Immune-mediated Inflammatory Myopathies Research Articles

Plasma Exchange in Anti-Signal Recognition Particle Myopathy: A Systematic Review and Combined Analysis of Patient Individual Data.

Anti-signal recognition particle myopathy (anti-SRP myopathy) is a rare subtype of immune-mediated inflammatory myopathy characterized by muscle weakness and anti-SRP autoantibodies. Although plasma exchange (PE) is used in severe cases, its role remains unclear. A systematic review was conducted following PRISMA guidelines, identifying 23 patients with anti-SRP myopathy treated with PE. Data on demographics, clinical features, laboratory findings, treatments, and outcomes were analyzed combining individual patient data if available. Sixteen (69.6%) patients were male, with muscle weakness as the predominant symptom in 100% of cases. After PE, most patients showed improvement in symptoms, and the proportion of patients with muscle weakness was reduced (p = 0.001). Relapse occurred in 17.4% of the cases. The incidence of adverse events was low (8.7%). Despite limitations, including a small sample size and heterogeneous data, our systematic review suggests that PE may be effective in inducing remission and controlling symptoms in anti-SRP myopathy, particularly in severe cases. Since evidence on PE in anti-SRP myopathy is limited, further research, including prospective multicenter studies, is warranted to understand better its efficacy and safety and establish its role in treatment algorithms.

An odd case of immune-mediated necrotizing myopathy, complicated with sagittal, transverse and sigmoid sinus thrombosis

INTRODUCTION: Immune-mediated necrotizing myopathy (IMNM) is a rare variant of immune-mediated inflammatory myopathy (IMIM) that exhibits a severe prognosis and is unresponsive to conventional treatment. (1,2)Notably, the incidence of immune-mediated inflammatory myopathies (IMIMs) is low, estimated at 1.16 to 19/million/year and only 3-6% of IMIMs are diagnosed as IMNM. (1,3–5). Systemic inflammation has been found to play a crucial role in promoting the onset of cerebral venous thrombosis. (6,7) MATERIAL AND METHODS: We present the case of a 46-years-old Chinese woman, without any known prior pathology, who was referred to the Rheumatology Department for symmetrical, proximal muscle weakness of the limbs, dysphagia for solid food, and weight loss (5 kg within 2 months). The pathologic clinical examination revealed itchy erythematous plaques on the posterior thoracolumbar region and signs of muscle weakness. Laboratory workup showed significant inflammatory syndrome, severe muscle and hepatic cytolysis syndrome, and positivity for thyroid-specific autoantibodies but with normal thyroid function, positivity for antinuclear antibodies (more precisely: SS-A, Ro-52, SS-B), and myositis antibodies (SRP, Ro-52, SAE1, PM-Scl, MDA5). The CT scan of the thoracic, abdominal, and pelvis showed fibrosis of the lungs, hepatic hypertrophy, and an enlarged uterus, further diagnosed by transvaginal ultrasound as adenomyosis. The positive diagnosis is immune-mediated necrotizing myopathy. Differential diagnoses included dermatomyositis, toxic/infectious myositis, hypothyroidism, and neuro-muscular diseases (5,8). The initial treatment was made with glucocorticoids (pulse therapy followed by oral therapy) and immunosuppressants (Mycophenolate Mofetil – stopped because of severe dyspepsia and myelosuppression). After five days of pulse therapy, the patient developed muscle weakness and paresthesia on the left side of the body, and the cerebral CT scan revealed sagittal, transverse, and sigmoid sinus thrombosis. Thrombophilia screening uncovered the positivity of the lupus anticoagulant. (9) RESULTS: The patient was treated with anticoagulants (low molecular weight heparin, and afterward Vitamin K antagonist), low doses of oral glucocorticoids, and immunosuppressant (Methotrexate), without any other adverse event. CONCLUSION: In the presence of the lupus anticoagulant, even though the antiphospholipid syndrome is not confirmed, the only anticoagulant therapy that has proven its efficacy is the Vitamin K antagonist. Immune inflammatory myopathies, like IMNMs, create a significant inflammatory status that leads to hypercoagulability and endothelial injury, which exposes collagen and tissue factors, promoting further platelet aggregation, and can even lead to cerebral thrombosis. (2,6)

Dermatomyositis: severe acute respiratory syndrome coronavirus 2, an initiator or a trigger?

