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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

Objectives To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. Methods SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. Results We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

ObjectivesTo identify the changes in rheumatology service delivery across the five regions of Africa from the impact of the COVID-19 pandemic.MethodsThe COVID-19 African Rheumatology Study Group created an online survey consisting of 40 questions relating to the current practices and experiences of rheumatologists across Africa. The CHERRIES checklist for reporting results of internet e-surveys was adhered to.ResultsA total of 554 completed responses were received from 20 countries, which include six in Northern Africa, six in West Africa, four in Southern Africa, three in East Africa and one in Central Africa. Consultant grade rheumatologists constituted 436 (78.7%) of respondents with a mean of 14.5 ± 10.3 years of experience. A total of 77 (13.9%) rheumatologists avoided starting a new biologic. Face-to-face clinics with the use of some personal protective equipment continued to be held in only 293 (52.9%) rheumatologists’ practices. Teleconsultation modalities found usage as follows: telephone in 335 (60.5%), WhatsApp in 241 (43.5%), emails in 90 (16.3%) and video calls in 53 (9.6%). Physical examinations were mostly reduced in 295 (53.3%) or done with personal protective equipment in 128 (23.1%) practices. Only 316 (57.0%) reported that the national rheumatology society in their country had produced any recommendation around COVID-19 while only 73 (13.2%) confirmed the availability of a national rheumatology COVID-19 registry in their country.ConclusionCOVID-19 has shifted daily rheumatology practices across Africa to more virtual consultations and regional disparities are more apparent in the availability of local protocols and registries.

INTRODUCTION Smoking is now well recognized not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. METHODS Studies, mostly recent, which have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smoking-related RA, as well as the possible involvement of other types of outdoor and indoor pollution form the basis of this review. RESULTS Smoking initiates chronic inflammatory events in the lungs. These, in turn, promote the release of the enzymes, peptidylarginine deiminases 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. Peptidylarginine deiminases mediate conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide, pathogenic autoantibodies, an event which precedes the development of RA. CONCLUSIONS An increasing body of evidence has linked chronic inflammatory events in the lungs of smokers, to the production of anti-citrullinated peptide autoantibodies and development of RA. Creation of awareness of the associated risks, assessment of smoking status and implementation of compelling antismoking strategies must be included in the routine clinical management of patients presenting with suspected RA. IMPLICATIONS Chronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of RA. These mechanistic insights not only reinforce the association between smoking and risk for RA, but also the necessity to increase the level of awareness in those at highest risk.

OBJECTIVE The aim of this study was to explore the clinical utility of the clinical disease activity index (CDAI). We compared the disease control with protocolized treatment adjustment following a tight control strategy utilizing either the simplified disease activity index (SDAI) or the CDAI. METHODS In a prospective 12 month study, DMARD-naive RA patients were randomized to either a CDAI or SDAI arm and were treated with traditional DMARDs, increased on a monthly basis according to a predefined protocol to achieve low disease activity. RESULTS Of 102 patients (84 females, 96 Black Africans), the mean symptom duration was 3.0 years (s.d. 3.8) and the mean 28-joint DAS (DAS28) at baseline was 6.2 (s.d. 1.2). By 12 months, the proportion of patients in the CDAI and SDAI groups achieving low disease activity (30% and 32%) and remission (33 and 34%) were similar. There were no significant differences in the mean DAS28 or its components or in HAQ Disability Index or health-related quality of life scores. Baseline predictors of low disease activity at 12 months were shorter symptom duration (P = 0.03) and lower HAQ-DI score (P = 0.04). CONCLUSION Given that the CDAI performed as well as the SDAI, and considering the cost savings and convenience because no acute phase reactant test is necessary, we suggest the CDAI may be an appropriate tool for monthly disease activity monitoring as part of a tight control strategy in developing countries.

Objective. To investigate the differential expression of MMP-1, tissue inhibitor of metalloproteinase-1 (TIMP-1) and hepatocyte growth factor (HGF) in clinically involved (affected) and uninvolved (unaffected) skin in patients with SSc. Methods. Punch biopsies from affected forearm and unaffected upper back skin of 16 black South Africans with dcSSc and skin samples of 15 ethnically matched healthy controls were studied. Quantitative mRNA expression of MMP-1, TIMP-1 and HGF was performed by relative reverse transcription quantitative PCR. Results. Compared with controls, TIMP-1 expression was significantly upregulated in patients, a 796- and 397-fold difference for affected and unaffected skin (P < 0.00001 for both), respectively. Conversely, MMP-1 expression was significantly decreased in patients, a 10- and 12.5-fold difference for affected and unaffected skin (P = 0.0004 for both), respectively. HGF expression was up-regulated in both affected and unaffected skin, a 14- and 18-fold difference (P = 0.004 and P = 0.002), respectively. Within the patient group, HGF expression in affected skin of patients correlated significantly with the European scleroderma disease activity score (r = 0.60, P = 0.013). Conclusion. Perturbations in gene expression of TIMP-1, MMP-1 and HGF were evident in both affected and unaffected skin of the dcSSc patients. Targeting TIMP-1, which showed the greatest dysregulation, needs to be explored as a way of reducing collagen deposition and fibrosis in dcSSc.

