Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in rheumatoid arthritis patients and relatives from Brazil.

OBJECTIVES: To evaluate the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and RF in RA patients and their relatives from Southern Brazil. METHODS: Anti-CCP2 and IgM-RF were evaluated in 156 RA patients and 200 relatives. Sera from 100 healthy unrelated individuals were used as control. The anti-CCP2 was detected by ELISA and the IgM-RF using the latex agglutination test. RESULTS: We identified 117 anti-CCP2 (75%)-positive and 106 RF (67.9%)-positive patients. Anti-CCP2 was increased in relatives (5.5%; 11/200) when compared with unrelated individuals (1%; P = 0.050). Titre of anti-CCP2 in RA patients did not differ from relatives [140.4 (75.7) vs 115.6 (84.2) U, respectively; P = 0.30]. Positive relatives were younger than patients for anti-CCP2 (P = 0.0081), RF (P < 0.001) and both concomitantly (P = 0.012), and although there was no difference for anti-CCP2 positivity according to gender, increased RF positivity and concomitant anti-CCP2/RF were observed in the female relatives (P = 0.067 and 0.082, respectively). No difference regarding the relative degree of tobacco use in relatives was detected. Among the 11 anti-CCP2-positive relatives, 2 females had RA diagnosis established and 6 individuals presented with joint symptoms suggestive of RA. CONCLUSION: The results demonstrate a significant positivity of anti-CCP2 in relatives of RA patients from Brazil and reinforce the importance of serological tools to identify undiagnosed RA.

Cardiovascular risk and mannose binding lectin in patients with rheumatoid arthritis from southern Brazil.

BACKGROUND: Mannose binding lectin (MBL) appears to be involved in susceptibility to rheumatoid arthritis (RA), in the inflammatory process and in the genesis of atherosclerotic disease. OBJECTIVE: To study the association of MBL serum levels and its genotypic variation with carotid arteries intimal thickness (IMT) in RA patients from Southern Brazil. METHODS: MBL serum levels, MBL2 genotyping and IMT were investigated in 90 RA patients along with their demographic, clinical and laboratory profile. MBL levels and MBL2 genotyping were evaluated in 90 healthy controls. RESULTS: A significant lower MBL serum concentration was observed in patients with RA in relation to controls (528 ng/mL vs 937.5 ng/mL, p = 0.05, respectively). The median IMT in RA patients was 0.59 mm (0.51 to 0.85 mm). There was no correlation between levels of MBL with disease activity, erythrocyte sedimentation rate, autoantibodies presence or IMT (p = NS). A weak and negative correlation was found between MBL and CRP levels (Rho = -0.24; p = 0.02;). The MBL2 variant at codon 54 (variant B) and HYPA haplotype were the most frequently observed in the RA sample (67.5% and 31.7%). MBL2 wild type (A/A) were associated with lower IMT when compared with heterozygotes (A/O; p = 0.04) and low producers (O/O; p = 0.05). In addition, high producers genotypes had lower levels of CRP when compared with medium (p = 0.04) or with low producers (p = 0.05). CONCLUSION: RA patients had lower MBL levels than controls. MBL were negatively associated with CRP serum levels; low MBL genotypes producers increased thickness of the IMT than high producers.

Analysis of four serum biomarkers in rheumatoid arthritis: association with extra articular manifestations in patients and arthralgia in relatives.

