High-resolution HLA genotyping in inclusion body myositis refines 8.1 ancestral haplotype association to DRB1*03:01:01 and highlights pathogenic role of arginine-74 of DRß1 chain.

OBJECTIVES: Inclusion body myositis (IBM) is a progressive inflammatory-degenerative muscle disease of older individuals, with some patients producing anti-cytosolic 5'-nucleotidase 1A (NT5C1A, aka cN1A) antibodies. Human Leukocyte Antigens (HLA) is the highest genetic risk factor for developing IBM. In this study, we aimed to further define the contribution of HLA alleles to IBM and the production of anti-cN1A antibodies. METHODS: We HLA haplotyped a Western Australian cohort of 113 Caucasian IBM patients and 112 ethnically matched controls using Illumina next-generation sequencing. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. Allele frequencies were compared using Fisher's exact test. Age at onset analysis was performed using the ggstatsplot package. All analysis was carried out in RStudio version 1.4.1717. RESULTS: Our findings validated the independent association of HLA-DRB1*03:01:01 with IBM and attributed the risk to an arginine residue in position 74 within the DRß1 protein. Conversely, DRB4*01:01:01 and DQA1*01:02:01 were found to have protective effects; the carriers of DRB1*03:01:01 that did not possess these alleles had a fourteenfold increased risk of developing IBM over the general Caucasian population. Furthermore, patients with the abovementioned genotype developed symptoms on average five years earlier than patients without. We did not find any HLA associations with anti-cN1A antibody production. CONCLUSIONS: High-resolution HLA sequencing more precisely characterised the alleles associated with IBM and defined a haplotype linked to earlier disease onset. Identification of the critical amino acid residue by advanced biostatistical analysis of immunogenetics data offers mechanistic insights and future directions into uncovering IBM aetiopathogenesis.

Clinical associations of patients with anti-3-hydroxy-3-methylglutaryl CoA reductase antibody-associated immune-mediated necrotising myopathy.

BACKGROUND: Anti-3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune-mediated necrotising myopathy (IMNM). AIMS: To determine clinical associations of anti-HMGCR antibodies for anti-HMGCR-associated IMNM (HMGCR-IMNM) among a cohort of patients in Western Australia and to determine whether serial HMGCR antibody levels parallel disease activity. METHODS: Adult patients with positive anti-HMGCR antibodies detected by enzyme-linked immunosorbent assay between January 2015 and November 2019 were included. Symptoms, examination findings, imaging findings and blood test results were reviewed retrospectively using patient records and laboratory database results. RESULTS: Among 26 patients with positive anti-HMGCR antibodies, 23 were diagnosed with HMGCR-IMNM representing a positive predictive value (PPV) of 88%. Myopathy was frequently severe at diagnosis with limb weakness graded as Medical Research Council score 3 or below in 78% of patients, bulbar muscle weakness in 39% and an average creatine kinase (CK) at diagnosis of 7986 U/L. The majority (83%) required at least two therapies to maintain remission, 48% had at least one flare of disease and 57% did not achieve CK normalisation. Correlation between CK and anti-HMGCR antibody level at diagnosis was low (r = 0.04). Anti-HMGCR antibodies fell with treatment in 10 of 12 patients, but remained persistently positive in 83% of patients. CONCLUSIONS: The PPV of anti-HMGCR antibodies for HMGCR-IMNM in this Western Australian cohort is 88%. Patients typically present with proximal limb weakness, dysphagia and markedly elevated CK, and, despite multiagent immunosuppression, a significant number of patients have evidence of persistent biochemical myositis. Anti-HMGCR antibodies did not correlate with CK levels at diagnosis.

Idiopathic inflammatory myopathies: a review.

