[Peripheral neuroimmunological diseases - Neuropathological insights and clinical perspectives]. / Periphere neuroimmunologische Erkrankungen ­ neuropathologische Einsichten und klinische Perspektiven.

This article deals with peripheral neuroimmunological diseases and briefly outlines the currently most important aspects and treatment developments. Idiopathic inflammatory myopathies have different mechanisms of development, manifestations and prognoses. New classification systems and more specific treatment concepts have been developed. The IIMs include different subgroups. These entities can have specific autoantibodies. Diagnostically, a muscle biopsy is generally desirable for a precise diagnosis and is essential in unclear cases. Primary systemic vasculitides can be divided into different groups based on the predominant pattern of involvement, while secondary vasculitides and single organ vasculitides are also differentiated. Vasculitic myopathy cannot be equated with myositis and a reliable distinction is currently only possible by a muscle biopsy. Treatment concepts should be developed on an interdisciplinary basis. Chronic inflammatory demyelinating polyneuropathy is the most frequent immune-mediated neuropathy and is characterized by a predominant demyelination of the motor and sensory nerves. The disease course runs in phases or is progressive and leads to significant disability and reduction in quality of life, despite current standard treatment. Novel treatment approaches are currently undergoing clinical trials. Myasthenia gravis, with the leading symptom of exercise-induced muscle weakness, is caused by autoantibodies against structures of the neuromuscular endplate. Autoantibody testing is the most important pillar in the diagnosis and is now also increasingly guiding treatment decisions. Overall, peripheral neuroimmunological diseases represent a heterogeneous group. Increasing knowledge of the pathophysiology is the key to numerous developments in diagnostics and treatment, which could lead to far-reaching practical changes in the future.

High-intensity resistance training improves quality of life, muscle endurance and strength in patients with myositis: a randomised controlled trial.

Myositis is associated with reduced quality of life, which is accompanied by significant impairments in muscle endurance and strength, altogether representing cardinal traits in patients with myositis. This randomised controlled trial aimed to investigate the effect of high-intensity resistance training on quality of life in patients with myositis. Thirty-two patients with established, stable myositis were randomised to 16 weeks of high-intensity resistance training (intervention group) or 16 weeks of usual care (control group). Primary outcome was quality of life assessed as the change in the physical component summary score (PCS) of the Short Form-36 health questionnaire from baseline to post-intervention. Secondary outcomes included functional capacity measures, such as functional index 3, and International Myositis Assessment and Clinical Studies Group (IMACS) disease activity and damage core set measures, including manual muscle testing 8 (MMT8). The primary outcome PCS showed an improvement in favour of high-intensity resistance training with a between-group difference of 5.33 (95% CI 0.61; 10.05) (p = 0.03). Additionally, functional index 3 showed a between-group difference indicating greater gains with high-intensity resistance training 11.49 (95% CI 3.37; 19.60) (p = 0.04), along with a between-group improvement in MMT8 1.30 (95% CI 0.09; 2.51) (p = 0.04). High-intensity resistance training for 16 weeks effectively improved quality of life in patients with myositis. Clinical measures of muscle endurance and muscle strength were also found to improve with high-intensity resistance training, while patients stayed in disease remission. Consequently, progressively adjusted high-intensity resistance training is feasible and causes no aggravation of the disease, while benefitting patients with myositis.Clinical trial registration: Clinicaltrials.gov ID: NCT04486261- https://clinicaltrials.gov/study/NCT04486261 .

Direct and indirect costs of idiopathic inflammatory myopathies in adults: A systematic review.