OBJECTIVES: To evaluate the frequency of four serum biomarkers in RA patients and their relatives and identify possible associations with clinical findings of the disease. METHODS: This was a transversal analytical study. Anti-cyclic citrullinated peptide (anti-CCP), anti-mutated citrullinated vimentin (anti-MCV) and IgA-rheumatoid factor (RF) were determined by ELISA and IgM-RF by latex agglutination in 210 RA patients, 198 relatives and 92 healthy controls from Southern Brazil. Clinical and demographic data were obtained through charts review and questionnaires. RESULTS: A higher positivity for all antibodies was observed in RA patients when compared to relatives and controls (p<0.0001). IgA-RF was more frequent in relatives compared to controls (14.6% vs. 5.4%, p=0.03, OR=2.98; 95% CI=1.11-7.98) whereas anti-CCP was the most common biomarker among RA patients (75.6%). Concomitant positivity for the four biomarkers was more common in patients (46.2%, p<0.0001). Relatives and controls were mostly positive for just one biomarker (20.2%, p<0.0001 and 15.2%, p=0.016, respectively). No association was observed between the number of positive biomarkers and age of disease onset, functional class or tobacco exposure. In seronegative patients predominate absence of extra articular manifestations (EAMs) (p=0.01; OR=3.25; 95% CI=1.16-10.66). Arthralgia was present in positive relatives, regardless the type of biomarker. CONCLUSIONS: A higher number of biomarkers was present in RA patients with EAMs. Positivity of biomarkers was related to arthralgia in relatives. These findings reinforce the link between distinct biomarkers and the pathophysiologic mechanisms of AR.

Mannose-binding lectin deficiency and miscarriages in rheumatoid arthritis.

OBJECTIVE: To investigate the association between mannose-binding lectin (MBL) serum level and MBL2 polymorphisms, and the frequency of spontaneous miscarriages in rheumatoid arthritis (RA) patients. METHODS: One hundred seventy seven women (mean age 50 years) with RA from Southern Brazil were studied and 4.5% had a history of abortion (8/177). The MBL levels were determined by ELISA. MBL2 polymorphisms in the promoter (-550H/L, -221X/Y), 5' untranslated region (4 P/Q) and exon 1 (p.Gly54Asp: B allele, p.Arg52Cys: D allele and p.Gly57Glu: C allele; collectively labelled O) were genotyped by sequencing. RESULTS: Mannose-binding lectin levels of RA patients ranged from ≤100 ng/mL to 6640 ng/mL (median 541.5 ng/mL). There was a significant difference in MBL median levels (100 ng/mL vs. 625 ng/mL, respectively, p = .001) and frequency of MBL deficiency (75.0% vs. 24.1%, p = .007, OR = 10.3, 95%CI = 1.9-55.4), in patients with a history of miscarriage vs those without it. Patients with RA and miscarriage had more frequently haplotypes related with low MBL levels (p = .007, OR = 10.5, 95%CI = 1.3-84) than high producers. Moreover, LYPB haplotype and O allele were significantly associated with the occurrence of miscarriage (p = .001, OR = 9.7, 95%CI = 2.4-39.1 and p = .009, OR = 5.9, 95%CI = 1.4-23.4, respectively). CONCLUSIONS: The results suggest that MBL deficiency and the presence of MBL2 gene polymorphisms that lead to MBL deficiency are risk factors for the occurrence of miscarriage in patients with RA.

Mannose-binding lectin polymorphisms and rheumatoid arthritis: A short review and meta-analysis.

Mannose-binding lectin (MBL) is a pattern recognition receptor of the lectin pathway of complement system. MBL binds to carbohydrates on microorganism's surfaces leading to complement activation, opsonization and phagocytosis. Polymorphisms in the MBL gene (MBL2) are associated with variations on MBL serum levels and with the susceptibility to various infectious and autoimmune diseases. The involvement of the lectin pathway in rheumatoid arthritis (RA) has been demonstrated by several studies and although MBL has been considered to have a dual role in the pathogenesis of the disease, the association between MBL and RA remains inconclusive. In an attempt to clarify this relationship, we developed this short review summarizing accumulated evidences in regard to MBL and RA and a meta-analysis to evaluate the influence of MBL2 polymorphisms on the susceptibility to RA. Among a total of 217 articles that were identified following a predefined search strategy on PubMed, Scopus, Scielo, EMBASE and Cochrane databases, only 13 met all inclusion criteria and were included in the meta-analysis. Data assessment was conducted by three independent investigators and presented in odds ratio (OR) and 95% confidence intervals (CIs) using forest plot charts. Both heterogeneity and publication bias were analyzed. The results of the meta-analysis evidenced that MBL2 low producing OO and XX genotypes do not confer higher risk to RA, even when data were analyzed according to cohort's ethnicity. Further studies are needed in order to clarify the importance of other genes of the lectin pathway in the pathogenesis of RA.