Dermatomyositis is an immune-mediated inflammatory myopathy. In adults, the common triggering factors for its onset include viral infections, malignancy, and drugs. The clinical manifestation of these group of disorders may be cutaneous, neurological, pulmonary, or a combination of all. The cutaneous manifestations are helpful in the early clinical diagnosis. The detection of myositis-specific autoantibodies serves as specific biomarkers for the diagnosis and helps in predicting the prognosis. We are presenting two cases of dermatomyositis, temporally related to the severe acute respiratory syndrome coronavirus 2 infection and vaccination.

Vaccination in pediatric acquired inflammatory immune-mediated neuromuscular disorders.

To analyse literature data on vaccine related induction, worsening of the disease and disease reccurrences as well as vaccine safety and efficacy among pediatric patients with acquired inflammatory immune-mediated neuromuscular disorders (NMD). Medline, Pub Med and Scopus database search from 1975 to 2020 focused on pediatric age was conducted including peer reviews, meta analyses and epidemiological studies on vaccination and Guillain-Barré syndrome (GBS), Bell's palsy, optic neuritis (ON), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP) and immune-mediated inflammatory myopathy (IM). s: There are no strong evidence supporting relationship between vaccination with different pediatric vaccines and development of first episodes or reccurrences of GBS, Bell's palsy, optic neuritis (ON), juvenile MG, CIDP, and IM. The vaccination and revaccination with inactivated vaccines is considered safe in children with medical history of GBS, Bell's palsy, ON, MG and IM. Caution when immunization against influenza, quadrivalent conjugated meningococcal vaccine (MCV4) and pneumococcal disease and avoiding tetanus toxoid immunization in CIDP patients is suggested. Patients with immune mediated acquired NMD should be vaccinated with live vaccines before the initiation of immunosupressive treatment. Immunosuppressed patients with low protective antibody titers should be considered for revaccination.

The changing spectrum of drug-induced myopathies.

Drug-induced myopathies are a group of disorders whose importance lies in the fact that they are potentially treatable and usually reversible if the causative agent is identified and withdrawn. A wide variety of medications used in many different branches of medicine have been recognised as causing muscle adverse effects, ranging from myalgia and asymptomatic hyperCKaemia to severe weakness and at times fatal rhabdomyolysis. There has been increased awareness of these complications since the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor group of drugs (statins) in the 1980s, and their subsequent association with a range of necrotising and immune-mediated inflammatory myopathies and muscle symptoms. More recently, since the introduction of the immune checkpoint inhibitors for the treatment of advanced malignancies, it has been increasingly recognised that these drugs also have a propensity to induce or exacerbate a variety of immune-mediated myopathies, neuropathies, myasthenic disorders and atypical overlap syndromes, and it is anticipated that these complications will become even more prevalent with increasing use of these medications in the future. This review focusses mainly on these two groups of drugs, and on cytokine-based therapies and VEGF inhibitors which have also been implicated in the induction of immune-mediated inflammatory myopathies.

AB1237 Diagnostic value of proteasomal and autophagic markers in muscular diseases

