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.

[How to Perform Autoantibody Testing for Autoimmune and Inflammatory Diseases of Peripheral Nerves and Muscles].

Measurement of autoantibodies is essential for the management of several peripheral nerve and muscle diseases. The clinical significance of autoantibody testing differs for each antibody. In addition, clinicians must understand several issues including the accuracy of the test, isotype and subclass distribution, and its relationship to disease activity. Moreover, many autoantibody tests are not covered by health insurance. With limited medical resources, clinicians are required to be up-to-date with the latest information to utilize test results in daily practice without misunderstanding.

[Peripheral Neuropathy and Muscle Disorders as Immune-Related Adverse Events].

Neurological immune-related adverse events (irAEs) associated with cancer treatment with immune checkpoint inhibitors (ICI) present diverse clinical characteristics. Neurological irAEs affect the peripheral nervous system and muscles more than they affect the central nervous system. Among the various subsets of peripheral neuropathies, polyradiculoneuropathy, which includes Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, stands out as the most severe form, leading to significant muscle weakness. ICIs can induce dysautonomia, including autoimmune autonomic ganglionopathy. Autonomic neuropathy represents a neurological irAE. Neurological irAEs of neuromuscular junctions include myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Diagnosing MG or myositis independently can be challenging when they occur as irAEs. Myocarditis is sometimes observed as an irAE in patients with MG and can cause both severe heart failure and lethal arrhythmias, resulting in fatal outcomes. Anti-Kv1.4 antibodies are biomarkers of the severe form of MG and myocarditis. The administration of ICI in patients with small cell lung cancer increases the risk of LEMS. The distinction between LEMS is an irAE or a manifestation of paraneoplastic neurological syndrome is unclear as both conditions share common immunological mechanisms.

Mushroom supplements triggering a flare of HMGCR immune mediated necrotising myopathy.

Hydroxyl-methyl-glutaryl-Co-A reductase (HMGCR) immune mediated necrotising myopathy (IMNM) is a rare autoimmune myositis that is thought to be triggered by statins and responds to immunomodulation. We report a case of a woman in her 30s with HMGCR IMNM without a history of statin exposure who had a clear flare of her myositis after beginning mushroom supplements. Mushrooms are natural HMGCR inhibitors, and this is the first case to demonstrate a flare triggered by mushrooms in a patient with known HMGCR IMNM. This case highlights the importance of reviewing diet and supplements in patients with IMNM. It also emphasises the importance of strict statin avoidance for patients with IMNM even when the myositis is under good control.

Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell­ and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFß1). Blocking TGFß signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell­stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

Myeloid mineralocorticoid receptors contribute to skeletal muscle repair in muscular dystrophy and acute muscle injury.

Suppressing mineralocorticoid receptor (MR) activity with MR antagonists is therapeutic for chronic skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. Although mechanisms underlying clinical MR antagonist efficacy for DMD cardiomyopathy and other cardiac diseases are defined, mechanisms in skeletal muscles are not fully elucidated. Myofiber MR knockout improves skeletal muscle force and a subset of dystrophic pathology. However, MR signaling in myeloid cells is known to be a major contributor to cardiac efficacy. To define contributions of myeloid MR in skeletal muscle function and disease, we performed parallel assessments of muscle pathology, cytokine levels, and myeloid cell populations resulting from myeloid MR genetic knockout in muscular dystrophy and acute muscle injury. Myeloid MR knockout led to lower levels of C-C motif chemokine receptor 2 (CCR2)-expressing macrophages, resulting in sustained myofiber damage after acute injury of normal muscle. In acute injury, myeloid MR knockout also led to increased local muscle levels of the enzyme that produces the endogenous MR agonist aldosterone, further supporting important contributions of MR signaling in normal muscle repair. In muscular dystrophy, myeloid MR knockout altered cytokine levels differentially between quadriceps and diaphragm muscles, which contain different myeloid populations. Myeloid MR knockout led to higher levels of fibrosis in dystrophic diaphragm. These results support important contributions of myeloid MR signaling to skeletal muscle repair in acute and chronic injuries and highlight the useful information gained from cell-specific genetic knockouts to delineate mechanisms of pharmacological efficacy.

Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail. METHODS: This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs. RESULTS: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4). CONCLUSION: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement.

Belimumab for Immune-Mediated Necrotizing Myopathy Associated With Anti-SRP Antibodies: A Case Report and Retrospective Review of Patients Treated With Anti-B-Cell Therapy in a Single Center and Literature.

Background: Immune-mediated necrotizing myopathy (IMNM) is characterized by markedly elevated creatinine kinase and histologically scattered necrotic muscle fibers and generally associated with autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coA-reductase (HMGCR). Poor clinical response to conventional therapies and relapses commonly occur in severe cases. Anti-B-cell therapies have been used in refractory/relapsing cases. Methods: The characteristics of a patient with IMNM associated with anti-SRP antibodies including physical examination, laboratory tests, and disease activity assessment were evaluated. Conventional therapy, belimumab treatment schedule, and follow-up data were recorded. Medical records of IMNM patients treated in our department from September 2014 to June 2021 were reviewed to evaluate the efficacy and safety of anti-B-cell therapy for anti-SRP IMNM. A literature review of patients with anti-SRP IMNM treated with anti-B-cell therapies was performed. Results: We describe a case of a 47-year-old woman with IMNM associated with anti-SRP antibodies who relapsed twice after conventional therapy but showed good response and tolerance to belimumab at 28 weeks follow-up. In this review, three patients from our department were treated with rituximab. Two of the three patients rapidly improved after treatment. Twenty patients and five retrospective studies were included in the literature review. All patients were administered rituximab as an anti-B-cell drug. Conclusion: Despite a lack of rigorous clinical trials, considerable experience demonstrated that anti-B-cell therapy might be effective for patients with IMNM associated with anti-SRP antibodies. Belimumab in association with steroids might be an encouraging option for refractory/relapsing cases.

Vitamin D, Its Role in Recovery after Muscular Damage Following Exercise.

Aside from its role in bone metabolism, vitamin D is a key immunomodulatory micronutrient. The active form of vitamin D (1,25(OH)D) seems to modulate the innate immune system through different mechanisms. The vitamin is involved in the differentiation of monocytes into macrophages, increasing the phagocytic and chemotactic functions of these cells. At the same time, vitamin D enables efferocytosis and prevents immunopathology. In addition, vitamin D is involved in other processes related to immune function, such as inflammation. Regarding muscle tissue, vitamin D plays an active role in muscle inflammatory response, protein synthesis, and regulation of skeletal muscle function. Two mechanisms have been proposed: A direct role of 1,25(OH)D binding to vitamin D receptors (VDRs) in muscle cells and the modulation of calcium transport in the sarcoplasmic reticulum. This second mechanism needs additional investigation. In conclusion, vitamin D seems to be effective in cases of deficiency and/or if there is a great muscular commitment, such as in high intensity exercises.

Immunomodulation and Biomaterials: Key Players to Repair Volumetric Muscle Loss.

Volumetric muscle loss (VML) is defined as a condition in which a large volume of skeletal muscle is lost due to physical insult. VML often results in a heightened immune response, resulting in significant long-term functional impairment. Estimates indicate that ~250,000 fractures occur in the US alone that involve VML. Currently, there is no active treatment to fully recover or repair muscle loss in VML patients. The health economics burden due to VML is rapidly increasing around the world. Immunologists, developmental biologists, and muscle pathophysiologists are exploring both immune responses and biomaterials to meet this challenging situation. The inflammatory response in muscle injury involves a non-specific inflammatory response at the injured site that is coordination between the immune system, especially macrophages and muscle. The potential role of biomaterials in the regenerative process of skeletal muscle injury is currently an important topic. To this end, cell therapy holds great promise for the regeneration of damaged muscle following VML. However, the delivery of cells into the injured muscle site poses a major challenge as it might cause an adverse immune response or inflammation. To overcome this obstacle, in recent years various biomaterials with diverse physical and chemical nature have been developed and verified for the treatment of various muscle injuries. These biomaterials, with desired tunable physicochemical properties, can be used in combination with stem cells and growth factors to repair VML. In the current review, we focus on how various immune cells, in conjunction with biomaterials, can be used to promote muscle regeneration and, most importantly, suppress VML pathology.

