A Case of Statin-Induced Necrotizing Autoimmune Myopathy.

Statins, commonly used for hyperlipidemia and more importantly having proven efficacy in lowering cardiovascular risk, are a very popular class of medications. Side effects are usually mild, and the class as a whole is generally well-tolerated by patients. However, one rare and more serious side effect is statin-induced autoimmune necrotizing myopathy. A 65-year-old woman with a past medical history of hyperlipidemia on atorvastatin for four years, type 2 diabetes, sciatica, and a prior history of endometrial cancer, presented to the emergency department due to proximal muscle weakness worsening over 2-3 months. On labs, her aspartate transaminase (AST) and alanine transaminase (ALT) were both elevated at 344 and 244, respectively. Additionally, creatine kinase (CK) was 13,000, C-reactive protein (CRP) was 42, and aldolase was 80.4. She was antinuclear antibody (ANA) negative but found to be anti-3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMGCR ab) positive. Her magnetic resonance imaging (MRI) showed significant edema in bilateral thighs. During her hospital course, she was started on prednisone, fluids, and intravenous immunoglobulin (IVIG). Once completing two days of IVIG, the patient was discharged to rehab with rheumatology follow-up. The purpose of this case is to elucidate a rare side effect of a medication despite being on it for several years and to increase awareness and attention to an adverse effect that may one day lead to stratifying patients' risk on the medication.

Myositis-specific and myositis-associated autoantibodies: their clinical characteristics and potential pathogenic roles.

In recent years, various myositis-specific and myositis-associated autoantibodies have been identified in idiopathic inflammatory myopathies, including dermatomyositis (DM), anti-synthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). These autoantibodies exhibit unique characteristics in terms of organ involvement, severity, and treatment response, making their understanding crucial for accurate diagnosis and effective therapy. This review provides a comprehensive overview of the clinical features of recently discovered myositis-specific and associated autoantibodies, while exploring their potential roles in the pathogenesis and exacerbation of myositis. Key findings include the production of anti-TIF1γ antibodies in model mice, the upregulation of Mi2-related genes in anti-Mi2 antibody-positive dermatomyositis muscle tissue, and Jo-1 antigen-induced T cell activation, shedding light on whether disease mechanisms are driven by autoantibodies or autoantigens.

Immune-Mediated Necrotizing Myopathy With Anti-3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) Antibodies Following Viral Infection and Without Association With Statin Use: A Case Report.

Immune-mediated necrotizing myopathy (IMNM) is a rare form of inflammatory myopathy characterized by severe muscle weakness, elevated serum creatine kinase (CK) levels, and myofiber necrosis with minimal inflammatory infiltrates. IMNM is frequently associated with autoantibodies, particularly anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and is often linked to statin use. However, it can also develop in statin-naïve patients, especially following viral infections. We present the case of a 47-year-old woman who developed anti-HMGCR-positive IMNM without prior statin exposure, following a viral respiratory infection and subsequent dengue fever. She initially presented with proximal muscle weakness and elevated CK levels, which worsened after contracting dengue. Diagnostic testing confirmed the presence of anti-HMGCR antibodies, and a muscle biopsy revealed necrotizing myopathy. Treatment with methylprednisolone, intravenous immunoglobulin, and rituximab resulted in significant clinical improvement. This case underscores the need to consider IMNM in patients with unexplained muscle weakness and elevated CK levels, even in the absence of statin use. Viral infections may trigger IMNM, highlighting the importance of early recognition and aggressive immunosuppressive therapy to prevent severe complications. Further research is required to better understand the pathophysiology of IMNM and optimize treatment approaches.

Overlap of Sjögren's Syndrome and Immune-Mediated Necrotizing Myopathy With Interstitial Lung Disease: A Case Report.

Immune-mediated necrotizing myopathy (IMNM), an inflammatory muscle disease, typically presents as severe muscle weakness due to immunologic mechanisms. Some cases also show cutaneous manifestations, interstitial lung disease, and sicca symptoms. In this report, we present a unique case of an elderly man with a history of mild and stable Sjögren's syndrome (SS) for over 10 years, who later developed interstitial lung disease and myositis, leading to a diagnosis of IMNM confirmed by the presence of anti-signal recognition particle antibodies. The coexistence of IMNM and SS is a rare occurrence, underscoring the need for our expertise and a comprehensive understanding of the unique characteristics of each disease for accurate diagnosis and effective treatment.

Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy.

Introduction: Statin use can lead to various muscle-related issues, including benign creatine kinase (CK) elevations, myalgias, toxic myopathies, rhabdomyolysis, and immune-mediated necrotizing myositis (IMNM), which primarily affects older males. IMNM presents with proximal muscle weakness, elevated CK levels, and specific antibodies. Case presentation: We describe a 72-year-old patient with muscle weakness persisting for over 3 years after statin therapy. Initially suspected to have a genetic disorder, further testing revealed elevated anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibodies, indicating immune-mediated myopathy. Despite the absence of inflammatory changes on biopsy, the patient responded positively to immune therapy. Conclusion: This case highlights challenges in diagnosing immune-mediated myopathy, especially in older patients with atypical presentations. Testing for HMGCR antibodies can aid in diagnosis, particularly when inflammatory markers are absent. Awareness of red flags, such as delayed symptom onset and response to prednisone, is crucial for accurate diagnosis and management.

Evaluating CA-125 and PET/CT for cancer detection in idiopathic inflammatory myopathies.

OBJECTIVE: This study aims to evaluate the diagnostic accuracy of CA-125 and PET/CT in detecting cancer among adult patients with idiopathic inflammatory myopathy (IIM). METHODS: We conducted a retrospective study of a single-centre cohort of adult IIM patients enrolled from 2003 to 2020. Data on CA-125 and PET/CT tests conducted within five years of IIM symptom onset were extracted from electronic medical records. The outcomes assessed included true positive, false-positive, true negative, and false-negative results. RESULTS: Among 1432 patients with IIM, 250 CA-125 tests were conducted on 205 patients within the first five years of symptom onset, yielding a false-positive rate of 3.1% and a false-negative rate of 14.3%. Most false positives were associated with endometriosis or uterine fibroids, but additional medical procedures were often carried out to investigate the false-positive results. For PET/CT, 149 tests were performed on 139 patients, resulting in a false-positive rate of 5.5% and a false-negative rate of 28.6%. Lymphadenopathy and lung nodules were the predominant causes of false positives, while melanoma, low-stage breast cancer, and prostate cancer were the most frequent cancers missed (false negatives). CONCLUSION: False positive and false-negative results are prevalent in CA-125 and PET/CT testing for adult patients with newly diagnosed idiopathic inflammatory myopathy. Understanding the causes of these inaccuracies can aid clinicians in making informed decisions during patient care.

Association of anti-HMGCR antibodies of the IgM isotype with refractory immune-mediated necrotizing myopathy.

OBJECTIVE: Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies are one of the myositis-specific antibodies which is associated with immune-mediated necrotizing myopathy (IMNM). However, the relationship between anti-HMGCR isotypes and prognosis has not yet been fully investigated. This study was conducted to gain insight into the association between anti-HMGCR isotypes and clinical, and prognosis in IMNM patients who were positive for anti-HMGCR antibodies. METHODS: Levels of anti-HMGCR isotypes (IgG, IgA and IgM) were assessed by enzyme-linked immunosorbent assay (ELISA) in 123 consecutive serum samples obtained from 71 patients who were positive for anti-HMGCR IgG at baseline. Disease activity was assessed by manual muscle testing (MMT) 8, Physician's Global Assessment (PGA) visual analog scale (VAS), and muscle VAS. RESULTS: Baseline anti-HMGCR IgG levels were correlated with PGA VAS (r = 0.24; p = 0.04), muscle VAS (r = 0.32; p < 0.01), and MMT8(r=-0.24; p = 0.04), and baseline anti-HMGCR IgM levels were positively correlated with PGA VAS (r = 0.27, p = 0.02), muscle VAS (r = 0.24, p = 0.04). Anti-HMGCR IgM positive patients had a lower age of onset [29(25,46) vs. 51(33,65), p = 0.006], and a higher proportion of neck weakness (63.5% vs. 34.6%, p = 0.031) compared with anti-HMGCR IgM negative patients. Longitudinal analysis showed that the changes in anti-HMGCR IgG levels were correlated with the changes in the PGA VAS (ß = 3.830; p < 0.0001), muscle VAS (ß = 2.893; p < 0.0001), MMT8 (ß=-19.368; p < 0.0001), and creatine kinase (CK) levels (ß = 3900.05, p < 0.0001). Anti-HMGCR IgM levels were weakly correlated with anti-HMGCR IgA levels at baseline (r = 0.33, p < 0.01), and the variations in anti-HMGCR IgA levels were correlated with the changes in anti-HMGCR IgM levels during follow-up (ß = 0.885; p < 0.0001). There were more patients with anti-HMGCR IgM who showed a refractory course than those who were with anti-HMGCR IgM negative (polycyclic course: 40% vs. 25%; chronic continuous course: 46.7% vs. 20.5%, p = 0.018). CONCLUSION: In anti-HMGCR IgG-positive IMNM patients, the levels of anti-HMGCR IgG are associated with disease activity, and anti-HMGCR IgM is associated with refractory outcome and poor prognosis.

