Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy.

INTRODUCTION: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. METHODS: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. RESULTS: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR(+) patients there was a trend toward increased malignancy (P = 0.15). CONCLUSIONS: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11. Muscle Nerve 52: 196-203, 2015.

Cognitive Impairment and Risk Factors in Post-COVID-19 Hospitalized Patients.

Introduction: Numerous reports regarding cognitive deficits after the coronavirus disease 2019 (COVID-19), described as "brain fog," have been published. However, the clinical presentations and risk factors of post-COVID-19 cognitive impairment are controversial. This study aimed to assess (a) the prevalence of cognitive impairment after COVID-19 hospitalization, (b) characteristics of the cognitive deficits, (c) risk factors of post-COVID-19 cognitive impairment, and (d) comparison of cognitive function between post-COVID-19 patients and healthy people. Methods: The study comprised 34 SARS-CoV-2-infected patients, admitted to the Neurological Institute of Thailand during the peak of COVID-19 pandemic in 2021-2022. These patients came for neuropsychological and clinical evaluations at 2-week follow-up visit. The cognitive impairment and characteristics were measured by TMSE and MoCA. Clinical risk factors and post-COVID-19 cognitive impairment were assessed. The comparison of cognitive function in post-acute COVID-19 patients and 22 healthy controls was also performed. Results: The prevalence of post-COVID-19 cognitive impairment defined by a total MoCA score below 25 points was 61.76%. Years of education were the only predictive factors related to cognitive impairment. Our multivariate analysis revealed no statistical difference in cognitive outcomes between post-acute COVID-19 patients and healthy controls. Conclusion: This study showed a moderate prevalence of cognitive dysfunction after COVID-19 hospitalization similar to previous reports. However, there was no significant difference in cognitive measurements between these patients and healthy people. Whether SARS-CoV-2 infection causes cognitive dysfunction is a myth or fact that still has a long way to prove via further longitudinal study.

Good recovery of immunization stress-related responses presenting as a cluster of stroke-like events following CoronaVac and ChAdOx1 vaccinations.

BACKGROUND: Immunization stress-related responses presenting as stroke-like symptoms could develop following COVID-19 vaccination. Therefore, this study aimed to describe the clinical characteristics of immunization stress-related responses causing stroke-like events following COVID-19 vaccination in Thailand. METHODS: We conducted a retrospective study of the secondary data of reported adverse events after COVID-19 immunization that presented with neurologic manifestations. Between March 1 and July 31, 2021, we collected and analyzed the medical records of 221 patients diagnosed with stroke-like symptoms following immunization. Two majority types of vaccines were used at the beginning of the vaccination campaign, including CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca). Demographic and medical data included sex, age, vaccine type, sequence dose, time to event, laboratory data, and recovery status as defined by the modified Rankin score. The affected side was evaluated for associations with the injection site. RESULTS: Overall, 221 patients were diagnosed with immunization stress-related responses (stroke-like symptoms) following CoronaVac (Sinovac) or ChAdOx1 (AstraZeneca) vaccinations. Most patients (83.7%) were women. The median (interquartile range) age of onset was 34 (28-42) years in patients receiving CoronaVac and 46 (33.5-60) years in those receiving ChAdOx1. The median interval between vaccination and symptom onset for each vaccine type was 60 (16-960) min and 30 (8.8-750) min, respectively. Sensory symptoms were the most common symptomology. Most patients (68.9%) developed symptoms on the left side of the body; 99.5% of the patients receiving CoronaVac and 100% of those receiving ChAdOx1 had a good outcome (modified Rankin scores ≤2, indicating slight or no disability). CONCLUSIONS: Immunization stress-related responses presenting as stroke-like symptoms can develop after COVID-19 vaccination. Symptoms more likely to occur on the injection side are transient (i.e., without permanent pathological deficits). Public education and preparedness are important for administering successful COVID-19 vaccination programs.

Idiopathic hypertrophic cranial pachymeningitis.

Idiopathic hypertrophic cranial pachymeningitis is a rare chronic inflammatory process of unknown origin that can cause neurological deficits owing to thickening of the dura. Patients with this condition commonly present with cranial neuropathy accompanied by localized headache. The clinical features, neuroimaging findings, histopathological features and treatment outcomes for three patients with this condition are reported here. The first patient presented with subacute dull headache in the left temporal area followed by left abducens nerve palsy. The second patient suffered from a cranial nerve IX-XII lesion accompanied by an occipital headache and the third patient presented with left optic neuropathy and mild headache in the frontal area. In all patients, MRI of the brain revealed prominent dural thickening, and histopathological study of the dura revealed chronic inflammatory cell infiltration. Combined therapy with corticosteroid and immunosuppressive drugs was effective, resulting in almost complete resolution of the symptoms and signs, except for visual impairment in one patient.

Diagnostic performance of a commercial immunoblot assay for myositis antibody testing.