Idiopathic inflammatory myopathies (IIMs) are rare disorders characterized by inflammation of skeletal muscle, which can result in fatty replacement of muscle, muscle atrophy, and subsequent weakness. Therapeutic advancements have improved clinical outcomes but impose an economic impact on healthcare systems. We aimed to summarize the direct and indirect costs associated with IIMs in a systematic review (PROSPERO Registration #CRD42023443143). Electronic databases (MEDLINE, Embase, CINAHL, and Scopus) were systematically searched for full-length articles (excluding case reports) reporting costs specific to patients diagnosed with an IIM, published between database inception and April 19, 2023. Direct cost categories included inpatient, outpatient, medication, home/long-term care, and durable medical equipment such as mobility and respiratory aids. Indirect costs included lost productivity. Eligibility criteria were met by 21 of the 3,193 unique titles identified. Costs are expressed in 2023 United States of America dollars, with adjustments for differences in purchasing power applied to currency conversions. As no study reported on all cost categories, annualized cost of IIM per patient was estimated by calculating the mean cost per category, and then adding the means of the different cost categories. By this method, IIM was estimated to cost $52,210 per patient per year. Proportional contributions by category were lost productivity (0.278), outpatient care (0.214), medications (0.171), inpatient care (0.161), home/long-term care (0.122), and durable medical equipment (0.053). Newer findings with intravenous immunoglobulin considered first line therapy for IIM demonstrated markedly higher annual medication costs per patient, upwards of $33,900 compared to an average of $3,908 ± $1,042 in older studies. Future cost-effectiveness studies require updated cost-of-illness studies reflecting the evolving sub-classification and treatment options for IIM, and should consider the impact of IIM on patients and their families.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Immune-mediated necrotizing myopathy: A comprehensive review of the pathogenesis, clinical features, and treatments.

Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies.

Clinical profiles and treatment outcomes of outpatients with interstitial lung disease and mechanic's hands: A retrospective and observational cohort.

Idiopathic inflammatory myopathies, especially antisynthetase syndrome, often appear outside of the muscles as interstitial lung disease (ILD). Another typical finding is the presence of mechanic's hands. The aim of the present study was to describe the clinical, functional, tomographic, and serological data of patients with ILD and mechanic's hands and their response to treatment and survival rates. This is a retrospective study of ILD with concurrent myopathy. Among the 119 patients initially selected, 51 had mechanic's hands. All the patients were screened for anti-Jo-1 antibodies. An expanded panel of myopathy autoantibodies was also performed in 27 individuals. Of the 51 patients, 35 had 1 or more antibodies. The most common were anti-Jo-1, anti-PL-7, and anti-PL-12, while of the associated antibodies, anti-Ro52 was present in 70% of the 27 tested individuals. A significant response to treatment was characterized by an increase in predicted forced vital capacity (FVC) of at least 5% in the last evaluation done after 6 to 24 months of treatment. A decrease in predicted FVC of at least 5%, the need for oxygen therapy, or death were all considered treatment failures. All patients were treated with corticosteroids, and 71% with mycophenolate. After 24 months, 18 patients had an increase in FVC, 11 had a decrease, and 22 remained stable. After a median follow-up of 58 months, 48 patients remained alive and three died. Patients with honeycombing on high-resolution chest tomography (log-rank = 34.65; P < .001) and a decrease in FVC ≥5% (log-rank = 18.28, P < .001) had a poorer survival rate. Patients with ILD and mechanic's hands respond well to immunosuppressive treatment.

[Idiopathic inflammatory myopathies : An interdisciplinary challenge]. / Idiopathische inflammatorische Myopathien : Eine interdisziplinäre Herausforderung.

Idiopathic inflammatory myopathies (IIM) are rare diseases (incidence 1:100,000) with a wide range of clinical symptoms and manifestations. Typical indicators of IIM are proximally emphasized muscle weakness and myalgias, which are usually accompanied by elevated creatine kinase levels and muscle atrophy. The autoantibody diagnostics separate IIM into different entities, which are each associated with a typical risk of organ manifestations and the occurrence of tumors. The IIM represents an interdisciplinary challenge and the diagnostics and treatment require the involvement of several disciplines including rheumatology, neurology, neuropathology, dermatology and pneumology. An accurate diagnosis and careful tumor screening are essential because of the association between certain subgroups of IIM and the occurrence of malignant tumors.

Benign acute myositis in an adult: case-based review.

Myositis is a clinical condition with a wide spectrum of clinical presentation. We present the case of 33 years old woman with acute history of pain and swelling of both legs. Investigations confirmed acute bilateral myositis of both calf muscles. She responded well to conservative management with full recovery. Benign acute myositis is more common in children and usually follows viral infection. Although our case may represent an adult form of benign acute childhood myositis, she had no history of preceding infections. Benign acute myositis is increasingly reported in adults. It appears to be self-limited with spontaneous full recovery. The diagnosis is largely based on clinical features. Therefore, clinicians should be aware of this type of myositis to avoid unnecessary invasive investigations.

