Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation.

OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

Secondary myoadenylate deaminase deficiency is not a common feature of inflammatory myopathies: A descriptive study.

Background: Myoadenylate deaminase (MAD) deficiency is a form of metabolic myopathy, which generally causes only mild symptoms in the primary inherited form. Inflammatory myopathies are a group of autoimmune diseases which result in skeletal muscle weakness. In addition to inflammatory pathology, it has been speculated that non-inflammatory mechanisms, and possibly secondary MAD-deficiency, may potentially contribute to weakness in these conditions. Methods: We investigated for an association between these two myopathic processes through two complementary methods. Firstly, muscle biopsy records in South Australia over a 17-year period were retrospectively reviewed for diagnosis of myositis or MAD-deficiency, as well as associated clinical features. Secondly, a prospective arm histochemically tested all incident biopsy specimens over a 12-month period for MAD-deficiency. Results: In the retrospective arm, 30 MAD-deficient cases were identified (1.3% of all biopsies), with no significant difference observed in overall rates of myositis diagnosis between patients with intact and deficient MAD activity (21.3% vs 26.7%, P = 0.47). No cases of MAD-deficiency were detected in the prospective arm, despite 39 cases of myositis being identified over this period. Conclusion: Secondary MAD deficiency is unlikely to be a major driver of symptoms in inflammatory myopathies.

Autoantibodies against four-and-a-half-LIM domain 1 (FHL1) in inflammatory myopathies: results from an Australian single-centre cohort.

OBJECTIVES: To determine the prevalence and associations of autoantibodies targeting a muscle-specific autoantigen, four-and-a-half-LIM-domain 1 (FHL1), in South Australian patients with histologically-confirmed idiopathic inflammatory myopathies (IIM) and in patients with SSc. MATERIAL AND METHODS: Sera from patients with IIM (n = 267) from the South Australian Myositis Database (SAMD), SSc (n = 174) from the Australian Scleroderma Cohort Study (ASCS) and healthy controls (HC, n = 100) were analysed for anti-FHL1 autoantibodies by Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: Autoantibodies to FHL1 were more frequent in patients with IIM (37/267, 13.8%) compared with SSc (12/174, 7%) (P < 0.02) and HC (2/100, 2%) (P < 0.001). The most common IIM subtypes among FHL1+ IIM patients were (32%) and IBM (2/37, 32%). No statistically significant differences in muscular or extra-muscular manifestations of IIM were found when comparing patients who were anti-FHL1+ with their anti-FHL1- counterparts. In 29/37 (78%) anti-FHL1+ patients, no myositis-specific autoantibodies (MSA) were present. In FHL1+ muscle biopsies, there was less frequent infiltration by CD45+ cells (P = 0.04). There was a trend for HLA alleles DRB1*07 and DRB1*15 to be more frequent in anti-FHL1+ compared with anti-FHL1- patients (9/25 vs 19/113, P = 0.09 and 8/25 vs 15/114, P = 0.09, respectively). CONCLUSIONS: We report a substantial prevalence (13.8%) of anti-FHL1 autoantibodies in a large cohort of patients with histologically confirmed IIM; 75% of these cases did not have a detectable myositis-specific autoantibody. Anti-FHL1 autoantibodies were also detected in a subgroup of patients with SSc (7%), indicating that anti-FHL1 autoantibodies may not be myositis-specific. The trend towards an HLA-DR association might indicate a specific immune response to the FHL1 protein.

Outcome predictors of immune-mediated necrotizing myopathy-a retrospective, multicentre study.

OBJECTIVES: Evidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-term outcomes of patients with IMNM. METHODS: Muscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package. RESULTS: Female sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate-severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months. CONCLUSION: Early IVIG was associated with clinical improvement in the short-term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.

A case of inflammatory myopathy in graft vs host disease - A potential role for ibrutinib.

