Bridget Hodkinson

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.

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.

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-1β, IL-2, IL-4, IL-10, IL-12, G-CSF, GM-CSF, IFN-γ, and TNF (P < .0001), and aCCP and aMCV with IL-1β, 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-1β, 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.

Osteoarticular tuberculosis in patients with systemic lupus erythematosus

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.

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

IntroductionThe 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).MethodsGenomic 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.ResultsOf 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.ConclusionsRA 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.

Functional disability and health-related quality of life in South Africans with early rheumatoid arthritis

Background: The severity and predictors of functional disability and health-related quality of life (HRQoL) in a cohort of South Africans with early rheumatoid arthritis (RA) were investigated. Methods: Changes in the Health Assessment Questionnaire Disability Index (HAQ) and the 36-Item Short Form Health Survey (SF-36) following 12 months of traditional disease-modifying anti-rheumatic drugs (DMARDs) were studied in previously DMARD-naïve adults with disease duration ≤ 2 years. Results: The majority of the 171 patients were female (82%), Black Africans (89%) with a mean (SD) symptom duration of 11.6 (7.0) months. In the 134 patients seen at 12 months, there were significant improvements in the HAQ and all domains of the SF-36 but 92 (69%) still had substantial functional disability (HAQ > 0.5) and 89 (66%) had suboptimal mental health [SF-36 mental composite score (MCS) < 66.6]. Multivariate analysis showed that female sex (p = 0.05) and high baseline HAQ score (p < 0.01) predicted substantial functional disability at 12 months. Unemployment (p = 0.03), high baseline pain (p = 0.02), and HAQ score (p = 0.04) predicted suboptimal mental health, with a trend towards a low level of schooling being significant (p = 0.08). Conclusions: Early RA has a broad impact on HRQoL in indigent South Africans, with a large proportion of patients still showing substantial functional disability and suboptimal mental health despite 12 months of DMARD therapy. Further research is needed to establish the role of interventions including psychosocial support, rehabilitation programmes, and biological therapy to improve physical function and HRQoL in this population.

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.

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 (β = - 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 (β = 0.694, P = 0.035 and β = -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.

Biologic therapy for rheumatoid arthritis in developing countries—a place for non-TNF inhibitors as first-line treatment?

The introduction of TNF inhibitors more than a decade ago marked the beginning of an exciting era in the management of RA. Despite the development of biologics with alternative modes of action, TNF inhibitors remain today the most widely prescribed class of biologics for RA. However, tuberculosis (TB) is a major safety concern with TNF inhibitors. The risk of active TB is increased up to 56-fold compared with the general population, more so with the monoclonal antibody agents, and greatest in the first year of TNF inhibitor therapy, with a relative excess of extra-pulmonary TB [1, 2]. The background prevalence of latent TB infection (LTBI), previous TB infection, oral corticosteroid use, older age, high-risk occupation (e.g., health workers, prison staff) and low socio-economic status, all contribute to the ongoing TB risk. Mandatory screening for LTBI before commencing TNF inhibitor therapy has resulted in a marked reduction but not complete eradication of the TB risk. One important reason for the ongoing TB risk is the uncertainty surrounding the sensitivity and specificity of the tuberculin skin test (TST) and newer IFN-g release assays (IGRA) as screening tests for LTBI, particularly in high TB-burden settings [3]. In part this is because the pathobiology and nature of LTBI is poorly understood. At the pathological level, the concept of presumed LTBI is based largely on historical autopsy findings indicating that dormant Mycobacterium tuberculosis bacilli in tissues of macroscopically normalappearance and healed granulomas in lymph nodes and the lung could be cultured when inoculated into guinea pigs [4]. More recent work based on in situ PCR and RT-PCR has suggested the presence of viable bacilli throughout apparently normal lung tissue [5]. The TST and IGRA are in reality only a measure of the magnitude of an effector memory T cell response to M. tuberculosis from either recent or remote exposure [3]. Previous Bacillus Calmette Guerin (BCG) vaccination can produce a false positive TST but does not affect the IGRAs. At a clinical level, neither of these tests distinguishes LTBI (either transient or long standing) from subclinical or apparently active TB. The premise that a positive TST/IGRA result may be indicative of LTBI arises from observations that patients with a positive test are at greater risk of developing active TB in the short term ( 2 years) compared with those who test negative [6]. However, the positive predictive value of these tests for the development of active TB is only of the order of 1 2%. Poor implementation of LTBI screening and treatment recommendations is a further contributing factor to ongoing risk of active TB in patients. European registry data and a Korean study have shown that screening or treatment for LTBI is incorrectly carried out in 12 39.5% of cases [1, 2]. In a Greek study of patients on TNF inhibitors, of nine patients who fulfilled criteria for LTBI treatment but who took chemoprophylaxis either incorrectly or not at all, three developed active TB [7]. To complicate matters further, even when there is apparent adherence and completion of chemoprophylaxis, there is incomplete protection against active TB. Early large randomized controlled trials showed that treating TST-positive persons with isoniazid decreases the subsequent risk of developing active TB by only 60% [8]. Not surprisingly, there have been cases of patients treated with TNF inhibitors who have developed active TB after completing chemoprophylaxis [2, 7]. New infection occurring after prophylactic therapy rather than reactivation of LTBI may explain the lack of complete protection and is likely to be particularly important in high-burden settings. In the developing world, mainly in Africa and parts of Asia, the incidence of TB reaches endemic proportions. For example, the annual incidence of TB in South Africa in 2010 was 808 per 100 000 [9]. There are currently no registry data on the impact of TNF inhibitors on TB risk in RA patients resident in TB-endemic areas. There are two possible options to reduce the risk of TB in this setting. Offering chemoprophylaxis to all patients commencing TNF inhibitors, regardless of TST/IGRA result, is one option. The potential downside of this approach is isoniazid-related hepatotoxicity, particularly in elderly patients and where there is co-prescription of other potentially hepatotoxic agents such as MTX. The risk of introducing drug resistance through the use of single-drug therapy seems to be small, but only if active TB has been excluded before starting chemoprophylaxis. The safer alternative is to avoid TNF inhibitors as firstline biologics in DMARD-resistant RA now that biologics with other modes of action are available. Countries like Morocco, Algeria and South Africa have recommended this approach [9]. The choice of the non-TNF inhibitor is dependent on resources, convenience of administration

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 LOC389203IRBPJ, 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.