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Typical Clinicopathologic features of anti-HMGCR Myopathy. (A) Summary of clinical findings on exam and ancillary testing. (B) muscle MRI of the lower extremities. Note selective involvement of paraspinal, gluteals in the hip and posterior and medial compartments of the thigh. Short tau inversion recovery (STIR) signal increase can be patchy and asymmetric. (C) A typical hematoxylin and eosin stain of a patient with anti-HMGCR myopathy showing myofiber atrophy, degeneration, and regeneration without prominent lymphocytic inflammation.
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Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients...
Contexts in source publication
Context 1
... reported by multiple international groups, albeit with some variations [20][21][22][23][24][25]. Nonetheless, as we will show, these wide-ranging phenotypes can be grouped as one disease, anti-HMGCR myopathy, based on shared muscle biopsy features (∼80% have a pre- dominantly necrotizing myopathy) and the presence of anti-HMGCR autoantibodies (Fig. ...
Context 2
... biopsy findings in anti-HMGCR myopathy are typical of a pauci-immune necrotizing myopathy, showing myofiber degeneration and necrosis with a variable density of regenerating fibers (Fig. 1C). Quantification of myofiber atrophy has also high- lighted this as a dramatic feature of the muscle pathology [31]. In patients with chronic disease, fiber size variability, internally placed nuclei, and increased endomysial fibrosis can be seen. Perivas- cular chronic inflammation can occasionally be seen but lymphocytic invasion of ...
Context 3
... for proximal muscles. The three most affected mus- cle groups in the proximal lower extremities include the posterior thigh, gluteal, and medial thigh com- partments [22,26,28]. Distal muscles in the lower leg compartment are less studied. Short tau inver- sion recovery (STIR) signal is usually increased more diffusely and may be asymmetric (Fig. 1B). T1 hyperintensity reflects connective tissue and fatty replacement in the muscle; this is not likely to be reversed by immunosuppressive therapy. The portion of muscle weakness that is reflected by STIR signal increase without T1 change highlights the muscle at risk that can potentially benefit from ...
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Citations
... 28 The mechanism of muscle injury caused by statins was reported related to the overexpression of HMG-CoA reductase in various tissues and cell types, and then activate T cell receptors to induce autoimmunity, which ultimately leads to muscle fiber atrophy and degeneration. 29 ...
... 30 Myalgia can manifest as aches, tenderness, and cramps with normal CK level, while myopathy can characterized by muscle weakness, but the CK level may not elevated 28 Pathological staining of statin-induced myopathy showed atrophy, degeneration, and regeneration of muscle fibers, but without obvious lymphocyte inflammation. 29 If the muscle injury develops into myositis, it may manifest as pain, redness, and elevated temperature with histopathological features of macrophages and inflammatory T and B cells. Rhabdomyolysis is the most severe muscle injury state with dead tissue, manifested by myonecrosis with varying degrees of elevated CK levels, as well as the increase of serum creatinine ≥0.5 mg/dL from baseline. ...
Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.
... In some cases, trunk muscle weakness is the only symptom of the disease. Extramuscular symptoms, including skin lesions, arthritis, or Raynaud's phenomenon, are not frequent [22,23]. ...
... The diagnosis of IMNM is based on electromyography (EMG), MRI, muscle biopsy, and the presence of characteristic antibodies [24]. The elevation of creatine kinase (CK) activity may vary from 10 to 100 times above normal [23]. ...
Drug-induced myopathies are a common cause of muscle pain, and the range of drugs that can cause muscle side effects is constantly expanding. In this article, the authors comprehensively discuss the diagnostic and therapeutic process in patients with myalgia, and present the spectrum of drug-induced myopathies. The review provides a detailed analysis of the literature on the incidence of myopathy during treatment with hypolipemic drugs, beta-blockers, amiodarone, colchicine, glucocorticosteroids, antimalarials, cyclosporine, zidovudine, and checkpoint inhibitors, a group of drugs increasingly used in the treatment of malignancies. The article considers the clinical course of the different types of myopathies, their pathogenesis, histopathological features, and treatment methods of these disorders. The aim of this paper is to gather from the latest available literature up-to-date information on the course, pathophysiology, and therapeutic options of drug-induced myopathies, to systematize the knowledge of drug-induced myopathies and to draw the attention of internists to the fact that these clinical issues are an important therapeutic problem.