Myositis is a known complication of chronic graft-vs-host disease (cGVHD) following allogeneic haematopoietic stem cell transplantation, but can be difficult to diagnose and manage. We present the case of a 57 year old man with cGVHD in whom the full manifestations of myositis were suppressed for some time, likely due to partial treatment of his condition with immunosuppression including ibrutinib. Though initial muscle biopsy showed necrotising myopathy without significant inflammation, on cessation of ibrutinib he developed increasing weakness and creatine kinase levels, with repeat muscle biopsy showing histological changes more in keeping with dermatomyositis. The close temporal correlation of his clinical course with commencement and cessation of ibrutinib suggests a potential role for ibrutinib in treating inflammatory myopathy in cGVHD.

Clinical Characteristics of Myositis Associated with Graft-Versus-Host Disease.

PURPOSE OF REVIEW: Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for inflammatory myositis; histological subsets reported include dermatomyositis, necrotising myopathy and chronic graft-versus-host disease (cGVHD)-related myositis. Though corticosteroids and various immunosuppressive therapies have been used, there is a lack of consensus guidelines dictating therapy. RECENT FINDINGS: Recent evidence suggests the fascia as a preferential target in cGVHD myositis, with conditioning regimens promoting fascial microtrauma. Positron emission tomography (PET) can be a useful diagnostic tool, and case reports suggest that the Bruton's tyrosine kinase inhibitor ibrutinib may have therapeutic potential. Emerging therapies include targeted B cell depletion with rituximab, and extracorporeal photophoresis. Clinicians need to be vigilant for the development of inflammatory myositis post-allogeneic HSCT as most patients respond to treatment. Advances in immunohistochemistry to determine the dominant cell type and cytokine profile may enable targeted and individualised therapies.

Health-related quality of life and work impairment in idiopathic inflammatory myopathies in South Australia.

AIM: The idiopathic inflammatory myopathies (IIM) are rare autoimmune diseases that are usually chronic and often present with skeletal muscle inflammation and weakness. We sought to examine the impact of IIM in a cohort of 50 South Australian patients on health-related quality of life (HRQOL) and work productivity (WP). We uniquely categorized patients across gender, IIM subtypes, employment status, and also whether there was extramuscular involvement from IIM. METHODS: Multiple modalities were used, as recommended by the International Myositis Assessment and Clinical Studies Group (IMACS), to assess the impact of IIM, including manual muscle strength testing (MMT-8), the Physician and Patient Global Activity Assessments (PHGAA, PTGAA), Myositis Disease Activity Assessment Tool (MDAAT), and serum creatinine kinase (CK) levels. The impacts of IIM on HRQOL and WP were analyzed using the Medical Outcomes Study 36-items Short Form (SF-36) and Work Productivity and Activity Impairment (WPAI) questionnaires, respectively. RESULTS: We found significantly lower HRQOL outcome scores in most of the SF-36 domains when compared to the most recent population norms (P ≤ .01). Physical health was predominantly affected with relative preservation of emotional health. There were also significant associations between MMT-8, PHGAA and PTGAA scores and HRQOL and WP. CONCLUSIONS: Our findings highlight the significant impact of IIM on HRQOL and WP in a well-characterized cohort of patients with IIM within Australia, and therefore the importance of a holistic approach to the management of these patients.

Interstitial pneumonia with autoimmune features in a patient with melanoma differentiation-associated gene 5 (MDA5) antibody.

Melanoma differentiation-associated gene 5 (MDA5) antibody, also known as anti-CADM140 antibody is recognised to be associated with rapidly progressive interstitial lung disease, which can be fatal within 3 months. It is also known to be associated with amyopathic dermatomyositis. We report a case of MDA5 antibody-associated interstitial pneumonia with autoimmune features, without cutaneous features of dermatomyositis, in a Sudanese patient with dual positive antibodies to Ro52. The patient notably had several features associated with poor prognosis, including age, high serum ferritin level, anti-Ro52 antibodies and progressive lung infiltrates during treatment.

Aberrant Expression of High Mobility Group Box Protein 1 in the Idiopathic Inflammatory Myopathies.