Serum pentraxin 3 levels are negatively associated with carotid intima media thickness in non-obese rheumatoid arthritis patients.

BACKGROUND: Pentraxin-3 (PTX3) is a long pentraxin that is supposed to participate in the inflammatory process and in atherosclerosis. AIM: To study PTX3 serum levels in rheumatoid arthritis (RA) patients to know if its serum levels may reflect disease activity and/or subclinical atherosclerosis. METHODS: PTX3 and carotid intima media thickness (IMT) were studied in 85 RA patients (83.5% females, median age of 59years old, median disease duration of 13years) along with its demographic, clinical, serological and lipid profile. For comparison PTX3 was measured in 85 healthy volunteers. RESULTS: PTX3 levels in RA patients were similar to controls (p=0.21) and did not correlate with inflammatory activity measured by ESR (p=0.39) CRP (p=0.18) and DAS28 (p=0.67). Serum PTX3 levels were higher in nonobese RA patients than in obese (BMI vs PTX3 with rho=-0.27; 95%IC=-0.46 to -0.06; p=0.009). In non-obese patients, PTX3 correlated negatively with carotid IMT (rho=-0.40; 95%IC=-0.66 to -0.06; p=0.01) but not in the obese ones (p=0.26). In the obese RA patients there was a negative correlation between PTX3 levels and LDL/HDL ratio (Rho=-0.29; 95%IC=-0.53-0.01; p=0.03). CONCLUSIONS: PTX3 levels do not reflect inflammatory process in RA. However, it exerts a protective role in the process of atherogenesis in non-obese RA patients.

MBL-associated serine proteases (MASPs) and infectious diseases.

The lectin pathway of the complement system has a pivotal role in the defense against infectious organisms. After binding of mannan-binding lectin (MBL), ficolins or collectin 11 to carbohydrates or acetylated residues on pathogen surfaces, dimers of MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2) activate a proteolytic cascade, which culminates in the formation of the membrane attack complex and pathogen lysis. Alternative splicing of the pre-mRNA encoding MASP-1 results in two other products, MASP-3 and MAp44, which regulate activation of the cascade. A similar mechanism allows the gene encoding MASP-2 to produce the truncated MAp19 protein. Polymorphisms in MASP1 and MASP2 genes are associated with protein serum levels and functional activity. Since the first report of a MASP deficiency in 2003, deficiencies in lectin pathway proteins have been associated with recurrent infections and several polymorphisms were associated with the susceptibility or protection to infectious diseases. In this review, we summarize the findings on the role of MASP polymorphisms and serum levels in bacterial, viral and protozoan infectious diseases.

The lectin pathway of complement and rheumatic heart disease.

The innate immune system is the first line of host defense against infection and is comprised of humoral and cellular mechanisms that recognize potential pathogens within minutes or hours of entry. The effector components of innate immunity include epithelial barriers, phagocytes, and natural killer cells, as well as cytokines and the complement system. Complement plays an important role in the immediate response against microorganisms, including Streptococcus sp. The lectin pathway is one of three pathways by which the complement system can be activated. This pathway is initiated by the binding of mannose-binding lectin (MBL), collectin 11 (CL-K1), and ficolins (Ficolin-1, Ficolin-2, and Ficolin-3) to microbial surface oligosaccharides and acetylated residues, respectively. Upon binding to target molecules, MBL, CL-K1, and ficolins form complexes with MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2), which cleave C4 and C2 forming the C3 convertase (C4b2a). Subsequent activation of complement cascade leads to opsonization, phagocytosis, and lysis of target microorganisms through the formation of the membrane-attack complex. In addition, activation of complement may induce several inflammatory effects, such as expression of adhesion molecules, chemotaxis and activation of leukocytes, release of reactive oxygen species, and secretion of cytokines and chemokines. In this chapter, we review the general aspects of the structure, function, and genetic polymorphism of lectin-pathway components and discuss most recent understanding on the role of the lectin pathway in the predisposition and clinical progression of Rheumatic Fever.

