Immune-mediated Myositis Research Articles

Efficacy and safety of triplet nivolumab, relatlimab, and ipilimumab (NIVO + RELA + IPI) in advanced melanoma: Results from RELATIVITY-048.

9504 Background: NIVO (anti–PD-1 antibody) is approved as monotherapy and in combination with either RELA (anti–LAG-3 antibody) or IPI (anti–CTLA-4 antibody) for the treatment of patients (pts) with advanced melanoma. RELATIVITY-048 (NCT03459222) is a phase 1/2, nonrandomized trial evaluating immuno-oncology (I-O) triplets, including NIVO + RELA + IPI, for pts with select solid tumors. This analysis from RELATIVITY-048 focused on NIVO + RELA + IPI use in the advanced melanoma cohort and is the first disclosure from the study. Methods: Pts with advanced melanoma were treated with first-line NIVO 480 mg Q4W + RELA 160 mg Q4W + IPI 1 mg/kg Q8W until progression or unacceptable toxicity. Prior neoadjuvant/adjuvant therapy, including I-O agents, was permitted if completed > 6 mo before enrollment. Pts with controlled brain metastases were allowed to enroll. Primary endpoints were safety and confirmed objective response rate (ORR), disease control rate (DCR), and median duration of response (DOR) per investigator. The secondary endpoint was progression-free survival (PFS) per investigator (median and 6-mo/12-mo rates). Exploratory endpoints included overall survival (OS; median and 12-mo/24-mo rates). Results: In total, 46 pts were treated. Median follow-up was 49.4 mo (range, 0.4–55.0; database lock, Nov. 1, 2023). Median age was 61.0 y, 8.7% had cutaneous acral melanoma, 50.0% were BRAF positive, 73.9% were LAG-3 positive (≥ 1%), 26.1% were tumor cell PD-L1 positive (≥ 1%), and 6.5% had received prior adjuvant therapy. Median duration of treatment was 5.0 mo (range, 0.0–49.0). NIVO + RELA + IPI had a confirmed ORR of 58.7% and a 48-mo OS rate of 71.7% (table). Any-grade and grade 3/4 treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%) and 18 pts (39.1%), respectively. Any-grade TRAEs led to treatment discontinuation in 19 pts (41.3%). Deaths due to TRAEs occurred in 2 pts (4.3%; rectal hemorrhage and dyspnea [n = 1], immune-mediated myositis [n = 1]). Conclusions: In RELATIVITY-048, NIVO + RELA + IPI demonstrated encouraging efficacy, with a confirmed ORR of 58.7% and a 48-mo OS rate of 69.1%. There were no new safety signals with NIVO + RELA + IPI, and the safety profile was generally consistent with I-O combinations. Given the small sample size, additional studies are needed to confirm the efficacy and safety of NIVO + RELA + IPI. Clinical trial information: NCT03459222 . [Table: see text]

Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Mycoplasma pneumoniae-Associated Encephalitis: Favorable Aggressive Immunosuppression in a Patient

AbstractMeningoencephalitis is the most important extrapulmonary manifestation of Mycoplasma pneumoniae infection. It is complicated by seizures in at least 40% of cases, and in half of them, status epilepticus can occur during the acute phase, often leading to severe neurological sequelae. Brain imaging ranges from normal to diffuse edema, focal changes, and abnormal signals in the white matter, basal ganglia, and hippocampi. Here, we describe a boy who presented with an acute onset of transient alteration of behavior, meningeal irritation, fever, vomiting, and leg pain. Meningoencephalitis due to M. pneumoniae infection was confirmed by focal pneumonia, positive immunological tests, and increased protein content in cerebrospinal fluid. Magnetic resonance imaging of the brain showed bilateral focal abnormalities in the temporoinsular cortex, and electroencephalographic recordings showed slow waves in the same regions. After early infusion of acyclovir on the first day, aggressive combination therapy with oral erythromycin, and intravenous methylprednisolone and immunoglobulin was promptly initiated once a complete diagnosis was obtained on the second day, and the boy recovered within a few days. Two weeks later, brain imaging findings had resolved completely. The rapid clinical and neuroradiological recovery after immunosuppressive therapy suggests an immune-mediated pathogenetic mechanism. He developed immune-mediated myositis 2 years later demonstrating the instability of his immunological status.