Muscle involvement in systemic sclerosis: high mortality not associated with nature of histological lesions.

OBJECTIVES: The aim of this study was to determine the association between different histological patterns and prognosis in patients with SSc and histologically proven muscle involvement. METHODS: A multicentre retrospective study was conducted of a cohort of scleroderma patients who had undergone muscle biopsy. The biopsies were reviewed in a coordinated manner to classify patients based on histological findings. Three different patterns were observed: fibrosing myopathy (FM), inflammatory myopathy (IM) and necrotizing myopathy (NM). Rates of survival, muscle relapse, and cardiac and pulmonary events were compared between these three groups. RESULTS: Among 71 scleroderma patients with muscle biopsy specimens available for review, 33 (46.5%) were classified in the FM group, 18 (25.5%) in the IM group, and 20 (28%) in the NM group. The median follow-up time was 6.4 years (interquartile range, 2.2-10.9 years) and 21 patients died during follow-up, primarily from heart disease and infections. The 10-year survival rate after the first non-Raynaud's disease symptom was 80% and the cumulative incidence of muscle relapse was 25%. Neither factor differed significantly between the three groups. The risk of pulmonary events was lowest in the OM group, significantly lower than in the FM group (hazard ratio, 0.17; 95% CI, 0.04-0.67) and non-significantly lower than in the IMNM group (hazard ratio, 0.28; 95% CI, 0.06-1.24). The risk of cardiac events did not differ significantly between the three groups. CONCLUSION: The mortality rate of scleroderma patients with muscle involvement was not associated with their histological patterns.

Distinct phenotype and prognosis of immune-mediated necrotizing myopathy based on clinical-serological-pathological classification.

OBJECTIVE: The aim of the study was to investigate the characteristics and prognosis of patients with immune-mediated necrotizing myopathy (IMNM) based on clinical, serological and pathological classification. METHODS: A total of 138 patients with IMNM who met the 2018 European Neuromuscular Center criteria for IMNM including 62 anti-SRP, 32 anti-HMGCR-positive and 44 myositis specific antibody-negative were involved in the study. All patients were followed up and evaluated remission and relapse. Clustering analysis based on clinical, serological, and pathological parameters was used to define subgroups. RESULTS: Clustering analysis classified IMNM into three clusters. Cluster 1 patients (n = 35) had the highest CK levels, the shortest disease course, severe muscle weakness, and more inflammation infiltration in muscle biopsy. Cluster 2 patients (n = 79) had the lowest CK level and moderate inflammation infiltrate. Cluster 3 patients (n = 24) had the youngest age of onset, the longest disease course and the least frequency of inflammatory infiltration. Patients in cluster 3 had the longest time-to-remission (median survival time: 61[18.3, 103.7] vs 20.5[16.2, 24.9] and 27[19.6, 34.3] months) and shortest relapse-free time than those in cluster 1 and 2 (median remission time 95%CI: 34[19.9, 48.0] vs 73[49.0, 68.7] and 73[48.4, 97.6] months). Patients with age of onset >55 years, more regeneration of muscle fibers, more CD4+T infiltration, and MAC deposition had more favorable outcomes regarding time to achieving remission. CONCLUSIONS: Stratification combining clinical, serological, and pathological features could distinguish phenotypes and prognosis of IMNM. The pathological characteristics may impact the long-term prognosis of patients with IMNM.

