Rituximab and intravenous immunoglobulin treatment in PM/Scl antibody-associated disease: case-based review

Autoantibodies to the 75-kDa and 100-kDa subunits of the PM/Scl nucleolar protein complex are associated with an overlap syndrome, manifesting with clinical features of systemic sclerosis and idiopathic inflammatory myopathy. We describe the diverse clinical features in a series of 4 cases with anti-PM/Scl-75 and/or anti-PM/Scl-100 antibodies, including severe proximal muscle weakness, oesophageal dysfunction, respiratory weakness requiring mechanical ventilation, Raynaud’s, calcinosis cutis, sclerodactyly and critical digital ischaemia. Despite the severity of striated and oesophageal muscle weakness, all patients responded very well to immune suppression, and calcinosis cutis in one case regressed substantially. We highlight the efficacy of Rituximab and intravenous immunoglobulin therapy (IVIg) in these cases, enabling return to normal muscle function within six months. Rituximab was preferentially chosen for cases with hyper-gammaglobulinemia and multiple autoantibodies in addition to anti-PM/Scl, and IVIg was utilised for cases where a rapid onset of effect was required, such as severe ventilator-dependent respiratory muscle weakness and oesophageal dysfunction.

ECG Changes Through Immunosuppressive Therapy Indicate Cardiac Abnormality in Anti-MDA5 Antibody-Positive Clinically Amyopathic Dermatomyositis

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a dermatomyositis (DM)-specific antibody, is strongly associated with interstitial lung disease (ILD). Patients with idiopathic inflammatory myopathy (IIM) who are anti-MDA5 antibody positive [anti-MDA5 (+)] often experience chest symptoms during the active disease phase. These symptoms are primarily explained by respiratory failure; nevertheless, cardiac involvement can also be symptomatic. Thus, the aim of this study was to investigate cardiac involvement in anti-MDA5 (+) DM. A total of 63 patients with IIM who underwent electrocardiography (ECG) and ultrasound cardiography (UCG) during the active disease phase from 2016 to 2021 [anti-MDA5 (+) group, n = 21; anti-MDA5-negative (-) group, n = 42] were enrolled in the study, and their clinical charts were retrospectively reviewed. The ECG and UCG findings were compared between the anti-MDA5 (+) and anti-MDA5 (-) groups. All anti-MDA5 (+) patients had DM with ILD. The anti-MDA5 (+) group showed more frequent skin ulcerations and lower levels of leukocytes, muscle enzymes, and electrolytes (Na, K, Cl, and Ca) than the anti-MDA5 (-) group. According to the ECG findings obtained during the active disease phase, the T wave amplitudes were significantly lower for the anti-MDA5 (+) group than for the anti-MDA5 (-) group (I, II, and V4–6 lead; p < 0.01; aVF and V3, p < 0.05). However, the lower amplitudes were restored during the remission phase. Except for the E wave, A wave and Sep e’, the UCG results showed no significant differences between the groups. Four patients with anti-MDA5 (+) DM had many leads with lower T wave and cardiac abnormalities (heart failure, diastolic dysfunction, myocarditis) on and after admission. Though anti-MDA5 (+) patients clinically improved after immunosuppressive therapy, some of their ECG findings did not fully recover in remission phase. In conclusion, anti-MDA5 (+) DM appears to show cardiac involvement (electrical activity and function) during the active phase. Further studies are necessary to clarify the actual cardiac condition and mechanism of these findings in patients with anti-MDA5 (+) DM.

Transcriptomes of peripheral blood mononuclear cells from juvenile dermatomyositis patients show elevated inflammation even when clinically inactive

In juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, weakness is accompanied by a characteristic rash that often becomes chronic and is associated with vascular damage. We hoped to understand the molecular underpinnings of JDM, particularly when untreated, which would facilitate the identification of novel mechanisms and clinical targets that might disrupt disease progression. We studied the RNA-Seq data from untreated JDM peripheral blood mononuclear cells (PBMCs; n = 11), PBMCs from a subset of the same patients when clinically inactive (n = 8/11), and separate samples of untreated JDM skin and muscle (n = 4 each). All JDM samples were compared to non-inflammatory control tissues. The untreated JDM PBMCs showed a strong signature for type1 interferon response, along with IL-1, IL-10, and NF-κB. Surprisingly, PBMCs from clinically inactive JDM individuals had persistent immune activation that was enriched for IL-1 signaling. JDM skin and muscle both showed evidence for type 1 interferon activation and genes related to antigen presentation and decreased expression of cellular respiration genes. Additionally, we found that PBMC gene expression correlates with disease activity scores (DAS; skin, muscle, and total domains) and with nailfold capillary end row loop number (an indicator of microvascular damage). This included otoferlin, which was significantly increased in untreated JDM PBMCs and correlated with all 3 DAS domains. Overall, these data demonstrate that PBMC transcriptomes are informative of molecular disruptions in JDM and provide transcriptional evidence of chronic inflammation despite clinical quiescence.