Symposium 11

Autoimmune diseases are conditions of immune dysfunction, leading to inappropriate hyperactivation of the adaptive immunity and subsequent damage to various tissues of the host. Autoimmune conditions presenting in the rheumatology clinics (rheumatoid arthritis, systemic lupus erythematosus or immune mediated myositis) are often treated by immunosuppression, which are almost invariably associated with increased susceptibility to infections. However, immunosuppression can sometimes be used to conversely treat susceptibility to infections. An emerging group of autoimmune diseases which target the host’s own immune system (or associated cytokines) are becoming increasing recognized which phenotypically mimics various immunodeficiency syndromes – known as “phenocopies of PID”. One particular phenocopy of a PID known as Mendelian Susceptibility to Mycobacterial Disease (MSMD) has been increasingly recognized in our locality. This “acquired MSMD” is due to autoantibodies against anti-IFN[Formula: see text], leading to increased susceptibility to mycobacterial and other “IFN-[Formula: see text] dependent” infections. Alike other autoimmune diseases, appropriate and targeted immunosuppression can alleviate the effect of anti-IFN-[Formula: see text] antibodies and aid treatment of associated infections. During this talk, our experience in the diagnosis and management toward acquired MSMD in our locality will be discussed. We will also share findings from our novel diagnostic and functional tests, as well as outcomes of acquired MSMD patients treated with B-cell depleting therapies.

P54 T-cell response to SRP-9001 dystrophin transgene in a patient treated with Delandistrogene Moxeparvovec: a case of immune-mediated myositis

P54 T-cell response to SRP-9001 dystrophin transgene in a patient treated with Delandistrogene Moxeparvovec: a case of immune-mediated myositis

Real-World Experience of Tixagevimab and Cilgavimab (Evusheld) in Rheumatologic Patients on Rituximab.

Although vaccination is the primary strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), rheumatologic patients on B-cell depleting agent rituximab may have a suboptimal response. Tixagevimab and cilgavimab (Evusheld) could be administered under Food and Drug Administration emergency use authorization as pre-exposure prophylaxis. A cohort study of rheumatologic patients on rituximab therapy who received Evusheld was followed longitudinally. Adverse events were monitored. Forty-three patients received Evusheld, with diagnoses including rheumatoid arthritis, ANCA vasculitis, immune-mediated myositis, Sjögren disease, and systemic lupus erythematosus. Average time to follow-up was 100 ± 33 days. One patient experienced symptomatic infection with SARS-CoV-2 confirmed by home antigen test twice. A total of 97.8% of patients during follow-up did not contract acute SARS-CoV-2 infection. At the same time, 32,074 new local cases were reported with a local cumulative SARS-CoV-2 incidence rate of 4.32%. Adverse events included myalgia, flu-like symptoms, fevers, injection site pain, or headache. No serious adverse events, anaphylaxis, or cardiac events occurred. Evusheld demonstrated effectiveness in preventing symptomatic SARS-CoV-2 infection in a real-world cohort of rheumatologic patients on rituximab therapy. Administration of Evusheld may be considered as part of a multilayered approach to risk mitigation in this high-risk population as pre-exposure prophylaxis.

Abnormality Pattern of F-18 FDG PET Whole Body with Functional MRI Brain in Post-Acute COVID-19.

