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Objectives: The aim of this study was to add to the descriptive data pertaining to the epidemiology, presentation, and clinical course of multisystem inflammatory syndrome (MIS) temporally associated with coronavirus disease 2019 in adults and adolescents from low- and middle-income countries. Methods: Patients presenting to the adult wards (14 years and older) of three academic hospitals in South Africa, who were diagnosed with MIS between August 1, 2020 and May 31, 2021, were reviewed retrospectively. The presentation, laboratory and radiographic findings, and clinical course are described. Results: Eleven cases of MIS were reported, four in adolescents (14–19 years) and seven in adults (≥19 years). Fever was universal. Gastrointestinal symptoms (90.9%), cardiorespiratory abnormalities (90.9%), and mucocutaneous findings (72.7%) were prominent. Echocardiography in 10/11 patients (90.9%) showed a median left ventricular ejection fraction of 26.3% (interquartile range 21.9–33.6%). All patients required high care admission and 72.7% required inotropic support. Glucocorticoids were initiated in all cases and 72.7% received intravenous immunoglobulin. Conclusions: This constitutes the largest multicentre review of adults and adolescents with MIS in Africa. MIS may be overlooked in resource-limited settings, and heightened suspicion is needed in patients with multi-organ dysfunction, especially where repeated investigations for other aetiologies are negative.

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-resolutionHLA-DRB1genotyping 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.

Background Microvasculopathy is an important feature of systemic sclerosis (SSc), making its assessment a key issue in SSc clinical research. Nailfold videocapillaroscopy (NVC) is a valuable tool to detect and classify microvascular structural alterations. In contrast, laser speckle contrast analysis (LASCA), a non-invasive microvascular imaging tool, has been proposed as an objective technique to dynamically evaluate the peripheral blood perfusion (PBP). Objectives The specific objectives were 1) to perform a pilot study to investigate as first both the intra- and inter-rater reliability of LASCA in an unselected SSc cohort and descriptively in healthy subjects (HS) and 2) to identify the available literature on the reliability of LASCA in SSc by a systematic literature review. Methods First, a pilot study was performed to assess the reliability of LASCA to measure the PBP at the level of the fingers in an unselected cohort SSc patients and descriptively in HS. Intra-rater reliability was assessed by having a first anchor rater performing the measurements at 2 time-points (within 15 min) and inter-rater reliability by subsequently having the first anchor rater and a team of 3 s raters performing the measurements in 15 SSc and 30 HS (see figure 1). As external validation, the measurements were repeated with a second anchor rater in a distinct cohort of 15 SSc patients. Reliability was described by calculating the intraclass correlation coefficient (ICC). The systematic search was performed to identify relevant full-text articles in PubMed, EMBASE and Web of Science. All retrieved articles were screened on title, abstract and full-text level, reference lists were additionally searched. Results Thirty SSc patients (5 men, 25 women; mean age 52±17 y; 1LSSc, 25LcSSc, 4DcSSc; 14 vasodilatory therapy) and 30 HS (8 men, 22 women; mean age 33±11 y) underwent LASCA measurements. ICC for intra-rater reliability of the first anchor was 0.95 (95% CI 0.86–0.98) in SSc and 0.93 (95%CI 0.83–0.97) in HS, the ICC for inter-rater reliability was 0.97 (95%CI 0.90–0.99) in SSc and 0.93 in HS. Intra- and inter-rater reliability of anchor 2 was 0.78 (95%CI 0.46–0.92) and 0.87 (95%CI 0.67–0.96) respectively. The systematic search identified 64 unique articles, of which 12 were eligible for full-text review. Two additional references were identified through a reference search of retrieved articles. Only 1 of the 14 selected references that met the inclusion criteria documented reliability as outcome and was included in the final analysis. This pilot study by Lambrecht et al measured the PBP at the level of the fingertips and reported ICC values varying from 0.82–0.91 for the dorsal and 0.74–0.86 for the volar fingertips. Conclusions The body of knowledge regarding intra- and inter-rater reliability of LASCA in SSc is very limited. Only one manuscript reporting very good inter-rater reliability of PBP measurements of the distal fingertips by LASCA could be withheld. These results could be confirmed by our pilot study. In addition, we demonstrated excellent intra-rater reliability of LASCA measurements for the evaluation of the PBP of the hands in SSc patients and HS. Disclosure of Interest None declared