Novel Therapeutic Approaches in Connective Tissue Disease-Associated Interstitial Lung Disease.

Connective tissue diseases (CTD) comprise a group of autoimmune diseases that can affect multiple organs in the body including the lungs. The most common form of pulmonary involvement is interstitial lung disease (ILD). CTD-associated ILD (CTD-ILD) can take one of several courses including nonprogressive, chronically progressive, or rapidly progressive. Chronically and rapidly progressive patterns are associated with increased mortality. Limited randomized controlled trial data are available for treatment of CTD-ILD, with most data coming from systemic sclerosis-related ILD. The current first-line treatment for all CTD-ILD is immunosuppression with consideration of antifibrotics, stem cell transplant, and lung transplant in progressive disease. In this article, we review data for ILD treatment options in systemic sclerosis, rheumatoid arthritis, myositis, and primary Sjögren's syndrome-related ILDs.

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

Immune-Mediated Necrotizing Myopathies: Current Landscape.

PURPOSE OF REVIEW: Immune-mediated necrotizing myopathy (IMNM), characterized by acute or subacute onset, severe weakness, and elevated creatine kinase levels, poses diagnostic and therapeutic challenges. This article provides a succinct overview of IMNM, including clinical features, diagnostic strategies, and treatment approaches. RECENT FINDINGS: Recent insights highlight the different clinical presentations and therapeutic options of IMNM stratified by autoantibody positivity and type. Additionally, recent findings call into question the reported link between statin use and IMNM. This review synthesizes current knowledge on IMNM, emphasizing its distinct clinical features and challenging management. The evolving understanding of IMNM underscores the need for a comprehensive diagnostic approach that utilizes a growing range of modalities. Early and aggressive immunomodulatory therapy remains pivotal. Ongoing research aims to refine diagnostic tools and therapeutic interventions for this challenging muscle disorder, underscoring the importance of advancing our understanding to enhance patient outcomes.

Immune Checkpoint Inhibitor-induced Myositis.

Myositis induced by immune checkpoint inhibitors (ICIs) is an infrequent, potentially fatal, immune-related adverse event. It has higher incidence in patients who receive combination ICI therapy compared to monotherapy. Patients can present with clinical manifestation symptoms of myositis alone or in combination with myocarditis and/or myasthenia gravis, which significantly worsens the course and prognosis. Diagnosis can generally be made on the basis of clinical presentation, elevation of muscle enzymes, and electromyographic changes, but some patients may require a muscle biopsy. The first line of therapy is high-dose corticosteroids, followed by immunosuppression, plasmapheresis, or intravenous immunoglobulin in patients with severe disease.

Diagnosing and characterizing inflammatory myopathies at an Australian tertiary public hospital: Resource utilization and direct healthcare costs.

AIM: To determine the direct health service costs and resource utilization associated with diagnosing and characterizing idiopathic inflammatory myopathies (IIMs), and to assess for limitations and diagnostic delay in current practice. METHODS: A retrospective, single-center cohort analysis of all patients diagnosed with IIMs between January 2012 and December 2021 in a large tertiary public hospital was conducted. Demographics, resource utilization and costs associated with diagnosing IIM and characterizing disease manifestations were identified using the hospital's electronic medical record and Health Intelligence Unit, and the Medicare Benefits Schedule. RESULTS: Thirty-eight IIM patients were identified. IIM subtypes included dermatomyositis (34.2%), inclusion body myositis (18.4%), immune-mediated necrotizing myopathy (18.4%), polymyositis (15.8%), and anti-synthetase syndrome (13.2%). The median time from symptom onset to diagnosis was 212 days (IQR: 118-722), while the median time from hospital presentation to diagnosis was 30 days (8-120). Seventy-six percent of patients required emergent hospitalization during their diagnosis, with a median length of stay of 8 days (4-15). The average total cost of diagnosing IIM was $15 618 AUD (STD: 11331) per patient. Fifty percent of patients underwent both MRI and EMG to identify affected muscles, 10% underwent both pan-CT and PET-CT for malignancy detection, and 5% underwent both open surgical and percutaneous muscle biopsies. Autoimmune serology was unnecessarily repeated in 37% of patients. CONCLUSION: The diagnosis of IIMs requires substantial and costly resource use; however, our study has identified potential limitations in current practice and highlighted the need for streamlined diagnostic algorithms to improve patient outcomes and reduce healthcare-related economic burden.