Idiopathic inflammatory myopathy (IIM) is the umbrella term including dermatomyositis (DM), polymyositis (PM), overlap myositis (OM), sporadic inclusion body myositis (IBM) and necrotising autoimmune myopathy (NAM), also known as immune-mediated necrotising myopathy. There is some debate as to whether PM exists as a discrete entity, or perhaps is an overly generalising term encompassing connective tissue disease associated myositis, or OM, and the previously poorly recognised NAM. As such, PM will not be covered in detail in this review. DM, OM and NAM all present similarly, with proximal weakness and elevated creatine kinase (CK) level. By contrast, IBM preferentially involves the long finger flexors and quadriceps, and presents with a normal or only mildly elevated CK. Developments in serological testing and imaging are shifting the diagnostic paradigm away from a reliance on histopathology. The therapeutic armamentarium for IIM continues to evolve, with intravenous immunoglobulin and rituximab proving to be successful for refractory disease. This review will provide a diagnostic algorithm for the clinician to help distinguish between IIM subtypes - with emphasis on clinical assessment, serology and imaging, as well as discussion of therapeutic options and escalation of immunotherapy.

The use of omalizumab for treatment-refractory chronic spontaneous urticaria in a West Australian outpatient cohort.

There is a lack of real-world data on the use of omalizumab in treatment-refractory chronic spontaneous urticaria (CSU). A single-centre retrospective cohort study was performed to assess the efficacy and safety of omalizumab for treatment-refractory CSU. The overall response rate of 67% is comparable with that reported in the literature. Disease control and sustained remission can be achieved with omalizumab, even in patients with treatment-resistant CSU.

The significance of anti-granulocyte-macrophage colony-stimulating factor antibodies in cryptococcal infection: case series and review of antibody testing.

We report two cases of cryptococcosis, associated with anti-granulocyte-macrophage colony-stimulating factor antibodies. We review this recently identified acquired form of autoimmune immune deficiency and discuss the potential applications of granulocyte-macrophage colony-stimulating factor antibody testing by enzyme-linked immunosorbent assay.

Exploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis.

Neuromuscular blocking agents (NMBAs) are the most commonly implicated drugs in IgE-mediated anaphylaxis during anaesthesia that can lead to perioperative morbidity and mortality. The rate of NMBA anaphylaxis shows marked geographical variation in patients who have had no known prior exposure to NMBAs, suggesting that there may be external or environmental factors that contribute to the underlying aetiology and pathophysiology of reactions. Substituted ammonium ions are shared among NMBAs and are therefore thought to be the main allergenic determinant of this class of drugs. Substituted ammonium ions are found in a wide variety of chemical structures, including prescription medications, over-the-counter medications and common household chemicals, such as the quaternary ammonium disinfectants. Epidemiological studies have shown parallels in the consumption of pholcodine, a nonprescription antitussive drug which contains a tertiary ammonium ion, and the incidence of NMBA anaphylaxis. This link has prompted the withdrawal of pholcodine in some countries, with an ensuing fall in the observed rate of NMBA anaphylaxis. While such observations are compelling in their suggestion of a relationship between pholcodine exposure and NMBA hypersensitivity, important questions remain regarding the mechanisms by which pholcodine is able to sensitize against NMBAs and whether there are other, as yet unidentified, agents that can elicit similar hypersensitivity reactions. This review aims to explore the evidence linking pholcodine exposure to NMBA hypersensitivity and discuss the implications for our understanding of the pathophysiology of these reactions.

Drug reaction with eosinophilia and systemic symptoms syndrome secondary to acetazolamide associated with markedly elevated procalcitonin.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important cause of multi-organ dysfunction and can mimic other disorders including sepsis. We describe a patient presenting with septic shock and accompanying high procalcitonin. Although initially treated empirically with antibiotics, the emergence of eosinophilia during the admission lead to a revised diagnosis of DRESS syndrome, presumed secondary to acetazolamide. This case highlights the importance of regular clinical assessment and re-evaluation is key in identifying emerging features such as eosinophilia, rash and organ dysfunction, which can secure the diagnosis. Furthermore, the case also highlights that acetazolamide may be a rare cause of DRESS syndrome.

Polyarteritis nodosa isolated to muscles-A case series with a review of the literature.