PurposeThe study aimed to investigate imaging abnormalities associated with post-acute COVID-19 using F-18 FDG PET/CT and PET/ rsfMRI brain.MethodsWe retrospectively recruited 13 patients with post-acute COVID-19. The post-acute COVID-19 symptoms and neuropsychiatric tests were performed before F-18 FDG PET/CT whole body with PET/rsfMRI brain. Qualitative and semiquantitative analyses were also conducted in both whole body and brain images.ResultsAmong the 13 patients, 8 (61.5%) had myositis, followed by 8 (61.5%) with vasculitis (mainly in the thoracic aorta), and 7 (53.8%) with lung abnormalities.. Interestingly, one patient with a very high serum RBD IgG antibody demonstrated diffuse myositis throughout the body which potentially associated with immune-mediated myositis. One patient experienced psoriasis exacerbation with autoimmune-mediated after COVID-19. Most patients had multiple areas of abnormal brain connectivity involving the frontal and parieto-temporo-occipital lobes, as well as the thalamus.ConclusionThe whole body F-18 FDG PET can be a potential tool to assess inflammatory process and support the hyperinflammatory etiology, mainly for lesions in skeletal muscle, vascular wall, and lung, as well as, multiple brain abnormalities in post-acute COVID-19. Nonetheless, further studies are recommended to confirm the results.

Epidemiology, mortality and effectiveness of prophylaxis for Pneumocystis jiroveci pneumonia among rheumatic patients: a territory-wide study

BackgroundPneumocystis jiroveci pneumonia (PJP) is an opportunistic infection affecting immunocompromised individuals. However, evidence regarding the burden and effectiveness of prophylaxis among rheumatic patients remains limited. Delineating the epidemiology and efficacy of prophylaxis among rheumatic patients is urgently needed.MethodsWe performed a territory-wide cohort study of rheumatic patients in Hong Kong. All patients with a diagnosis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), immune-mediated myositis (IMM), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or spondyloarthritis (SpA) between 2015 and 2019 were included. Prevalence, frequency of prophylaxis and mortality of PJP were calculated. Number needed to treat (NNT) analysis was also performed.ResultsOut of 21,587 patients (54% RA, 25% SLE, 13% SpA, 5% IMM, 2% AAV and 1% SSc), 1141 (5.3%) patients were prescribed PJP prophylaxis. 48/21,587 (0.2%) developed PJP. No patients who developed PJP received prophylaxis prior to infection. The incidence of PJP was highest among SSc, AAV, and IMM patients. Among these diseases, the majority of PJP occurred while patients were on glucocorticoids at daily prednisolone-equivalent doses of 15 mg/day (P15) or above. PJP prophylaxis was effective with NNT for SSc, AAV and IIM being 36, 48 and 114 respectively. There were 19 PJP-related mortalities and the mortality rate was 39.6%.ConclusionPJP is an uncommon but important infection among rheumatic patients, PJP prophylaxis is effective and should be considered in patients with SSc, AAV and IMM, especially those receiving glucocorticoid doses above P15.

Phase 2 Study of Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-Hodgkin Lymphomas

