Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction.

The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.

Correction: Epidemiology and treatment patterns of rheumatoid arthritis in a large cohort of Arab patients.

[This corrects the article DOI: 10.1371/journal.pone.0208240.].

Epidemiology and treatment patterns of rheumatoid arthritis in a large cohort of Arab patients.

OBJECTIVES: There is limited information on the epidemiology and treatment patterns of rheumatoid arthritis (RA) across the Arab region. We aim in this study to describe the demographic characteristics, clinical profile, and treatment patterns of patients of Arab ancestry with RA. METHODS: This is a cross sectional study of 895 patients with established rheumatoid arthritis enrolled from five sites (Jordan, Lebanon, Qatar, Kingdom of Saudi Arabia (KSA), and United Arab Emirates). Demographic characteristics, clinical profile, and treatment patterns are compared between the five countries. RESULTS: The majority of our patients are women, have an average disease duration of 10 years, are married and non-smokers, with completed secondary education. We report a high (>80%) ever-use of methotrexate (MTX) and steroids among our RA population, while the ever-use of disease modifying anti-rheumatic drugs (DMARDs) and TNF-inhibitors average around 67% and 33%, respectively. There are variations in RA treatment use between the five country sites. Highest utilization of steroids is identified in Jordan and KSA (p-value < 0.001), while the highest ever-use of TNF-inhibitors is reported in KSA (p-value < 0.001). CONCLUSION: Disparities in usage of RA treatments among Arab patients are noted across the five countries. National gross domestic product (GDP), as well as some other unique features in each country likely affect these. Developing treatment guidelines specific to this region could contribute in delivering standardized therapies to RA patients.

Correction to: Recommendations for the management of rheumatoid arthritis in the Eastern Mediterranean region: an adolopment of the 2015 American College of Rheumatology guidelines.

In the original version of this article the first name of the co-author was incorrectly spelled as "Khaled A. Alnaqbi". The correct spelling should have been "Khalid A. Alnaqbi". This is now presented correctly in this article.

Recommendations for the management of rheumatoid arthritis in the Eastern Mediterranean region: an adolopment of the 2015 American College of Rheumatology guidelines.

Clinical practice guidelines can assist rheumatologists in the proper prescription of newer treatment for rheumatoid arthritis (RA). The objective of this paper is to report on the recommendations for the management of patients with RA in the Eastern Mediterranean region. We adapted the 2015 American College of Rheumatology guidelines in two separate waves. We used the adolopment methodology, and followed the 18 steps of the "Guidelines 2.0" comprehensive checklist for guideline development. For each question, we updated the original guidelines' evidence synthesis, and we developed an Evidence Profile (EP) and an Evidence to Decision (EtD) table. In the first wave, we adoloped eight out of the 15 original questions on early RA. The strength changed for five of these recommendations from strong to conditional, due to one or more of the following factors: cost, impact on health equities, the balance of benefits, and harms and acceptability. In the second wave, we adoloped eight out of the original 44 questions on established RA. The strength changed for two of these recommendations from strong to conditional, in both cases due to cost, impact on health equities, balance of benefits and harms, and acceptability. The panel also developed a good practice recommendation. We successfully adoloped 16 recommendations for the management of early and established RA in the Eastern Mediterranean region. The process proved feasible and sensitive to contextual factors.

Rheumatic manifestations of inflammatory bowel diseases: A study from the Middle East.

Objective To examine the prevalence of rheumatic manifestations among patients with inflammatory bowel disease (IBD). Methods This prospective study enrolled patients with IBD in whom the diagnosis and extent of IBD were confirmed by colonoscopy and histopathology. Patients were interviewed and examined by a rheumatologist. A complete rheumatological examination, X-rays of the lumbosacral and sacroiliac joints and HLA-B27 blood tests were performed. Results A total of 127 adult patients were recruited: 46 (36.2%) with Crohn's disease (CD) and 81 (63.8%) with ulcerative colitis (UC). Rheumatic manifestations of any type were present in 57.5% (73 of 127 patients) with no significant differences between CD and UC. Peripheral manifestations were present in 43.3% (55 of 127 patients), four patients (3.1%) had axial arthritis alone and 14 patients (11.0%) had both types. Among those with peripheral manifestations, five patients (7.2%) had type 1 arthritis (pauciarticular) and one patient (1.4%) had type 2 arthritis (polyarticular). A higher proportion of patients with CD had axial manifestations with or without peripheral manifestations (eight of 46; 17.4%) compared with patients with UC (10 of 81; 12.3%), but no difference was observed in patients with peripheral manifestations alone. Conclusions Rheumatic manifestations in patients with IBD in Qatar are more prevalent than in other regions of the world. Peripheral manifestations were more prevalent than axial.

