Abatacept as Monotherapy and in Combination With Methotrexate in Patients With Juvenile Idiopathic Arthritis: Analysis of 2 Phase III Trials.

OBJECTIVE: To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or ABA monotherapy when prior MTX use was either ineffective or not tolerated. METHODS: Posthoc analysis of 2 phase III trials of subcutaneous (SC) and intravenous (IV) ABA over 2 years in patients with pcJIA (aged 2-17 years). Patients were stratified by treatment with ABA + MTX or ABA monotherapy and further by prior biologic use. Efficacy outcomes included JIA-American College of Rheumatology (JIA-ACR) responses, Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP), and safety. Descriptive pharmacokinetic analyses were also performed. RESULTS: Efficacy responses (JIA-ACR and JADAS27-CRP) were similar between patients receiving ABA + MTX (n = 310) or ABA monotherapy (n = 99) and persisted over 2 years. Clinical response rates were similar in biologic-naïve patients and prior biologic users; this was independent of MTX use. Across both studies, ABA + MTX and ABA monotherapy displayed similar safety profiles. Pharmacokinetic results revealed similar minimum steady-state trough ABA concentrations between studies. Further, baseline MTX did not influence ABA clearance and was not a significant predictor of JIA-ACR responses. CONCLUSION: ABA monotherapy (SC and IV) was effective and well tolerated in children with pcJIA when prior MTX use was ineffective or not tolerated. Treatment effects of ABA appear to be independent of MTX coadministration. Consequently, ABA monotherapy can be considered for those with prior biologic therapy if MTX use is inappropriate. (ClinicalTrials.gov: NCT01844518 and NCT00095173).

Simple Erosion Narrowing Score of the hands as a predictor of cervical spine subluxation in rheumatoid arthritis.

BACKGROUND: Involvement of the cervical spine is common in patients with rheumatoid arthritis and can lead to devastating or even fatal consequences. Currently no guidelines exist as to whether radiographs of the cervical spine should be included in follow-up visits. OBJECTIVES: To determine whether the Simple Erosion Narrowing Score (SENS) of the hands correlate with the presence of cervical spine subluxation in patients with rheumatoid arthritis. METHOD: This was a retrospective, observational, cross-sectional study. A total of 56 rheumatoid arthritis patients with hand radiographs and lateral radiographs of the cervical spine were evaluated. The SENS of the hands and the presence of cervical spine subluxation were compared. The SENS of the hands was correlated with the prevalence of cervical spine subluxation, as was the erosion and joint space narrowing scores of the hands. RESULTS: A correlation between the SENS of the hands and the prevalence of cervical spine subluxation was confirmed. A higher prevalence of cervical spine subluxation correlated with an increase in the SENS of the hands (p = 0.0002). The erosion and joint space narrowing scores of the hands also correlated with the prevalence of cervical spine subluxation (p = 0.0001). CONCLUSION: This study confirmed that a correlation exists between cervical spine subluxation, peripheral joint space erosions and joint space narrowing in patients with rheumatoid arthritis and SENS may therefore be used as a predictor of cervical spine 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.

Tobacco-Derived Lipopolysaccharide, Not Microbial Translocation, as a Potential Contributor to the Pathogenesis of Rheumatoid Arthritis.

Microbial lipopolysaccharides (LPS) have been implicated in the pathogenesis of rheumatoid arthritis (RA), possibly driving a systemic inflammatory response that may trigger the development and/or exacerbation of the disease. To explore the existence of this mechanism in African RA patients, we have measured systemic levels of LPS and its surrogate, LPS-binding protein (LBP), as well as those of intestinal fatty acid-binding protein (I-FABP), pulmonary surfactant protein D (SP-D), and cotinine in serum to identify possible origins of LPS, as well as associations of these biomarkers with rheumatoid factor (RF) and anticitrullinated peptide (aCCP) autoantibodies and the DAS 28-3 clinical disease severity score. A cohort of 40 disease-modifying antirheumatic drug-naïve, black South African RA patients rated by compound disease scores and 20 healthy subjects and 10 patients with chronic obstructive pulmonary disease (COPD) as controls were included in this study. Levels of the various biomarkers and autoantibodies were measured using a combination of ELISA and immunofluorimetric and immunoturbidometric procedures. LPS levels were lowest in the RA group compared to the healthy controls (p = 0.026) and COPD patients (p = 0.017), while LBP levels were also significantly lower in RA compared to the healthy individuals (p = 0.036). Levels of I-FABP and SP-D were comparable between all three groups. Categorisation of RA patients according to tobacco usage revealed the following significant positive correlations: LBP with C-reactive protein (p = 0.0137); a trend (p = 0.073) towards an association of LBP with the DAS 28-3 disease severity score; RF-IgG antibodies with both LPS and LBP (p = 0.033 and p = 0.041, respectively); aCCP-IgG antibodies with LPS (p = 0.044); and aCCP-IgG with RF-IgM autoantibodies (p = 0.0016). The findings of this study, several of them novel, imply that tobacco products, as opposed to microbial translocation, represent a potential source of LPS in this study cohort of RA patients, again underscoring the risks posed by tobacco usage for the development and severity of RA.

