Lack of replication of interactions between polymorphisms in rheumatoid arthritis susceptibility: case-control study

Introduction: Approximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they explain only a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) × protein tyrosine phosphatase nonreceptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including their replication in a second sample collection. In one of them, researchers identified interactions between PTPN22 and seven single-nucleotide polymorphisms (SNPs). The other showed interactions between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide-positive (anti-CCP+) patients. In the present study, we aimed to replicate association with RA susceptibility of interactions described in these two high-quality studies. Methods: A total of 1,744 patients with RA and 1,650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single-base extension. SE genotypes of 736 patients were available from previous studies. Interaction analysis was done using multiple methods, including those originally reported and the most powerful methods described. Results: Genotypes of one of the SNPs (rs4695888) failed quality control tests. The call rate for the other eight polymorphisms was 99.9%. The frequencies of the polymorphisms were similar in RA patients and controls, except for PTPN22 SNP. None of the interactions between PTPN22 SNPs and the six SNPs that met quality control tests was replicated as a significant interaction term the originally reported finding or with any of the other methods. Nor was the interaction between GSTM1 and the SE replicated as a departure from additivity in anti-CCP+ patients or with any of the other methods. Conclusions: None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that whether interactions are significant contributors to RA susceptibility remains unknown and that strict standards need to be applied to claim that an interaction exists

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. Methods: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. Results: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. Conclusions: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE

Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry

Objectives. This article estimates the frequency of polyautoimmunity and associated factors in a large retrospective cohort of patients with SLE. Methods. RELESSER (Spanish Society of Rheumatology Lupus Registry) is a nationwide multicentre, hospital-based registry of SLE patients. This is a cross-sectional study. The main variable was polyautoimmunity, which was defined as the co-occurrence of SLE and another autoimmune disease, such as autoimmune thyroiditis, RA, scleroderma, inflammatory myopathy and MCTD. We also recorded the presence of multiple autoimmune syndrome, secondary SS, secondary APS and a family history of autoimmune disease. Multiple logistic regression analysis was performed to investigate possible risk factors for polyautoimmunity. Results. Of the 3679 patients who fulfilled the criteria for SLE, 502 (13.6%) had polyautoimmunity. The most frequent types were autoimmune thyroiditis (7.9%), other systemic autoimmune diseases (6.2%), secondary SS (14.1%) and secondary APS (13.7%). Multiple autoimmune syndrome accounted for 10.2% of all cases of polyautoimmunity. A family history was recorded in 11.8%. According to the multivariate analysis, the factors associated with polyautoimmunity were female sex [odds ratio (95% CI), 1.72 (1.07, 2.72)], RP [1.63 (1.29, 2.05)], interstitial lung disease [3.35 (1.84, 6.01)], Jaccoud arthropathy [1.92 (1.40, 2.63)], anti-Ro/SSA and/or anti-La/SSB autoantibodies [2.03 (1.55, 2.67)], anti-RNP antibodies [1.48 (1.16, 1.90)], MTX [1.67 (1.26, 2.18)] and antimalarial drugs [0.50 (0.38, 0.67)]. Conclusion. Patients with SLE frequently present polyautoimmunity. We observed clinical and analytical characteristics associated with polyautoimmunity. Our finding that antimalarial drugs protected against polyautoimmunity should be verified in future studies

Anakinra versus Baricitinib: Different Strategies for Patients Hospitalized with COVID-19

Background: Immunomodulatory drugs have been used in patients with severe COVID-19. The objective of this study was to evaluate the effects of two different strategies, based either on an interleukin-1 inhibitor, anakinra, or on a JAK inhibitor, such as baricitinib, on the survival of patients hospitalized with COVID-19 pneumonia. Methods: Individuals admitted to two hospitals because of COVID-19 were included if they fulfilled the clinical, radiological, and laboratory criteria for moderate-to-severe disease. Patients were classified according to the first immunomodulatory drug prescribed: anakinra or baricitinib. All subjects were concomitantly treated with corticosteroids, in addition to standard care. The main outcomes were the need for invasive mechanical ventilation (IMV) and in-hospital death. Statistical analysis included propensity score matching and Cox regression model. Results: The study subjects included 125 and 217 individuals in the anakinra and baricitinib groups, respectively. IMV was required in 13 (10.4%) and 10 (4.6%) patients, respectively (p = 0.039). During this period, 22 (17.6%) and 36 (16.6%) individuals died in both groups (p = 0.811). Older age, low functional status, high comorbidity, need for IMV, elevated lactate dehydrogenase, and use of a high flow of oxygen at initially were found to be associated with worse clinical outcomes. No differences according to the immunomodulatory therapy used were observed. For most of the deceased individuals, early interruption of anakinra or baricitinib had occurred at the time of their admission to the intensive care unit. Conclusions: Similar mortality is observed in patients treated with anakinra or baricitinib plus corticosteroid

Relationship between damage clustering and mortality in systemic lupus erythematosus in early and late stages of the disease: cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry.

To identify patterns (clusters) of damage manifestations within a large cohort of SLE patients and evaluate the potential association of these clusters with a higher risk of mortality. This is a multicentre, descriptive, cross-sectional study of a cohort of 3656 SLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestations were identified. Then, overall clusters were compared as well as the subgroup of patients within every cluster with disease duration shorter than 5 years. Three damage clusters were identified. Cluster 1 (80.6% of patients) presented a lower amount of individuals with damage (23.2 vs 100% in clusters 2 and 3, P In a large cohort of SLE patients, cardiovascular and musculoskeletal damage manifestations were the two dominant forms of damage to sort patients into clinically meaningful clusters. Both in early and late stages of the disease, there was a significant association of these clusters with an increased risk of mortality. Physicians should pay special attention to the early prevention of damage in these two systems