An Underlooked Cause of Periodic Fever (PFAPA) in an Adult Patient with No Response to Tonsillectomy.

Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is an autoinflammatory disease manifested as recurrent febrile episodes associated with one of the following cardinal features: aphthous ulceration, pharyngitis, and cervical adenitis. It was initially described in children and thought to be a disease of pediatric age group. Few adult cases were also reported in the literature. We describe the case of a 39-year-old female affected by PFAPA who presented with a history of febrile episodes associated with aphthous ulceration, stomatitis, and tonsillitis for 4 years. The febrile episodes occurred at a regular interval of 4 weeks and resolved within 5 days. The patient underwent tonsillectomy without any significant improvement. The patient responded only to a single high dose of steroid during the attack. Although PFAPA was initially thought to be a disease of pediatric age group, it should be considered in patients with recurrent febrile illness in all age groups.

Oral Manifestations of Systemic Lupus Erythematosus Patients in Qatar: A Pilot Study.

OBJECTIVE: The purpose of this pilot study was to assess the prevalence of oral manifestations among systemic lupus erythematosus (SLE) patients in Qatar, in order to warrant future studies that would investigate each one of these manifestations with detail and further scrutiny. METHODS: Study procedures took place between November 2014 and April 2016. All patients visiting the outpatient rheumatology clinics at Hamad General Hospital, Doha, Qatar, were asked to join. The American College of Rheumatology (ACR) 1997 criteria of SLE were used. The patients were examined initially by a rheumatologist and were later scheduled for an appointment with a dentist at the same institution. A total of 77 patients were recruited for the study. RESULTS: Prevalence rates for the different oral manifestations ranged from 2.4% for soft palate ulcers, cheilitis, and oral candida to 88.1% for the presence of cavitation. Gingivitis, periodontal disease, cavities, and missing teeth were observed in more than 50% of the sample. The prevalence of periodontal disease and missing teeth was higher among those with an SLE duration > 8 years. On the contrary, the prevalence of gingivitis and cavities was higher among those with an SLE duration ≤ 8 years. CONCLUSION: This study found high rates of gingivitis, periodontal disease, cavities, and missing teeth among SLE patients in Qatar. It is recommended that healthcare providers of such patients monitor the presence of any oral manifestations in order to arrange for early treatment and prevention efforts. Future prospective longitudinal studies with adequate sample size and power are needed in order to ascertain any causation factors or common etiology pathways.

Large Scale Metabolic Profiling identifies Novel Steroids linked to Rheumatoid Arthritis.

Recent metabolomics studies of Rheumatoid Arthritis (RA) reported few metabolites that were associated with the disease, either due to small cohort sizes or limited coverage of metabolic pathways. Our objective is to identify metabolites associated with RA and its cofounders using a new untargeted metabolomics platform. Moreover, to investigate the pathomechanism of RA by identifying correlations between RA-associated metabolites. 132 RA patients and 104 controls were analyzed for 927 metabolites. Metabolites were tested for association with RA using linear regression. OPLS-DA was used to discriminate RA patients from controls. Gaussian Graphical Models (GGMs) were used to identify correlated metabolites. 32 metabolites are identified as significantly (Bonferroni) associated with RA, including the previously reported metabolites as DHEAS, cortisol and androstenedione and extending that to a larger set of metabolites in the steroid pathway. RA classification using metabolic profiles shows a sensitivity of 91% and specificity of 88%. Steroid levels show variation among the RA patients according to the corticosteroid treatment; lowest in those taking the treatment at the time of the study, higher in those who never took the treatment, and highest in those who took it in the past. Finally, the GGM reflects metabolite relations from the steroidogenesis pathway.

An assessment of the current treatment landscape for rheumatology patients in Qatar: Recognising unmet needs and moving towards solutions.

Objective This study assessed the mode of application (oral, intravenous or subcutaneous (SC)) currently employed in the treatment of rheumatoid arthritis (RA) in patients from Qatar in comparison with patients' individual preferences for the mode of application of their treatment. Methods This study included 294 RA patients visiting three clinics at the main referral hospital in Qatar who were interviewed using a standard questionnaire to determine their preference of mode of application for their disease-modifying antirheumatic drug (DMARD) treatment in relation to their currently employed mode of application. Results The majority of patients were female (76%), and 93% of male patients and 61% of female patients in the study clinics were of a nationality other than Qatari. The highest patient preference recorded was for an oral therapy (69%), compared with injection (23%) and intravenous (8%) therapy. In total, 85% of patients expressed a preference to remain on oral therapy compared with 63% and 58% of intravenous and SC injection patients indicating a preference to remain on their current method of administration. Conclusions This high preference for oral therapies highlights the considerable need for incorporation of new oral targeted synthetic DMARD therapies into clinical practice within the region.

