Autoimmune Myopathy Research Articles

Mechanical-Stretch of C2C12 Myoblasts Inhibits Expression of Toll-Like Receptor 3 (TLR3) and of Autoantigens Associated with Inflammatory Myopathies

Recent studies in patients suffering from inflammatory autoimmune myopathies suggested that moderate exercise training improves or at least stabilizes muscle strength and function without inducing disease flares. However, the precise mechanisms involved in this beneficial effect have not been extensively studied. Here we used a model of in vitro stretched C2C12 myoblasts to investigate whether mechanical stretch could influence myoblast proliferation or the expression of proinflammatory genes. Our results demonstrated that cyclic mechanical stretch stimulated C2C12 cell cycling and early up-regulation of the molecules related to mechanical-stretch pathway in muscle (calmodulin, nNOS, MMP-2, HGF and c-Met). Unexpectedly, mechanical stretch also reduced the expression of TLR3 and of proteins known to represent autoantigens in inflammatory autoimmune myopathies (Mi-2, HRS, DNA-PKcs, U1-70). Interestingly, stimulation or inhibition of calmodulin, NOS, HGF or c-Met molecules in vitro affected the expression of autoantigens and TLR3 proteins confirming their role in the inhibition of autoantigens and TLR3 during mechanical stretch. Overall, this study demonstrates for the first time that mechanical stretch could be beneficial by reducing expression of muscle autoantigens and of pro-inflammatory TLR3 and may provide new insight to understand how resistance training can reduce the symptoms associated with myositis.

The spectrum of statin myopathy

This review discusses the spectrum of myopathies associated with statin use, with special attention given to a recently identified statin-associated autoimmune-necrotizing myopathy. The clinical characteristics of these patients, pathologic findings, associated autoantibody and immunogenetic risk factors are discussed. In the past several years, a novel form of autoimmunemyopathy associated with statin use has been described. Patients with this form of myositis have unique clinical, pathologic and pathophysiologic features when compared with those with self-limited statin toxic myopathy. An autoantibody directed against HMG-CoA reductase (HMGCR), the pharmacologic target of statins, characterizes the disease and can be used in clinical practice to identify these patients and direct therapy. Still, many questions remain to be answered regarding the pathogenic mechanisms at play, risk factors for developing the disease, long-term prognosis and effects of rechallenge with statins or other cholesterol-lowering drugs. Statins can cause a spectrum of muscle diseases, most of which are self-limited and improve with discontinuation of the offending agent. In a subgroup, an autoimmune necrotizing myopathy develops that persists after discontinuation of statins. Specific autoantibody testing can help identify these patients in clinical practice and determine the need for immunosuppressive therapy.

Antisynthetase syndrome: Not just an inflammatory myopathy

In recent years, antisynthetase syndrome has been recognized as an important cause of autoimmune inflammatory myopathy in a subset of patients with polymyositis and dermatomyositis. It is associated with serum antibodies to aminoacyl-transfer RNA synthetases and is characterized by a constellation of manifestations, including fever, myositis, interstitial lung disease, "mechanic's hands," Raynaud phenomenon, and polyarthritis. Physicians should be familiar with its variety of clinical presentations and should include it in the differential diagnosis in patients presenting with unexplained interstitial lung disease.

Acquired necrotizing myopathies

Necrotizing myopathy exhibits a specific histological pattern, characterized by significant necrosis, with simultaneous muscle fiber regeneration, but without or with little inflammation. This histological pattern may be observed in acquired myopathies but also in muscular dystrophy. Acquired necrotizing myopathy can be secondary to drugs or toxics agents, and if not, autoimmune mechanisms have to be suspected. Necrotizing autoimmune myopathy (NAM) is now recognized as a subgroup of idiopathic inflammatory myopathies. This review aims to further describe the different acquired myopathies, with special focus on NAM since specific autoantibodies have been discovered. Usually, acquired myopathy has an acute onset, but a slower progression may sometimes be observed that could lead to erroneous diagnosis of muscular dystrophy. NAM may be associated with specific autoantibodies against signal recognition particle, or, as more recently described, against 3-hydroxy-3-methylglutaryl-coenzyme A reductase, especially in statin-exposed patients. Their presence permits affirmation that muscular necrosis is immune-mediated. The antibody titer is correlated to the disease activity. NAMs are now considered as a new entity, treatable by immunosuppressants, and should not be misdiagnosed as a muscular dystrophy.