... Two of the four patients reported in an initial case series of anti-HMGCR IMNM from New Zealand were Pacific Islanders [51]. Finally, in reviewing records from a hospital which exclusively services an American Indian population of 18,000 people (and 1,800 statin-users) with relatively low migration, six patients over a period of three years were affected by anti-HMGCR IMNM, once again Table 1 The spectrum of statin myotoxicity and features distinguishing statin-related immune-mediated necrotising myopathy from myotoxicity adapted from [9,[12][13][14]. Statin suggesting higher prevalence in this population [52]. ...
... Loss of immune tolerance resulting in anti-HMGCR synthesis and immune-mediated muscle damage is influenced by genetic and environmental factors. It has also been theorised that statins may directly affect the immune system, predisposing to autoimmunity [14]. The endoplasmic reticulum (ER) stress response and upregulation of HMGCR in regenerating muscle fibres perpetuates self-antigen presentation and activation of endogenous MHC I [14,109]. ...
... It has also been theorised that statins may directly affect the immune system, predisposing to autoimmunity [14]. The endoplasmic reticulum (ER) stress response and upregulation of HMGCR in regenerating muscle fibres perpetuates self-antigen presentation and activation of endogenous MHC I [14,109]. APC, antigen-presenting cell; BMI, body mass index; ER, endoplasmic reticulum; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase. ...
... Anti-HMGCR antibodies were first described in 2010 in a population of patients with a biopsy consistent with necrotizing myopathy and negative for other autoantibodies (6). Although they were initially associated with taking statins, due to their higher prevalence in this type of patient compared to other myopathies (2-3 of every 100,000 patients treated with statins), new subtypes of patients such as unexposed adults, adolescents, and even children were emerging (2). The estimated incidence of anti-HMGCR is 1.94-10.3 ...
... The estimated incidence of anti-HMGCR is 1.94-10.3 per million adults per year, depending on the testing criteria (7) and the proportion of patients who have been exposed to statins and have anti-HMGCR antibodies positive varies by geographic region, ranging from 44.4% to 72.7% in the European population, with a similar percentage in the North American population, and a lower association in Asian populations (8), where higher consumption of foods rich in natural statins, such as mushrooms or red tea, may act as triggers of non-drug anti-HMGCR myopathy (2). ...
Anti-HMGCR, which was first identified in 2010, has emerged as an important mechanism of myopathogenesis in patients with exposure to statins. The availability of new detection methods has expanded the phenotypic spectrum with a subtype of population that hasn't been exposed to the drug and whose clinical, analytical, and pathological manifestations are similar. The observation by immunofluorescence of a highly specific pattern known as HALIP (HMGCR Associated Liver Immunofluorescence Pattern) can be useful in the detection of these antibodies.
... There is a strong association between IMNM in patients exposed to statins and anti-HMGCR antibodies: antibody levels correlate with the severity of myopathy [60]. ...
... Therefore, statins may have immunomodulatory effects on the immune system changing autoantigen processing [60]. ...
... This was originally identified in nearly 70% of patients and now has been validated in multiple cohorts of patients with different racial and ethnic origins as an immunogenetic risk factor. A second allele, HLA-DRB1*07:01, has been reported in pediatric patients [60,62]. ...