The objective of this study was to establish a population based reference range for a commercial immunoblot assay detecting myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs), and to assess the diagnostic performance of this reference range against the manufacturer's recommended ranges in a myositis patient cohort. A total of 124 patients from a myositis cohort and 197 healthy controls were serologically assessed using a commercial immunoblot containing eleven autoantigens (Jo-1, EJ, OJ, PL7, PL12, Mi-2, SRP, Ku, PMScl75, PMScl100 and Ro52) according to the manufacturer's instructions. Use of the manufacturer's reference ranges resulted in detection of MSAs in 19.4% of myositis patients and 9.1% of controls; MAAs were detected in 41.1% of myositis patients and 14.2% of controls. Reference values derived from the healthy control population resulted in significant differences in cut-off values for some autoantibodies, particularly Ro52 and PMScl75. Use of local reference ranges reduced detection of MSAs to 16.9% of myositis patients and 3% of healthy controls, with MAAs 23.4% of patients and 2% of healthy controls. Application of population based reference ranges resulted in significant differences in detection of MSAs and MAAs compared to the manufacturer's recommended ranges. Cut-off levels should be assessed to ensure suitability for the population tested.

Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy.

OBJECTIVE: We examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy. METHODS: Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR. RESULTS: All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase (CK) levels ranged from 2,700 to 16,200 IU/L. EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the reinstitution of immunotherapy, in particular steroids and IV immunoglobulin (IVIg). All patients required treatment with varying multiagent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIg (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1). CONCLUSIONS: Recognition of HMGCR antibody-associated NAM is important because these patients are responsive to immunosuppression, and early multiagent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes.

Complement-mediated muscle cell lysis: a possible mechanism of myonecrosis in anti-SRP associated necrotizing myopathy (ASANM).

The mechanism of necrotizing myopathy associated with antibodies to signal recognition particle (SRP) remains unclear. We investigated the effect of anti-SRP+serum and complement on cell viability in myoblast cultures. Cell viability was only slightly reduced by incubation with anti-SRP+serum compared with control serum. However, the addition of fresh complement resulted in a marked reduction in cell survival. Surface immunostaining for SRP, C3c and C5b-9 was demonstrated in cultures pre-incubated with anti-SRP+serum and complement, and in muscle biopsies from patients with myopathy. These findings provide further support for a complement-dependent antibody-mediated mechanism in anti-SRP associated myopathy.

Analysis of HLA-DRB3 alleles and supertypical genotypes in the MHC Class II region in sporadic inclusion body myositis.

We compared the carriage frequencies of HLA-DRB3 and its major alleles and of HLA-DRB4 and HLA-DRB5 in an Australian sIBM cohort and a population control group who had previously been genotyped for the HLA-DRB1*03:01 risk allele. There was a strong disease association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. The carriage of HLA-DRB4 was found to be strongly protective and abrogated the risk effect of HLA-DRB1*03:01. The findings indicate that haplotypic combinations of alleles at the HLA-DRB1 and secondary HLA-DRB loci have important risk modifying effects in sIBM.

Frequency of autoantibodies and correlation with HLA-DRB1 genotype in sporadic inclusion body myositis (s-IBM): a population control study.

The frequency of myositis-associated and myositis-specific autoantibodies (AAb) was compared in 51 s-IBM patients and a population control group. Non-organ specific AAb (ANA, anti-Ro52, anti-Ro60, anti-La, anti-RNP) but not anti-thyroid peroxidase, anti-tissue transglutaminase or myositis-specific antibodies, were more frequent in s-IBM patients, and 14/51 (27%) had another autoimmune disease (Sjögren's syndrome, thyroiditis, psoriasis, vitiligo). The presence of AAb did not correlate with carriage of HLA-DRB1*0301, but there was a negative correlation between ANA/anti-Ro52 and carriage of HLA-DRB1*1301. The findings in this cohort confirm that patients with sIBM do not show evidence of a muscle-specific humoral immune process but have an increased frequency of non-organ specific AAb and other autoimmune disorders.

High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: an analysis of disease-associated alleles and diplotypes.

We performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105s-IBM patients and 189 controls. Our findings showed that whilst the strongest association was with the HLA-DRB1*03:01 allele and the HLA-DRB1*03:01/*01:01 diplotype, HLA-DRB1*01:01 and HLA-DRB1*13:01 are also risk alleles. A number of other alleles, HLA-DRB1*04:01, *04:04, *07:01, *09:01, *11:01 and *15:01, as well as the HLA-DRB1*03:01/*04:01 and HLA-DRB1*03:01/*07:01 diplotypes were reduced in s-IBM cases and may be protective. The HLA-DRB1*03:01 and HLA-DRB1*13:01 alleles also appear to have an influence on the age at onset of the disease and severity of muscle weakness. Our findings indicate that the influence of HLA-DRB1 in s-IBM is complex and that epistatic interactions at the HLA-DRB1 locus contribute both to disease susceptibility and to the clinical phenotype.

Paraspinal and scapular myopathy associated with scleroderma.

OBJECTIVE: To describe a form of inflammatory myopathy with prominent involvement of the paraspinal and scapular muscles in patients with scleroderma. METHODS: Review of clinical records, laboratory investigations, and muscle biopsies. RESULTS: Patients presented with a "dropped head" resulting from weakness of the posterior cervical muscles (three cases) or camptocormia ("bent spine") resulting from weakness of the paraspinal muscles (two cases) and variable weakness and atrophy of shoulder girdle muscles with mild or absent pelvic girdle involvement. Biopsies from the deltoid or paraspinal muscles showed myositis of variable severity and scleroderma vasculopathy in all cases. The response to prednisolone and cytotoxic agents was poor, but there was a good response to intravenous immunoglobulin therapy in one case. CONCLUSIONS: Patients with scleroderma may develop a restricted form of immune-mediated inflammatory myopathy with a predilection for the paraspinal and scapular muscles, which is poorly responsive to treatment with glucocorticoids and immunosuppressive agents and may require consideration of other treatment modalities.