Statin‐associated autoimmune myopathy and anti‐HMGCR autoantibodies

Statins are among the most commonly prescribed medications that significantly reduce cardiovascular risk in selected individuals. However, these drugs can also be associated with muscle symptoms ranging from mild myalgias to severe rhabdomyolysis. Although statin myotoxicity is usually self-limited, in some instances statin-exposed subjects can develop an autoimmune myopathy typically characterized by progressive weakness, muscle enzyme elevations, a necrotizing myopathy on muscle biopsy, and autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the pharmacologic target of statins. These antibodies are also found in some autoimmune myopathy patients without statin exposure. Importantly, anti-HMGCR antibodies are not found in the vast majority of statin-exposed subjects without autoimmune myopathy, including those with self-limited statin intolerance. Thus, testing for these antibodies may help differentiate those with self-limited statin myopathy who recover after statin discontinuation from those with a progressive statin-associated autoimmune myopathy who typically require immunosuppressive therapy.

P.14.7 Anti-SRP antibody induces muscle cell lysis through complement mediated pathway

The signal recognition particle (SRP), an intracytoplasmic complex of ribonucleoprotein, binds to the endoplasmic reticulum (ER) localising signal sequences of elongating polypeptide chains during their synthesis and translocates nascent peptides to the ER membrane. Anti-SRP antibodies to one or more of the components have been associated with a necrotising autoimmune myopathy (NAM) characterised by severe subacute progressive proximal muscle weakness with very high serum CK levels. The muscle biopsies from such patients show abundant necrotic and regenerating fibres but only a sparse inflammatory infiltrate. These findings suggest that cytotoxic T cells and cell-mediated muscle fibre destruction are not involved. The possibility of a humoral mechanism has been proposed but this has not been investigated. In the present study, we utilised an in vitro human myoblast culture system to investigate a possible antibody-mediated cytotoxic mechanism of cell death. Anti-SRP positive sera from NAM patients or anti-SRP negative sera from healthy controls were incubated with myoblasts in the presence or absence of fresh complement. In the absence of complement, there was no difference in cell viability between two groups. In contrast, when complement was added, the survival of myoblasts incubated with anti-SRP positive serum was significantly reduced compared to cultures incubated with anti-SRP negative sera. In anti-SRP positive sera, we also observed complement deposition onto the membrane of normal human myoblast. Complement deposition was also observed on biopsies from three NAM patients who muscle sections were available. We conclude that one of the pathological pathways involved in muscle cell death in anti-SRP positive NAM is antibody-dependent complement mediated cell lysis. However, the possibility that more than one mechanism might be involved cannot be excluded and further studies would be helpful in understanding the pathogenesis of anti-SRP associated NAM.

P.21.9 Responsiveness of muscle testing and functions in a retrospective 51 inflammatory myopathies patient series

Some criteria have been developed to assess muscle strength in inflammatory myopathies, but with no consensus. We evaluated at baseline and 6 month later severely affected patients (excluding inclusion body myositis) who required a treatment combining steroids (at least 1 mg/kg), methotrexate, azathioprine or cyclophosphamide and intravenous immunoglobulins. We assessed by MRC testing: neck flexors, upper arm abductors, elbow flexors, hip flexors, knee extensors and flexors, and gluteus medius. We also recorded Barre and Mingazzini tests and CK level. Responsiveness of muscle testing was assessed with the calculation of Standardized Response Mean (SRM), and Effect Size (ES). Values of 0.8 were considered as small, moderate and large responsiveness, respectively. We included 51 patients (mean age 46.3), including 19 overlap myositis (OM, mostly anti-synthetase syndrome), 14 dermatomyositis (DM), and 18 necrotizing auto-immune myopathies (NAM). Baseline CK was 5533 ± 10798 U/L. OM and DM patients had a very close clinical presentation, while NAM had a poorer Mingazzini test (31.3, 37.7 and 10.1 s, respectively, p = 0.04) with a lower hip flexors testing (median: 3.5, 4, and 2, respectively, p = 0.003). Highest responsiveness was observed for hip flexors testing (SRM: 1.25, ES: 0.99), upper arm abductors (SRM: 1.11, ES: 0.99), elbow flexion (SRM: 0.96, ES: 0.91), and neck flexion (SRM: 0.89, ES: 0.82). Other muscular groups testing showed a moderate responsiveness, with knee extensors showing the weakest one (SRM: 0.51, ES: 0.53). CK level had a small responsiveness (mean decrease: −5208 UI/L, SRM: 0.48, ES: 0.48). Mingazzini and Barre’s tests had a noticeably large responsiveness (Barre: SRM: 1.01, ES: 0.78, Mingazzini: SRM: 0.89, ES: 0.2). When assessing myositis, responsive testing such as hip flexors and upper arm abductors testing should be preferred. Some simple clinical tests such as Barre and Mingazzini’s tests could also be an aid.

