ABSTRACT
Introduction: It is unclear whether quantitating muscle endurance adds nonredundant information useful for the care of patients with muscular disease. Methods: Records were retrospectively ...reviewed for all Johns Hopkins Myositis Center patients with a muscle endurance assessment (n = 128, 226 patient‐visits). Muscle endurance and strength were quantitated with the Myositis Functional Index‐2 (FI2) and manual muscle testing (MMT), respectively. Results: Composite FI2 muscle endurance scores were comparable in inclusion body myositis (n = 58), dermatomyositis (n = 31), and polymyositis (n = 39). Overall, muscle endurance correlated with and evolved similarly to strength, inversely to serum creatine kinase. However, in patients with normal or near‐normal strength (mean MMT > 9.75/10), muscle endurance was typically abnormal and highly variable (mean FI2, 5.6/10; interquartile range, 3.3‐7.8/10). Discussion: Muscle endurance testing may identify muscle impairment inadequately described by MMT, particularly in patients with high MMT scores. Muscle Nerve 59:70–75, 2019
Although generally well tolerated, statin users frequently report muscle-related side effects, ranging from self-limiting myalgias to rhabdomyolysis or the rare clinical entity of statin-associated ...immune-mediated necrotizing myopathy (IMNM). Statin-associated IMNM is based on the development of autoantibodies against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the pharmacologic target of statins, and leads to a necrotizing myopathy requiring immunosuppressive therapy. This review attempts to recapitulate the diverse aspects of anti-HMGCR IMNM, including clinical presentation, diagnostic modalities, genetic risk associations, therapeutic options and potential pathogenetic pathways.
Objective
Antibodies against the small ubiquitin‐like modifier (SUMO) activating enzyme (SAE) are one of the rarer specificities associated with dermatomyositis (DM). The purpose of this study is to ...describe the clinical characteristics of patients with anti‐SAE autoantibodies in a North American cohort and to ascertain cancer prevalence. We also describe the performance characteristics of the line blotting (Euroimmun) method for antibody detection compared with an immunoprecipitation‐based assay.
Methods
Sera from 2127 patients suspected of having myositis were assayed for myositis‐specific autoantibodies using the Euroimmun platform. Those positive for SAE autoantibodies were assayed by a second method (immunoprecipitation) for confirmation. Only those cases positive by both methods were taken as definite cases of anti‐SAE–positive DM. Chart reviews of these patients were completed to obtain information on clinical characteristics, cancer history, and treatment.
Results
Forty‐three of 2127 sera were anti‐SAE autoantibody positive by Euroimmun (≥15 units, +); of these, only 19 were confirmed positive by immunoprecipitation. All 19 cases had skin involvement and varying presentations of muscle, lung, and joint disease. Cancer occurred coincident with DM in two patients, and cancers were detected more than 5 years from symptom onset in three patients. In a population of suspected inflammatory myositis, a higher cutoff on line blot testing (≥36 units, ++) yielded better agreement with immunoprecipitation methods.
Conclusion
SAE autoantibodies associate with a clinical phenotype of DM, which most commonly presents with a rash first, followed by muscle involvement and varying extramuscular involvement. As coincident cancer was seen in anti‐SAE–positive DM, judicious malignancy screening may be warranted.
The use of statins has increased exponentially over the last 2 decades. Consequently, side effects have also increased, with muscle-related side effects commonly reported.
Although once thought to be ...only associated with self-limited direct myotoxicity, statins have recently been described in association with an autoimmune myopathy in association with antibodies directed against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate limiting enzyme in cholesterol synthesis and the pharmacologic target of statins. Since this discovery, various cohorts have been identified worldwide and highlight both similarities and differences among them.
Recent studies from different fields have revealed diverse aspects of anti-HMGCR-associated immune-mediated necrotizing myopathy (IMNM). HMGCR IMNM is a unique autoimmune disease characterized by a well defined environmental trigger (statins) and a strong association with a genetic risk factor (Human leukocyte antigen D related B 111 : 01). New diagnostic modalities have been established to confirm the presence of anti-HMGCR antibody and confirm the diagnosis of HMGCR IMNM. Clinical studies have shown that disease severity, as measured by muscle strength, as well as the rate of response to treatment have been associated with age at disease onset. Furthermore, a case series supported that intravenous immunoglobulin administration, perhaps even as monotherapy, may be a beneficial therapeutic intervention for selected patients.
The MHC class II antigen processing and presentation pathway has evolved to derive short amino acid peptides from proteins that enter the endocytic pathway, load them onto MHC class II molecules and ...display them on the surface of antigen presenting cells for recognition by CD4
T cells. Under normal circumstances, peptides bound to MHC class II molecules are derived from host (self) proteins and not recognized by T cells due to tolerance mechanisms. Pathogens induce significant changes in the biology of antigen presenting cells, including upregulation of MHC processing and presentation. We therefore hypothesized that exposure to pathogens may alter the repertoire of self-peptides bound to MHC class II molecules. To test this hypothesis, we isolated monocyte-derived dendritic cells from healthy subjects, exposed them to the TLR-2 agonist lipoteichoic acid or live
, the causative agent of Lyme disease, and isolated and characterized HLA-DR associated peptides using mass spectrometry. Our results show that lipoteichoic acid-stimulated,
-stimulated and unstimulated monocyte-derived dendritic cells largely derive their self-peptides from similar overlapping sets of host proteins. However, lipoteichoic acid and
stimulation promote the processing and presentation of new sets of HLA-DR associated self-peptides derived from unique protein sources. Examination of processes and compartments these proteins reside in, indicate that activation of monocyte-derived dendritic cells changes the range of host self-proteins available for processing and presentation on MHC class II molecules. These findings reveal that the HLA-DR-bound self-immunopeptidome presented by mo-DCs is dynamic in nature and changes with activation state reflective of cellular function. In addition, among the repertoire of self-peptides bound to HLA-DR are several epitopes known to be recognized by autoreactive T cells. These studies are relevant to our basic understanding of pathogen-induced changes in monocyte-derived dendritic cell function, and the mechanisms involved in infection-induced autoimmune illnesses such as Lyme arthritis.
