A comprehensive overview of pneumococcal vaccination recommendations for adults in South Africa, 2022.

Pneumococcal infections remain a common global cause of significant morbidity and mortality. The first recommendations for adult pneumococcal vaccination, published in South Africa in 1999, contained information only on the 23-valent polysaccharide vaccine (PPV23). With the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in adults and the perceived uncertainty that most clinicians had regarding use of these vaccines in adults, these vaccine recommendations were updated in 2022. A Working Group, which consisted of individuals in various fields of medical practice in South Africa, who were from different areas of the country, and included clinicians from both the public and private sectors, was assembled to revise the recommendations. The expertise of the participants varied widely, dependent on their training and specialty, and encompassed different organ systems, disease conditions, and/or practice types. Each participant was allocated a different section, based on their expertise, for which they were required to do an extensive review of the current literature and write their section. The entire working group then reviewed the complete document several times, following additional comments and recommendations. This update contains recommendations for the use of both PPV23 and PCV13, either alone, or in sequence, both in vaccine naïve and in previously vaccinated individuals. It includes both age and risk categories, and encompasses the elderly (≥65 years), as well as younger adults (<65 years) with comorbid conditions or with high-risk conditions and/or immunocompromise. It is hoped that this review and its associated vaccine recommendations will clarify for clinicians, from all spheres of practice in South Africa, how, where, and when pneumococcal vaccines should be used in adults, with the ultimate goal of significantly increasing the appropriate use of these vaccines, in order to decrease the substantial morbidity and mortality associated with pneumococcal infections in adults in South Africa. Furthermore, it is hoped that this review of local epidemiological data and the manner in which this information was interpreted in the development of these local vaccine recommendations, could be used as an example for other regions of the world, to tailor their recommendations to locally available epidemiological data.

Global epidemiology of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that predominantly affects the joints. The prevalence of RA varies globally, with generally a higher prevalence in industrialized countries, which may be explained by exposures to environmental risk factors, but also by genetic factors, differing demographics and under-reporting in other parts of the world. Over the past three decades, strong trends of the declining severity of RA probably reflect changes in treatment paradigms and overall better management of the disease. Other trends include increasing RA prevalence. Common risk factors for RA include both modifiable lifestyle-associated variables and non-modifiable features, such as genetics and sex. A better understanding of the natural history of RA, and of the factors that contribute to the development of RA in specific populations, might lead to the introduction of specific prevention strategies for this debilitating disease.

Points to consider in cardiovascular disease risk management among patients with rheumatoid arthritis living in South Africa, an unequal middle income country.

BACKGROUND: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. METHODS: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. RESULTS: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n = 4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n = 3), lipid lowering agents (n = 8), antihypertensive drugs (n = 1), low dose aspirin (n = 1) and lifestyle modification (n = 1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. CONCLUSIONS: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA.

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.

Comparison of the diagnostic potential of three anti-citrullinated protein antibodies as adjuncts to rheumatoid factor and CCP in a cohort of South African rheumatoid arthritis patients.

PURPOSE: A retrospective comparison of the prevalence and diagnostic value of anti-Sa, anti-CEP-1, and anti-MCV autoantibodies relative to those of the established autoantibodies, composite RF and anti-CCP-IgG used routinely for RA diagnosis as a component of the ACR 2010 criteria, in a cohort of disease-modifying anti-rheumatic drug naïve African RA patients (n = 75). METHODS: Serum concentrations of anti-Sa, anti-CEP-1 and anti-MCV autoantibodies were measured using ELISA procedures, while anti-CCP-IgG antibodies were determined by fluorescence enzyme immunoassay, and composite RF by latex-enhanced laser nephelometry. RESULTS: The seropositivity frequencies of anti-Sa, anti-CEP-1 and anti-MCV antibodies for the RA patients were 82, 72, 85%, respectively, while that of anti-CCP-IgG and RF was 87% for both. Overall, anti-MCV demonstrated the best specificity, positive predictive value (PPV), odds ratio and positive likelihood ratio of all the types of autoantibody tested. CONCLUSION: These observations in this unique cohort of RA patients indicated novel associations of all three autoantibodies in regard to HLA-SE risk alleles, disease severity and tobacco use that were not reported before. Elevated anti-Sa titers designated a propensity of higher disease and high-risk alleles in our cohort. Anti-CEP-1 association with HLA-SE homozygosity and high-risk alleles is also novel in this group. Of note, measurement of anti-MCV antibodies on presentation, either as an adjunctive or even as a stand-alone test, surpassed all other biomarkers investigated here and, therefore, may add value to clinical management.