INTRODUCTION: High Mobility Group Box Protein 1 (HMGB1) is a DNA-binding protein that exerts inflammatory or pro-repair effects upon translocation from the nucleus. We postulate aberrant HMGB1 expression in immune-mediated necrotising myopathy (IMNM). METHODS: Herein, we compare HMGB1 expression (serological and sarcoplasmic) in patients with IMNM with that of other myositis subtypes using immunohistochemistry and ELISA. RESULTS: IMNM (n = 62) and inclusion body myositis (IBM, n = 14) patients had increased sarcoplasmic HMGB1 compared with other myositis patients (n = 46). Sarcoplasmic HMGB1 expression correlated with muscle weakness and histological myonecrosis, inflammation, regeneration and autophagy. Serum HMGB1 levels were elevated in patients with IMNM, dermatomyositis and polymositis, and those myositis patients with extramuscular inflammatory features. DISCUSSION: Aberrant HMGB1 expression occurs in myositis patients and correlates with weakness. A unique expression profile of elevated sarcoplasmic and serum HMGB1 was detected in IMNM.

Clinical and histological features of immune-mediated necrotising myopathy: A multi-centre South Australian cohort study.

Immune-mediated necrotising myopathy (IMNM) is a recently described entity. We describe a cohort of South Australian IMNM patients in order to define the spectrum of disease, characterise features that distinguish IMNM from other idiopathic inflammatory myopathy (IIM) subtypes and identify factors associated with clinically severe disease. Subjects were identified from the South Australian Myositis Database (SAMD), a histologically defined registry. Consecutive muscle sections from patients with IMNM (n = 62), other forms of IIM (n = 60) and histologically normal muscle (n = 17) were stained using immunohistochemistry and graded. Clinical information was collected from the SAMD and through retrospective chart review. IMNM patients displayed clinical and histological heterogeneity. While most (67%) were profoundly weak at presentation, 24% exhibited mild to moderate weakness and 9% had normal power. Histological myonecrosis ranged from minor to florid. The amount of myofibre complement deposition was closely associated with clinical severity. Patients of Aboriginal and Torres Strait Islander heritage and those with anti-SRP autoantibodies present with a severe phenotype. Despite intense immunotherapy, few IMNM patients recovered full power at one year follow up. The identification of clinical, serological and histological features which are associated with severe forms of the disease may have diagnostic and therapeutic utility.

Inclusion-body myositis and primary Sjögren syndrome: mechanisms for shared etiologies.

Herein we report a case of sporadic inclusion-body myositis (sIBM) occurring at an unusually young age in a patient with primary Sjögren syndrome, and use the case to explore possible shared mechanisms for disease susceptibility. Possible factors may include the association of both conditions with the 8.1 ancestral haplotype; the presence of anti-cN1A antibodies, which, although considered specific for sIBM, are also seen in pSS; and the shared association with T-cell large granular lymphocyte leukemia (T-LGLL). Further evaluation of this patient did in fact reveal underlying T-LGLL and mechanisms by which T cells in sIBM may escape immune regulation and contribute to disease phenotype are explored. Despite myofiber infiltration with CD8-positive T cells in sIBM, and, although sIBM is traditionally considered treatment-refractory, we report a significant response to the anti-CD20 monoclonal antibody, rituximab, and discuss possible mechanisms by which this response may be mediated.

Prevalence of polymyalgia rheumatica in a cohort of patients with idiopathic inflammatory myopathy.