A Multinational Arab Genome-Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis.

OBJECTIVE: Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome-wide association study (GWAS) was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab-specific genetic loci. METHODS: The Genetics of Rheumatoid Arthritis in Some Arab States Study was designed to examine the genetics and clinical features of RA patients from Jordan, the Kingdom of Saudi Arabia, Lebanon, Qatar, and the United Arab Emirates. In total, >7 million single-nucleotide polymorphisms (SNPs) were tested for association with RA overall and with seropositive or seronegative RA in 511 RA cases and 352 healthy controls. In addition, replication of 15 signals was attempted in 283 RA cases and 221 healthy controls. A genetic risk score of 68 known RA SNPs was also examined in this study population. RESULTS: Three loci (HLA region, intergenic 5q13, and 17p13 at SMTNL2/GGT6) reached genome-wide significance in the analyses of association with RA and with seropositive RA, and for all 3 loci, evidence of independent replication was demonstrated. Consistent with the findings in European and East Asian populations, the association of RA with HLA-DRB1 amino acid position 11 conferred the strongest effect (P = 4.8 × 10-16 ), and a weighted genetic risk score of previously associated RA loci was found to be associated with RA (P = 3.41 × 10-5 ) and with seropositive RA (P = 1.48 × 10-6 ) in this population. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci. CONCLUSION: This first RA GWAS in Arab populations confirms that established HLA-region and known RA risk alleles contribute strongly to the risk and severity of disease in some Arab groups, suggesting that the genetic architecture of RA is similar across ethnic groups. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population-specific insights into the pathophysiology of RA.

The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study.

BACKGROUND: Patients with ankylosing spondylitis (AS), who by definition have radiographic sacroiliitis, typically experience symptoms for a decade or more before being diagnosed. Yet, even patients without radiographic sacroiliitis (i.e., nonradiographic axial spondyloarthritis [nr-axSpA]) report a significant disease burden. The primary objective of this study was to estimate the prevalence and clinical characteristics of nr-axSpA among patients with inflammatory back pain (IBP) in rheumatology clinics in a number of countries across the world. A secondary objective was to estimate the prevalence of IBP among patients with chronic low back pain (CLBP). METHODS: Data were collected from 51 rheumatology outpatient clinics in 19 countries in Latin America, Africa, Europe, and Asia. As consecutive patients with CLBP (N = 2517) were seen by physicians at the sites, their clinical histories were evaluated to determine whether they met the new Assessment of SpondyloArthritis international Society criteria for IBP. For those who did, their available clinical history (e.g., family history, C-reactive protein [CRP] levels) was documented in a case report form to establish whether they met criteria for nr-axSpA, AS, or other IBP. Patients diagnosed with nr-axSpA or AS completed patient-reported outcome measures to assess disease activity and functional limitations. RESULTS: A total of 2517 patients with CLBP were identified across all sites. Of these, 974 (38.70 %) fulfilled the criteria for IBP. Among IBP patients, 29.10 % met criteria for nr-axSpA, and 53.72 % met criteria for AS. The prevalence of nr-axSpA varied significantly by region (p < 0.05), with the highest prevalence reported in Asia (36.46 %) and the lowest reported in Africa (16.02 %). Patients with nr-axSpA reported mean ± SD Ankylosing Spondylitis Disease Activity Scores based on erythrocyte sedimentation rate and CRP of 2.62 ± 1.17 and 2.52 ± 1.21, respectively, indicating high levels of disease activity (patients with AS reported corresponding scores of 2.97 ± 1.13 and 2.93 ± 1.18). Similarly, the overall Bath Ankylosing Spondylitis Disease Activity Index score of 4.03 ± 2.23 for patients with nr-axSpA (4.56 ± 2.17 for patients with AS) suggested suboptimal disease control. CONCLUSIONS: These results suggest that, in the centers that participated in the study, 29 % of patients with IBP met the criteria for nr-axSpA and 39 % of patients with CLBP had IBP. The disease burden in nr-axSpA is substantial and similar to that of AS, with both groups of patients experiencing inadequate disease control. These findings suggest the need for early detection of nr-axSpA and initiation of available treatment options to slow disease progression and improve patient well-being.