Objectives A reliable tool to evaluate flow is paramount in systemic sclerosis (SSc). We describe herein on the one hand a systematic literature review on the reliability of laser speckle contrast analysis (LASCA) to measure the peripheral blood perfusion (PBP) in SSc and perform an additional pilot study, investigating the intra- and inter-rater reliability of LASCA. Methods A systematic search was performed in 3 electronic databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the pilot study, 30 SSc patients and 30 healthy subjects (HS) underwent LASCA assessment. Intra-rater reliability was assessed by having a first anchor rater performing the measurements at 2 time-points and inter-rater reliability by having the anchor rater and a team of second raters performing the measurements in 15 SSc and 30 HS. The measurements were repeated with a second anchor rater in the other 15 SSc patients, as external validation. Results Only 1 of the 14 records of interest identified through the systematic search was included in the final analysis. In the additional pilot study: intra-class correlation coefficient (ICC) for intra-rater reliability of the first anchor rater was 0.95 in SSc and 0.93 in HS, the ICC for inter-rater reliability was 0.97 in SSc and 0.93 in HS. Intra- and inter-rater reliability of the second anchor rater was 0.78 and 0.87. Conclusions The identified literature regarding the reliability of LASCA measurements reports good to excellent inter-rater agreement. This very pilot study could confirm the reliability of LASCA measurements with good to excellent inter-rater agreement and found additionally good to excellent intra-rater reliability. Furthermore, similar results were found in the external validation.

To investigate the frequency, severity and predictors of interstitial lung disease (ILD) in a cohort of South Africans with systemic sclerosis (SSc). Retrospective record review of SSc patients attending a tertiary Connective Tissue Diseases Clinic. Patients with ILD, defined by a combination of clinical findings, imaging, and lung function tests were compared to patients without ILD in terms of demographics, clinical features and autoantibodies. The majority (86.8%) of the 151 patients included were of Black ethnicity, 40% had ILD, of whom 39% had moderate-severe lung disease. Univariate predictors of ILD included: disease duration (OR 1.08, 95% CI 1.01-1.15); cough (OR 2.93, 95% CI 1.37-6.29); dyspnoea (OR 2.44, 95% CI 1.23-4.87); bibasal crackles (OR 7.58, 95% CI 3.31-17.37); diffuse cutaneous SSc (dcSSc) (OR 4.55, 95% CI 2.10-9.86) and a speckled anti-nuclear antibody (ANA) pattern (OR 2.47, 95% CI 1.25-4.90). Conversely, limited cutaneous disease (OR 0.22, 95% CI 0.09-0.50) and anti-centromere antibody (ACA) (OR 0.12, 95% CI 0.02-0.97) were protective. Independent predictors of ILD on multivariate analysis were bibasal crackles (OR 9.43, 95% CI 3.25-27.39), disease duration (OR 1.19, 95% CI 1.09-1.30) and speckled ANA (OR 2.95, 95% CI 1.22-7.15). Almost all (86.4%) patients received immunosuppressive treatment and the leading cause of death was related to ILD itself (44.4%). In this cohort of predominantly Black South Africans, SSc ILD was common and carried a poor prognosis. ILD occurred mainly, but not exclusively, in patients with dcSSc, especially those with a speckled ANA pattern. Conversely, the presence of ACA was protective against ILD.

Osteoarthritis (OA) is a common chronic degenerative joint disorder and a major cause of pain and disability, especially in the elderly. The prevalence is steadily rising due to an increase in life expectancy and certain lifestyle factors. OA is a complex dynamic process involving all tissues of the joint organ. Multiple risk factors are associated with the occurrence and progression of OA. There is extreme variability in presentation at different joint sites and between individuals. Management of OA involves a comprehensive approach consisting of preventative measures and numerous therapeutic modalities which should be tailored to individual needs. The family practitioner plays a vital role in the diagnosis of OA, the initiation of treatment and the ongoing monitoring of the condition.

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.

This study aimed to determine the pattern and predictors of joint damage measured by the rheumatoid arthritis articular damage (RAAD) score and to describe its relationship to functional disability in patients with established rheumatoid arthritis (RA). One hundred Black patients with RA of disease duration ≥5 years were studied cross-sectionally. Data collected included socio-demographics, disease duration, smoking, body mass index (BMI), extraarticular features, rheumatoid factor (RF), haemoglobin (Hb), disease activity (DAS28), delay in disease-modifying antirheumatic drug initiation (DMARD lag) and treatment history. As outcome measures, the RAAD score and modified Health Assessment Questionnaire (mHAQ-DI) were used to assess joint damage and disability, respectively. Data were analysed by univariate and multivariate analyses. The mean RAAD score was 28.2 ± 12.8 for a mean disease duration of 17.5 ± 8.5 years. The majority of patients still had active disease (mean DAS28 4.4) and severe disability (mean mHAQ-DI 1.9), reflected in part by a long mean DMARD lag (9 years). Wrist and ankle joints were commonly involved. Multivariate analysis revealed that longer disease duration, higher RF titres and lower BMI were significant independent predictors of a higher RAAD score. The mHAQ-DI was significantly associated with DAS28, RAAD, education and Hb. Our results provide support for aspects of validity of the RAAD score and for its use in under-resourced settings. Further longitudinal studies are needed to evaluate its sensitivity to change in monitoring joint damage. Patterns of joint involvement and the inverse relationship between BMI and joint damage also merit further investigation in Black RA patients.