I.I.2 Role of cytokines and chemokines in inflammatory myopathies

Corticosteroids remain standard treatment for dermatomyositis (DM), polymyositis (PM) and necrotizing autoimmune myopathy (NAM) but they may be only partially effective or cause serious side effects. Moreover, inclusion body myositis (IBM) patients do not respond to any immunosuppressive and immunomodulatory drugs currently available. A better understanding of the deleterious and beneficial effects of the different immune proteins that make up the muscle microenvironment may identify new and better targeted immunotherapies. In this respect, knowledge of cytokines and the chemotactic subgroup of cytokines termed chemokines is of utmost importance. Three chemokine ligand-receptor pairs are primarily involved in each type of inflammatory myopathy (IM): CXCL10/CXCR3, CXCL12/CXCR4, CCL2/CCRR, further supporting these being Th1-mediated diseases. Disturbances in the cytokine balance have been unraveled, characterized by down regulation of immunomodulatory and/or upregulation of pro-inflammatory cytokines. Tumor necrosis factor alpha (TNF α ), type 1 interferons ( α / β ), Interleukin-1 (IL-1), IL-2 and IL-6 stand out as the most important cytokines, some of them differentially involved in DM vs. PM/IBM. DM is specifically associated with type 1 interferon-mediated immune processes. The prominent expression of the catabolic cytokine TNF α in the IM warranted exploration of anti-TNF α therapeutic strategies. Results so far have mainly been disappointing, but subgroups may benefit. Several other cytokines, chemokines or their receptors can now be targeted with biologicals or small molecule drugs, holding promise to find specific and efficacious therapies, whilst avoiding the toxicity seen in existing systemic anti-inflammatory therapeutics. Also, the cytokine and chemokine expression patterns could serve as biomarkers to predict responsive and non-responsive patients, or their levels may be monitored as surrogate outcome measures in clinical trials.

P.14.11 Auto-immune necrotizing myopathies with anti-HMGCR antibodies are related to statin-exposure only for a minority of cases

Necrotizing autoimmune myopathy (NAM) is a group of severe acquired myopathies, characterized by prominent myofiber necrosis with little or no muscle inflammation. They can be misdiagnosed as muscular dystrophies, preventing initiation of appropriate therapy. Specific auto-antibody anti-Signal recognition protein is observed in 16% of cases. Recently, auto-antibodies against 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) were identified in NAM patients by one group, especially in statin exposed patients. Here we report the first European series of patients. We detected and quantified anti-HMGCR auto-antibodies using addressable laser bead immunoassay that we developed. Patients (n = 38) were 44 ± 19 years old (3 pediatric cases) and sex ratio male: female was 0.22. Statin exposure was recorded in 40% of patients. Patients suffered from myalgia (44%), and had a muscular deficit (92%). Subacute onset (less than 6 months) was noted for most of them (n = 18), nevertheless 10 patients had a slow progressive muscular deficit (10 months to years). Severe proximal weakness was observed (72%) and three patients were bedridden at the diagnosis. All patients had increase CK level (6630 ± 5990 UI/L). CK level correlated with muscular strength (r2 = −0.64, p = 0.005) and to anti-HMGR titer (r2 = −0.5, p = 0.04). None patients presented signs of pulmonary involvement. Mean duration of treatments (steroids, immunosupressant and/or IgIV) was 30.1 ± 36.1 [3–42] months, and to date it was not possible to stop the treatment for any patient. This the first study confirming the observation and the description of anti-HMGCR NAM. The majority of patients we detected was statin-naive, had a severe weakness and need prolonged treatments. Anti-HMGCR auto-antibodies testing may be warranted in dystrophic like patients. Anti-HMGR titer correlates with CK level suggesting their role in physiopathogenesis.