Exercise recommendations for patients with myositis: a narrative review of safety and efficacy.

Idiopathic inflammatory myopathies (IIM) are marked by progressive muscle weakness and lasting disability. Therapies targeting patient well-being include the use of prescription drugs as well as exercise. Maintaining or increasing muscular strength and endurance as well as cardiorespiratory fitness (CRF) improves quality of life (QoL) as well as functional status in IIM patients. This narrative review highlights exercise interventions in patients of different IIM subtypes with the intent to provide a summary table with exercise recommendations that will safely and effectively improve QoL in myositis patients.

Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

Polymyositis is a rare and favourable outcome subtype of idiopathic inflammatory myopathy in Chinese patients.

OBJECTIVES: To investigate the prevalence and characteristics of typical polymyositis (PM) in Chinese patients with idiopathic inflammatory myopathy (IIM). METHODS: Patients diagnosed with IIM according to the 2017 EULAR/ACR criteria were included. Serological aspects including myositis-specific antibodies (MSA) and pathological data were re-evaluated. The diagnosis of typical PM was strictly done using the pathological criteria, while excluding other IIM subtypes such as dermatomyositis (DM), immune-mediated necrotising myopathies (IMNM), anti-synthetase syndrome (ASS), and sporadic inclusion body myositis (sIBM), based on their respective diagnostic criteria. RESULTS: A total of 544 IIM patients with muscle biopsy were involved, and 129 of them were diagnosed with initial PM according to the 2017 EULAR/ACR criteria. Only 6 (1.1%, 6/544) patients met the strict definition of typical PM after re-evaluation. Patients with typical PM were MSA-negative (100% vs. 35.7%, p=0.003) and had CD8+ T cells surrounding or invading non-necrotic muscle fibres in muscle biopsies (100% vs. 7.8%, p<0.001) compared to the initially diagnosed PM patients. All typical PM patients achieved clinical remission at the second-year follow-up. Typical PM patients had a favourable prognosis compared to MSA-negative IMNM and unspecific myositis patients. CONCLUSIONS: Strictly defined typical PM is a rare clinical subtype in Chinese IIM patients. Typical PM patients with classical pathology were MSA-negative and responded well to treatment and had a favourable prognosis. It is crucial for clinicians to combine clinical, serological, and pathological features to properly distinguish PM from other IIM subtypes.

Mental health in paediatric and adult myositis-related diseases: current state of research, interventions, and future steps from the MIHRA Psychological Impact Scientific Working Group.

Psychological and emotional well-being are critical aspects of overall health for individuals with chronic rheumatologic conditions. Mental health-related literature, however, predominantly focuses on systemic lupus erythematosus or rheumatoid arthritis, with limited emphasis on idiopathic inflammatory myopathies (IIMs). High proportions of those with juvenile myositis report psychological distress at levels warranting mental health referral. Adults with dermatomyositis diagnosed with depression or anxiety do not receive adequate mental health care. Mental health symptoms in those with IIMs are associated with worse health-related quality of life, medication adherence, and disease outcomes. Despite demonstrated high rates of mental health burden, access to mental health care remains severely lacking.Data related to mental health burden is limited by small sample size, limited generalisability, variable methods of assessment, and inconsistent diagnosis codes to define mental health conditions. Additional research is needed to validate current screening tools in myositis populations. Other relevant measurable factors include disease severity, non-health- and health-related trauma exposure, loneliness, isolation, loss of control, sleep difficulties, fatigue, pain, self-esteem, body image, sexual health, and health inequities. Studiesare needed investigating the efficacy of therapeutic and pharmacologic interventions among patients with myositis who experience depression and anxiety. Currently, knowledge and resources are limited around mental health burden and potential intervention for those living with IIMs. The Myositis International Health & Research Collaborative Alliance (MIHRA) Psychological Impact Scientific Working Group offers a preliminary road map to characterise and prioritise the work ahead to understand baseline mental health burden and compare avenues for intervention.