Poncet's Disease in the Preclinical Phase of Rheumatoid Arthritis.

We report on a patient with seropositive polyarthritis retrospectively diagnosed as Poncet's disease in the preclinical phase of seropositive rheumatoid arthritis. Our patient developed rheumatoid arthritis more than 2 years after being successfully treated for pulmonary tuberculosis and an initial inflammatory polyarthritis consistent with the diagnosis of Poncet's disease. This case illustrates the importance of recognizing Poncet's disease in a patient presenting with polyarthritis in order to avoid inappropriate long-term disease modifying antirheumatic treatment. It also illustrates the need for adequate follow-up of patients with Poncet's disease after treatment with antituberculosis treatment so that progression to a primary inflammatory arthritis such as rheumatoid arthritis may be identified timeously. Although seropositivity for rheumatoid arthritis has been reported in Poncet's disease as well as in tuberculosis, it is rather uncommon, and long-term follow-up of patients with Poncet's disease is essential particularly if they have positive serological tests for rheumatoid arthritis. In this case report, we describe the first reported case of Poncet's disease in the preclinical phase of rheumatoid arthritis and review the literature related to this rare disease presentation.

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.

Rheumatoid arthritis and risk of cardiovascular disease.

In developing countries, rheumatoid arthritis (RA) remains a seriously under-prioritised disease, particularly among the underprivileged, often resulting in presentation of patients late in the course of their disease, further complicated by limited therapeutic options and inconsistent follow up. The consequences are often severe with irreversible disability, increased frequency of co-morbidities, especially cardiovascular disease (CVD), and higher mortality rates, relative to developed countries. Despite addressing traditional cardiovascular risk factors, the impact of subclinical or 'residual' inflammation from uncontrolled RA needs to be considered. This narrative review explores the prevalence and pathogenesis of CVD in RA, including the impact of tobacco use. It discusses pitfalls in the risk assessment of CVD in patients with RA, and the effect of disease-modifying anti-rheumatic therapy on cardiovascular co-morbidity.

Subcutaneous Abatacept in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Results From a Phase III Open-Label Study.

OBJECTIVE: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 µg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.

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.

The role of imaging in rheumatoid arthritis.

Conventional radiographs of the hands and feet have traditionally been used in the diagnosis, management and monitoring of patients with rheumatoid arthritis (RA). However, they are not sensitive enough to detect changes early in the disease process. Erosions may only be visible up to two years after the onset of disease, and soft tissue involvement may not be detected at all. Early diagnosis can also be made challenging as markers such as erythrocyte sedimentation rate and C-reactive protein may be normal in up to 20% - 25% of cases. The latest classification criteria (American College of Rheumatology/European League Against Rheumatism [ACR/EULAR] Rheumatoid Arthritis Classification criteria 2010), often used to diagnose RA, incorporate the role of ultrasound and magnetic resonance imaging detection of synovitis, enabling earlier diagnosis and correct classification of patients. This article looks at the role of the various imaging modalities used in the diagnosis and management of RA.

Human immunodeficiency virus infection and inflammatory arthritis: A review of clinical and imaging features.

The reported prevalence of articular manifestations of human immunodeficiency virus (HIV) varies, but with sub-Saharan Africa accounting for almost 70% of the people living with HIV, this results in a considerable burden of disease in the region. The spectrum of clinical presentation described, includes articular pain syndrome, HIV-associated arthropathy and seronegative spondyloarthropathies, among others. This brief review serves to create awareness of the clinical and imaging presentation of this spectrum of disease as there is significant morbidity associated with these conditions if treatment is delayed.

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.

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis.

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.

Reliable and cost-effective serodiagnosis of rheumatoid arthritis.

