PBMC) subsets expressing TRIM63 and Atrogin-1 and the serum amount of theses ubiquitin ligases, cytokines, and chemokines, using multiparametric flow-cytometry, ELISA and luminometry respectively. The muscle expression of TRIM63 and Atrogin-1 was assessed by confocal microscopy. We compared the quantitative variables with the Mann-Whitney U test and assessed the correlations with Spearman Rho.

Results: IIM patients had a higher proportion of TRIM63+ CD4+ T cells (24.56 (7.71-53.23) vs. 2.55 (0.42-4.51), p<0.0001), TRIM63+ CD8+ T cells (15.1 (3.22-37.40) vs. 1.06 (0.83-2.45), p=0.0002), TRIM63+ monocytes (14.09 (3.25-29.80) vs. 1.97 (0.59-7.64), p=0.011), Atrogin-1+ CD4+ T cells (27.30 (6.61-64.19) vs. 2.55 (0.42-4.51), p<0.0001), Atrogin-1+ CD8+ T cells (14.88 (5.99-34.30) vs. 2.33 (0.60-8.01), p=0.001), and Atrogin1+ monocytes (17.38 (8.93-47.37) vs. 1.41 (0.79-3.77), p<0.0001). Muscle from IIM patients had a higher expression of TRIM63 and Atrogin-1. TRIM63+ CD8+ T cells mainly correlated with serum IL-2, IL-4, IL-8, IL-10, G-CSF, and TNF-a.

Conclusions: TRIM63 and Atrogin-1 are expressed in PBMC and muscle from patients with IIM and correlate with serum cytokines, and chemokines. This mechanism may contribute to the inflammation-induced muscle atrophy in IIM.

Objectives: Inclusion body myositis (IBM) is a complex inflammatory muscle disease in adults over 40, with histological features of autoinflammation, cell stress and autophagic abnormalities, and marked clinically by relentless progression with no effective disease-modifying therapy. Sirolimus (rapamycin) may help maintain function by inhibiting T effector cells, preserving T regulatory cells, inducing autophagy, and improving mitochondrial function. This international trial follows a phase II pilot study.

Methods: This phase IIb/III double-blind, randomised, controlled trial (RCT) of sirolimus involves 140 IBM patients randomly assigned with equal allocation to sirolimus (2 mg) or matching placebo. This RCT aims to assess the efficacy of sirolimus compared to placebo in slowing or stabilising IBM progression, as measured by the mean change in patient function using the IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84. Secondary outcomes will evaluate efficacy and safety to inform future clinical trial design.

Results: Ethical approval has been granted in Australia (St Vincent's Hospital Melbourne HREC-D 311/20) and the USA (University of Kansas Medical Center Human Research Protection Program FWA no. 00003411), with European approval pending. The protocol is version 3.0 (02-Dec-2022).

Trial registration: ANZCTR: ACTRN12620001226998p, ClinicalTrials.gov: NCT04789070, UTN: U1111-1258-1354, and EU CT 2024-514575-17-00.

Conclusions: This phase IIb/III trial builds on prior findings to assess sirolimus's potential in slowing or halting IBM progression, preserving patient function and independence, and advancing IBM therapeutic strategies and trial design.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases characterised by skeletal muscle inflammation and frequently by other organs involvement, in particular lung and skin, but also joints, heart and gastrointestinal tract.Although they are rare diseases, the literature on IIMs has been growing rapidly and many studies have been published in order to clarify the pathogenesis and to better define diagnosis, clinical manifestations (muscular and extra-muscular) and treatment. The purpose of this review is to summarise the most relevant contributions published over the last year on this topic.