Statins are drugs widely prescribed in high-risk patients for cerebrovascular or cardiovascular diseases and are, usually, safe and well tolerated. However, these drugs sometimes may cause neuromuscular side effects that represent about two-third of all adverse events. Muscle-related adverse events include cramps, myalgia, weakness, immune-mediated necrotizing myopathy and, more rarely, rhabdomyolysis. Moreover, they may lead to peripheral neuropathy and induce or unmask a preexisting neuromuscular junction dysfunction. A clinical follow up of patients assuming statins could reveal early side effects that may cause neuromuscular damage and suggest how to better modulate their use. In fact, statin dechallenge or cessation, or the alternative use of other lipid-lowering agents, can avoid adverse events. This review summarizes the current knowledge on statin-associated neuromuscular adverse effects, diagnosis, and management. It is conceivable that the incidence of neuromuscular complications will increase because, nowadays, use of statins is even more diffused than in the past. On this purpose, it is expected that pharmacogenomic and environmental studies will help to timely predict neuromuscular complications due to statin exposure, leading to a more personalized therapeutic approach.
... 4 Typically, anti-HMGCR myopathy occurs in patients with rapidly progressive weakness, prior exposure to statins, 5 and a muscle biopsy that shows necrotizing myopathy with minimal or no lymphocytic infiltrate. 3 MHC-1 staining is absent in normal muscle, yet is present on the sarcolemmal membrane in anti-HMGCR myopathy and most other types of inflammatory myopathy. 6 The positive anti-NXP-2 was unexpected, considering anti-HMGCR and anti-NXP-2 have not been reported to co-occur, and in general, MSAs are found in isolation. ...
A 67-year-old woman was admitted to our hospital for progressive weakness, dysphagia, muscle pain, and weight loss. Here we detail the clinical problem solving involved in diagnosing and treating her immune-mediated necrotizing myopathy caused by anti-HMGCoA reductase autoantibodies. Interestingly, this diagnosis coincided with discovery of a gastrointestinal stromal tumor (GIST) and positivity for anti-nuclear matrix protein (anti-NXP2), another myositis specific autoantibody.
... SLCO1B1 521T > C has been associated with the spectrum of myotoxicity, at least for simvastatin, except for IMNM. A subtype of IMNM is anti-HMGCR myopathy [101]; most patients with anti-HMGCR myopathy have a history or statin exposure, develop muscle weakness with highly elevated CK levels that persist despite statin cessation, are identified by the presence of circulating anti-HMGCR autoantibodies that can be directly pathogenic, and normally require treatment with immunosuppressive drugs or intravenous immunoglobulins [102]. Interestingly, HLA-DRB1*11:01 has been significantly associated with anti-HMGCR myopathy [103,104] with estimated OR of 25-57 dependent on ethnicity. ...
Most of the prescribing and dispensing of medicines happens in primary care. Pharmacogenomics (PGx) is the study and clinical application of the role of genetic variation on drug response. Mounting evidence suggests PGx can improve the safety and/or efficacy of several medications commonly prescribed in primary care. However, implementation of PGx has generally been limited to a relatively few academic hospital centres, with little adoption in primary care. Despite this, many primary healthcare providers are optimistic about the role of PGx in their future practice. The increasing prevalence of direct-to-consumer genetic testing and primary care PGx studies herald the plausible gradual introduction of PGx into primary care and highlight the changes needed for optimal translation. In this article, the potential utility of PGx in primary care will be explored and on-going barriers to implementation discussed. The evidence base of several drug-gene pairs relevant to primary care will be outlined with a focus on antidepressants, codeine and tramadol, statins, clopidogrel, warfarin, metoprolol and allopurinol. This review is intended to provide both a general introduction to PGx with a more in-depth overview of elements relevant to primary care.
... Statin-associated autoimmune myopathy is a relatively newly described disorder and the presence of autoantibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) have only recently been identified [1,2]. Anti-HMGCR myopathy is a rare side effect of statin therapy, even though it can also develop in statin-naïve patients [3][4][5]. Its incidence is not well defined, though it is estimated in approximately 2-3 of every 100,000 statin-treated patients [6,7]. ...