Background:Deficient cellular degradation pathways such as autophagy and the ubiquitin proteasome system (UPS) show a correlation with the onset of neurodegenerative diseases. Especially immune-mediated inflammatory myopathies often show therapy-resistant phenotypes with medical need for further understanding of pathogenesis und possible treatment.Objectives:The aim of this work was to study an association of these two degradation pathways in a large group of different muscle entities and to examine a possible influence in the pathogenesis of the investigated muscle diseases. Furthermore, a potential benefit in diagnostics was studied using factors such as ubiquitin, p62, NBR1 and LC3 and their role as adapter molecules.Methods:We examined ubiquitin, p62, NBR1 and LC3 on muscle biopsies from patients with the diagnosis of s-IBM, dermato- and polymyositis, muscular dystrophy, neurogenic atrophy, myotonic dystrophy type II (PROMM) and metabolic myopathies such as Pompe and McArdle disease. Immunohistochemical single and double stainings as well as immunofluorescence stainings were performed on cryosections. Furthermore, Western blot analysis was performed. The use of a histological score, defined as the product of the frequency of positive fibres and staining intensity, was used to investigate possible differences between the diseases in the expression of the investigated factors.Results:Especially in s-IBM, myofibrillar myopathies and Pompe disease, proteasomal and autophagic markers were detected. On the other hand, neurogenic atrophy, McArdle disease and the majority of the myotonic dystrophies type II showed no positive signals, except for p62, which was detected especially in internalized nuclei and regenerative fibres. Overall, in all entities in regenerative and necrotic as well as in atrophic fibres, a positive staining for ubiquitin, p62, NBR1 and LC3 could be shown. Dermatomyositis showed a moderate immunoreactivity for p62 and NBR1 in the area of the perifascicular atrophy. Polymyositis showed a strong endomysial reaction in the area of the attacked muscle fibres, especially in the area of the lymphocytic infiltrates. The histological score showed that ubiquitin was significantly higher in s-IBM than in polymyositis. NBR1 was significantly higher in s-IBM than in dermatomyositis and muscular dystrophies. LC3 and p62 showed a significantly higher level in s-IBM as compared to dermatomyositis and polymyositis. Except for NBR1, a positive correlation of autophagic and proteasomal markers was shown in dermatomyositis. There was also a positive correlation between LC3 and ubiquitin in polymyositis. Using multivariate analysis and recursive partitioning, we could show a predictability of the diagnosis of s-IBM with a LC3 score above 3. On the other hand, a value below 3 excluded the diagnosis of s-IBM.Conclusion:In particular, s-IBM, myofibrillar myopathies and Pompe disease showed a possible involvement disturbed proteasomal and autophagic degradation pathways in their pathogenesis. In addition, p62 and NBR1 seemed to have an important role in the immune response. Furthermore, the altered autophagic and proteasomal degradation pathways may be involved in ageing processes, sarcopenia and disease. In particular, LC3 seems to be suitable as a screening marker to recognize an idiopathic inflammatory myopathy. The other markers, such as p62, LC3, and NBR1, would be able to distinguish between the subgroups of idiopathic inflammatory myopathies. Therefore, LC3 could be included as a marker in the routine of neuropathological diagnostics. Further studies are needed to fully understand the role of proteasomal and autophagic factors in possible immune suppressive and immune modulatory therapies and to assess possible side effects.Disclosure of Interests:Ulrich Drott: None declared, Patrick Harter: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Michel Mittelbronn: None declared

76-Year-Old Woman With Generalized Weakness

76-Year-Old Woman With Generalized Weakness

P.183 - Clinical and histopathological features of immune-mediated necrotising and inflammatory myopathy in relation to treatment with immune checkpoint blockers (ICBs) in cancer patients

P.183 - Clinical and histopathological features of immune-mediated necrotising and inflammatory myopathy in relation to treatment with immune checkpoint blockers (ICBs) in cancer patients

New insights of myositis-specific and -associated autoantibodies in juvenile and adult type myositis