Introduction: Immune tolerance and evasion plays a significant role in the pathogenesis of EBV+ lymphoproliferative disorders (LPD) and non-Hodgkin lymphomas (NHL). Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. PD-L1 expression is a marker of poor prognosis in aggressive lymphomas and most EBV+ LPDs demonstrate high levels of PD-L1 expression. Chronic viral infections, such as EBV, also result in T-cell exhaustion that can be reversed by PD-1 blockade. Nivolumab is a fully human IgG4 monoclonal anti-PD-1 antibody which has demonstrated activity and favorable safety in lymphoid malignancies. We hypothesized that PD-1 blockade may reverse the inactivation of tumor-specific effector T-cells and result in anti-tumor responses in EBV+ LPD and NHL.Methods: Relapsed/refractory (R/R) EBV+ LPD and B-cell NHL pts age ≥ 12y with adequate organ function are eligible. Untreated pts are eligible if EBV+ LPD. Exclusions include prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, prior solid organ transplant and HIV. Pts with immunodeficiency or autoimmune illness are eligible if not requiring steroids or immunosuppression. CNS involvement is permitted if no seizure activity within 4 weeks of study. Nivolumab 480mg IV is given every four weeks for up to 2y. Pts who achieve CR discontinue nivolumab after 1y of treatment. Baseline evaluation includes CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy along with optional tumor biopsy. CT scans are performed after cycles 3, 6, 13 and 19 and end of treatment (EoT). PET is performed after cycles 1, 3 and EoT. Surveillance CT scans are performed q3m for 1y, q6m for yrs 2-5, and annually thereafter.Results: 9 pts, 7 (78%) R/R and 2 (22%) untreated, enrolled between April 2018 and May 2021; 5 (56%) with EBV+ LPD [4 G1-2 lymphomatoid granulomatosis (LYG) and 1 chronic active EBV disease (CAEBV)] and 4 (44%) with EBV+ NHL (all DLBCL, NOS). Median age was 48y (range 30-63) and all pts (100%) had stage III/IV disease. Four pts (44%) had elevated LDH (all DLBCL). Median baseline CD4 and CD8 count (cells/mcL) was 378 (range 99-984) and 86 (range 22-1237), respectively, for LPD and 190 (range 133-255) and 90 (range 9-630), respectively, for NHL. Median EBV VL at baseline (Log10 IU/mL) was 2.55 (range 0-6.78) and 2.53 (range 0-5.33) for LPD and NHL, respectively. Eight (89%) pts had extranodal disease with pulmonary involvement most common in 6 (67%). Median prior therapies were 1 (range 0-1) and 2 (range 1-4) for LPD and NHL pts, respectively. Three (43%) R/R pts were refractory (i.e., <PR) to last therapy.Of 9 pts enrolled, 7 were evaluable for response (1 NHL pt died prior to restaging and 1 NHL pt has not yet been restaged). In 6 measurable pts, tumor reduction was observed in 67% (Fig 1A). ORR and CR rate was 57% (4/7) and 43% (3/7), respectively; 60% (3/5) and 40% (2/5) in LPD and 50% (1/2) and 50% (1/2) in NHL. Median TTR was 3.0m with 3 (75%) of 4 responses ongoing from 6.9m to 35.2m after first response (Fig 1B).Most common adverse events (AEs) (% pts) included maculopapular rash (38%), ALT elevation (25%), AST elevation (25%), CPK elevation (25%) and fatigue (25%). One pt discontinued therapy due to G2 immune-mediated myositis that required prolonged steroid therapy. >G3 AEs included AST elevation in 1 (13%) pt with no G4/G5 or serious adverse events.With a median potential follow up of 12.6m, 12-month PFS and OS was 50.8% (95% CI: 15.7-78.1) and 75.0% (95% CI: 31.5-93.1). In LPD pts, 12-month PFS and OS was 80% (95% CI: 20.4-96.9) and 100%. Three (75%) NHL pts progressed and 2 (50%) died of disease progression. One NHL pt stopped therapy due to apparent disease progression after 2 cycles but later developed CR without further therapy and remains in remission 35.2m after stopping therapy.Conclusion: Nivolumab appears safe in pts with EBV+ LPD and NHL without unexpected toxicities. Preliminary clinical activity, including CRs, is noted in pts with EBV+ LPD and NHL. Additional pts are needed for a better assessment of true activity in these rare entities and correlates of response including PD-1/PD-L1 expression and/or 9p24.1 alterations are ongoing and will be presented at the meeting. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Nivolumab for EBV+ LPD and EBV+ NHL.

Leishmania spp.-Infected Dogs Have Circulating Anti-Skeletal Muscle Autoantibodies Recognizing SERCA1.

Leishmania spp. infection is associated with an inflammatory myopathy (IM) in dogs. The pathomechanism underlying this disorder is still elusive, however, the pattern of cellular infiltration and MHC I and II upregulation indicate an immune-mediated myositis. This study aimed to investigate the presence of autoantibodies targeting the skeletal muscle in sera of leishmania-infected dogs and individuate the major autoantigen. We tested sera from 35 leishmania-infected dogs and sera from 10 negative controls for the presence of circulating autoantibodies with indirect immunofluorescence. Immunoblot and mass spectrometry were used to identify the main target autoantigen. Immunocolocalization and immunoblot on immunoprecipitated muscle proteins were performed to confirm the individuated major autoantigen. We identified circulating autoantibodies that recognize skeletal muscle antigen(s) in sera of leishmania-infected dogs. The major antigen was identified as the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1 (SERCA1). We also found that canine SERCA1 presents several identical traits to the calcium-translocating P-type ATPase of Leishmania infantum. In the present study, we defined circulating anti-SERCA1 autoantibodies as part of the pathogenesis of the leishmania-associated IM in dogs. Based on our data, we hypothesize that antigen mimicry is the mechanism underlying the production of these autoantibodies in leishmania-infected dogs.