Abstract
Anti-HMGCR+ IMNM is characterized by IgG antibodies against HMGCR and a strong association with HLA-DRB1* 11:01. Although this implicates HMGCR-specific CD4+ T cells in disease pathogenesis, ...no such cells have been identified thus far.
Monocyte derived dendritic cells from 6 anti-HMGCR+ IMNM patients were incubated with HMGCR protein and presented peptides were identified using a natural antigen processing assay (NAPA). Briefly, HLA-DR/peptide complexes were isolated by immunoprecipitation and bound peptides were sequenced by mass spectrometry. HMGCR peptides corresponding to putative T cell epitopes were synthesized and used to stimulate peripheral blood mononuclear cells from: 10 anti-HMGCR+ IMNM patients, 10 dermatomyositis patients (DM), 5 HLA-DRB1* 11:01+ healthy controls (HC). HMGCR-reactive CD4+ T cells were identified by flow cytometry based on CD154 upregulation.
A total of 7 different naturally processed HMGCR peptides were identified. The number of distinct peptides presented per patient ranged from 1 to 5, with 5 being presented by at least 2 patients. All HMGCR peptides elicited robust CD4+ T cell responses in 9/10 anti-HMGCR+ IMNM patients, compared to 4/10 DM patients (p=0.017), 1/5 of HC (p=0.0119). The anti-HMGCR+ IMNM patients responded to more epitopes (p=0.0163) and had higher total number of positive CD4+ T cell cells (p= 0.0001).
Our findings represent the first report of antigen-specific CD4+ T cells in anti-HMGCR+ IMNM. Leveraging NAPA, we defined a core set of naturally presented HMGCR peptides defining precise immunologically relevant CD4+ T cell epitopes. Definition of these epitopes is key in understanding disease pathogenesis and will aid in the development of antigen-specific therapeutic tools.
Supported by grants from Rheumatology Research Foundation and the Buck Foundation.
To study disease severity and response to therapy in a large cohort of patients with anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)-associated myositis.
Muscle strength, creatine kinase ...levels and treatments were assessed in anti-HMGCR-positive patients at each clinical visit. Univariate and multivariate analyses were used to analyse the influence of clinical characteristics on strength and the change in strength over time. Whole exome sequencing was performed in a subset of patients.
. Among 50 patients followed for ⩾2 years, only 22 (44%) reached full strength with immunosuppressive therapy; even among those with full strength, 55% continued to have CK levels in excess of 500 IU/l and only three could be tapered off immunosuppressive therapy. Both univariate and multivariate analysis showed that patients who were older at disease onset were stronger at all time points (P < 0.001) and improved faster (P < 0.008) than younger patients; a history of statin exposure was not independently associated with the improvement rate. Younger patients were more likely to have refractory disease (P = 0.02) than older patients. Among eight refractory patients with DNA available for testing, whole exome sequencing did not reveal pathogenic mutations in known dystrophy genes. The risk of cancer was not increased in anti-HMGCR myositis patients compared with the general population.
Anti-HMGCR myositis is usually a chronic disease requiring long-term immunosuppression. Although younger patients had more severe disease and a worse prognosis than older patients, they did not have evidence of a known co-existing muscular dystrophy to explain their persistent, and sometimes progressive, muscle weakness.
Objective
To determine the safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with statin‐associated anti–3‐hydroxy‐3‐methlyglutaryl coenzyme A reductase ...(anti‐HMGCR)–positive immune‐mediated necrotizing myopathy (IMNM).
Methods
Muscle strength was assessed in anti‐HMGCR–positive patients at each visit before and after initiation of PCSK9 inhibitors. The trends in creatine kinase (CK) levels and serum anti‐HMGCR antibody titers were monitored over time.
Results
Among 122 anti‐HMGCR–positive patients, we identified 8 patients who were receiving PCSK9 inhibitors for hyperlipidemia. Patients were followed up for an average of 1.5 years (range 3–37 months), and none exhibited reduction in muscle strength. The mean ± SD CK level prior to the initiation of PCSK9 inhibitors was 956 ± 1,137 IU/liter, which was reduced to 419 ± 393 IU/liter at their last visit. Anti‐HMGCR antibody titers followed a similar trend. Notably, in 2 patients, the initiation of the lipid‐lowering medication was followed by unanticipated spontaneous clinical improvement and reduction in immunosuppression.
Conclusion
PCSK9 inhibitors are safe for long‐term use as a cholesterol‐lowering agent in patients with statin‐associated IMNM.
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