Diffuse Large B-cell Lymphoma Complicated with Anti-3-hydroxy-3-methylglutaryl-Coenzyme A Reductase Immune-mediated Necrotizing Myopathy: A Case Report.

A 75-year-old woman presented with significant muscle weakness after statin use. A muscle biopsy revealed necrotizing myopathy, and the patient tested positive for serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, leading to a diagnosis of anti-HMGCR immune-mediated necrotizing myopathy (IMNM). Computed tomography revealed intraperitoneal lymphadenopathy, which was diagnosed as a diffuse large B-cell lymphoma. Immunostaining confirmed HMGCR expression in the lymphoma cells. The patient received chemotherapy and achieved complete remission of the lymphoma, along with nearly complete recovery from IMNM. Although the etiologies of IMNM and lymphoma remain unclear, HMGCR expression in lymphoma cells is likely to be associated with the development of IMNM.

Immune-Mediated Necrotizing Myopathy Associated With Anti-signal Recognition Particle Antibody Complicated With Acute Respiratory Distress Syndrome: A Report of Two Cases.

Immune-mediated necrotizing myopathy (IMNM) represents a rare category of inflammatory myopathies characterized by more severe and rapid progression of symmetrical proximal muscle weakness. It is also marked by notably elevated serum muscle enzyme levels and distinct histological features, setting it apart from other types of myositis. Moreover, acute chronic lung respiratory dysfunction is a major comorbidity of great concern. We herein present two cases of IMNM associated with anti-signal recognition particle antibodies complicated by acute respiratory distress syndrome.

Management of immune-mediated necrotizing myopathy.

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

Atypical skin conditions of the neck and back as a dermal manifestation of anti-HMGCR antibody-positive myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an idiopathic inflammatory myopathy (IIM). Though patients with IMNM were not considered to show skin rash, several reports have showed atypical skin conditions in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-positive IMNM (HMGCR-IMNM). The incidence and phenotype of skin conditions in patients with HMGCR-IMNM are not fully known. RESULTS: Among the 100 IIM patients diagnosed from April 2015 through August 2022, 34 (34%) presented some form of skin condition, with 27 having typical skin rashes; this included 13 patients with dermatomyositis (DM), 8 with anti-synthetase syndrome (ASS), and 6 with IMNM. Meanwhile, 8 of 19 patients with HMGCR-IMNM (42%) presented atypical skin lesions, but no patients with other IIMs did (p < 0.001). Skin eruption with ash-like scales was observed in four HMGCR-IMNM patients, and non-scaly red patches and lumps in the other four patients; accordingly, their skin manifestations were considered as other dermal diseases except for IIM. However, skin and muscle biopsies revealed the atypical skin conditions of patients with HMGCR-IMNM to have the same pathological background, formed by Bcl-2-positive lymphocyte infiltrations. CONCLUSIONS: HMGCR-IMNM patients frequently have atypical skin conditions of the neck and back. Skin biopsy specimens from these lesions showed the same Bcl-2-positive lymphocytic infiltrations as muscle biopsy specimens regardless of the different gross dermal findings. Thus, such atypical skin conditions may be suggestive for HMGCR-IMNM.

Immune-Mediated Necrotizing Myopathies: Current Landscape.

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

Evaluation of the effectiveness of using prednisolone, tacrolimus, and intravenous immunoglobulin combination therapy on immune-mediated necrotizing myopathy-A non-randomized, observational research.