Mannose binding lectin and susceptibility to rheumatoid arthritis in Brazilian patients and their relatives.

INTRODUCTION: Rheumatoid arthritis (RA) is a commonly occurring systemic inflammatory auto immune disease and is believed to be associated with genetic factors. The innate immune complement protein Mannose binding lectin (MBL) and their MBL2 genetic variants are associated with different infectious and autoimmune diseases. METHODS: In a Brazilian cohort, we aim to associate the functional role of circulating MBL serum levels and MBL2 variants in clinically classified patients (n = 196) with rheumatoid arthritis including their relatives (n = 200) and ethnicity matched healthy controls (n = 200). MBL serum levels were measured by ELISA and functional MBL2 variants were genotyped by direct sequencing. RESULTS: The exon1+54 MBL2*B variant was significantly associated with an increased risk and the reconstructed haplotype MBL2*LYPB was associated with RA susceptibility. Circulating serum MBL levels were observed significantly lower in RA patients compared to their relatives and controls. No significant contribution of MBL levels were observed with respect to functional class, age at disease onset, disease duration and/or other clinical parameters such as nodules, secondary Sjögren syndrome, anti-CCP and rheumatoid factor. Differential distribution of serum MBL levels with functional MBL2 variants was observed in respective RA patients and their relatives. CONCLUSIONS: Our results suggest MBL levels as a possible marker for RA susceptibility in a Brazilian population.

Association of MASP-2 levels and MASP2 gene polymorphisms with rheumatoid arthritis in patients and their relatives.

BACKGROUND: Mannan-binding lectin-associated serine protease 2 (MASP-2) is a key protein of the lectin pathway of complement. MASP-2 levels have been associated with different polymorphisms within MASP2 gene as well as with the risk for inflammatory disorders and infections. Despite its clinical importance, MASP-2 remains poorly investigated in rheumatoid arthritis (RA). METHODS: In this case-control study, we measured MASP-2 serum levels in 156 RA patients, 44 patient relatives, and 100 controls from Southern Brazil, associating the results with nine MASP2 polymorphisms in all patients, 111 relatives, and 230 controls genotyped with multiplex SSP-PCR. RESULTS: MASP-2 levels were lower in patients than in controls and relatives (medians 181 vs. 340 or 285 ng/ml, respectively, P<0.0001). Conversely, high MASP-2 levels were associated with lower susceptibility to RA and to articular symptoms independently of age, gender, ethnicity, smoking habit, anti-CCP and rheumatoid factor positivity (OR = 0.05 [95%CI = 0.019-0.13], P<0.0001 between patients and controls; OR = 0.12, [95%CI = 0.03-0.45], P = 0.002 between patients and relatives; OR = 0.06, [95%CI = 0.004-0.73], P = 0.03 between relatives with and without articular symptoms). MASP2 haplotypes *2A1 and *2B1-i were associated with increased susceptibility to RA (OR = 3.32 [95%CI = 1.48-7.45], P = 0.004). Deficiency-causing p.120G and p.439H substitutions were associated with five times increased susceptibility to articular symptoms in relatives (OR = 5.13 [95%CI = 1.36-20.84], P = 0.02). There was no association of MASP-2 levels or MASP2 polymorphisms with autoantibodies, Sjögren's syndrome, nodules and functional class. CONCLUSIONS: In this study, we found the first evidence that MASP-2 deficiency might play an important role in the development of RA and articular symptoms among relatives of RA patients.

Leprosy association with low MASP-2 levels generated by MASP2 haplotypes and polymorphisms flanking MAp19 exon 5.