... Unlike other immune-mediated myopathies, there are few reports of extra-muscular involvement. Nevertheless, non-specific systemic and extra-muscular symptoms, such as arthritis, Raynaud's phenomenon and rash, are uncommon [3]. A predisposing genetic background has been also documented, since anti-HMGCR myopathy has one of the strongest associations between an immunogenetic risk factor and autoimmune disease, in particular with the class II human leukocyte antigen (HLA) allele D related B (DRB)1*11:01 [12]. ...
Statin-associated autoimmune myopathy is a rare muscle disorder, characterized by autoantibodies against HMGCR. The anti-HMGCR myopathy persists after statin, and often requires immunosuppressive therapy. However, there is not a standardized therapeutic approach. The purpose of this study is to report the effectiveness of the immunosuppressive treatment employed in a multi-center and multi-disciplinary cohort of patients affected by anti-HMGCR myopathy, in which an immunoglobulin (IVIG)-based treatment strategy was applied. We collected 16 consecutive patients with a diagnosis of anti-HMGCR myopathy, between 2012 and 2019, and recorded data on clinical and laboratory presentation (i.e., muscle strength, serum CK levels, and anti-HMGCR antibody titer) and treatment strategies. Our results highlight the safety and efficacy of an induction therapy combining IVIG with GCs and/or methotrexate to achieve persistent remission of the disease and steroid-free maintenance. Under IVIG-based regimens, clinical improvement and CK normalization occurred in more than two thirds of patients by six months. Relapse rate was low (3/16) and 2/3 relapses occurred after treatment suspension. Nearly 90% of the patients who successfully discontinued GCs were treated with a triple immunosuppressive regimen. In conclusion, an IVIG-based regimen, which particularly includes high-dose immunoglobulin, GCs and methotrexate, can provide a fast remission achievement with GC saving.
... Less frequently, other MSA detected include anti-MDA-5/CADM-140, anti-155/140 (TIF1-γ/α), anti-MJ/NXP-2, anti-PMS1, anti-SAE, and anti-HMGCR. [15][16][17][18][19][20][21][22][23] The MAA most commonly found in myositis patients and overlap syndromes include anti-U1-RNP present in 10% of patients with overlap syndromes and in virtually all patients with mixed connective tissue disease; anti-SSA/Ro in more than 35% of patients with IIM and ILD, anti-PM-Scl present in patients with PM-systemic sclerosis overlap, 24 and anti-Ku antibodies are found in PM-SLE overlap (20%-30% in Japanese patients) and can be frequently associated with corticosteroid sensitive IIM and severe, corticosteroid-resistant ILD. 25,26 In the present study, we evaluated the presence of ANA, MSA, and MAA in the sera of IIM patients from rheumatology clinics in 6 Latin American countries that participate in the Panamerican League against Rheumatism (PANLAR) Myositis Study Group. ...
... Anti-HMGCR is detected in approximately 62% of statinrelated immune-mediated necrotizing myopathies. [21][22][23] Our results shown a high frecuency of anti-HMGCR (18.8%) only in patients from Dominican Republic with DM diagnosis. ...
Background:
Dermatomyositis (DM) and polymyositis (PM) are forms of idiopathic inflammatory myopathies (IIMs), which are associated with the production of autoantibodies that are useful in the diagnosis and prognosis of the disease.
Objective:
The aim of this study was to determine the frequency of antinuclear autoantibodies (ANAs), myositis-specific autoantibodies (MSAs), and myositis-associated autoantibodies (MAAs) in 6 Latin American countries.
Methods:
Two hundred ten patients with IIM were included in this cross-sectional study from 2014 to 2017: 112 from Mexico, 46 from Colombia, 20 from Peru, 16 from the Dominican Republic, 10 from Argentina, and 6 from Guatemala. Antinuclear autoantibodies were detected by indirect immunofluorescence on HEp-2 cells. MSAs and MAAs were tested by a line immunoassay method. Mann-Whitney U and χ tests were used for statistical analysis.