Background: Systemic lupus erythematosus (SLE) patients are at increased risk of developing tuberculosis (TB), particularly extrapulmonary TB (ExP-TB). Aim: The present study was undertaken to investigate whether SLE patients showed increased susceptibility to develop osteoarticular TB (OA-TB). Design and Methods: We retrospectively reviewed and compared the frequency of ExP-TB, in particular OA-TB, in patients with SLE at a tertiary hospital in South Africa, to a non-SLE control TB group seen at the same hospital. Results: TB was diagnosed 111 times in 97 (17%) of the 568 SLE patients. The relative frequency of ExP-TB in the SLE group (25.2%) was significantly lower than in the control group (38.5%) (OR = 1.9, P = 0.006). In contrast, OA-TB was diagnosed in the SLE group in nine (8.1%) patients (seven with peripheral arthritis and two with TB spine) compared to 54 (0.4%) in the overall control group (OR = 20.8, P < 0.001) and 13 (0.2%) in the subgroup of known HIV positive patients in the control group (OR = 44.4, P < 0.001). Within the SLE group, Black ethnicity ( P = 0.003), lymphopaenia ( P = 0.001), C3/C4 hypocomplementaemia ( P = 0.05), corticosteroids [maximum dose ( P = 0.002) and duration of treatment ( P = 0.02)] and immunosuppressive agents ( P = 0.02) were risk factors for TB. Duration of corticosteroid therapy was the only risk factor for OA-TB ( P = 0.04). Conclusion: While the relative frequency of ExP-TB was lower in the SLE group compared to the control group, our findings suggest that SLE patients are at particular risk of developing OA-TB. Further prospective studies are needed to better understand the mechanisms that predispose SLE patients to OA-TB.

Objective To compare the clinical efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis (RA). Methods In this multicentre, double-blind trial, 999 subjects with active RA were randomized to leflunomide (n = 501; loading dose 100 mg/day for 3 days, maintenance dose 20 mg/day) or methotrexate (n = 498; 10-15 mg/week) for 52 weeks. After 1 yr the subjects could choose to stay for a second year of double-blind treatment. The primary end-points were tender and swollen joint counts and overall physician and patient assessments. Analyses were of the intent-to-treat group. Results After 1 yr, the mean changes in the leflunomide and methotrexate groups, respectively, were -8.3 and -9.7 for tender joint count; -6.8 and -9.0 for swollen joint count; -0.9 and -1.2 for physician global assessment; -0.9 and -1.2 for patient global assessment; -14.4 and -28.2 for erythrocyte sedimentation rate. Improvements seen with methotrexate were significantly greater than those with leflunomide. No further improvement occurred after the second year of treatment and the distinction between the two treatments in terms of tender joint count and patient global assessment was lost. During the first year of treatment, a small and equivalent degree of radiographically assessed disease progression was seen with both drugs. After 2 yr, disease progression was significantly less with methotrexate. The most common treatment-related adverse events in both groups were diarrhoea, nausea, alopecia, rash, headache, and elevated plasma liver enzyme levels. Over 2 yr, 21 subjects receiving methotrexate were withdrawn due to elevated plasma liver enzymes vs eight subjects taking leflunomide. Two drug-related deaths from pulmonary causes were recorded with methotrexate vs no drug-related deaths among the subjects receiving leflunomide. Conclusions Both leflunomide and methotrexate are efficacious for prolonged treatment of RA. At the doses used, some clinical benefit of methotrexate over leflunomide was observed in the first year of treatment. This benefit must be weighed against the potential toxicity of this drug when used without folate supplementation.

A retrospective study of systemic sclerosis (SSc) in Blacks attending a tertiary hospital on the Witwatersrand, South Africa, was undertaken. The female:male ratio of the 63 patients was 4.6:1 and the mean age of onset of SSc was 36.1 yr. Four of the 11 males were ex-goldminers and nine females resided close to goldmines. Forty-one patients had diffuse cutaneous SSc (dcSSc), 18 had limited cutaneous SSc (lcSSc) and four were unclassified. Overall, 56% had pulmonary fibrosis, 37% had myositis and 98% were antinuclear antibody (ANA) positive, with a notable absence of anti-centromere antibodies. Subset comparisons showed myositis and a reduced forced vital capacity to be significantly more common with dcSSc than lcSSc. The only significant sex differences were that arthralgia/arthritis was more common in women, while calcinosis occurred more frequently in men. Seven of the eight known deaths occurred in patients with dcSSc. These findings, particularly the age of disease onset, predominance of the dcSSc subset, inflammatory features of myositis and a raised erythrocyte sedimentation rate, and absence of anti-centromere antibodies, are similar to those reported previously in African-Americans.