Early diagnosis of patients with rheumatoid arthritis (RA) optimises therapeutic benefit and the probability of achieving disease remission. Notwithstanding clinical acumen, early diagnosis is dependent on access to reliable serodiagnostic procedures, as well as on the discerning application and interpretation of these. In the case of RA, however, no disease-specific serodiagnostic procedure is available due to the multi-factorial and polygenic nature of this autoimmune disorder. This has resulted in the development of an array of serodiagnostic procedures based on the detection of autoantibodies reactive with various putative autoantigens. Other procedures based on measurement of elevations in the concentrations of systemic biomarkers of inflammation, most commonly acute phase reactants and cytokines/chemokines, are used as objective indices of disease activity. Following a brief overview of RA research in African populations, the current review is focused on those autoantibodies/biomarkers, specifically rheumatoid factor, anti-citrullinated peptide antibodies and C-reactive protein, which are currently recognised as being the most reliable and cost-effective with respect to disease prediction and diagnosis, as well as in monitoring activity and outcome.

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.

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.

Suboptimal management of rheumatoid arthritis in the Middle East and Africa: could the EULAR recommendations be the start of a solution?

Although the prevalence of RA in the Middle East and Africa is comparable with that in other parts of the world, evidence indicates that its management in this region is suboptimal for a variety of reasons, including misconceptions and misunderstandings about the disease's prevalence and severity in the region, compounded by the lack of local epidemiological and health-economic data around the disease; the perception that RA is a low priority compared with other more prevalent conditions; delayed diagnosis, referral and treatment; and a lack of a region-specific, evidence-based management approach. In the absence of such an approach, the EULAR treatment recommendations may provide a useful starting point for the creation of guidelines to suit local circumstances. However, although agreement with the EULAR recommendations is high, many barriers prevent their implementation in clinical practise, including lack of timely referral to rheumatologists; suboptimal use of synthetic DMARDs; poor access to biologics; lack of awareness of the burden of RA among healthcare professionals, patients and payers; and lack of appropriate staffing levels.To optimise the management of RA in the Middle East and Africa, will require a multi-pronged approach from a diverse group of stakeholders-including local, national and regional societies, such as the African League of Associations in Rheumatology and International League of Associations for Rheumatology, and service providers-to collect data on the epidemiology and burden of the disease; to increase awareness of RA and its burden among healthcare professionals, payers and patients through various educational programmes; to encourage early referral and optimise use of DMARDs by promoting the EULAR treatment recommendations; to encourage the development of locally applicable guidelines based on the EULAR treatment recommendations; and to facilitate access to drugs and the healthcare professionals who can prescribe and monitor them.

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.

The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor in South Africans with early rheumatoid arthritis.

To establish the diagnostic utility of the anti-cyclic-citrullinated peptide antibody (aCCP) test in Black South Africans with early rheumatoid arthritis (RA). A cross-sectional study comparing the rheumatoid factor (RF) and aCCP status in RA patients and a control group consisting of healthy subjects, and patients with systemic lupus erythematosus (SLE) and scleroderma. The sensitivity, specificity, positive (PPV) and negative predictive values of the aCCP test alone were 82.5%, 84.9%, 87.6% and 79% versus 81.7%, 90.7%, 92.5% and 78% for RF alone. The best specificity (95.3) and PPV (95.8%) was observed when both aCCP and RF tests were positive. Patients with erosive disease had a significantly higher mean RF titre compared with those with non-erosive disease (p = 0.007). There was a trend towards an association of smoking (OR = 4.1, 95% CI = 0.9-18.6) and functional disability (p = 0.07) with RF-positive status. No similar clinical associations were observed with aCCP. Almost a third of SLE patients were aCCP positive. Despite the best specificity and PPV observed when both the aCCP and RF tests were positive, our findings suggest that testing for aCCP is only cost-effective in the RF-negative patient in whom there is a strong clinical suspicion of RA.

Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis.

Our objective was to analyse the relationship between circulating cytokines, autoantibodies, acute phase reactants, and disease activity in DMARDs-naïve rheumatoid arthritis (RA) patients (n = 140). All cytokines were significantly higher in the RA cohort than in healthy controls. Moderate-to-strong positive intercorrelations were observed between Th1/Th2/macrophage/fibroblast-derived cytokines. RF correlated significantly with IL-1ß, IL-2, IL-4, IL-10, IL-12, G-CSF, GM-CSF, IFN-γ, and TNF (P < .0001), and aCCP and aMCV with IL-1ß, IL-2, IL-4, and IL-10 (P < .0002), while IL-6 correlated best with the acute phase reactants, CRP, and SAA (P < .0001). In patients with a DAS28 score of ≥5.1, IFN-γ, IL-1ß, IL-1Ra, TNF, GM-CSF, and VEGF were significantly correlated (P < .04-.001) with high disease activity (HDA). Circulating cytokines in RA reflect a multifaceted increase in immune reactivity encompassing Th1 and Th2 cells, monocytes/macrophages, and synovial fibroblasts, underscored by strong correlations between these cytokines, as well as their relationships with RF, aCCP, and aMCV, with some cytokines showing promise as biomarkers of HDA.