|CASE BASED REVIEW
|Ahead of print publication
Immune-mediated necrotizing myositis with hydroxy-3-methyl-glutaryl-coenzyme A reductase antibody positivity in MSA-negative and statin-naive profile
Kothapalli Nagamounika1, Josna Joseph1, R Hemanth Kumar2, John Mathew1
1 Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||20-Apr-2022|
|Date of Acceptance||13-Jun-2022|
|Date of Web Publication||18-Aug-2022|
Department Clinical Immunology and Rheumatology, Prince Manor Bldng, Christian Medical College, Vellore - 632 006, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Statin-naïve immune-mediated necrotizing myopathy (IMNM) is a rare disease entity, the diagnosis of which is complicated in the absence of a reliable biomarker. In this context, this case, which is the first one reported from a tertiary care center in South India, is unique. The presence of hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody supplements the clinical diagnosis, specifically in the serological absence of myositis-specific antibodies. A comprehensive diagnostic approach including HMGCR antibody positivity is advisable in IMNM.
Keywords: Diagnosis, hydroxy-3-methyl-glutaryl-coenzyme A reductase antibody, immune-mediated necrotizing myopathy, myositis
|How to cite this URL:|
Nagamounika K, Joseph J, Kumar R H, Mathew J. Immune-mediated necrotizing myositis with hydroxy-3-methyl-glutaryl-coenzyme A reductase antibody positivity in MSA-negative and statin-naive profile. Indian J Rheumatol [Epub ahead of print] [cited 2023 Feb 7]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=353996
| Introduction|| |
Myositis specific autoantibody-negative immune-mediated necrotizing myopathy (IMNM) is a rare disease entity and its diagnosis is often delayed due to the lack of supporting clinical history and serological evidence. In this review, we present a unique case of seronegative statin-naïve IMNM reported to our tertiary care facility, which has been detected based on clinical, histopathological, and serological cues including the positivity of anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) autoantibody. Over the time, the treatment strategy was changed to intravenous immunoglobulin (IVIG), as previous steroid and methotrexate therapy was found noneffective.
| Case Report|| |
A 36-year-old woman with no known comorbidities was admitted to our hospital in August 2021 with complaints of gradually progressive limb muscle weakness for the past 3 years and truncal and neck muscle weakness for 6 months. She started having complaints since 2018. She initially had complaints of painless, proximal muscle weakness in both the lower limbs for 3 years followed by proximal upper-limb weakness for the past 1 year. Nerve conduction studies revealed motor axonopathy predominantly involving the upper limb, and electromyography showed a myogenic process suggestive of inflammatory myopathy. Cardiovascular, respiratory, abdominal, and musculoskeletal examination was normal. She had no distal muscle, respiratory, or facial muscle weakness. She had no sensory or cranial nerve complaints. She also had no history of fever, Raynaud's disease, skin rashes or thickening, oral ulcers, photosensitivity, dry eyes, and dry mouth. She had no significant family history or history of statin usage. Limited evaluation to rule out malignancies was also done, and there was no evidence of malignancies. HMGCR antibody was tested positive, and based on antibody positivity and muscle biopsy findings, supported with clinical symptoms, the patient was diagnosed with necrotizing myositis.
Evaluation carried out and treatment adopted is depicted in the timeline [Figure 1].
With the change in treatment method using IVIG and Mycophenolate Mofetil, the patient had partial improvement of upper-limb weakness, but lower-limb and neck muscle weakness persisted. In the latest evaluation, there was a significant improvement in her stability and could walk with support, when compared to her earlier supported restricted movement.