Myositis, which means inflammation of the muscles, is a general term used for inflammatory myopathies. Myositis is a rare idiopathic autoimmune disease. It is believed that environmental factors such as virus, bacteria, parasites, direct injuries, drugs side effect can trigger the immune system of genetically susceptible individuals to act against muscle tissues. There are several types of myositis with the same systemic symptoms such as muscle weakness, fatigue, muscle pain and inflammation. These include dermatomyositis, juvenile dermatomyositis, inclusion-body myositis, polymyositis, orbital myositis and myositis ossificans. Juvenile and adult dermatomyositis are chronic, immune-mediated inflammatory myopathies characterized by progressive proximal muscle weakness and typical skin symptoms. The aim of the authors was to compare the symptoms, laboratory and serological findings and disease course in children and adult patients with idiopathic inflammatory myopathy. Early diagnosis and aggressive immunosuppressive treatment improve the mortality of these patients. Myositis-specific autoantibodies have predictive and prognostic values regarding the associated overlap disease, response to treatment and disease course. The authors intend to lighten the clinical and pathogenetic significance of the new target autoantigens. Orv. Hetil., 2016, 157(29), 1179-1184.

Immunotherapies for Immune-Mediated Myopathies: A Current Perspective.

Until recently, the treatment of immune-mediated inflammatory myopathies has largely been empirical with glucocorticoids, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin. However, a proportion of patients are only partially responsive to these therapies, and there has been a need to consider alternative treatment approaches. In particular, patients with inclusion body myositis are resistant to conventional immunotherapies or show only a transient response, and remain a major challenge. With increasing recognition of the different subtypes of immune-mediated inflammatory myopathies, and improved understanding of their pathogenesis, more targeted treatments are now being trialled. The overall approach to treatment, and novel therapies targeting B cells, T cells, and specific cytokines are discussed in this review.

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications.

The idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine-driven infiltration of immune cells into the muscle tissue. Recent studies have further dissected the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.

Poster 13 Assessment of the Application of Exercise Prescription for Physical Medicine and Rehabilitation Resident Physicians During Medical Training

exacerbated with toe walking. Examination revealed supple leg compartments with diffuse posterior calf tenderness. Leg strength, sensation, reflexes, pulses, and skin were normal. Leg radiographs and ultrasound showed only mild subcutaneous edema. Superficial and deep posterior leg compartment pressure measurements were normal. Erythrocyte sedimentation rate and C-reactive protein were elevated and anti-nuclear antibodies weakly positive. Bilateral leg MRI showed diffuse patchy areas of increased T2 signal involving the muscles and subcutaneous tissues of all leg compartments. Electromyography showed borderline short duration, low amplitude motor units in multiple calf muscles.A lateral gastrocnemius biopsy demonstrated scattered necrotic muscle fibers and heavy inflammatory exudate, consistent with a severe, active, immunemediated inflammatory myopathy. Setting: Sports Medicine Clinic Results or Clinical Course: With the diagnosis confirmed, oral prednisone (40 mg QD) was initiated and tapered to discontinuation over 14 weeks. Leg pain and swelling quickly improved, and she returned to jogging pain-free within a few weeks. After 8 weeks, she was released to high-intensity activity and returned to soccer practice without difficulty. Discussion: Inflammatory myopathy (IM) is an uncommon cause of acute leg pain in athletes. An atraumatic onset of leg pain and tenderness should raise suspicion for IM. MRI can be helpful in making the diagnosis and guiding a biopsy. There is emerging evidence that moderate-intensity aerobic and resistance exercise is safe and beneficial in IM. However, no studies to date have addressed return to play guidelines for athletes with this condition. Conclusions: IM should be considered in the differential diagnosis for acute leg pain. MRI can be helpful for diagnosis. This case demonstrates that return to high-intensity contact sport is possible with IM, but more research is needed to inform return to play decisions.

A novel form of immune inflammatory myopathy associated with antibodies to γ/δ sarcoglycan

Immune mediated inflammatory myopathies are a heterogeneous group of acquired diseases characterised by inflammation of skeletal muscle. In recent years, this group of conditions has become better characterised by the...