Meningoradiculitis and Immune Mediated Myositis in a Patient with Lyme disease: A Case Report of a Probably Underestimated Association

We describe the association of cervical meningoradiculitis and focal immune mediated myositis secondary to Borrelia infection in a 62 year old immune competent patient. Diagnosis was made by lumbar puncture, nerve conduction studies and muscle magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) analysis found evidence of an inflammatory process with elevated production of Borrelia IgG antibodies. Deltoid muscle biopsy detected the presence of spirochetal DNA with immunohistochemical changes corresponding to dermatomyositis. The clinical – pathological associations made in this case can help clarify the intricate processes that take place on a cellular level in patients with Lyme disease.

Immune-Mediated Necrotizing Myositis Presenting with Cutaneous Lesions.

Immune-Mediated Necrotizing Myositis Presenting with Cutaneous Lesions.

An E321G MYH1 mutation is strongly associated with nonexertional rhabdomyolysis in Quarter Horses.

BackgroundAn E321G mutation in MYH1 was recently identified in Quarter Horses (QH) with immune‐mediated myositis (IMM) defined by a phenotype of gross muscle atrophy and myofiber lymphocytic infiltrates.Hypothesis/ObjectivesWe hypothesized that the MYH1 mutation also was associated with a phenotype of nonexertional rhabdomyolysis. The objective of this study was to determine the prevalence of the MYH1 mutation in QH with exertional (ER) and nonexertional (nonER) rhabdomyolysis.AnimalsQuarter Horses: 72 healthy controls, 85 ER‐no atrophy, 56 ER‐atrophy, 167 nonER horses selected regardless of muscle atrophy.MethodsClinical and histopathologic information and DNA was obtained from a database for (1) ER > 2 years of age, with or without atrophy and (2) nonER creatine kinase (CK) ≥ 5000 U/L, <5 years of age. Horses were genotyped for E321G MYH1 by pyrosequencing.ResultsThe MYH1 mutation was present in a similar proportion of ER‐no atrophy (1/56; 2%) and in a higher proportion of ER‐atrophy (25/85; 29%) versus controls (4/72; 5%). The MYH1 mutation was present in a significantly higher proportion of nonER (113/165; 68%) than controls either in the presence (39/42; 93%) or in absence (72/123; 59%) of gross atrophy. Lymphocytes were present in <18% of muscle samples with the MYH1 mutation.Conclusions and Clinical ImportanceAlthough not associated with ER, the MYH1 mutation is associated with atrophy after ER. The MYH1 mutation is highly associated with nonER regardless of whether muscle atrophy or lymphocytic infiltrates are present. Genetic testing will enhance the ability to diagnose MYH1 myopathies (MYHM) in QH.

A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses

BackgroundThe cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The histopathologic hallmark of IMM is lymphocytic infiltration of myofibers. The purpose of this study was to identify putative functional variants associated with equine IMM.MethodsA genome-wide association (GWA) study was performed on 36 IMM QHs and 54 breed matched unaffected QHs from the same environment using the Equine SNP50 and SNP70 genotyping arrays.ResultsA mixed model analysis identified nine SNPs within a ~ 2.87 Mb region on chr11 that were significantly (Punadjusted < 1.4 × 10− 6) associated with the IMM phenotype. Associated haplotypes within this region encompassed 38 annotated genes, including four myosin genes (MYH1, MYH2, MYH3, and MYH13). Whole genome sequencing of four IMM and four unaffected QHs identified a single segregating nonsynonymous E321G mutation in MYH1 encoding myosin heavy chain 2X. Genotyping of additional 35 IMM and 22 unaffected QHs confirmed an association (P = 2.9 × 10− 5), and the putative mutation was absent in 175 horses from 21 non-QH breeds. Lymphocytic infiltrates occurred in type 2X myofibers and the proportion of 2X fibers was decreased in the presence of inflammation. Protein modeling and contact/stability analysis identified 14 residues affected by the mutation which significantly decreased stability.ConclusionsWe conclude that a mutation in MYH1 is highly associated with susceptibility to the IMM phenotype in QH-related breeds. This is the first report of a mutation in MYH1 and the first link between a skeletal muscle myosin mutation and autoimmune disease.

Immune-Mediated Muscle Diseases of the Horse.

In horses, immune-mediated muscle disorders can arise from an overzealous immune response to concurrent infections or potentially from an inherent immune response to host muscle antigens. Streptococcus equi ss. equi infection or vaccination can result in infarctive purpura hemorrhagica (IPH) in which vascular deposition of IgA-streptococcal M protein complexes produces ischemia and complete focal infarction of skeletal muscle and internal organs. In Quarter Horse-related breeds with immune-mediated myositis, an apparent abnormal immune response to muscle antigens results in upregulation of major histocompatibility complex class (MHC) I and II on muscle cell membranes, lymphocytic infiltration of lumbar and gluteal myofibers, and subsequent gross muscle atrophy. Rarely, an inflammatory event results in myositis with subsequent systemic calcinosis characterized by a pathognomonic hyperphosphatemia and high fatality rate. This review presents an overview of these immune-mediated myopathies and highlights clinical and pathological features as well as the suspected pathophysiology.

Major Histocompatibility Complex I and II Expression and Lymphocytic Subtypes in Muscle of Horses with Immune-Mediated Myositis.

BackgroundMajor histocompatibility complex (MHC) I and II expression is not normally detected on sarcolemma, but is detected with lymphocytic infiltrates in immune‐mediated myositis (IMM) of humans and dogs and in dysferlin‐deficient muscular dystrophy.Hypothesis/ObjectivesTo determine if sarcolemmal MHC is expressed in active IMM in horses, if MHC expression is associated with lymphocytic subtype, and if dysferlin is expressed in IMM.AnimalsTwenty‐one IMM horses of Quarter Horse‐related breeds, 3 healthy and 6 disease controls (3 pasture myopathy, 3 amylase‐resistant polysaccharide storage myopathy [PSSM]).MethodsImmunohistochemical staining for MHC I, II, and CD4+, CD8+, CD20+ lymphocytes was performed on archived muscle of IMM and control horses. Scores were given for MHC I, II, and lymphocytic subtypes. Immunofluorescent staining for dysferlin, dystrophin, and a‐sarcoglycan was performed.ResultsSarcolemmal MHC I and II expression was detected in 17/21 and 15/21 of IMM horses, respectively, and in specific fibers of PSSM horses, but not healthy or pasture myopathy controls. The CD4+, CD8+, and CD20+ cells were present in 20/21 IMM muscles with CD4+ predominance in 10/21 and CD8+ predominance in 6/21 of IMM horses. Dysferlin, dystrophin, and a‐sarcoglycan staining were similar in IMM and control muscles.Conclusions and clinical importanceDeficiencies of dysferlin, dystrophin, and a‐sarcoglycan are not associated with IMM. Sarcolemmal MHC I and II expression in a proportion of myofibers of IMM horses in conjunction with lymphocytic infiltration supports an immune‐mediated etiology for IMM. The MHC expression also occured in specific myofibers in PSSM horses in the absence of lymphocytic infiltrates.

Secondary myopathy due to systemic diseases.