P.14.10 Respiratory failure as presenting symptom of paraneoplastic necrotizing autoimmune myopathy

Necrotizing autoimmune myopathy (NAM) is associated with cancer, connective tissue disorders, and statin use. Respiratory failure as a presenting symptom has been reported in rare cases of other inflammatory myopathies, but not in NAM. A 48-year-old woman was acutely admitted with severe hypercapnia which required immediate endotracheal intubation. History revealed that she experienced shortness of breath since one month. Her past medical history included a mastectomy 2years prior to admission, because of noninvasive ductal mammacarcinoma. On admission there was mild symmetrical proximal weakness of her arms and legs and slightly more pronounced distal weakness of her legs, as well as weakness of her neck flexor muscles, which in retrospect had been gradually progressive in the weeks before presentation. Serum creatine kinase activity was five times the upper limit of normal and electromyography exhibited extensive myopathic changes. Magnetic resonance imaging (T2 weighted images) showed hyperintensity of the pelvic girdle and proximal leg muscles. Muscle biopsy showed extensive muscle fibre necrosis in the absence of inflammatory cells. Myositis immunoblot did not show myositis specific antibodies. A diagnosis of paraneoplastic NAM was made and monthly courses of oral dexamethasone pulse therapy was started which led to prompt extubation and remarkable recovery of muscle strength in weeks. Acute respiratory failure can be a presenting symptom in paraneoplastic necrotizing autoimmune myopathy. Paraneoplastic NAM should be considered in all patients with (sub) acute onset of symmetrical and progressive limb weakness and a history of malignancy. Immunosuppressive therapy can lead to substantial recovery.

Les myopathies nécrosantes auto-immunes

Necrotizing autoimmune myopathies are included in the spectrum of inflammatory myopathies, together with polymyosis, dermatopolymyosis and inclusion body myositis, despite the characteristic feature of marked muscular necrosis without inflammatory infiltrates. The clinical presentation is highly variable, often similar to the other inflammatory myopathies. The most common finding is nevertheless the severe form with rhabdomyolysis. The creatine kinase level is elevated (around 10,000IU/l) and electromyography shows myopathic changes with increased spontaneous activities reflecting the importance of the muscular necrosis. Muscle biopsy is required for diagnosis, revealing active necrosis of the muscle fibers without inflammatory invasion by CDA+ or CD8+ T-cells. Deposition of a microvascular membrane attack complex (C5b9) is often noted, whereas the upregulation of MHC class 1 is rarely detected. Signs of endomysial microangiopathy are frequently reported. Necrotizing autoimmune myopathies can be associated with antisignal recognition particle (SRP) antibodies or more rarely with the usual inflammatory myopathy antibodies. Paraneoplasic forms are described but remain exceptional. Lastly, necrotizing autoimmune myopathies, sometimes associated with statin therapy, have been recently described. They are linked with an antibody directed against 3-hydroxy-3-methyglutaryl-coenzyme A. Treatment is based on corticosteroid therapy, immunosuppressive drugs or intravenous immunoglobulins. Response is variable, depending on the clinical form.

Myopathie nécrosante auto-immune associée aux anticorps anti-hydroxy-méthyl-glutaryl-coenzyme A réductase

IntroductionStatins or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (HMGCR) are among the most commonly prescribed treatment in France. They may be responsible for muscular intolerance with variable severity. They have been recently involved in the occurrence of an acquired inflammatory myopathy associated with anti-HMGCR antibodies. This new type of toxic myopathy remains poorly known by clinicians. ObservationWe report a 61-year-old woman treated with a statin for many years who developed a lower and upper limb disabling myopathy with a rapid unfavourable course despite treatment withdrawal. Clinical history and investigations, especially including an assay for anti-HMGCR antibodies led to the diagnosis of autoimmune necrotizing myopathy with anti-HMGCR antibodies. Subsequent initiation of an immunosuppressive treatment by corticosteroids and methotrexate was effective. ConclusionStatins may unmask or cause an autoimmune necrotizing myopathy associated with the presence of anti-HMGCR antibodies. Their identification is now routinely available. An immunosuppressive treatment is necessary and justified by the autoimmune nature of the disease.

SP0089 Necrotising myopathy - the new kid on the block that the old kids need to recognise

Necrotizing autoimmune myopathy (NAM) is a newly recognized group of idiopathic inflammatory myopathies, characterized by pathological features of prominent myofiber necrosis without significant inflammation nor HLA re-expression. Although their precise...

Statin-Associated Polymyositis Following Omeprazole Treatment

Statins are an extensively used class of drugs, and myopathy is an uncommon, but well-described side effect of statin therapy. Inflammatory myopathies, including polymyositis, dermatomyositis, and necrotizing autoimmune myopathy, are even more rare, but debilitating, side effects of statin therapy that are characterized by the persistence of symptoms even after discontinuation of the drug. It is important to differentiate statin-associated inflammatory myopathies from other self-limited myopathies, as the disease often requires multiple immunosuppressive therapies. Drug interactions increase the risk of statin-associated toxic myopathy, but no risk factors for statin-associated inflammatory myopathies have been established. Here we describe the case of a man, age 59 years, who had been treated with a combination of atorvastatin and gemfibrozil for approximately 5 years and developed polymyositis after treatment with omeprazole for 7 months. Symptoms did not resolve after discontinuation of the atorvastatin, gemfibrozil, and omeprazole. The patient was treated with prednisone and methotrexate followed by intravenous immunoglobulin, which resulted in normalization of creatinine kinase levels and resolution of symptoms after 14 weeks. It is unclear if polymyositis was triggered by interaction of the statin with omeprazole and/or gemfibrozil, or if it developed secondary to long-term use of atorvastatin only.