Paraspinal and Scapular Myopathy Associated With Scleroderma

To describe a form of inflammatory myopathy with prominent involvement of the paraspinal and scapular muscles in patients with scleroderma. Review of clinical records, laboratory investigations, and muscle biopsies. Patients presented with a "dropped head" resulting from weakness of the posterior cervical muscles (three cases) or camptocormia ("bent spine") resulting from weakness of the paraspinal muscles (two cases) and variable weakness and atrophy of shoulder girdle muscles with mild or absent pelvic girdle involvement. Biopsies from the deltoid or paraspinal muscles showed myositis of variable severity and scleroderma vasculopathy in all cases. The response to prednisolone and cytotoxic agents was poor, but there was a good response to intravenous immunoglobulin therapy in one case. Patients with scleroderma may develop a restricted form of immune-mediated inflammatory myopathy with a predilection for the paraspinal and scapular muscles, which is poorly responsive to treatment with glucocorticoids and immunosuppressive agents and may require consideration of other treatment modalities.

Eosinophilic Myositis Induced by Anti-tuberculosis Medication

－Abstract－Eosinophilic myositis is a rare idiopathic inflammatory muscle disease, and the patients with this malady present with diverse signs and symptoms such as muscle swelling, tenderness, pain, weakness, cutaneous lesions and eosinophilia. The etiology and pathogenesis of eosinophilic myositis remain elusive. Several drugs may occasionally initiate an immune mediated inflammatory myopathy, including eosinophilic myositis. We report here on a case a 17-year-old female patient who had taken anti-tuberculosis medicine for tuberculosis pleurisy. She presented with many clinical manifestations, including fever, skin rash, proximal muscle weakness, dyspnea, dysphagia and hypereosinophilia. She was diagnosed with eosinophilic myositis by the pathologic study. The muscle weakness progressed despite of stopping the anti-tuberculosis medicine, but the myositis promptly improved following the administration of glucocorticoid. Although drug induced myopathies may be uncommon, if a patient presents with muscular symptoms, then physicians have to consider the possibility of drug induced myopathies.KeyWords:Eosinophilic myositis, Anti-tuberculosis medicine

Vacuolar myopathy in a dog resembling human sporadic inclusion body myositis

Sporadic inclusion body myositis (sIBM) is the most common myopathy in people over the age of 50 years. While immune-mediated inflammatory myopathies are well documented in dogs, sIBM has not been described. An 11-year-old dog with chronic and progressive neuromuscular dysfunction was evaluated for evidence of sIBM using current pathologic, immunohistochemical and electron microscopic diagnostic criteria. Vacuoles and congophilic intracellular inclusions were identified in cryostat sections of multiple muscle biopsies and immunostained with antibodies against amyloid-β peptide, amyloid-β precursor protein, and proteosome 20S of the ubiquitin–proteosome system. Cellular infiltration and increased expression of MHC Class I antigen were observed. Cytoplasmic filamentous inclusions, membranous structures, and myeloid bodies were identified ultrastructurally. These observations constitute the first evidence that both the inflammatory and degenerative features of human sIBM can occur in a non-human species.

Review: Therapeutic advances and future prospects in immune-mediated inflammatory myopathies

THE INFLAMMATORY MYOPATHIES INCLUDE THREE DISTINCT ENTITIES: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). A T-cell-mediated cytotoxic process in PM and IBM and a complement-mediated microangiopathy in DM are the hallmarks of the underlying autoimmune processes. The most consistent therapeutic problem remains the distinction of PM from the difficult-to-treat mimics such as s-IBM, necrotizing myopathies and inflammatory dystrophies. This review provides a step-by-step approach to the treatment of inflammatory myopathies, highlights the common pitfalls and mistakes in therapy, and identifies the emerging new therapies. In uncontrolled studies, PM and DM respond to prednisone to some degree and for some period of time, while a combination with one immu-nosuppressive drug (azathioprine, cyclosporine, mycophenolate, methotrexate) offers additional benefit or steroid-sparing effect. In contrast, IBM is resistant to most of these therapies, most of the time. Controlled studies have shown that IVIg is effective and safe for the treatment of DM, where is used as a second, and at times first, line therapy. IVIg seems to be also effective in the majority of patients with PM based on uncontrolled series, but it offers transient help to a small number of patients with IBM especially those with dysphagia. Bona fide patients with PM and DM who become resistant to the aforementioned therapies, may respond to rituximab, tacrolimus or rarely to an tumor necrosis factor alpha inhibitor. For IBM patients, experience with alemtuzumab, a T-cell-depleting monoclonal antibody, is encouraging.

