A genome-wide association study for rheumatoid arthritis replicates previous HLA and non-HLA associations in a cohort from South Africa.

The complex pathogenesis of rheumatoid arthritis (RA) is not fully understood, with few studies exploring the genomic contribution to RA in patients from Africa. We report a genome-wide association study (GWAS) of South-Eastern Bantu-Speaking South Africans (SEBSSAs) with seropositive RA (n = 531) and population controls (n = 2653). Association testing was performed using PLINK (logistic regression assuming an additive model) with sex, age, smoking and the first three principal components as covariates. The strong association with the Human Leukocyte Antigen (HLA) region, indexed by rs602457 (near HLA-DRB1), was replicated. An additional independent signal in the HLA region represented by the lead SNP rs2523593 (near the HLA-B gene; Conditional P-value = 6.4 × 10-10) was detected. Although none of the non-HLA signals reached genome-wide significance (P < 5 × 10-8), 17 genomic regions showed suggestive association (P < 5 × 10-6). The GWAS replicated two known non-HLA associations with MMEL1 (rs2843401) and ANKRD55 (rs7731626) at a threshold of P < 5 × 10-3 providing, for the first time, evidence for replication of non-HLA signals for RA in sub-Saharan African populations. Meta-analysis with summary statistics from an African-American cohort (CLEAR study) replicated three additional non-HLA signals (rs11571302, rs2558210 and rs2422345 around KRT18P39-NPM1P33, CTLA4-ICOS and AL645568.1, respectively). Analysis based on genomic regions (200 kb windows) further replicated previously reported non-HLA signals around PADI4, CD28 and LIMK1. Although allele frequencies were overall strongly correlated between the SEBSSA and the CLEAR cohort, we observed some differences in effect size estimates for associated loci. The study highlights the need for conducting larger association studies across diverse African populations to inform precision medicine-based approaches for RA in Africa.

Phenotype and treatment of elderly onset compared with younger onset rheumatoid arthritis patients in international daily practice.

OBJECTIVE: To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset. METHODS: Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45-65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders. RESULTS: The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02 HAQ points per month in the <45 and 45-65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant. CONCLUSION: In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.

Inequity in access to bDMARD care and how it influences disease outcomes across countries worldwide: results from the METEOR-registry.

OBJECTIVE: To establish in a global setting the relationships between countries' socioeconomic status (SES), measured biological disease modifying antirheumatic drug (bDMARD)-usage and disease outcomes. To assess if prescription and reimbursement rules and generic access to medication relates to a countries' bDMARD-usage. METHODS: Data on disease activity and drug use from countries that had contributed at least 100 patients were extracted from the METEOR database. Mean disease outcomes of all available patients at the final visit were calculated on a per-country basis. A questionnaire was sent to at least two rheumatologists per country inquiring about DMARD-prices, access to treatment and valid regulations for prescription and reimbursement. RESULTS: Data from 20 379 patients living in 12 different countries showed that countries' SES was positively associated with measured disease activity (meanDAS28), but not always with physical functioning (HAQ-score). A lower country's SES, stricter rules for prescription and reimbursement of bDMARDs as well as worse affordability of bDMARDs were associated with lower bDMARD-usage. bDMARD-usage was negatively associated with disease activity (although not with physical functioning), but the association was moderate at best. CONCLUSIONS: Disease activity in patients with rheumatoid arthritis as well as bDMARD-usage varies across countries worldwide. The (negative) relationship between countries' bDMARD-usage and level of disease activity is complex and under the influence of many factors, including-but not limited to-countries' SES, affordability of bDMARDs and valid prescription and reimbursement rules for bDMARDs.

Pitfalls in the assessment of smoking status detected in a cohort of South African RA patients.