Renal involvement in autoimmune connective tissue diseases

Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation, leading to autoantibody production. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. Alterations of kidney function in Sjögren syndrome, systemic scleroderma (SSc), auto-immune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus (SLE), antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that.In SLE, renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings. Patients with scleroderma renal crisis (SRC), which is usually characterized by severe hypertension, progressive decline of renal function and thrombotic microangiopathy, show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome, auto-immune myopathies, APSN and RA.In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions.

Therapie der Myositiden

Idiopathic inflammatory myopathy consists of dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and necrotizing autoimmune myopathy (NAM). At all stages of myositis, physiotherapy is effective in improving muscle strength, endurance and in maintaining joint motion. In DM and PM the therapy is initiated with glucocorticosteroids. Steroid-sparing agents (azathioprine, methotrexate and cyclosporin A) are added to prevent Cushing's syndrome or an unsatisfactory response. Therapy can also be escalated with intravenous immunoglobulins. Tacrolimus and mycophenolate mofetil (MMF) were effective in small case series. Cyclophosphamide is restricted to patients not responding to previous agents. For treatment intensification immunoglobulins can also be combined with MMF. There is not enough evidence to routinely recommend rituximab. The results with TNF-alpha inhibitors and plasmapheresis were negative or inconsistent. In DM skin involvement responds to sun blockers, antimalarials, topical corticosteroids or calcineurin inhibitors. In NAM statins should be discontinued and treatment with prednisone and immunosuppressants initiated. In IBM a therapeutic trial with prednisone, methotrexate or azathioprine may be warranted, especially in cases in which the serum creatine kinase (CK) is elevated or an inflammatory infiltrate is present in the muscle biopsy.

Pathological Changes of Necrotizing Autoimmune Myopathy Associated with Anti-Signal Recognition Particle Antibody (P07.044)

Pathological Changes of Necrotizing Autoimmune Myopathy Associated with Anti-Signal Recognition Particle Antibody (P07.044)

Statin-associated necrotizing autoimmune myopathy

Necrotizing autoimmune myopathy (NAM) is a severe adverse effect of statins. We report a 66-year-old Caucasian female who had progressive proximal muscle weakness after treatment with statins. Results of a muscle biopsy showed necrotizing myopathy with minimal inflammatory cell infiltrate and increased major histocompatibility class I antigen expression in muscle fibers. The clinical and laboratory parameters improved significantly with immunosuppressive treatment. Although it is a rare event, statin-induced NAM should be included as a differential diagnosis of myopathies.

Role of the promoter polymorphism IL-6 -174G/C in dermatomyositis and systemic lupus erythematosus.

The promoter polymorphism −174G/C within the interleukin-6 gene (IL-6) has been reported to have a functional importance through the modulation of IL-6 gene expression in vitro and in vivo. IL-6 is thought to play an important role in autoimmune diseases and the effect of its receptor inhibitor—tocilizumab—has been recently studied. The aim of this case-control study was to investigate the association between the interleukin-6 −174G/C single nucleotide polymorphism and the susceptibility to dermatomyositis (DM) and systemic lupus erythematosus (SLE) in Bulgarian patients. Altogether, 87 patients—52 with SLE and 35 with DM—as well as 80 unrelated healthy controls were included in this study. All of them were analyzed by restriction fragment length polymorphism analysis (RFLP). The GG genotype and the G allele appeared to be associated with SLE, especially in women. None of the genotypes showed an association with DM. However, the G allele appeared to be associated with muscle weakness and it is a risk factor for elevated muscle enzymes. Our results indicate that IL-6 −174G/C polymorphism might be associated with the susceptibility to SLE especially in women. Although it is not associated with DM, it seems that IL-6 −174G/C polymorphism could modulate some clinical features in the autoimmune myopathies.

A case of polymyositis associated with Hashimoto's thyroiditis

A case of polymyositis associated with Hashimoto's thyroiditis