Inflammatory muscle diseases

The three major immune-mediated inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM), each have their own distinctive clinical features, underlying pathogenetic mechanisms and patterns of muscle gene expression. In DM a complement-dependent humoral process thought to be initiated by antibodies to endothelial cells results in a microangiopathy with secondary ischemic changes in muscles. On the other hand, in PM and IBM there is a T-cell response with invasion of muscle fibers by CD8+ lymphocytes and perforin-mediated cytotoxic necrosis. In IBM degenerative changes are also a feature and comprise autophagia with rimmed vacuole formation and inclusions containing beta-amyloid and other proteins whose accumulation may be linked to impaired proteasomal function. The relationship between the inflammatory and degenerative component remains unclear, as does the basis for the selective vulnerability of certain muscles and the resistance to conventional forms of immunotherapy in most cases of IBM. Patients with DM or PM usually respond to treatment with glucocorticoids and immunosuppressive agents but their use remains largely empirical. Intravenous immunoglobulin therapy can be used to achieve disease control in patients with severe weakness or dysphagia, or in patients with immunodeficiency, but its use is limited by expense. Emerging therapies for resistant cases include TNFalpha inhibitors (etanercept, infliximab) and monoclonal antibodies (rituximab, alemtuzumab). However, experience with these therapies is still limited and there is a need for randomized trials to test their efficacy and establish guidelines for their use in clinical practice.

Expression of major histocompatibility complex class I and class II antigens in canine masticatory muscle myositis

Studies in human immune-mediated inflammatory myopathies have documented expression of major histocompatibility complex class I (MHC class I) and class II (MHC class II) antigens on muscle fiber membranes in the presence or absence of cellular infiltration. Here we evaluate the presence and distribution of these antigens in canine masticatory muscle myositis, an immune-mediated inflammatory myopathy. Twelve samples of temporalis and masseter muscles from dogs with a clinical diagnosis of canine masticatory muscle myositis were examined by immunohistochemistry and double-immunofluorescence confocal microscopy. MHC class I and class II antigens were expressed in muscle fibers independent of inflammatory cell infiltration. Furthermore MHC class I and class II antigens were expressed on the sarcolemma and co-localized with dystrophin. Our results suggest that MHC class I and class II expression in canine masticatory muscle myositis may play a role in the initiation and maintenance of the pathological condition, rather than just a consequence of a preceding local inflammation.

Inflammatory myopathies: clinical, diagnostic and therapeutic aspects.

The three major forms of immune-mediated inflammatory myopathy are dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). They each have distinctive clinical and histopathologic features that allow the clinician to reach a specific diagnosis in most cases. Magnetic resonance imaging is sometimes helpful, particularly if the diagnosis of IBM is suspected but has not been formally evaluated. Myositis-specific antibodies are not helpful diagnostically but may be of prognostic value; most antibodies have low sensitivity. Muscle biopsy is mandatory to confirm the diagnosis of an inflammatory myopathy and to allow unusual varieties such as eosinophilic, granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be recognized. The treatment of the inflammatory myopathies remains largely empirical and relies upon the use of corticosteroids, immunosuppressive agents, and intravenous immunoglobulin, all of which have nonselective effects on the immune system. Further controlled clinical trials are required to evaluate the relative efficacy of the available therapeutic modalities particularly in combinations, and of newer immunosuppressive agents (mycophenolate mofetil and tacrolimus) and cytokine-based therapies for the treatment of resistant cases of DM, PM, and IBM. Improved understanding of the molecular mechanisms of muscle injury in the inflammatory myopathies should lead to the development of more specific forms of immunotherapy for these conditions.