This study was conceived in an attempt to explain the unexpectedly high frequency of elevated levels of serum cotinine measured retrospectively in a cohort of predominantly black South African females with rheumatoid arthritis (RA), findings that were inconsistent with the smoking histories derived from health questionnaires. The discrepant findings suggested either a greater tendency towards underreporting of smoking status in the study cohort, or possible confounding effects of the use of smokeless tobacco products. In addition to the cohort of RA patients (n = 138, of whom 115 (83 %) were female), blood samples were also taken from a second cohort consisting of 29 declared smokers, 18 (62 %) of whom where females, 29 smokeless tobacco (SLT) users (all female), and 22 non-users of any tobacco products, 18 (82 %) of whom were females. Serum cotinine levels were determined using an ELISA procedure. Cotinine levels of >10.0 ng/ml were detected in serum specimens from 43 (31 %), RA patients of whom 35 (81 %) were female, with a median value of 50.1 ng/ml and interquartile range (iqr) of 68.6. Only 18 of the 35 females indicated that they smoked. The groups of declared smokers and SLT users had equivalent median serum cotinine levels of 88.0 ng/ml (iqr = 10.8 ng/ml) and 87.0 ng/ml (iqr = 15.6 ng/ml), respectively, while cotinine was undetectable in specimens from non-tobacco product users (<0.2 ng/ml). Users of SLT products in South Africa are predominantly female and have serum cotinine levels which are comparable with those of current smokers, raising concerns about the validity of measurement of cotinine as the sole objective marker of smoking status in populations with high usage of SLTs. This situation can be rectified by ensuring that usage of SLT products is accurately recorded in health questionnaires, while inclusion of measurement of one or more additional, objective biomarkers of smoking in combination with cotinine may enable reliable distinction between smoking and usage of SLTs which, given the associated risks, is a strategy of particular relevance in RA.

Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans.

The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.

Genetic diversity in black South Africans from Soweto.

BACKGROUND: Due to the unparalleled genetic diversity of its peoples, Africa is attracting growing research attention. Several African populations have been assessed in global initiatives such as the International HapMap and 1000 Genomes Projects. Notably excluded, however, is the southern Africa region, which is inhabited predominantly by southeastern Bantu-speakers, currently suffering under the dual burden of infectious and non-communicable diseases. Limited reference data for these individuals hampers medical research and prevents thorough understanding of the underlying population substructure. Here, we present the most detailed exploration, to date, of genetic diversity in 94 unrelated southeastern Bantu-speaking South Africans, resident in urban Soweto (Johannesburg). RESULTS: Participants were typed for ~4.3 million SNPs using the Illumina Omni5 beadchip. PCA and ADMIXTURE plots were used to compare the observed variation with that seen in selected populations worldwide. Results indicated that Sowetans, and other southeastern Bantu-speakers, are a clearly distinct group from other African populations previously investigated, reflecting a unique genetic history with small, but significant contributions from diverse sources. To assess the suitability of our sample as representative of Sowetans, we compared our results to participants in a larger rheumatoid arthritis case-control study. The control group showed good clustering with our sample, but among the cases were individuals who demonstrated notable admixture. CONCLUSIONS: Sowetan population structure appears unique compared to other black Africans, and may have clinical implications. Our data represent a suitable reference set for southeastern Bantu-speakers, on par with a HapMap type reference population, and constitute a prelude to the Southern African Human Genome Programme.

Clinical spectrum and outcomes of idiopathic inflammatory myopathies in South Africans.