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value

Background The “shared epitope” (SE) encoded by HLA-DRB1 alleles are the strongest association with susceptibility for rheumatoid arthritis (RA). We have previously shown that 90% of black South African (BSA) RA patients carry at least one copy of the SE alleles (1). Recently, Valine at amino acid position 11 of the HLA-DRB1 chain was shown to confer the strongest risk in this region for RA in Europeans (2). Objectives To determine the role of amino acids at specific positions in the HLA-DRB1 chain in the risk for seropositive RA in BSA. Methods Consenting BSA RA patients (n=261) fulfilling the 1987 ACR criteria for RA, >18 years at disease onset, and/or RF or ACPA positive and seen at a single centre in South Africa were studied and compared to ethnically and geographically matched controls (n=362). DNA sequencing of exon 2 was performed using Allele SEQR HLA-DRB1 (Abbot). Four digit high resolution HLA typing was assigned using the Assign software (Conexio Genomics). Alleles were converted to binary variables indicating the presence/ absence of a specific amino acid residue at a given position. A series of linear models were fit to assess whether the joint effect of amino acid residues within each position was a significant source of variation for the presence of RA. Results Of the 29 amino acid positions examined, amino acid position 11 (p=3.4e-26), 13 (p=1.2e-27), and 33 (p=2.1e-28) were the most highly associated with affectation status. Positions 71 and 74 were less significantly associated with p values of 71 (p=2.6e-05) and 74 (p=0.15). After conditioning on position 11, the effects at the other positions were diminished (position 13: p=0.01; position 33: p=0.004), suggesting that in this sample amino acid position 11 was the primary contributor to the association with HLA DRB1. Within position 11 the odds ratios (95% CI) of association were: Valine= 5.1 (3.7, 7.0), p=1.63e-27; Leucine=1.2 (0.7, 2.0), p=0.5; Aspartic acid=1.1 (0.4, 2.9), p=0.8; Glycine=0.98 (0.6, 1.6), p=0.9; Serine=0.4 (0.3, 0.5), p=2.46e-16; with Proline as the referent. Conclusions Amino acid Valine at position 11 confers the strongest risk for RA in the HLA DRB1 region in black South Africans. Similar to Europeans Valine was the most highly associated amino acid and conversely Serine was protective. References Meyer, P. W., Hodkinson, B., Ally, M., Musenge, E., Wadee, A. A., Fickl, H. , et al. (2011) HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients. Arthritis Res Ther, 13 , R160. Raychaudhuri, S., Sandor, C., Stahl, E. A., Freudenberg, J., Lee, H. S., Jia, X. , et al. (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet, 44 , 291-6. Disclosure of Interest None Declared

Laser speckle contrast analysis (LASCA) is evolving as a promising non-invasive tool to assess cutaneous microvascular function in systemic sclerosis (SSc). Reliability studies have mainly focused on Caucasian populations. To determine for the first time the inter-rater reliability of fingertip blood perfusion (BP) using LASCA in Black South African patients with SSc.Consecutive Black adult patients with SSc were evaluated for peripheral BP using LASCA. Mean BP in defined regions of interest for dorsal fingertips and volar fingertips were measured in two subgroups of 20 SSc patients, each by three independent operators. Two operators were experienced in the use of the LASCA instrument and one was newly trained. Standardised protocols for conditions were followed for all measurements. Inter-rater reliability was tested using the intraclass correlation coefficient (ICC).The majority (87.5%) of the 40 patients included were females and 67.5% had diffuse cutaneous SSc. The mean age (standard deviation) was 48.5 (9.9) years and the median disease duration (interquartile range) was 8.5 (4, 13) years. There was good to excellent agreement, inter-rater ICC (dorsal fingertip range: 0.86-0.97 and volar fingertip range: 0.85-0.96), in both subgroups irrespective of operator skill.LASCA is a credible instrument in patients of Black ethnicity with SSc, and across operator experience.