| Discussion|| |
Diagnosis of idiopathic inflammatory myositis is carried out with clinical examination, patient records, supplemented by muscle biopsy findings, and myositis-specific autoantibody (MSA) detection. Whereas detection of seronegative (MSA-negative) IMNM is dependent upon the positivity of autoantibodies anti-HMGCR/ SRP (signal recognition particle) along with (hydroxy -3- methyl-glutaryl-coenzyme- A- reductase) myophagocytosis involving myofiber necrosis, in the absence or paucity of inflammatory infiltrates. Clinically, IMNM manifest with proximal upper and lower extremity weakness, which progress over time, with other symptoms of dysphagia or dyspnea, high Creatinine phosphokinase (CPK) levels, and nonresponse to monotherapy of steroids. In a retrospective electronic medical records (EMR) evaluation spanning 10 years including 63 adult necrotizing myopathy patients, who were stratified according to presumable cause and autoantibody status, 35% had a history of statin intake at onset, 9% had cancer, and 4% had connective tissue disease. Out of them, 34% were HMGCR-immunoglobulin g positive, of which one-third of whom had no prior statin intake. Here, the nonstatin triggers of inflammatory myopathy such as infections, malignancy and drug toxicities including immune checkpoint inhibitor exposure should be considered. The role of other environmental triggers such as UV light, smoking, pollution, and chulha exposure in genetically susceptible individuals for HMGCR positivity cannot be excluded. In another series of studies, statin exposure was found in 44–92% of patients with HMGCR autoantibodies., Aggarwal et al. report that anti-HMGCR positivity was significantly (P < 0.001) associated with MSA-negative myositis, and in those MSA-negative groups, 78% had prior statin exposure. Hence, it is evident that in a small proportion of these patients, the cause is not defined and a lack of history of statin exposure could lead to overlooking of other facts, necessitating testing for HMGCR antibody.
In 2010, HMGCR autoantibody presence in IMNM was reported for the first time. The pathogenic role of anti-HMGCR and anti-SRP antibodies has been described as an inducer of muscle fiber atrophy and MAFbx and TRIM63 gene expression, which have a role in atrophy and proteasomal degradation of muscle proteins. Thus, when clinical likelihood is there, separate testing for HMGCR/SRP autoantibody is essential, specifically due to the nonavailability of a MSA antibody panel including HMGCR. Furthermore, this would help to differentiate between patients with self-limited statin myopathy and progressive statin-associated autoimmune myopathy and specifically for distinguishing nonstatin-associated and MSA-negative necrotizing myopathy groups. Our patient also belonging to latter subgroup had benefited from the seropositivity of HMGCR in the context of a negative myositis panel test. In the absence of an earlier reported case of a similar background, we report it as the first case of diagnosed nonstatin exposed seronegative IMNM in South India from a tertiary care hospital. Our observation corroborates with the report from northern India by Gupta et al. describing four statin-naïve, Myositis specific autoantibody/ Myositis associated autoantibody-negative HMGCR-positive cases (3.6% prevalence/128 Idiopathic inflammatory myositis cases) [Table 1].
|Table 1: Cases of nonstatin-associated anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase+immune-mediated necrotizing myopathy reported in India|
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Although the absence or notable paucity of inflammatory infiltrates (pauci-immune) characterizes necrotizing myopathy from polymyositis or dermatomyositis, in 30% of patients with anti-HMGCR myopathy, predominant lymphocyte infiltrates were observed, with endomysial distribution. We have observed the typical presence of atrophied necrotic muscle fibers undergoing myophagocytosis with no significant intrafascicular inflammation [Figure 2].
|Figure 2: Photomicrograph showing cross-section of skeletal muscle fibers with foci of myophagocytosis (solid arrow) (a; H and E, ×400), scattered necrotic fibers (dotted arrow) (b; H and E, ×400), and many regenerating fibers (block arrows) (c: H and E, ×200). Significant intrafascicular inflammatory infiltrate is not identified|
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Regenerating muscle fibers could also act as an additional source of HMGCR than statin exposure. Thus, HMGCR, being a primary autoimmune muscle target antigen, explains the disease occurrence in statin-naïve patients. Genetic predisposition, with the presence of DRB1*11:01, has been reported in anti-HMGCR autoantibody-positive individuals, in both white and african-american populations, whereas B 5001 and DQA1 0104 are associated with anti-SRP antibodies. This shows a mechanistic connection between presentation of HMGCR-derived peptide (s) by DRB1*11:01 and autoantibody production.,
High-steroid treatment failure (92–100%) has been reported in HMGCR antibody-positive patients and steroids have nonsignificant role in remission of clinical symptoms in seronegative necrotizing myopathy. However, it has to be noted that the European Neuromuscular Center workshop consensus is that IMNM patients should be treated with both corticosteroids and a second-line immunosuppressant either immediately or within 1 month of presentation. They had also recommended the usage of IVIG for all HMGCR antibody-positive patients within 6 months of presentation. In our patient, a similar line of treatment strategy was adopted.
| Conclusions|| |
HMGCR antibody positivity could be an ideal diagnostic predictor for nectrotizing myopathy. Statin-naïve patients are often young women, with good response to treatment. Timely administration of IVIG before the occurrence of muscle damage is the key for an ideal outcome.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]