Diagnostic utility of, and influence of tobacco usage and genetic predisposition on, immunoglobulin A, rheumatoid factor and anti-citrullinated peptide auto-antibodies in South African rheumatoid arthritis patients.

BACKGROUND: The immunoglobulin A isotypes of anti-cyclic citrullinated peptide antibodies (ACPA) and rheumatoid factor (RF) are associated with disease severity and progression in Caucasian rheumatoid arthritis (RA) patients, as well as with genetic predisposition and tobacco use. OBJECTIVES: To compare levels of ACPA-IgA and RF-IgA with those of ACPA-IgG and cRF in a cohort of black South African RA patients and healthy controls.To investigate the relationship between IGA autoantibodies and disease severity, genetic predisposition and tobacco use. METHODS: RF-IgA and ACPA-IgA were determined in a cohort of predominantly black South African RA patients (n=75) in relation to serodiagnostic and prognostic potential, as well as tobacco use and genetic predisposition. Healthy control subjects were included to determine sensitivity, specificity and predictive values.ACPA-IgG/IgA and RF-IgA were determined by enzyme immunoassay and hs-CRP and cRF by nephelometry. Cotinine levels were determined by ELISA. RESULTS: The frequencies of ACPA-IgA and RF-IgA were 31% and 88% respectively compared to 88% for both types of traditional autoantibody procedures. ACPA-IgA was significantly higher (p=0.007) in patients with short disease duration, while linear regression analysis revealed a positive relationship with baseline disease activity scores. Levels of ACPA-IgG and ACPA-IgA were significantly higher in tobacco users who carried the HLA shared epitope. CONCLUSION: Although lacking in serodiagnostic superiority over cRF and ACPA-IgG, inclusion of RF-IgA and ACPA-IgA in autoantibody panels may provide insights into disease pathogenesis, interactions between tobacco usage and HLA genotype in the production of potentially disease-triggering ACPA-IgA antibodies.

Combination leflunomide and methotrexate in refractory rheumatoid arthritis: a biologic sparing approach.

BACKGROUND: In resource-constrained settings where biologic agents are not widely available, there are limited therapeutic options for patients with rheumatoid arthritis (RA) refractory to other synthetic disease modifying antirheumatic (DMARD) therapies. The aim of this study is to evaluate the effectiveness and safety of leflunomide (LEF) with methotrexate (MTX) in refractory RA. METHODS: A retrospective record review of adult RA patients treated with LEF/MTX. Demographic details, adverse reactions, and the 3-variable 28 joint disease activity score (DAS28-3) were recorded at initiation of LEF/MTX therapy, and after 4 and 12 months of treatment. RESULTS: Of 194 patients, most were middle-aged seropositive Black African females, with established disease [mean (standard deviation, SD) disease duration 9.4 (8.2) years] and time on previous DMARDs of 7.0 (5.5) years. Before adding LEF, the mean (SD) dose of MTX was 21.7 (3.5) mg/week, and 87.6% of patients used low dose oral corticosteroids. A good or moderate EULAR response was achieved by 44% and 42% of patients, and the retention rate was 71%. Major infections were seen in 6 patients: comprising 2 deaths, 3 cases of leucopaenia and septicaemia and 1 case of tuberculosis. Hepatotoxicity (n = 3), intolerable gastrointestinal symptoms (n = 3), and hypertension (n = 17) were the most common problems. Predictors of remission or low disease activity at 12 months was a baseline DAS28-3 ⩽ 5.5 [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.1-5.6; p = 0.01]. CONCLUSIONS: LEF/MTX was effective in the majority of patients in this cohort of mainly Black African women who failed other combination synthetic DMARDs, particularly in those with moderate disease activity at the time of addition of LEF. Infections and hypertension were important complications. In a setting where biologic DMARDs are not readily accessible, the combination of LEF/MTX is a cost-effective approach.