Anti-Synthetase Syndrome Complicated by Pyogenic Myositis

Background: Anti-synthetase syndrome is a rare autoimmune disorder characterized by autoantibodies against aminoacyl-tRNA-synthetases. Inflammatory myopathy and interstitial lung disease could be present among other manifestations. Anti-Jo-1 is the most common antisynthetase antibody and is the most likely to present with the classic triad (interstitial lung disease, myositis, and arthritis) and have more muscle and joint involvement than patients with other antisynthetase antibodies. Case report: Here, we present a case of a 60-year-old female patient, with a previous diagnosis of myositis, secondary to the anti-synthetase syndrome, with a complication by pyogenic myositis. Conclusion: Diagnosis is made by a multidisciplinary approach, occasionally muscle and/or lung biopsy are needed. Imaging studies, Especially magnetic resonance imaging, based on findings such as muscle and fascial edema, and fatty tissue replacement, allow an optimal approach.

A Muscle Biosignature Differentiating Between Limb-Girdle Muscular Dystrophy and Idiopathic Inflammatory Myopathy on Magnetic Resonance Imaging

Background: The overlapping clinical presentations of limb-girdle muscular dystrophy (LGMD) and idiopathic inflammatory myopathy (IIM) make clinical diagnosis challenging. This study provides a comprehensive evaluation of the distributions and characteristics of muscle fat substitution and edema and aims to differentiate those two diseases.Methods: This retrospective study reviewed magnetic resonance imaging (MRI) of seventeen patients with pathologically proved diagnosis, comprising 11 with LGMD and 6 with IIM. The fat-only and water-only images from a Dixon sequence were used to evaluate muscle fat substitution and edema, respectively. The degrees of muscle fat substitution and edema were graded and compared using the appropriate statistical methods.Results: In LGMD, more than 50% of patients had high-grade fat substitution in the majority of muscle groups in the thigh and calf. However, <50% of IIM patients had high-grade fat substitution in all muscle groups. Moreover, LGMD patients had significantly higher grade fat substitution than IIM patients in all large muscle groups (p < 0.05). However, there was no significant difference in edema in the majority of muscle groups, except the adductor magnus (p = 0.012) and soleus (p = 0.009) with higher grade edema in IIM. Additionally, all the adductor magnus muscles in LGMD (100%) showed high-grade fat substitution, but none of them showed high-grade edema.Conclusions: MRI could be a valuable tool to differentiate LGMD from IIM based on the discrepancy in muscle fat substitution, and the adductor magnus muscle could provide a biosignature to categorizing LGMD.

Assessment of disability in idiopathic inflammatory myopathy: a call for linearity

Objectives To evaluate the clinimetric properties of the Academic Medical Centre Disability Score (ALDS) in patients with idiopathic inflammatory myopathy (IIM). Methods We used prospectively collected data of IIM patients who completed a phase-2 study with first-line IVIg monotherapy. The ALDS is a patient reported questionnaire which contains 25 items relevant for disability in myositis. ALDS and all core set measures (CSMs) for myositis (including Health Assessment Questionnaire-Disability Index (HAQ-DI)) were evaluated at baseline and 9 weeks follow-up. In addition, the 2016 ACR/EULAR myositis response criteria outcome called Total Improvement Score (TIS) was evaluated at 9 weeks. We examined floor/ceiling effects, reliability and construct validity of the ALDS. To examine known-group validity, ALDS change scores over time were compared with TIS and physician impression of clinical response (PICR). Results Nineteen patients with IIM (median age 59 years, 12 (63%) female) were enrolled. At baseline, ALDS showed a median score of 65.4 (IQR 58.2–73.5), good Cronbach’s alpha (α = 0.84) and a small ceiling effect (11%). Construct validity was confirmed by moderate to strong correlations between ALDS and HAQ-DI (rs=-0.57 (baseline); -0.86 (follow-up)). ALDS change score correlated with TIS (rs=0.70), discriminated between responders and non-responders (TIS ≥ 40; p= 0.001), between groups based on PICR (p= 0.03), and detected deterioration. Conclusion The ALDS showed promising clinimetric properties and detected relevant changes in disability in patients with myositis. These results warrant further investigations.