Background: Idiopathic inflammatory myopathies (IIM) are rare diseases for which there is a paucity of data in Africa. We undertook a retrospective records review of clinical and laboratory features of patients with IIM attending a tertiary service in Gauteng, South Africa. Materials and methods: Case records of patients seen between January 1990 and December 2019 and fulfilling the Bohan and Peter criteria for IIM were reviewed for demographics, clinical features, special investigations and drug therapy. Results: Of 94 patients included in the study, 65 (69.1%) had dermatomyositis (DM) and 29 (30.9%) had polymyositis (PM). Overall, the mean (SD) age at presentation and disease duration were 41.5 (13.6) and 5.9 (6.2) years, respectively. 88 (93.6%) were Black Africans. The most common cutaneous features in DM patients were Gottron's lesions (72.3%) and abnormal cuticular overgrowth (67.7%). Dysphagia was the most common extra-muscular feature (31.9%), more so in PM than DM (p = 0.02). Creatine kinase, total leucocyte count and CRP were similarly higher in PM than DM patients (p = 0.006, 0.002, and 0.01, respectively). Anti-nuclear and anti-Jo-1 antibodies were positive in 62.2 and 20.4% of patients tested, respectively, the latter significantly more in PM than DM patients (OR = 5.1, p = 0.03) and more likely to be positive with ILD (p = 0.001). Corticosteroids were prescribed in all patients, 89.4% had additional immunosuppressive drugs and 6.4% required intensive/high care. Malignancies occurred in three patients, all of whom had DM. There were seven known deaths. Conclusion: The present study provides further insights into the spectrum of clinical features of IIM, especially cutaneous features of DM, anti-Jo-1 antibodies and associated ILD, in a cohort of predominantly black African patients.

Probable endometrial tuberculosis in a patient with rhupus.

Endometrial tuberculosis (TB) is an uncommon manifestation of disseminated TB. Rhupus is the coexistence of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We describe a case of endometrial TB in rhupus patient an immunosuppressed. Contribution: We describe an uncommon presentation of disseminated TB, endometrial TB, in a rare rheumatic disease, rhupus. A high index of suspicion for TB is imperative in immunocompromised patients presenting with chronic urogenital symptoms especially in an endemic area.

Osteoporosis in Black South Africans With Rheumatoid Arthritis.

Background Osteoporosis is a common comorbidity associated with rheumatoid arthritis (RA). The aim of this study was to determine the risk factors and possible predictors of osteoporosis in black patients with RA. Methods A retrospective study of 120 randomly selected RA patients attending an arthritis clinic in Johannesburg, South Africa, was carried out, in which 60 patients were with and 60 without osteoporosis. The demographics, disease activity, American College of Rheumatology (ACR) functional status, treatment, and dual-energy X-ray absorptiometry (DEXA) characteristics were compared. Statistical analysis was performed using SPSS version 25.0 (IBM Corp, Armonk, NY). Bivariate comparisons of demographic factors, disease factors, and T-scores between patients with and without osteoporosis were performed, using two-sided t-tests for continuous variables and chi-squared tests for categorical variables. Possible predictors of osteoporosis were subsequently entered into a multivariate logistic regression model with osteoporosis being the dependent variable. The level of significance for all analyses was set at p < 0.05. Results The median (IQR) age of the overall cohort was 67 (61.0, 72.8) years, the majority (95.5%) were female, of which 97.4% were postmenopausal. The mean disease duration from diagnosis to the DEXA was 8.6 ± 6.2 years. Rheumatoid factor (RF) positivity was 89.2% and anti-cyclic citrullinated peptide (ACCP) positivity was 82.7%. The median (IQR) for disease activity score 28 swollen and tender joint count using the erythrocyte sedimentation rate (DAS-28 ESR) was 3.4 (2.8-4.7) and the median (IQR) for ESR was 41 (22, 64.3) mm/h. There were significantly more patients treated with triple therapy in the no osteoporosis group, 38 (63.3%), than in the osteoporosis group, 21 (35%) (p = 0.00). The ACR functional class was significantly worse in the RA patients with osteoporosis than in the RA patients without osteoporosis [median (IQR), 2 (2, 3) vs 2 (1, 2), (p = 0.03)], respectively. Conclusion This study found that a worse ACR functional class was significantly associated with osteoporosis. In addition, the use of triple therapy had a protective effect. Early recognition of the risk factors for osteoporosis should be sought, with prompt preventative measures, screening, and treatment.

Geo-epidemiology of autoantibodies in rheumatoid arthritis: comparison between four ethnically diverse populations.