Cutaneous involvement in anti-HMGCR positive necrotizing myopathy.

OBJECTIVE: Anti-3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive immune-mediated necrotizing myopathy (IMNM) is a rare disease. It is induced by exogenous substances, most often by statins. Little is known about cutaneous manifestations of HMGCR positive IMNM and about HMGCR antibody positivity in other diseases. METHODS: The characteristics of patients with anti-HMGCR autoantibodies measured at our laboratory between January 2012 and September 2020 were studied. Characteristics of patients with IMNM were compared to those patients with positive antibodies but without muscle involvement. Associations of IMNM with other organ involvements were searched for. RESULTS: Of the 32 patients studied, 23 showed characteristics of IMNM, 9 did not fulfill current classification criteria but most showed signs of connective tissue diseases. Patients with IMNM were older (66 and 35 years, respectively; 0.92 (0.73-0.98); p < 0.001), had more frequent statin exposure (87% and 33%, respectively; 0.84 (0.61-0.94); p = 0.005) and higher mean peak CK (8717U/l and 329U/l, respectively; 1.0 (0.85-1.0); p < 0.001). 13/23 (56%) of IMNM patients showed cutaneous lesions; none of the patients suffered from cancer; only three IMNM patients showed drug-free complete remission. Incidence of IMNM in the catchment area of our center is at least 2.7/Mio/year. CONCLUSION: Cutaneous lesions were found to be more frequent in anti-HMRCR positive IMNM than previously reported. Titer of anti-HMGCR antibodies and CK levels were significantly higher in IMNM than in other autoimmune connective tissue diseases. The data support the hypothesis of an antigen-driven response in IMNM, and suggests an activation of autoreactive B-lymphocytes in non-IMNM patients.

Expert Perspective: Management of Refractory Inflammatory Myopathy.

The idiopathic inflammatory myopathies (IIMs) are chronic disorders characterized by inflammation in skeletal muscle but also in other organs such as the skin, lungs, joints, gastrointestinal tract, and heart. The effect of immunosuppressive treatment varies between individual patients and between organ manifestations within the same individual. Many patients respond poorly to first-line treatment with glucocorticoids and other immunosuppressive agents such as methotrexate or azathioprine, with symptoms persisting in the muscles, skin, and lungs, leading to refractory disease. Management of refractory IIM is a clinical challenge, and a systematic approach is proposed to better understand the lack of treatment response, in order to guide disease management. The first step in the management of refractory IIM is to recognize whether remaining symptoms are caused by persistent inflammation in the affected tissue or whether the symptoms may be attributable to damage preceding inflammation. Thus, a second diagnostic examination is recommended. Second, in particular for patients with remaining muscle weakness, it is important to ascertain whether the diagnosis of myositis is correct or whether another underlying muscle disorder could explain the symptoms. Third, with confirmation of remaining inflammation in the tissues, a strategy to change treatment needs to be undertaken. Few controlled trials are available to guide our treatment strategies. Furthermore, different subgroups of patients may benefit from different therapies, and different organ manifestations may respond to different therapies. In this context, subgrouping of patients with IIM based on autoantibody profile may be helpful, as there are emerging data from open studies and case series to support the notion of a varying treatment response in different autoantibody-defined subgroups of IIM patients.

Immunotherapy reversed myopathy but not cardiomyopathy in a necrotizing autoimmune myopathy patient with positive anti-SRP and MDA-5 autoantibodies.