BACKGROUND: The gene MASP2 (mannan-binding lectin (MBL)-associated serine protease 2) encodes two proteins, MASP-2 and MAp19 (MBL-associated protein of 19 kDa), bound in plasma to MBL and ficolins. The binding of MBL/MASP-2 and ficolin/MASP-2 complexes to microorganisms activates the lectin pathway of complement and may increase the ingestion of intracellular pathogens such as Mycobacterium leprae. METHODS: We haplotyped 11 MASP2 polymorphisms with multiplex sequence-specific PCR in 219 Brazilian leprosy patients (131 lepromatous, 29 borderline, 21 tuberculoid, 14 undetermined, 24 unspecified), 405 healthy Brazilians and 291 Danish blood donors with previously determined MASP-2 and MAp19 levels. We also evaluated MASP-2 levels in further 46 leprosy patients and 69 Brazilian controls. RESULTS: Two polymorphisms flanking exon 5 of MASP2 were associated with a dominant effect on high MASP-2 levels and an additive effect on low MAp19 levels. Patients presented lower MASP-2 levels (P = 0.0012) than controls. The frequency of the p.126L variant, associated with low MASP-2 levels (below 200 ng/mL), was higher in the patients (P = 0.0002, OR = 4.92), as was the frequency of genotypes with p.126L (P = 0.00006, OR = 5.96). The *1C2-l [AG] haplotype, which harbors p.126L and the deficiency-causing p.439H variant, has a dominant effect on the susceptibility to the disease (P = 0.007, OR = 4.15). Genotypes composed of the *2B1-i and/or *2B2A-i haplotypes, both associated with intermediate MASP-2 levels (200-600 ng/mL), were found to be protective against the disease (P = 0.0014, OR = 0.6). Low MASP-2 levels (P = 0.022), as well as corresponding genotypes with *1C2-l and/or *2A2-l but without *1B1-h or *1B2-h, were more frequent in the lepromatous than in other patients (P = 0.008, OR = 8.8). CONCLUSIONS: In contrast with MBL, low MASP-2 levels increase the susceptibility to leprosy in general and to lepromatous leprosy in particular. MASP2 genotypes and MASP-2 levels might thus be of prognostic value for leprosy progression.

Relevance of the lectin pathway of complement in rheumatic diseases.

Due to its importance both in the clearance of pathogens that contribute as rheumatic etiological agents and in the disposal of apoptotic bodies and potential autoimmune initiators, deficiencies of the components of the lectin pathway of complement have been found to increase susceptibility and modulate the severity of most rheumatic disorders. This chapter introduces the general aspects of the structure, function, and genetics of lectin pathway components and summarizes current knowledge of the field regarding rheumatic diseases predisposition and modulation.

Analysis of four serum biomarkers in rheumatoid arthritis: association with extra articular manifestations in patients and arthralgia in relatives / Análise de quatro marcadores sorológicos na artrite reumatoide: associação com manifestações extra-articulares no paciente e artralgia em familiares

ABSTRACT Objectives: To evaluate the frequency of four serum biomarkers in RA patients and their relatives and identify possible associations with clinical findings of the disease. Methods: This was a transversal analytical study. Anti-cyclic citrullinated peptide (anti-CCP), anti-mutated citrullinated vimentin (anti-MCV) and IgA-rheumatoid factor (RF) were determined by ELISA and IgM-RF by latex agglutination in 210 RA patients, 198 relatives and 92 healthy controls from Southern Brazil. Clinical and demographic data were obtained through charts review and questionnaires. Results: A higher positivity for all antibodies was observed in RA patients when compared to relatives and controls (p < 0.0001). IgA-RF was more frequent in relatives compared to controls (14.6% vs. 5.4%, p = 0.03, OR = 2.98; 95% CI = 1.11-7.98) whereas anti-CCP was the most common biomarker among RA patients (75.6%). Concomitant positivity for the four biomarkers was more common in patients (46.2%, p < 0.0001). Relatives and controls were mostly positive for just one biomarker (20.2%, p < 0.0001 and 15.2%, p = 0.016, respectively). No association was observed between the number of positive biomarkers and age of disease onset, functional class or tobacco exposure. In seronegative patients predominate absence of extra articular manifestations (EAMs) (p = 0.01; OR = 3.25; 95% CI = 1.16-10.66). Arthralgia was present in positive relatives, regardless the type of biomarker. Conclusions: A higher number of biomarkers was present in RA patients with EAMs. Positivity of biomarkers was related to arthralgia in relatives. These findings reinforce the link between distinct biomarkers and the pathophysiologic mechanisms of AR.