Dermatomyositis: Muscle Pathology According to Antibody Subtypes

Background and Objectives:Discoveries of dermatomyositis specific antibodies (DMSAs) in dermatomyositis patients raised awareness of various myopathological features among antibody subtypes. However, only perifascicular atrophy and perifascicular myxovirus resistant protein A (MxA) overexpression were officially included as the definitive pathological criteria for dermatomyositis classification. We aimed to demonstrate myopathological features in MxA-positive dermatomyositis to determine characteristic myopathological features in different DMSA subtypes.Method:We performed a retrospective pathology review of muscle biopsies of dermatomyositis patients diagnosed between January 2009 and December 2020 in a tertiary laboratory for muscle diseases. We included all muscle biopsies with sarcoplasmic expression for MxA and seropositivity for DMSAs. MxA-positive muscle biopsies which tested negative for all DMSAs were included as seronegative dermatomyositis. We evaluated histological features stratified according to four pathology domains (muscle fiber, inflammatory, vascular, and connective tissue) and histological features of interest by histochemistry, enzyme histochemistry, and immunohistochemical study commonly used in the diagnosis of inflammatory myopathy. We performed ultrastructural studies of 54 available specimens.Result:A total of 256 patients were included. Of these, 249 patients were positive for one of the five DMSAs (seropositive patients: 87 anti-TIF1-γ; 40 anti-Mi-2; 29 anti-MDA5; 83 anti-NXP-2; and 10 anti-SAE DM) and 7 patients were negative for all five DMSAs (seronegative patients). Characteristic myopathological features in each DMSA subtype were as follows: anti-TIF1-γ with vacuolated/punched out fibers (64.7%, P<.001) and perifascicular enhancement in HLA-ABC stain (75.9%, P<.001); anti-Mi-2 with prominent muscle fiber damage (score 4.8±2.1, P<.001), inflammatory cell infiltration (score 8.0±3.0, P=.002), perifascicular atrophy (67.5%, P=.02), perifascicular necrosis (52.5%, P<.001), increased perimysial alkaline phosphatase activity (70.0%, P<.001), central necrotic peripheral regenerating fibers (45.0%, P<.001), and sarcolemmal membrane attack complex deposition (67.5%, P<.001); anti-MDA5 with scattered/diffuse staining pattern of MxA (65.5%, P<.001) with less muscle pathology and inflammatory features; anti-NXP2 with microinfarction (26.5%, P<.001); and anti-SAE and seronegative DM with HLA-DR expression (50.0%, P=.02 and 57.1%, P=.02, respectively).Discussion:We described a comprehensive serological-pathological correlation of DM primarily using MxA expression as an inclusion criterion. In our study, DMSAs were associated with distinctive myopathological features suggesting different underlying pathobiological mechanisms in each subtype.

OptimisAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies (ADAPT study): a protocol for a prospective diagnostic accuracy study of multimodality testing in patients suspected of a treatable idiopathic inflammatory myopathy

IntroductionIdiopathic inflammatory myopathies (IIMs) excluding inclusion body myositis (IBM) are a group of heterogeneous autoimmune disorders characterised by subacute-onset and progressive proximal muscle weakness, which are frequently part of a multisystem autoimmune disorder. Reaching the diagnosis can be challenging, and no gold standard for the diagnosis of IIM exists. Diagnostic modalities include serum creatine kinase activity, muscle imaging (MRI or ultrasound (US)), electromyography (EMG), myositis autoantibody testing and muscle biopsy. Several diagnostic criteria have been developed for IIMs, varying in reported sensitivity and specificity.HypothesisWe hypothesise that an evidence-based diagnostic strategy, using fewer and preferably the least invasive diagnostic modalities, can achieve the accuracy of a complete panel of diagnostic tests, including MRI, US, EMG, myositis-specific autoantibody testing and muscle biopsy.Methods and analysisThe OptimizAtion of Diagnostic Accuracy in idioPathic inflammaTory myopathies study is a prospective diagnostic accuracy study with an over-complete study design. 100 patients suspected of an IIM excluding IBM will be included. A reference diagnosis will be assigned by an expert panel using all clinical information and all results of all ancillary tests available, including 6 months of follow-up. Several predefined diagnostic strategies will be compared against the reference diagnosis to find the optimal diagnostic strategy.Ethics and disseminationEthical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam, The Netherlands (2019-814). The results will be distributed through conference presentations and peer-reviewed publications.Trial registration numberNetherlands trial register; NL8764.