Polymyalgia rheumatica (PMR) is a common rheumatological condition occurring in adults aged over 50 years. The association of PMR with other autoimmune diseases such as rheumatoid arthritis is complex. There is a clear relationship with giant cell arteritis. We sought to determine whether there is any association between PMR and idiopathic inflammatory myopathy (IIM). We undertook a database study of adult patients with a diagnosis of IIM under the care of the Rheumatology Department of the Royal Adelaide Hospital, and retrospectively determined the frequency of PMR in this patient cohort. Patients were considered to have PMR if this had been diagnosed by a physician or if they satisfied all five of the following clinical criteria: (1) bilateral shoulder and/or pelvic girdle aching, (2) morning stiffness exceeding 45 min, (3) age greater than 50 years, (4) duration more than 2 weeks, and (5) evidence of an elevated erythrocyte sedimentation rate or C-reactive protein. Amongst 82 patients with IIM, seven (8.5%) were found to have PMR. There was a disproportionate representation of necrotizing autoimmune myopathy (NAM) in patients with IIM/PMR (5/7) compared with patients with IIM alone (19/75), p = 0.02. There was a high prevalence of antibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with IIM/PMR (4/7, 57%) compared with those with IIM alone (9/32, 28%), p = 0.19. The prevalence of PMR in our IIM cohort was much higher than the population prevalence 0.91-1.53% and it appears there is a specific association with NAM and anti-HMGCR antibodies. Further studies are required to confirm these findings and explore mechanisms of shared disease susceptibility.Key Points• Idiopathic inflammatory myositis, in particular, statin-associated necrotizing myositis and anti-HMG co-A reductase antibodies, may have a previously unrecognized association with polymyalgia rheumatica.

Biologic therapy in the idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases resulting from inflammation of muscle and manifesting as weakness, though a range of extra-muscular manifestations are observed. These are often correlated closely with disease subtype and the presence of myositis-specific/myositis-associated antibodies. IIM are notoriously difficult to treat and often refractory to glucocorticoid therapy and synthetic immunosuppressants. Both the innate and adaptive immune systems are implicated in the pathogenesis of IIM. A growing understanding of the key cytokines as well as the cell-mediated and antibody effectors of disease has identified multiple potential targets for biologic therapy. The most widely used of these is B-cell depletion via rituximab though the tumour necrosis factor inhibitors and other biologic therapies used in diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis have also been trialled. This review summarises the literature thus far on biologic therapy in IIM, highlighting both the significant trials that influence current treatment regimens and also the continuing need for further research to inform more effective therapies.

External Validation and Evaluation of Adding MRI or Extended Myositis Antibody Panel to the 2017 EULAR/ACR Myositis Classification Criteria.

OBJECTIVE: To externally validate the European League Against Rheumatism/American College of Rheumatism (EULAR/ACR) classification criteria for idiopathic inflammatory myositis (IIM) and determine the optimal cut points for Australian patients. To determine the level of agreement with traditional criteria and assess the effect of including magnetic resonance imaging (MRI) and an extended myositis antibody panel as well as extending histological criteria to include myofiber invasion. METHODS: Data were collected on adult patients referred for muscle biopsy to two Australian teaching hospitals. Patients were scored for "risk of IIM" according to EULAR/ACR criteria, using clinician diagnosis as the gold standard. RESULTS: Overall, 87 of 204 patients had IIM. For patients with muscle biopsy, the optimal cut point of 5.25 (sensitivity 90%, specificity 89%) was lower than the EULAR/ACR cut point of 6.7, which in our cohort showed reduced sensitivity (71% vs 93%) but comparable specificity (89% vs 88%). We found moderate agreement between the EULAR/ACR criteria and Bohan and Peter (κ = 0.45, 95% confidence interval [CI] = 0.28, 0.62, P < 0.001) and Targoff (κ = 0.40, 95% CI = 0.23, 0.57, P < 0.001). Inclusion of MRI (area under curve [AUC] = 0.86, 95% CI = 0.79, 0.93) or non-Jo1 antibodies (AUC = 0.84, 95% CI = 0.77, 0.91) as covariates improved the probability of IIM diagnosis (AUC = 0.80, 95% CI = 0.75, 0.86). Extending histologic criteria to include myofiber invasion slightly improved sensitivity (75% vs 71%) with the same level of specificity (89% vs 89%). CONCLUSION: Application of the EULAR/ACR criteria to an Australian cohort showed comparable specificity but lower sensitivity, and a lower optimal cut point. Inclusion of MRI or non-Jo1 antibodies as covariates may improve the accuracy of determining the probability of IIM diagnoses. Extending the histologic criteria to include myofiber invasion did not reduce specificity.