RESUMO Objetivos: Avaliar a frequência de quatro marcadores sorológicos em pacientes com AR e seus familiares e identificar possíveis associações com achados clínicos da doença. Métodos: Estudo analítico transversal. Determinaram-se os níveis de anticorpos antipeptídeo citrulinado cíclico (anti-CCP), anticorpos antivimentina citrulinada-mutada (anti-MCV) e fator reumatoide (FR) IgA por Elisa e de FR-IgM por aglutinação em látex em 210 pacientes com AR, 198 familiares e 92 controles saudáveis do sul do Brasil. Coletaram-se dados clínicos e demográficos por meio da revisão de prontuários e questionários. Resultados: Observou-se maior positividade para todos os anticorpos em pacientes com AR em comparação com os familiares e controles (p < 0,0001). O FR-IgA era mais frequente em familiares quando comparados com os controles (14,6% versus 5,4%, p = 0,03, OR = 2,98; IC95% = 1,11 a 7,98). O anti-CCP foi o biomarcador mais comum entre pacientes com AR (75,6%). A positividade concomitante para os quatro biomarcadores foi mais comum nos pacientes (46,2%, p < 0,0001). Familiares e controles eram positivos em sua maioria para apenas um biomarcador (20,2%, p < 0,0001 e 15,2%, p = 0,016, respectivamente). Não foi observada associação entre o número de biomarcadores positivos e a idade de início da doença, classe funcional ou exposição ao fumo. Em pacientes soronegativos, predominou a ausência de manifestações extra-articulares (MEA) (p = 0,01; OR = 3,25; IC95% = 1,16 a 10,66). A artralgia estava presente em familiares positivos, independentemente do tipo de biomarcador. Conclusões: Um maior número de biomarcadores estava presente em pacientes com AR com MEA. A positividade dos biomarcadores estava relacionada com a artralgia em familiares. Esses achados reforçam a ligação entre os diferentes biomarcadores e os mecanismos fisiopatológicos da AR.

Autoantibodies for gastrointestinal organ-specific autoimmune diseases in rheumatoid arthritis patients and their relatives.

BACKGROUND: Clustering of autoimmune diseases is common and may be due to genetic background and exposition to environmental triggers. OBJECTIVE: The aim is to carry out a laboratory and clinical study of the prevalence of gastrointestinal organ-specific autoantibodies in rheumatoid arthritis (RA) patients and their relatives. METHODS: Serum samples of 156 RA patients, 200 relatives, and 100 healthy controls were studied for anti-smooth muscle antibody (ASMA), anti-mitochondrial (AMA), anti-parietal cell (APCA), anti-liver-kidney microsome (LKM), and anti-endomysium antibodies (IgA-EmA) by indirect immunofluorescence. RESULTS: A total of eight out of the 156 (5.1%) RA patients were positive for the autoantibodies (ASMA = 1; AMA = 2, APCA = 5). In the relative group, 12/200 (6%) had at least one positive autoantibody (ASMA = 1; AMA = 2, APCA = 7, IgA-EmA = 2). In the control group, two out of the 100 (2%) healthy controls were positive (ASMA = 1, APCA = 1). No statistical difference was found between RA patients, their relatives, and controls in relation to the frequency of autoantibodies evaluated. CONCLUSION: Although RA patients and their relatives have positivity of AMA, ASMA, and APCA without statistical difference in relation to healthy individuals, the findings may be of value for adequate clinical approach of these subjects.

Association of anticyclic citrullinated peptide antibodies with extra-articular manifestations, gender, and tabagism in rheumatoid arthritis patients from southern Brazil.