Results:
Of the 210 IIM patients, 139 (66.2%) had DM, 59 (28%) PM, and 12 (5.7%) juvenile DM. The mean age was 43.5 (6-79 years); 158 (75.2%) were female, and 52 (24.8%) were male. The overall frequency of ANA was 60%. The most frequent patterns were fine speckled (AC-4) (78.3%) and cytoplasmic (AC-19) (6.45%). The most frequent MSA were anti-Mi-2 (38.5%) and anti-Jo-1 (11.9%). Anti-Mi-2 was more frequent in patients from Colombia (40.1%). The MAA more frequent were anti-Ro-52/TRIM21 (17.6%) and anti-PM-Scl75 (7.5%).
Conclusions:
This is the first study of ANA, MSA, and MAA in patients from 6 countries from the Panamerican League against Rheumatism myositis study group. We observed a general prevalence of 60% of ANA. In relation to MSA and MAA, anti-Mi-2 was the more frequent (38.5%).
... The pathogenesis of SINAM is an area of active investigation. Studies have suggested that interaction between host immunogenetic background (specific class II HLA alleles, i.e.,, HLA-DRB1*11: 01 and 07: 01) and environmental triggers (statin or mushroom which is a natural source of statin) leads to multiple immune mechanisms ultimately converging on sustained autoimmune muscle injury and/or inadequate attempt at muscle regeneration [6]. Our case is unique as this rare side effect occurred after 10 years of statin use. ...
... Unlike the self-limiting statin myopathy, SINAM is much more severe and is associated with significant symmetric proximal muscle (posterior thigh, medial thigh and gluteal compartments) weakness, markedly elevated CK level and persistent symptoms despite statin discontinuation [6]. It may rarely present with dysphagia, arthralgia or Raynaud's phenomena [7]. ...
... Once diagnosed, discontinuation of the offending agent and avoidance of this class of medication are the most important steps in the management of these patients [6]. Most patients show improvement after initiation of steroid, immunosuppressant and, in severe case, IVIG. ...
Statins are widely prescribed medications to prevent cardiovascular events. While self-limited statin myopathy is relatively common, statin-induced necrotizing autoimmune myopathy (SINAM) is extremely uncommon, with incidence of two cases per million per year. We present a case of SINAM after a decade of atorvastatin use, leading to debilitating weakness. A 71-year-old male presented with recurrent falls due to extreme bilateral lower-extremity weakness without pain or sensory changes. No fever, chills, rash, joint pain, recent infection or medication changes were reported. Reported taking atorvastatin 80 mg daily for 10 years. Physical examination revealed significant muscle wasting on right deltoid and proximal muscle weakness in all extremities. Lab tests included elevated creatinine kinase, aldolase, ESR, CRP and transaminases. Anti-HMGCR antibody was significantly elevated. TSH, serum protein electrophoresis and RPR were unremarkable. ANA, Anti-Jo-1, anti-Mi2, anti-SRP, anti-ds-DNA, anti-SSA and anti-SSB antibodies were negative. MRI of thigh revealed diffuse myositis. Electromyogram revealed an acute myopathic process. Muscle biopsy showed muscle necrosis and C5b-9 sarcolemmal deposits on non-necrotic fibers without rimmed vacuoles. He was diagnosed with SINAM. Statin was discontinued, and steroid, immunoglobulins and azathioprine were started with gradual improvement. Unlike the self-limiting statin myopathy, SINAM is more severe and is associated with significant proximal muscle weakness, markedly elevated CK and persistent symptoms despite statin discontinuation. Anti-HMGCR antibodies are present in 100% of cases. Immunosuppressants are the mainstay of treatment, and statin rechallenge should never be done in these cases. Although relatively rare, physicians should be cognizant of SINAM.
