RESUMO
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.
Assuntos
Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/sangue , Fator Reumatoide/sangue , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , África do SulRESUMO
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.
Assuntos
Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/genética , Autoanticorpos/imunologia , Predisposição Genética para Doença/genética , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Fator Reumatoide/imunologia , Uso de Tabaco/efeitos adversos , Adolescente , Idoso , Anticorpos Antiproteína Citrulinada/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Valor Preditivo dos Testes , Prevalência , Fator Reumatoide/sangue , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Fumar/imunologia , África do Sul/epidemiologia , Uso de Tabaco/epidemiologia , Adulto JovemRESUMO
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.
Assuntos
Artrite Reumatoide/sangue , Cotinina/sangue , Fumar/sangue , Adulto , Idoso , Biomarcadores/sangue , População Negra , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , África do Sul , Tabagismo , Tabaco sem FumaçaRESUMO
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.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/sangue , Citocinas/sangue , Mediadores da Inflamação/sangue , Peptídeos Cíclicos/imunologia , Corticosteroides/uso terapêutico , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Biomarcadores/sangue , Países em Desenvolvimento , Quimioterapia Combinada , Genótipo , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , África do Sul/epidemiologia , Fatores de Tempo , Resultado do TratamentoAssuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Países em Desenvolvimento , Resistência a Medicamentos , Diagnóstico Precoce , Humanos , Fatores de Risco , Tuberculose/complicações , Tuberculose/diagnóstico , Tuberculose/prevenção & controle , Inibidores do Fator de Necrose TumoralRESUMO
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.
Assuntos
Artrite Reumatoide/genética , População Negra/genética , Predisposição Genética para Doença , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ligação a DNA/genética , DNA Polimerase Dirigida por DNA/genética , Feminino , Genótipo , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Fator Regulador 1 de Interferon/genética , Masculino , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Receptores Tipo I de Interleucina-1/genética , África do Sul , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
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.
Assuntos
Artrite Reumatoide/terapia , Algoritmos , Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/classificação , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Terapia Biológica , Infecções por HIV/complicações , Humanos , Osteoporose/complicações , Medição de Risco , Fatores de Risco , África do Sul , Tuberculose/epidemiologiaRESUMO
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.
Assuntos
Proteínas de Fase Aguda/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores/sangue , Metaloproteinase 3 da Matriz/sangue , Artrite Reumatoide/patologia , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Proteínas Matrilinas/sangue , Radiografia , Fumar/sangueRESUMO
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.