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.

Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis.

BACKGROUND: To measure circulating anti-citrullinated peptide antibodies (ACPA) and cytokines pre- and 6 months post-therapy as a strategy to predict and optimize responses to traditional disease-modifying antirheumatic drugs (DMARDs) in early RA, which is an unmet need in developing countries. PATIENTS AND METHODS: A cohort of 140 predominantly (88.5 %) black female South African patients with early RA was treated with synthetic DMARDs, mostly methotrexate (MTX) alone, or in combination with low-dose oral corticosteroids (CS). Circulating ACPA and a panel of circulating cytokines/chemokines/growth factors were measured at baseline and after 6 months of therapy in relation to disease activity and Shared Epitope (SE). RESULTS: Following 6 months of therapy, the median simplified disease activity index (SDAI) declined from a baseline of 41.4 to 16.0 (p = 0.0001) for the entire cohort, which was paralleled by significant falls in median serum ACPA levels (516.6 vs. 255.7 units/ml, p = <0.0001) and several of the circulating cytokines (IL-4, IL-7, IL-8, G-CSF, VEGF; p < 0.0010 - p < 0.0001) which were most evident in the subgroup of patients treated with a combination of MTX and CS. Although biomarker concentrations decreased most notably in the low-disease activity group post-therapy, no significant correlations between these biomarkers and disease activity were observed, Baseline ACPA levels, but not SDAI or cytokines, were significantly higher in the subgroup of risk allele-positive patients (561.1 vs. 331.9 units/ml, p < 0.05), while no associations with ACPA and a smoking history were evident. CONCLUSIONS: The use of DMARDs in RA is associated with significant decreases in ACPA and cytokines which did not correlate with changes in SDAI, precluding the utility of serial measurement of these biomarkers to monitor early responses to therapy, but may have prognostic value.

Tight control of rheumatoid arthritis in a resource-constrained setting: a randomized controlled study comparing the clinical disease activity index and simplified disease activity index.

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.

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.

Changes in physical activity measured by accelerometry following initiation of DMARD therapy in rheumatoid arthritis.

OBJECTIVE: The aim of this study was to assess changes in habitual physical activity levels in response to DMARD therapy in RA patients. METHODS: Eighteen drug-naive RA patients were prospectively assessed at baseline and following 3 months of DMARD therapy for habitual physical activity by accelerometry, disease activity using the clinical disease activity index (CDAI) and functional disability using the modified HAQ (mHAQ). Baseline physical activity was also compared with an equal number of healthy control participants matched for age, sex and BMI. RESULTS: Following 3 months of DMARD therapy, in parallel with significant improvements in CDAI scores (P < 0.001) and HAQ scores (P < 0.001), accelerometry measures in the RA cohort showed that the average activity counts in sedentary thresholds decreased (P = 0.012), while average activity counts within higher-intensity thresholds increased (P = 0.039). Multiple regression analysis showed that the change in moderate activity was associated with a decrease in CRP (ß = - 0.922, P = 0.026) while the decrease in sedentary activity and increase in moderate activity were associated with decreased morning stiffness of the joints (ß = 0.694, P = 0.035 and ß = -0.927, P = 0.024, respectively). At baseline, RA patients were less physically active than control participants in the morning (P = 0.048) and in the late afternoon (P = 0.016), but these diurnal differences were no longer significant after the DMARD intervention. CONCLUSION: These findings suggest that accelerometry may potentially be a viable objective method of assessing changes in physical disability in response to various disease-modifying drugs.