BACKGROUND: Rheumatoid arthritis (RA) occurs across the globe in different ethnic populations. Most RA patients harbor anti-modified protein antibodies (AMPA); however, it is unclear whether differences exist in autoantibody responses at different geographic locations and between different ethnic groups, which could provide new clues regarding factors underlying autoantibody development. We therefore investigated AMPA prevalence and association with HLA DRB1 alleles and smoking in four ethnically diverse populations on four different continents. METHODS: Anti-carbamylated (anti-CarP), anti-malondialdehyde acetaldehyde (anti-MAA), and anti-acetylated protein antibodies (anti-AcVim) IgG were determined in anti-citrullinated protein antibody-positive Dutch (NL, n = 103), Japanese (JP, n = 174), First Nations Peoples in Canada (FN, n = 100), and black South African (SA, n = 67) RA patients. Ethnicity-matched local healthy controls were used to calculate cut-offs. Risk factors associated with AMPA seropositivity in each cohort were identified using logistic regression. RESULTS: Median AMPA levels were higher in First Nations Peoples in Canada and especially South African patients, as reflected by percentage seropositivity: NL, JP, FN, and SA: anti-CarP: 47%, 43%, 58%, and 76% (p < 0.001); anti-MAA: 29%, 22%, 29%, and 53% (p < 0.001); and anti-AcVim: 20%, 17%, 38%, and 28% (p < 0.001). Total IgG levels also differed markedly, and when autoantibody levels were normalized to total IgG, differences between cohorts became less pronounced. Although there were some associations with AMPA and HLA risk alleles and smoking, none was consistent across all four cohorts. CONCLUSIONS: AMPA against various post-translational modifications could consistently be detected on different continents across ethnically diverse RA populations. Differences in AMPA levels corresponded to differences in total serum IgG levels. This suggests that, despite differences in risk factors, a common pathway may be involved in AMPA development across geographic locations and ethnicities.

Comorbidities in Black South Africans with established rheumatoid arthritis.

OBJECTIVE: Comorbidities contribute both to morbidity and mortality in rheumatoid arthritis (RA). The aim of the current study was to investigate the prevalence and spectrum of comorbidities in South Africans with established RA. METHODS: A retrospective, consecutive case record review of 500 Black South African patients with established disease of ≥5 years attending a tertiary rheumatology service was performed. Common comorbidities including those listed in the Charlson Comorbidity Score (CCS) were documented. RESULTS: Most patients, 463 known alive (AG) and 37 known deceased (DG), were female (87%). Mean (SD) age and disease duration were 60 (11.1) and 10.7 (5.0) years respectively, and 98% had ≥1 comorbidities. Median CCS was 2, significantly higher in DG than AG (4 vs 2, P < .0001). Despite hypertension (70%) and hypercholesterolemia (47%) being the commonest comorbidities overall and type 2 diabetes (T2D) occurring in 15.4%, clinical cardiovascular events were rare (0.6%). Peptic ulcer disease (odds ratio [OR] = 8.67), congestive cardiac failure (OR = 7.09), serious infections (OR = 7.02) and tuberculosis (OR = 2.56) were significantly more common in DG than AG. Multivariate analysis showed that American College of Rheumatology functional class 3/4 was associated with increased risk for serious infections (OR = 3.84) and tuberculosis (OR = 2.10). CONCLUSION: Despite the high burden of cardiometabolic comorbidities in South Africans with established RA, cardiovascular events were rare. Serious infections and tuberculosis, both associated with severe functional disability, are a major cause of morbidity and mortality.

Patterns and outcomes of admissions to the medical acute care unit of a tertiary teaching hospital in South Africa.