BACKGROUND: Necrotizing autoimmune myopathy (NAM) is pathologically characterized by myofiber necrosis and regeneration with paucity or absence of inflammatory cells in muscle biopsy. Two autoantibodies, namely anti-signal recognition particle (SRP)-antibodies and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-antibodies, are typically specific with NAM. Anti-SRP-positive NAM can be associated with cardiomyopathy which responds well to immunotherapy. Here we reported an anti-SRP-antibody and anti-MDA5-antibody NAM patient who developed severe cardiomyopathy after gaining significant improvement of myopathy and subsequently accepted heart transplantation. CASE PRESENTATION: A NAM case with both positive anti-SRP and MDA-5 antibodies who gained significant improvement of the skeletal muscle weakness with immunotherapy, but 3 years later he developed severe dilated cardiomyopathy and at last received heart transplantation. Myocardial biopsy showed disarranged and atrophic myofibers, remarkable interstitial fibrosis without inflammatory infiltrates. Immunohistochemistry analysis revealed increased polyubiquitin-binding protein p62/SQSTM1 protein expression and the positive staining of cleaved-caspase 3 in a few cardiomyocytes. After the transplantation, the patient was symptom-free on oral prednisone (10 mg/day) and tacrolimus (2 mg/day). CONCLUSIONS: We described the first case of anti-SRP and anti-MAD5 positive NAM who had received heart transplantation because of cardiopathy. Though the myopathy had been clinically improved after immunotherapy, the cardiomyopathy remained progressive and lethal. The processes of dysfunctional autophagy and augmented apoptosis were putatively pathophysiological mechanisms underlying cardiac damage in anti-SRP and anti-MAD5 positive NAM.

Alterations of macrophage and neutrophil content in skeletal muscle of aged versus young mice.

BACKGROUND: Skeletal muscle inflammation and oxidative stress are associated with aging-related loss of muscle mass and may be attributable to alterations in the number and types of leukocytes in skeletal muscle. Here, we tested the hypothesis that aging changes the number and composition of leukocyte subsets in skeletal muscle tissue. METHODS: Skeletal muscle was sampled from 4-mo-old (young) and 27-mo-old (old) C57BL/6J mice. Mononuclear cells of the gastrocnemius muscle were isolated, and flow cytometry was used to characterize the number and types of immune cells. RESULTS: The number of neutrophils and Ly-6C+ inflammatory macrophages in the skeletal muscle was significantly higher in old mice than in young mice. Inflammation and oxidative stress (measured using the markers phosphorylated JNK and nitrotyrosine) were also higher in the skeletal muscle of old mice than in that of young mice. CONCLUSIONS: Increasing age promotes skeletal muscle inflammation and oxidative stress, as well as infiltration of inflammatory macrophages and neutrophils.

Potential implications of six American Indian patients with myopathy, statin exposure and anti-HMGCR antibodies.

OBJECTIVES: Statin-associated autoimmune myopathy is a rare condition associated with the formation of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Underlying environmental and genetic risk factors remain poorly understood. American Indians have high rates of cardiovascular disease and associated co-morbidities that require lipid-lowering therapies. We observed this autoimmune myopathy in a series of American Indian statin users in rural Arizona. METHODS: We reviewed the charts of six American Indian patients with statin-associated autoimmune myopathy. We provide an illustrative case in addition to summaries of clinical presentations and treatment courses. RESULTS: This is the first report of statin-associated autoimmune myopathy in American Indians. These cases were all identified at the same geographically isolated hospital that exclusively serves an American Indian population with only 1800 statin users. There is relatively low migration. Each case was consistent with the previously described classical presentations for the disease. All six of our cases had diabetes and developed myopathy on high-dose atorvastatin, often with a recent change in statin type or dose. CONCLUSION: Providers serving American Indians need to be aware of the possibility of statin-associated autoimmune myopathy and familiar with its presentation. Larger, inclusive, population-based investigations are needed to elucidate risk factors for this condition, in particular the potential interactions between predisposing HLA alleles, diabetes and specific statin exposures. This is necessary to identify effective and safe lipid-lowering medications.