South African recommendations for the management of rheumatoid arthritis: an algorithm for the standard of care in 2013.

Updated treatment recommendations for the therapy of rheumatoid arthritis (RA) in South Africa advocate early diagnosis, prompt initiation of disease-modifying anti-rheumatic drugs (DMARDs), and an intense treatment strategy where disease activity is assessed with a composite score such as the Simplified Disease Activity Index (SDAI). Frequent assessments and escalation of therapy are necessary until low disease activity (LDA) (SDAI ≤11) or ideally remission (SDAI ≤3.3) is achieved. Synthetic DMARDs may be used as monotherapy or in combination, and can be co-prescribed with low-dose corticosteroids if necessary. Biologic DMARD therapy should be considered for patients who have failed a 6-month trial of at least 3 synthetic DMARDs. All RA patients in SA are at increased risk of tuberculosis (TB), in particular patients using anti-tumour necrosis factor (TNF) biologic therapy. These recommendations provide practical suggestions for the screening and management of TB and other comorbidities, and offer an approach to monitoring of RA patients.

The clinical utility of accelerometry in patients with rheumatoid arthritis.

OBJECTIVES: To assess habitual physical activity levels in patients with RA compared with healthy control participants and to compare these measures with health-related quality of life and disease activity in the RA patients. METHODS. Fifty RA patients [age 48 (13) years] and 22 BMI, sex and geographically matched control participants were recruited. Habitual physical activity was measured using an Actical accelerometer worn on the hip for 2 consecutive weeks. Patients completed the Short Form-36 (SF-36) and modified Health Assessment Questionnaires (HAQ-DI). Disease activity was assessed using the Simplified Disease Activity Index (SDAI). RA patients were further categorized as more physically active (n = 25) and less physically active (n = 25) according to their average activity counts. RESULTS: The RA group spent more time in sedentary activity than the control group (71% vs 62% of the day respectively, P = 0.002) and had bimodal decreases in diurnal physical activity compared with the control group in the morning (P < 0.001) and late afternoon (P < 0.001). HAQ-DI, when adjusted for age and disease duration, was negatively correlated with physical activity in the RA group (r = -0.343, P = 0.026). The more physically active patients scored better than the less physically active patients on every component of the SF-36. CONCLUSION: Patients with RA lead a significantly more sedentary lifestyle than healthy controls and show diurnal differences in physical activity due to morning stiffness and fatigue. Higher levels of habitual physical activity may be protective of functional capacity and are highly associated with improved health-related quality of life in RA patients.

Serum matrix metalloproteinase-3 in comparison with acute phase proteins as a marker of disease activity and radiographic damage in early rheumatoid arthritis.

Matrix metalloproteinase-3 (MMP-3) is involved in the immunopathogenesis of rheumatoid arthritis (RA), but little is known about its relationship to genetic susceptibility and biomarkers of disease activity, especially acute phase reactants in early RA. MMP-3 was measured by ELISA in serum samples of 128 disease-modifying, drug-naïve patients and analysed in relation to shared epitope genotype, a range of circulating chemokines/cytokines, acute phase reactants, autoantibodies, cartilage oligomeric protein (COMP), and the simplified disease activity index (SDAI). MMP-3 was elevated >1.86 ng/ml in 56.25% of patients (P < 0.0001), correlated with several biomarkers, notably IL-8, IL-6, IFN γ , VEGF and COMP (r values = 0.22-0.33, P < 0.014-0.0001) and with CRP and SAA levels (r = 0.40 and 0.41, resp., P < 0.0000) and SDAI (r = 0.29, P < 0.0001), but not with erosions or nodulosis. However, the correlations of CRP and SAA with SDAI were stronger (respective values of 0.63 and 0.54, P < 0.001 for both). COMP correlated with smoking, RF, and MMP-3. MMP-3 is significantly associated with disease activity, inflammatory mediators and cartilage breakdown, making it a potential biomarker of disease severity, but seemingly less useful than CRP and SAA as a biomarker of disease activity in early RA.