BACKGROUND: A Medical Acute Care Unit (MACU) was established at Chris Hani Baragwanath Academic Hospital (CHBAH) to provide comprehensive medical specialist care to the patients presenting with acute medical emergencies. Improved healthcare delivery systems at the MACU may result in shorter hospital stays, better outcomes, and less mortality. OBJECTIVES: The study's objective was to describe the demographics, diagnoses, disease patterns, and outcomes, including patient's mortality, admitted to the MACU at CHBAH. METHODS: Records of 200 patients admitted, between March 2015 to August 2015, to the MACU at CHBAH were reviewed. Patient demographics, diagnosis at admission, duration of stay, and outcomes were documented. Patients transferred to the medical ward, the Intensive Care Unit (ICU), or discharge. The leading causes of mortality were documented. RESULTS: Of the 200 patients, 59% were females. The patients' mean age was 46 (17.2) years, and the mean duration of stay at the MACU was 1.45 (1.25) days. Non-communicable diseases accounted for 76% of admissions. The most frequently diagnosed conditions included: diabetic ketoacidosis acidosis (DKA) and hyperosmolar non-ketotic (HONK) (17.5%), non-accidental self-poisoning (16%), hypertensive emergencies (9.5%), decompensated cardiac failure (8%) and ischemic heart disease (7%). Infectious diseases comprised 14% of the diagnoses, of which cases of pneumonia were the most common (5%). Most patients (77.5%) were transferred to medical wards, 12% to ICU, while 10% demised at the MACU. The leading causes of death included sepsis (25%), DKA/HONK (20%), non-accidental self-poisoning (10%), and cardiac failure (10%). CONCLUSION: Non-communicable diseases, particularly diabetic emergencies, were the leading causes of admission to the MACU at CHBAH. During the study period, high rates of case improvement, patient discharge, shorter hospital stay, and less mortality were observed. The leading cause of mortality was sepsis related.

African League Against Rheumatism (AFLAR) preliminary recommendations on the management of rheumatic diseases during the COVID-19 pandemic.

OBJECTIVES: To develop recommendations for the management of rheumatic and musculoskeletal diseases (RMDs) during the COVID-19 pandemic. METHOD: A task force comprising of 25 rheumatologists from the 5 regions of the continent was formed and operated through a hub-and-spoke model with a central working committee (CWC) and 4 subgroups. The subgroups championed separate scopes of the clinical questions and formulated preliminary statements of recommendations which were processed centrally in the CWC. The CWC and each subgroup met by several virtual meetings, and two rounds of voting were conducted on the drafted statements of recommendations. Votes were online-delivered and recommendations were pruned down according to predefined criteria. Each statement was rated between 1 and 9 with 1-3, 4-6 and 7-9 representing disagreement, uncertainty and agreement, respectively. The levels of agreement on the statements were stratified as low, moderate or high according to the spread of votes. A statement was retired if it had a mean vote below 7 or a 'low' level of agreement. RESULTS: A total of 126 initial statements of recommendations were drafted, and these were reduced to 22 after the two rounds of voting. CONCLUSIONS: The preliminary statements of recommendations will serve to guide the clinical practice of rheumatology across Africa amidst the changing practices and uncertainties in the current era of COVID-19. It is recognized that further updates to the recommendations will be needed as more evidence emerges. Key Points • AFLAR has developed preliminary recommendations for the management of RMDs in the face of the COVID-19 pandemic. • COVID-19 is an unprecedented experience which has brought new concerns regarding the use of some disease-modifying anti-rheumatic drugs (DMARDs), and these recommendations seek to provide guidelines to the African rheumatologists. • Hydroxychloroquine shortage has become rampart across Africa as the drug is being used as prophylaxis against COVID-19 and this may necessitate a review of treatment plan for some patients with RMDs. • Breastfeeding should continue for as long as possible if a woman is positive for SARS-CoV-2 as there is currently no evidence that the infection can be transmitted through breast milk.

HLA-DRB1 Amino Acid Positions and Residues Associated with Antibody-positive Rheumatoid Arthritis in Black South Africans.