Gender and environmental factors are known to influence the clinical heterogeneity and outcome of rheumatoid arthritis (RA). Some variables have been suggested to be associated with the severity of the disease, which can be of great value in the correct management of RA patients. The purpose of this study was to investigate the associations among anticyclic citrullinated antibody (anti-CCP2) positivity, extra-articular manifestations (EAM), gender, and tobacco exposure in a Brazilian RA population. We performed a transversal study comprising 156 RA patients which were investigated for EAM, functional class, presence of anti-CCP2, and IgM rheumatoid factor (IgM-RF). The determination of anti-CCP2 was performed using enzyme immunoassay (ELISA) kits and IgM-RF by latex agglutination test. Clinical and demographical data were obtained through review of charts. Anti-CCP positivity intensity was directly correlated with tobacco smoking, sex, and the development of rheumatoid nodules. Intense anti-CCP2 reaction was 19.8-fold higher in females vs. males, 2.7-fold higher in tobacco vs. non-tobacco users, 7.7-fold higher in female vs. male tobacco users, and 5.15-fold higher in patients with rheumatoid nodules. Tobacco smoking, gender, and rheumatoid nodules are significantly correlated with anti-CCP2 positivity in Brazilian RA patients.

Artrite reumatoide: uma visão atual / Rheumatoid arthritis: a current view

INTRODUÇÃO: A artrite reumatoide (AR) é uma doença autoimune inflamatória e crônica que afeta aproximadamente 1 por cento da população adulta mundial. A doença caracteriza-se pela inflamação do tecido sinovial de múltiplas articulações, levando a destruição tecidual, dor, deformidades e redução na qualidade de vida do paciente. Sua etiologia é complexa e em grande parte desconhecida, porém estudos demonstram a influência de fatores genéticos e ambientais em sua patogênese. Devido à forte influência genética, familiares de pacientes com AR formam um grupo de risco para o desenvolvimento da doença, principalmente em sua forma mais grave. Apesar de seu elevado potencial incapacitante, o curso da AR pode ser modificado por meio do diagnóstico precoce e do manejo adequado do paciente. No entanto, o diagnóstico precoce da AR é ainda bastante difícil diante da heterogeneidade das manifestações clínicas da doença, o que acaba retardando a implantação terapêutica. O tratamento da AR baseia-se no uso de anti-inflamatórios não esteroidais (AINEs), corticosteroides, drogas antirreumáticas modificadoras do curso da doença (DMARD) e agentes imunobiológicos. Além da terapia medicamentosa, também são adotadas medidas como educação do paciente e terapias psico-ocupacionais. Atualmente, estudos têm se voltado à identificação de fatores preditores de doença mais grave, como autoanticorpos como fator reumatoide (FR) e anticorpo antipeptídio cíclico citrulinado (anti-CCP), que constituem importantes marcadores imunológicos de diagnóstico e prognóstico da AR. DISCUSSÃO E CONCLUSÃO: Apesar dos significativos avanços tanto no entendimento como no diagnóstico e no tratamento da AR, ainda persistem inúmeros desafios a serem superados.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, which affects approximately 1 percent of the world's adult population. It is characterized by the inflammation of synovial tissue from multiple articulations, leading to tissue destruction, pain, deformities and reduced quality of life. RA etiology is complex and largely unknown, although studies support the influence of genetic and environmental factors on its pathogenesis. Due to its major genetic component, relatives from RA patients are part of the risk group, mainly as to the development of the most severe forms. In spite of its high disability risk, RA development can be affected through early diagnosis and adequate therapy. Nonetheless, its early diagnosis is still very demanding due to the heterogeneity of its clinical presentations, which delays therapeutic approach. RA treatment includes non-steroidal anti-inflammatory drugs, corticosteroids, disease-modifying antirheumatic drugs (DMARD), and immunobiologic agents. Furthermore, raising patient's awareness and developing psyco/occupational therapies are also part of the therapeutic approach. Currently, several studies focus on the identification of predictive factors for severe RA such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies, which are major immunological diagnostic and prognostic markers for RA. DISCUSSION AND CONCLUSION: Despite the fact that there has been substantial progress in the investigation, diagnosis and treatment of RA, there are still several challenges to be overcome.