OBJECTIVE: To recruit immune-mediated necrotizing myopathy (IMNM) patients with extramuscular manifestations who were refractory to initial therapy with either monotherapy with prednisolone or dual therapy with prednisolone and immunosuppressants. These patients subsequently received a combination of prednisolone, tacrolimus, and intravenous immunoglobulin (IVIG), and the efficacy of this treatment regimen was assessed in patients with IMNM. METHOD: ①Clinical data and treatment measures are as follows: This study enrolled IMNM patients who were treated at the Neurology Department of the First Medical Center of PLA General Hospital from April 2020 to May 2023. These patients received a combination therapy of prednisolone, tacrolimus, and IVIG. ②Observational indicators included manual muscle test for 8 groups of muscles (MMT-8), muscle enzyme levels (creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and myositis disease activity assessment tool (MDAAT). RESULTS: This study enrolled eight patients. All observational indicators declined after treatment compared to before treatment, and these changes were statistically significant. Moreover, extramuscular manifestations also ameliorated compared to before treatment. CONCLUSION: The combination therapy of prednisolone, tacrolimus, and IVIG has demonstrated favorable efficacy in IMNM and broadened the treatment options for this disease. However, the results still require further validation by large-scale and randomized controlled studies.

Paraneoplastic myopathies.

This chapter reviews the association between cancer and the idiopathic inflammatory myopathies (IIM), which includes dermatomyositis (DM), antisynthetase syndrome (ASyS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Accumulating evidence shows that the risk of a coexisting malignancy is high in patients with DM, especially among those with anti-Tif1γ autoantibodies. Patients with IMNM and no defined autoantibodies also have an increased risk of malignancy. Recent evidence demonstrates that many IBM patients have increased numbers of circulating CD57+ CD8+ T cells, consistent with a diagnosis of large granular lymphocytic leukemia. In contrast, IMNM patients with anti-SRP or anti-HMGCR autoantibodies as well as patients with ASyS syndrome do not have a definitively increased risk of cancer. Patients who have a cancer treated with one of the immune checkpoint inhibitors can develop myositis (ICI-myositis), sometimes along with myasthenia gravis and/or myocarditis.

Statin-induced immune-mediated necrotizing myopathy with concomitant increase of anti-HMGCR and anti-ACHR antibodies.

Statin-induced immune-mediated necrotizing myopathy (IMNM) is a rare systemic neuromuscular condition. We present a case of a patient with a severe phenotype of the disease that was found to have an increase in anti-HMGCR and anti-ACHR antibodies. A potential association between these antibodies have not been previously described. A 67-year-old male with hyperlipidemia, who was recently initiated on atorvastatin therapy, presented to the ED with progressive muscle weakness. Within a few days of admission, the patient developed complete flaccid paralysis and respiratory distress requiring intubation. The patient's CK was elevated to 24,000 and there was an increase of anti-HMGCR and anti-ACHR antibodies. Impressions from MRI and thigh biopsy solidified a diagnosis of statin-induced IMNM. The patient was treated with methylprednisolone, IVIG, and rituximab, which provided resolution of symptoms.

Rheumatoid Arthritis Associated With Anti-Signal Recognition Particle Immune-Mediated Necrotizing Myopathy: A Case Report.

Immune-mediated necrotizing myopathy (IMNM) is a rare subtype of idiopathic inflammatory myopathy that is characterized by severe subacute proximal weakness, myofiber necrosis, and significantly elevated serum creatine kinase. Anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme-A reductase autoantibodies have been found in about two-thirds of patients with IMNM. This myopathy is usually idiopathic and there is a scarce literature concerning its association with connective tissue diseases. Herein, we report an unusual case of a young woman who presented with both rheumatoid arthritis and severe anti-SRP IMNM. Thankfully to a therapeutic protocol combining rituximab and cyclophosphamide, an important improvement was achieved, and notably no serious side effect was observed.

Immune-Mediated Necrotizing Myopathy (IMNM): A Story of Antibodies.

Immune-mediated necrotizing myopathy (IMNM) is a rare and severe disease that corresponds to a specific entity of idiopathic inflammatory myopathy. Patients with IMNM suffer from proximal muscle weakness, and present high levels of creatine kinase and necrotic myofibers. Anti-Signal Recognition Particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies (HMGCR) have recently been identified in two thirds of patients with IMNM and are used as a hallmark of the disease. In this review, we provide a detailed description of these antibodies and the tests used to detect them in the serum of patients. Based on in vitro studies and mouse models of IMNM, we discuss the role of autoantibodies in the pathogenesis of the disease. Finally, in the light of the latest knowledge, we conclude with a review of recent therapeutic approaches in IMNM.