Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Investigation of the HIN200 locus in UK SLE families identifies novel copy number variants.

We undertook a candidate locus study of the HIN200 gene cluster on 1q21-23 in UK systemic lupus erythematosus (SLE) families. To date, despite mounting evidence demonstrating the importance of these proteins in autoimmune disease, cancer, apoptosis, inflammation, and cell cycle arrest, there has been a dearth of data with respect to the genetic characterisation of the HIN200 locus in SLE or any other disease. We typed 83 single nucleotide polymorphisms (SNPs) across 317 kb of the HIN200 cluster in 428 UK SLE families and sought replication from a European-American lupus cohort. We do not find strong evidence of SNP association in either cohort. Interestingly, we do observe a trend for association with certain HIN200 SNPs and serologic subphenotypes in UK SLE that parallels the association of lupus antibodies with the orthologous murine locus. Furthermore, we find the HIN200 locus to be unexpectedly complex in terms of genetic structural organisation. We have identified a number of copy number variants (CNVs) in this region in healthy French males, HapMap samples, and UK SLE families. In summary, candidate interferon signalling genes show evidence of common CNV in human SLE and healthy subjects. The impact of these CNVs in health and disease remains to be determined.

Defining the role of the MHC in autoimmunity: a review and pooled analysis.

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.

Conversion of discoid lupus to antiphospholipid syndrome and SLE.

BACKGROUND: A 64-year-old man was admitted to hospital with increasing seizure frequency, lethargy and confusion. He had a history of discoid lupus erythematosus, complex partial seizures, cerebral thromboses associated with antiphospholipid syndrome (APS) and hypertension. After admission to hospital, he developed autoimmune hemolytic anemia, thrombocytopenia, severe hypertension, proteinuria and a fluctuating level of consciousness. INVESTIGATIONS: Physical examination, biochemical and hematological indices, urine dipstick, electrocardiography and chest radiography on admission, with subsequent electroencephalography, lumbar puncture, septic screen, autoimmune screen, CT of the head, MRI of the brain and renal biopsy. DIAGNOSIS: Conversion of discoid lupus erythematosus with APS to systemic lupus erythematosus with APS. MANAGEMENT: Pulsed intravenous methylprednisolone and a single infusion of intravenous cyclophosphamide, followed by oral prednisolone, were initially administered for presumed cerebral lupus. When renal biopsy revealed dual pathology, another dose of intravenous cyclophosphamide was administered with intravenous heparin therapy to treat systemic lupus erythematosus and APS, respectively. Intravenous immunoglobulin was used to treat thrombocytopenia, which was unresponsive to immunosuppression and anticoagulation. Gradual improvement occurred with maximal antihypertensive therapy and supportive treatment. The patient was discharged after 9 months of hospital treatment. His medication at this stage included warfarin, clopidogrel, prednisolone, carbamazepine, ramipril, atenolol, calcium and vitamin D supplements, and alendronate.

Identification of two independent risk factors for lupus within the MHC in United Kingdom families.

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 x 10(-8), permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 x 10(-8), permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies.