Vidya Limaye

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

Clinical heterogeneity and prognostic features of South Australian patients with anti‐synthetase autoantibodies

Aim:  To determine the clinical, serological and prognostic features of patients with autoantibodies against three aminoacyl‐transfer RNA synthetases (ARS), namely Jo‐1 (histidyl‐tRNA synthetase), PL‐7 (threonyl‐tRNA synthetase) and PL‐12 (alanyl‐tRNA synthetase) in South Australia.

Diagnostic utility of anti-Ro52 detection in systemic autoimmunity

Objectives To determine the prevalence and diagnostic utility of monospecific anti-Ro52 (defined as an immune response against Ro-52 antigen in the absence of reactivity to Ro-60 antigen) reactivity in selected autoimmune diseases. Study design Stored diagnostic non-consecutive serum samples obtained from patients with systemic lupus erythematosus (SLE), primary Sjögrens syndrome (pSS), systemic sclerosis, idiopathic inflammatory myopathies (IIM), rheumatoid arthritis, primary biliary cirrhosis and mixed essential cryoglobulinaemia were analysed by line immunoassay to detect the presence of anti-Ro52 and other autoantibodies. Results Monospecific anti-Ro52 reactivity was found in 51 (12.7%) of the 402 samples tested. Anti-Ro52 was the most common serological marker in patients with IIM (35/147, 23.8%) and co-occurred with anti-Jo1 (10/18, 55.6%; p=0.02). The prevalence of anti-Ro52 reactivity was significantly more than anti-Ro60 reactivity in patients with IIM, systemic sclerosis, primary biliary cirrhosis, mixed essential cryoglobulinemia and pSS. The mean signal intensity of anti-Ro52 reactivity was significantly higher in pSS than SLE and associated with rheumatoid factor positivity. The mean signal intensity of anti-Ro52 correlated with anti-Ro60 and anti-La in pSS and SLE. Conclusions Monospecific anti-Ro52 reactivity is not disease specific but may be of importance in patients with IIM. Furthermore, as anti-Ro52 reactivity is more prevalent than anti-Ro60 reactivity in certain autoimmune conditions, specific testing for their distinction in clinical practice is recommended.

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

Objectives The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. Results The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. Conclusions This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.

Incidence and prevalence of idiopathic inflammatory myopathies in South Australia: a 30-year epidemiologic study of histology-proven cases

Aim:  To describe the epidemiology of biopsy‐proven idiopathic inflammatory myopathies (IIM) in South Australia (SA).

Mortality and its predominant causes in a large cohort of patients with biopsy-determined inflammatory myositis.

Background:  There is a paucity of literature on the patterns and predictors of mortality in idiopathic inflammatory myopathies (IIM).

Necrotizing myopathy: clinicoserologic associations.

Introduction: Necrotizing myopathy (NM) is distinguished from idiopathic inflammatory myositis (IIM) by dominance of myofiber necrosis, lack of mononuclear inflammatory infiltrates, and presence of antibodies to signal recognition particle (SRP). Methods: The clinical features of 64 cases of NM were determined. Measurement of autoantibodies was undertaken on stored sera from 23 patients with NM. The incidence of malignancy was determined from the South Australian Cancer Registry. Results: NM patients showed male predominance (61%), more frequent myalgias, and higher creatine kinase (CK) levels compared with IIM patients. Patients with NM had a high incidence of systemic lupus erythematosus (SLE) (21%), hypertension (11 of 17, 65%), and diabetes mellitus (3 of 13, 23%). No patient had antibodies to SRP. NM patients showed no altered risk for malignancy compared with the South Australian population (P = 0.86). Conclusions: NM is associated with SLE, hypertension, and diabetes mellitus. Comprehensive assessment of cardiovascular risk is indicated in NM, which raises the possibility of targeted interventions. Muscle Nerve, 2012

Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus

Aims:  The long‐terms complications of immunosuppressive and anti‐inflammatory treatment in idiopathic inflammatory myositis (IIM) are unknown. We sought to determine the complications of these treatments in a large cohort of patients with biopsy‐proven IIM.

Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells.

Sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1-phosphate (S1P), which has potent pro-inflammatory and pro-angiogenic effects. We investigated the effects of raised SK1 levels on endothelial cell function and the possibility that this signaling pathway is activated in rheumatoid arthritis. Human umbilical vein endothelial cells with 3- to 5-fold SK1 (ECSK) overexpression were generated by adenoviral and retroviralmediated gene delivery. The activation state of these cells and their ability to undergo angiogenesis was determined. S1P was measured in synovial fluid from patients with RA and OA. ECSK showed an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells showed constitutive activation as evidenced by the induction of basal VCAM-1 expression, and further showed a more augmented VCAM-1 and E selectin response to TNF compared with empty vector control cells (ECEV). These changes had functional consequences in terms of enhanced neutrophil binding in the basal and TNFstimulated states in ECSK. By contrast, over-expression of a dominant-negative SK inhibited the TNF-induced VCAM-1 and E selectin and inhibited PMN adhesion, confirming that the observed effects were specifically mediated by SK. The synovial fluid levels of S1P were significantly higher in patients with RA than in those with OA. Small chronic increases in SK1 activity in the endothelial cells enhance the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines. The SK1 signaling pathway is activated in RA, suggesting that manipulation of SK1 activity in diseases of aberrant inflammation and angiogenesis may be beneficial.

The role of sphingosine kinase and sphingosine-1-phosphate in the regulation of endothelial cell biology.

Sphingolipids, in particular sphingosine kinase (SphK) and its product sphingosine-1-phosphate (S1P), are now recognized to play an important role in regulating many critical processes in endothelial cells. Activation of SphK1 is essential in mediating the endothelial proinflammatory effects of inflammatory cytokines such as tumor necrosis factor (TNF). In addition, S1P regulates the survival and proliferation of endothelial cells, as well as their ability to undergo cell migration, all essential components of angiogenesis. Thus the inflammatory and angiogenic potential of the endothelium is in part regulated by intracellular components including the activity of SphK1 and levels of S1P. Herein a review of the sphingomyelin pathway with a particular focus on its relevance to endothelial cell biology is presented.