BackgroundSome systemic diseases also affect the skeletal muscle to various degrees and with different manifestations. This review aimed at summarizing and discussing recent advances concerning the management of muscle disease in systemic diseases.MethodLiterature review by search of MEDLINE, and Current Contents with appropriate search terms.ResultsSecondary muscle disease occurs in infectious disease, endocrine disorders, metabolic disorders, immunological disease, vascular diseases, hematological disorders, and malignancies. Muscle manifestations in these categories include pathogen‐caused myositis, muscle infarction, rhabdomyolysis, myasthenia, immune‐mediated myositis, necrotising myopathy, or vasculitis‐associated myopathy. Muscle affection may concern only a single muscle, a group of muscles, or the entire musculature. Severity of muscle affection may be transient or permanent, may be a minor part of or may dominate the clinical picture, or may be mild or severe, requiring invasive measures including artificial ventilation if the respiratory muscles are additionally involved. Diagnostic work‐up is similar to that of primary myopathies by application of non‐invasive and invasive techniques. Treatment of muscle involvement in systemic diseases is based on elimination of the underlying cause and supportive measures. The prognosis is usually fair if the causative disorder is effectively treatable but can be fatal in single cases if the entire musculature including the respiratory muscles is involved, in case of infection, or in case of severe rhabdomyolysis.ConclusionSecondary muscle manifestations of systemic diseases must be addressed and appropriately managed. Prognosis of secondary muscle disease in systemic diseases is usually fair if the underlying condition is accessible to treatment.

A case of myositis with immunological background associated with statin use

Abstract Statins might cause and/or aggravate the immune-mediated myositis in patients on long-term, stable treatment. We provide a case of polymyositis with an immunological background and gastrointestinal and urinary manifestations in patient on long-term, stable atorvastatin treatment for the past six years. The diagnose of polymyositis was established based on clinical symptoms and signs, electromyography and laboratory test results (elevated aspartate aminotransferase 279 U/L, reference range 0–40 U/L; alanine aminotransferase 198 U/L, 0–33 U/L; lactate dehydrogenase 2200 U/L, 103-227 U/L; creatine kinase 7820 U/L, 15–84 U/L; and positive antinuclear antibodies test, titer of 1:160, with suspect antisynthetase antibodies). Polymyositis was probably related to atorvastatin treatment (Naranjo score, 5). Other probable causes of the myositis were rejected. Coricosteroid therapy, methotrexate and supplementation with vitamin D did not improve the condition. The patient remained bedridden and died two months after the hospital discharge due to the acute myocardial infarction.

I.I.4 Autoimmune muscle diseases in dogs and cats: Spontaneous models for evaluation of therapies?

Spontaneously occurring autoimmune muscle diseases such as polymyositis (PM) and myasthenia gravis (MG) commonly affect dogs and to a lesser extent cats. A typical myopathic clinical phenotype including weakness, muscle atrophy and stiffness occurs in PM, and focal or generalized muscle weakness without atrophy occurs in MG. As in humans, diagnosis of PM is confirmed by muscle biopsies and immunophenotyping of cellular infiltrates, and of MG by a positive acetylcholine receptor antibody titer. Species-specific features of MG include frequent spontaneous immune remissions in the dog and a high incidence of thymoma associated MG in cats. Dermatomyositis in dogs is breed-associated and infrequently diagnosed. Most recently, a myopathy similar to spontaneous inclusion body myositis (sIBM) was identified in the dog recapitulating both the degenerative and inflammatory aspects of the human disease. Focal forms of immune-mediated myositis also occur in dogs including the apparently species-specific masticatory muscle myositis with muscle specific autoantibodies, and focal forms limited to other muscle groups. As rodent models have been largely unsuccessful in translation of new therapies for muscle diseases to human patients, large animal models of human muscle diseases are growing in importance and may be more clinically relevant. As autoimmune muscle diseases in large animals become better described and classified, these models of immune-mediated muscle disease will take a prominent role for therapeutic trials alongside the well established models of canine dystrophin deficient muscular dystrophy, centronuclear myopathy and myotubular myopathy.

Labordiagnostik von Myopathien

Laboratory investigations are an essential part in every work-up of primary myopathies and the results must be interpreted within the whole clinical context. The laboratory work-up should be arranged stepwise, beginning with basic screening measurements before more expensive special investigations including muscle biopsies or molecular genetic studies are undertaken. In this article the laboratory investigations for the group of immune-mediated myositis and metabolic myopathies are presented in detail. The laboratory tests for neuromyotonia, stiff person syndrome and neuromuscular transmission defects are also described. These disorders often present with clinical symptoms resembling those of primary myopathies.