Muscular polyarteritis nodosa where disease is isolated to skeletal muscle is a rare and often poorly recognised clinical entity. Patients typically present with fever and severe muscle pain limiting ability to ambulate without rise in creatine kinase. Often there is a significant delay between presentation and diagnosis, which requires histological confirmation. Musculoskeletal MRI is a sensitive investigation that can lead to timely biopsy and improve diagnostic yield. Early diagnosis of this condition is essential as patients typically respond favourably to corticosteroid treatment. Here we report 4 cases of muscular polyarteritis nodosa and review the reported literature.

Hybrid treatment of an isolated immunoglobulin G4-related internal thoracic artery aneurysm.

True aneurysms of the internal thoracic artery (ITA) are rare and are associated with vasculitides, connective tissue diseases, and infections. We report a case of a 3-cm immunoglobulin G4-positive ITA aneurysm that was excised by a hybrid approach involving open ligation of the ITA origin and video-assisted thoracoscopic aneurysmectomy. This novel technique was able to acquire tissue for histopathologic diagnosis through a minimally invasive means.

The high frequency of autoantibodies in HIV patients declines on antiretroviral therapy.

Autoantibodies have been described in samples from HIV positive patients, but the effects of antiretroviral therapy (ART) remain unclear. In a retrospective longitudinal study, we applied clinical assays for autoantibodies to sera collected from 13 HIV positive patients as they began ART with <210 CD4 T-cells/µL and over 2 years on treatment. Twelve of the 13 patients had at least one autoantibody. The frequency peaked before ART (21 from 156 assays) and declined to 8/143 positive reactions after 2 years. As anti-smooth muscle (ASM) antibodies remained common, these assays were applied to HIV patients (n = 67) who had <50 copies HIV RNA/mL plasma after 13 (2-17) years on ART, and healthy controls (n = 55). The frequency of ASM was high in these patients and correlated with levels of total IgG. Hence the high frequency of autoantibodies before ART declined, but did not disappear, with successful therapy. Autoantibody levels may reflect B-cell hyperactivity in patients stable on ART.

The Significance of Anti-Beta-2-Glycoprotein I Antibodies in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a thrombophilic disorder that classically presents with vascular thrombosis and/or obstetric complications. APS is associated with antiphospholipid antibodies: a heterogeneous group of autoantibodies that are directed against membrane phospholipids in complex with phospholipid-binding proteins. Beta-2-glycoprotein I (B2GPI) binds anionic phospholipids and is considered to be the predominant antigen in APS and antibodies against B2GPI (anti-B2GPI) are recognised in the laboratory criteria for APS diagnosis. This review focuses on the part played by anti-B2GPI in the pathogenesis of APS, their associations with different clinical phenotypes of the disorder and new avenues for refining the diagnostic potential of anti-B2GPI testing.

Immunoglobulin G is the only anti-beta-2-glycoprotein I isotype that associates with unprovoked thrombotic events among hospital patients.

This study aimed to determine the strength of association between anti-beta-2-glycoprotein I (anti-ß(2)GPI) isotypes and thrombotic events by phenotyping hospital patients tested for diagnostic purposes with at least one positive anti-ß(2)GPI isotype. A laboratory database search identified patients who had undergone anti-ß(2)GPI testing during a 3 year period. Medical records of patients with a positive anti-ß(2)GPI result were reviewed and clinical events ascertained. Thromboses were subdivided into provoked and unprovoked, depending on the stated aetiology. A total of 128 patients had at least one positive anti-ß(2)GPI isotype. There was a higher proportion of unprovoked thromboses among patients who were IgG anti-ß(2)GPI positive compared to those who lacked IgG anti-ß(2)GPI (20/30 versus 20/98). Median IgG anti-ß(2)GPI levels were higher among patients with unprovoked events compared to those without (22.5 SGU versus 2 SGU). Retrospective assessment of anti-ß(2)GPI testing strategies showed that testing IgM and/or IgA anti-ß(2)GPI after IgG anti-ß(2)GPI captured a greater number of non-thrombotic events and provoked thromboses than unprovoked thromboses. IgG anti-ß(2)GPI associates most strongly with clinical events characteristic of antiphospholipid syndrome (APS). These results suggest that IgG anti-ß(2)GPI is superior to IgM and IgA anti-ß(2)GPI in the assessment of hospital patients with potential APS.