Assessment and determinants of aesthetic discomfort in hand osteoarthritis.

BACKGROUND: Dissatisfaction with hand appearance is frequently the presenting complaint of patients with hand osteoarthritis (HOA), yet no tool exists for its measurement and few studies have examined aesthetic discomfort. OBJECTIVES: The aims of this study were to measure the extent and to explore the associations of aesthetic concerns in HOA. METHODS: 172 patients with HOA were assessed with tender joint and node count, global and pain scores, Functional Index for Hand Osteoarthritis, Short Form-12, Hospital Anxiety and Depression Scale and posterior-anterior hand radiographs. Patients scored the aesthetic impact of the disease on a Visual Analogue Scale of 0-100 mm and were classified into low, intermediate and high aesthetic concern (HAC) based on this score. RESULTS: Of 172 patients (155 women), the majority (92%) had nodes and 46% had erosive disease. The mean aesthetic score was 44.8 mm (SD 35.9), and 59 (34.3%) patients scored their aesthetic discomfort ≥ 66 mm. Factors associated with HAC were female gender, a high number of tender joints and nodes, high global and pain scores, high radiological damage scores, the presence of erosions and high depression and anxiety levels. The multivariate analysis identified two independent factors associated with HAC: patient's global assessment (p=0.0005) and radiographic erosions (p=0.03). CONCLUSIONS: Aesthetic discomfort is a major concern for a significant number of patients with HOA, particularly women, those with a high burden of HOA disease and those with erosive osteoarthritis, and is also associated with depression, anxiety and poor health-related quality of life.

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.

INTRODUCTION: The revised shared epitope (SE) concept in rheumatoid arthritis (RA) is based on the presence (S) or absence (X) of the SE RAA amino acid motif at positions 72 to 74 of the third hypervariable region of the various human leucocyte antigen (HLA)-DRB1 alleles. The purpose of this study was to investigate SE subtypes on the basis of the American College of Rheumatology 1987 revised criteria for the classification of RA in a cohort of South African RA patients (n = 143) and their association with clinical and circulating biomarkers of disease activity (autoantibodies, acute phase reactants and cytokines). METHODS: Genomic DNA was analysed using high-resolution recombinant sequence-specific oligonucleotide PCR typing of the HLA-DRB1 allele. Subtypes of the SE were classified according to the amino acids at positions 72 to 74 for the RAA sequence, and further sub-divided according to the amino acids at positions 70 and 71, which either contribute to (S2, S3P), or negate (S1, S3D) RA susceptibility. Disease activity was assessed on the basis of (1) Disease Activity Score in 28 joints using C-reactive protein (CRP), (2) rheumatoid factor (RF), (3) CRP and (4) serum amyloid A by nephelometry, anticyclic citrullinated peptide antibodies (aCCP) by an immunofluorometric procedure, and cytokines by multiplex bead array technology. RESULTS: Of the 143 RA patients, 81 (57%) were homozygous (SS) and 50 (35%) were heterozygous (SX) for the SE alleles with significant overexpression of S2 and S3P (respective odds ratios (ORs) 5.3 and 5.8; P < 0.0001), and 12 (8%) were classified as no SE allele (XX). Both the SS and SX groups showed a strong association with aCCP positivity (OR = 10.2 and P = 0.0010, OR = 9.2 and P = 0.0028, respectively) relative to the XX group. Clinical scores and concentrations of the other biomarkers of disease activity (RF, CRP and T helper cell type 1 (Th1), Th2, macrophage and fibroblast cytokines) were also generally higher in the SS group than in the SX and XX groups. CONCLUSIONS: RA susceptibility alleles investigated according to revised criteria for the classification of RA were significantly increased in South African RA patients and strongly associated with aCCP in particular as well as with circulating cytokines and disease severity.