OBJECTIVE: To investigate the association of specific amino acid positions, residues, and haplotypes of HLA-DRB1 in black South Africans with autoantibody-positive rheumatoid arthritis (RA). METHODS: High-resolution HLA-DRB1 genotyping was performed in 266 black South Africans with autoantibody-positive RA and 362 ethnically and geographically matched controls. The alleles were converted to specific amino acid residues at polymorphic sites for downstream analyses. Logistic regression models were used to test whether variability at site, specific amino acid residues, and haplotypes (constructed from positions 11, 71, and 74) were associated with RA. RESULTS: Of the 29 amino acid positions examined, positions 11, 13, and 33 (permutation p = 3.4e-26, 1.2e-27, and 2.1e-28, respectively) showed the strongest association with RA. Univariate analyses of individual amino acid residues showed valine at position 11 (OR 5.1, 95% CI 3.7-7.0) and histidine at position 13 (OR 6.1, 95% CI 4.2-8.6) conferred the highest risk. The valine containing haplotypes of position 11, 71, 74, V_K_A conferred the most risk (OR 4.52, 95% CI 2.68-7.61) and conversely the haplotype with serine at this position, S_K_R, conferred the most protection (OR 0.83, 95% CI 0.61-1.15). CONCLUSION: Autoantibody-positive RA in black South Africans is associated with histidine at position 13 and valine at position 11 of HLA-DRB1, and haplotypes with valine at position 11 conferred the highest risk; conversely, serine at position 11 conveyed protection.

Impact of the combined presence of erosions and ACPA on rheumatoid arthritis disease activity over time: results from the METEOR registry.

Objective: To investigate associations between baseline presence of erosions and/or anti-citrullinated protein antibodies (ACPA) on functional ability, disease activity and treatment survival over time. Methods: Real life data from newly diagnosed rheumatoid arthritis patients were identified in the international METEOR registry. Patients were grouped according to presence/absence of ACPA and/or erosions at baseline. Associations between the presence of ACPA and/or erosions (four groups) with the change of Disease Activity Score (DAS) and Health Assessment Questionnaire (HAQ) over time were assessed using linear mixed models during maximum 6 or maximum 12 months from baseline. Treatment survival was assessed using multiple failure-times Cox regression. Results: Data were included from 701 ACPA‒/erosions‒, 334 ACPA‒/erosions+, 1585 ACPA+/erosions‒ and 1993 ACPA+/erosions+ patients. We found statistically significant differences in DAS and HAQ change over time between the four groups, both after maximum follow-up durations of 6 and of 12 months, but after stratification differences proved small and not clinically meaningful. Patients in the ACPA‒/erosions‒ group were less likely to switch treatment compared with the ACPA+/erosions‒ reference group (p<0.001). The other two ACPA/erosions groups did not differ from the reference group. Conclusions: In this analysis of worldwide real life data, we found statistically significant, but clinically irrelevant differences in treatment response to initial disease modifying anti-rheumatic drug therapies as measured by DAS and HAQ in ACPA‒/erosions‒, ACPA‒/erosions+, ACPA+/erosions‒ and ACPA+/erosions+ rheumatoid arthritis patients. However, after maximum follow-up durations of 6 and 12 months all groups had a similar response to initial treatment, but with a lower likelihood to switch treatment for ACPA‒/erosions‒ patients during the first year of follow-up.

Sex-associated Treatment Differences and Their Outcomes in Rheumatoid Arthritis: Results from the METEOR Register.

OBJECTIVE: To assess differences in initial treatment and treatment response in male and female patients with rheumatoid arthritis (RA) in daily clinical practice. METHODS: The proportion of patients with RA starting different antirheumatic treatments (disease-modifying antirheumatic drugs; DMARD) and the response to treatment were compared in the international, observational METEOR register. All visits from start of the first DMARD until the first DMARD switch or the end of followup were selected. The effect of sex on time to switch from first to second treatment was calculated using Cox regression. Linear mixed model analyses were performed to assess whether men and women responded differently to treatments, as measured by Disease Activity Score (DAS) or Health Assessment Questionnaire. RESULTS: Women (n = 4393) more often started treatment with hydroxychloroquine, as monotherapy or in combination with methotrexate (MTX) or a glucocorticoid, and men (n = 1142) more often started treatment with MTX and/or sulfasalazine. Time to switch DMARD was shorter for women than for men. Women had a statistically significantly higher DAS over time than men (DAS improvement per year ß -0.69, 95% CI -0.75 to -0.62 for men and -0.58, 95% CI -0.62 to -0.55 for women). Subanalyses per DMARD group showed for the conventional synthetic DMARD combination therapy a slightly greater decrease in DAS over time in men (-0.89, 95% CI -1.07 to -0.71) compared to women (-0.59, 95% CI -0.67 to -0.51), but these difference between the sexes were clinically negligible. CONCLUSION: This worldwide observational study suggests that in daily practice, men and women with RA are prescribed different initial treatments, but there were no differences in response to treatment between the sexes.

Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis.

BACKGROUND: Aiming at rapid decrease of disease activity, there has been a trend to start with higher doses of methotrexate (MTX) in patients newly diagnosed with rheumatoid arthritis (RA), both as monotherapy and in combination with other antirheumatic drugs. We aimed to study the relationship between clinical response and MTX dose as monotherapy or combination therapy in patients with early RA. METHODS: Disease-modifying anti-rheumatic drug (DMARD)-naive patients with early RA, from a large international observational database, the METEOR database, were selected if MTX was part of their initial treatment. Patients were divided into four groups: MTX monotherapy, MTX + convention synthetic (cs)DMARDs, MTX + glucocorticoids or MTX + biologic (b)DMARDs. MTX dose was dichotomized: low dose ≤10 mg/week; high dose ≥15 mg/week. Linear mixed model analyses for the Disease Activity Score (DAS), DAS in 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were performed in each medication group, with MTX dose and time as covariates. Outcomes were assessed from baseline until 3-6 months follow up. Associations were adjusted for potential confounding by indication using propensity score (PS) modelling. RESULTS: For patients starting MTX monotherapy (n = 523), MTX + csDMARDs (n = 266) or MTX + glucocorticoids (n = 615), the PS-adjusted effects of MTX dose (high versus low) on the DAS, DAS28 and HAQ were small and not clinically meaningful. Patients starting MTX + bDMARDs were disregarded due to low numbers (n =11). CONCLUSIONS: In patients newly diagnosed with RA, no clinical benefit of high compared to low initial MTX doses was found for MTX monotherapy or for MTX combination therapy with csDMARDs or glucocorticoids.

Evaluation of the joint distribution at disease presentation of patients with rheumatoid arthritis: a large study across continents.

BACKGROUND: Genetic and environmental risk factors for rheumatoid arthritis (RA) are population dependent and may affect disease expression. Therefore, we studied tender and swollen joint involvement in patients newly diagnosed with RA in four countries and performed a subanalysis within countries to assess whether the influence of autoantibody positivity affected disease expression. METHODS: Patients with symptom duration <2 years fulfilling the American College of Rheumatology/European League Against Rheumatism 2010 RA classification criteria were selected from METEOR (Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology), an international observational database, and the Dutch Leiden Early Arthritis Clinic. Indian (n=947), Mexican (n=141), South African (n=164) and Dutch (n=947) autoantibody-positive and negative patients with RA, matched by symptom duration, were studied for swollen and tender joint distribution. RESULTS: Between countries, the reported distribution of swollen joint distribution differed, with more knee synovitis in Mexico, South Africa and India compared with the Netherlands (37%, 36%, 30% and 13%) and more elbow (29%, 23%, 7%, 7%) and shoulder synovitis (21%, 11%, 0%, 1%) in Mexico and South Africa compared with India and the Netherlands.Since the number of autoantibody-negative patients in Mexico and South Africa was limited, Indian and Dutch autoantibody-positive and negative patients with RA were compared. The number of swollen and tender joints was higher in autoantibody-negative patients, but the overall distribution of involved joints was similar. CONCLUSION: Joint involvement at diagnosis does not differ between autoantibody-positive and negative patients with RA in India and the Netherlands. However, joint involvement is reported differently across countries. More research is needed whether these differences are cultural and/or pathogenetic.