Challenges of diagnosis and management of axial spondyloarthritis in North Africa and the Middle East: An expert consensus.

Axial spondyloarthritis (SpA) is a spectrum of inflammatory disease with stages characterized by both nonradiographic and radiographic sacroiliitis. Nonradiographic axial SpA is associated with health-related quality-of-life impairment and may progress to ankylosing spondylitis. Axial SpA has a low prevalence in some countries in North Africa and the Middle East, and pooling of data and resources is needed to increase understanding of the regional picture. Early diagnosis and effective treatment are required to reduce disease burden and prevent progression. Anti-TNF therapy is recommended for patients with persistently high disease activity despite conventional treatment, and has been shown to be effective in patients without radiographic damage. Diagnostic delays can be an obstacle to early treatment and appropriate referral strategies are needed. In some countries, restricted access to magnetic resonance imaging and anti-TNF agents presents a challenge. In this article, a group of experts from North Africa and the Middle East evaluated the diagnosis and management of axial SpA with particular reference to this region.

Safety, Tolerability, and Efficacy of Tocilizumab in Rheumatoid Arthritis: An Open-Label Phase 4 Study in Patients from the Middle East.

This open-label study investigated the safety and efficacy of tocilizumab in Middle Eastern patients with rheumatoid arthritis (RA). Patients whose Disease Activity Score based on 28 joints (DAS28) was >3.2 received tocilizumab 8 mg/kg intravenously every 4 weeks for 24 weeks. Patients receiving aTNF ± nonbiologic disease-modifying antirheumatic drug(s) (DMARD(s)) switched to tocilizumab; patients receiving nonbiologic DMARD monotherapy added tocilizumab. Primary end points were adverse events (AEs), serious AEs (SAEs), and laboratory parameters; secondary end points were DAS28, Health Assessment Questionnaire-Disability Index, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Eighty-eight of 95 patients completed 24 weeks. Overall, 125 AEs were reported in 43 (45%) patients; the most common were increased hepatic enzymes (16%) and cholesterol (11%). Eight patients experienced SAEs. Significant changes from baseline to week 24 occurred for hemoglobin, neutrophils, platelets, total cholesterol, and liver enzymes (P < 0.05). DAS28, CRP, and ESR decreased significantly from baseline at each visit (P < 0.0001). At week 24, the proportions of patients reporting DAS28 clinically meaningful improvement (decrease ≥1.2), low disease activity (DAS28 ≥2.6 to ≤3.2), and remission (DAS28 <2.6) were 92%, 23%, and 64%, respectively. Safety and efficacy of tocilizumab were consistent with values reported in Western patients.

An assessment of patients' knowledge of osteoporosis in Qatar: A pilot study.

Osteoporosis is a disease that affects the bones. It leads to increased risk of fractures as a result of decreased bone mineral density. The goal of this study was to assess the general perception of osteoporosis as well as knowledge of lifestyle, risk factors, and preventive measures among patients in Qatar. The study was conducted between September 2013 and September 2014. The study subjects (n = 93) were patients diagnosed with osteoporosis who attended the Outpatient Rheumatology Clinic at Hamad General Hospital in Doha, Qatar. The results showed that those with a university or graduate degree had a significantly higher level of knowledge about osteoporosis (p = 0.009) than those with less education. Among those in our study, knowledge related to osteoporosis was principally obtained through media sources such as television and radio (39%). In conclusion, osteoporosis patients in Qatar need a better understanding of the disease. Identifying thought patterns related to the perception of osteoporosis and treatment might assist in building a foundation for management modalities and effective preventive strategies for the disease in Qatar.

Clinical Assessment and Management of Spondyloarthritides in the Middle East: A Multinational Investigation.

Data on spondyloarthritis (SpA) from the Middle East are sparse and the management of these diseases in this area of the world faces a number of challenges, including the relevant resources to enable early diagnosis and referral and sufficient funds to aid the most appropriate treatment strategy. The objective was to report on the characteristics, disease burden, and treatment of SpA in the Middle East region and to highlight where management strategies could be improved, with the overall aim of achieving better patient outcomes. This multicenter, observational, cross-sectional study collected demographic, clinical, laboratory, and treatment data on 169 consecutive SpA patients at four centers (Egypt, Kuwait, Qatar, and Saudi Arabia). The data collected presents the average time from symptom onset to diagnosis along with the presence of comorbidities in the region and comparisons between treatment with NSAIDs and biologics. In the absence of regional registries of SpA patients, the data presented here provide a rare snapshot of the characteristics, disease burden, and treatment of these patients, highlighting the management challenges in the region.