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ID PMID Title PublicationDate abstract
16881100 Reduction of cardiovascular risk factors with longterm fish oil treatment in early rheumat 2006 Oct OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA. METHODS: Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years. RESULTS: At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37% without fish oil (NS). Favorable changes in fasting blood lipids were seen with, but not without fish oil. Remission at 3 years was more frequent with fish oil use (72%) compared to no fish oil (31%). CONCLUSION: Fish oil reduces cardiovascular risk in patients with RA through multiple mechanisms.
16751383 A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell d 2006 Jun 15 In common with many other cell types, synovial fibroblasts produce exosomes. In this study, we show that the exosomes produced by synovial fibroblasts obtained from individuals with rheumatoid arthritis (RASF), but not exosomes produced by synovial fibroblasts obtained from individuals with osteoarthritis, contain a membrane bound form of TNF-alpha as demonstrated by colloidal gold immunostaining of TNF-alpha and confirmed by both Western blot and mass spectrometry. The RASF-derived exosomes, but not exosomes derived from fibroblasts obtained from individuals with osteoarthritis, are cytotoxic for the L929 cell, a TNF-alpha-sensitive cell line, and stimulate activation of NF-kappaB and induction of collagenase-1 in RASF. These effects are blocked by addition of soluble TNFR1 (sTNFbp), suggesting that a TNF-alpha-signaling pathway mediates these biological activities. sTNFbp also reduced the production of exosomes by RASF, suggesting the interruption of a positive amplification loop. Exosomes can transmit signals between cells, and RASF exosomes, effectively taken up by anti-CD3-activated T cells, activated AKT and NF-kappaB and rendered these activated T cells resistant to apoptosis. Neutralization of exosomal membrane TNF-alpha by sTNFbp partially reversed this resistance, suggesting that not only TNF-alpha but also additional exosomal proteins may contribute to the development of apoptosis resistance.
18228530 Sensitivity to change of the Rheumatoid Arthritis Self-Efficacy scale (RASE) and predictor 2008 Mar OBJECTIVES: Patient education in rheumatoid arthritis (RA) aims to improve health outcomes by prompting people to adopt self-management behaviours. One precursor for initiating behaviour change is self-efficacy (SE), a belief that you can do a task. This study tested the sensitivity to change of a new scale to measure SE for self-management in people with RA, the Rheumatoid Arthritis Self-Efficacy scale (RASE). Exploratory analysis examined potential predictors of change in SE. METHODS: People with RA at 11 rheumatology centres, who had accepted an education programme as part of clinical care, completed questionnaires at baseline, and two and eight weeks after their programme end. Programmes were not standardized, as this was a pragmatic study in clinical practice. RESULTS: A total of 128 patients participated. After controlling for baseline scores, the RASE showed small but significant improvements in SE from baseline (RASE 107.57, CI 105.42-109.72) to two weeks after programme end (RASE 110.80, CI 108.60-112.99), and eight weeks (RASE 110.62, CI 108.40-112.85, p<0.001). Standardized response means, calculated both by absolute and percentage change, were 0.339 and 0.371 at two weeks after programme end, and 0.321 and 0.352 at eight weeks. Changes in the RASE were associated with behaviour initiation at two and eight weeks (r=0.419, r=0.342, p<0.001). No substantial predictors of change in SE could be identified. CONCLUSIONS: The RASE is sensitive to change in a cohort of people with RA in the UK receiving education programmes as routine clinical care. Exploratory analysis did not identify clinical or psychological factors that predict change in SE, suggesting that programmes should not be restricted to particular patients.
16508968 Vasoactive intestinal peptide induces CD4+,CD25+ T regulatory cells with therapeutic effec 2006 Mar OBJECTIVE: CD4+,CD25+ T regulatory cells (Treg) control the immune response to a variety of antigens, including self antigens, and may offer opportunities to intervene in the course of autoimmune diseases. Several models support the idea of the peripheral generation of CD4+,CD25+ Treg from CD4+,CD25- T cells, but little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+,CD25+ Treg. We undertook this study to investigate the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive antiarthritic neuropeptide, to induce functional Treg in vivo during the development of collagen-induced arthritis (CIA). METHODS: We measured the number of CD4+,CD25+ Treg following VIP administration to CIA mice, and we characterized their phenotype and their ability to suppress activation of autoreactive T cells. We determined the capacity of VIP to induce Treg in vitro as well as the use of Treg in the treatment of CIA, measuring the clinical evolution and the inflammatory and autoimmune components of the disease. RESULTS: The administration of VIP to arthritic mice resulted in the expansion of CD4+,CD25+,Foxp3+ Treg in the periphery and joints, which inhibited autoreactive T cell activation/expansion. VIP induced more efficient suppressors on a per-cell basis. The VIP-generated CD4+,CD25+ Treg transfer suppressed and significantly ameliorated the progression of the disease. CONCLUSION: These results demonstrate the involvement of the generation of Treg in the therapeutic effect of VIP on CIA. The generation of highly efficient Treg by VIP ex vivo could be used as an attractive therapeutic tool in the future, avoiding the administration of the peptide to patients with rheumatoid arthritis.
18046758 Using linkage and association to identify and model genetic effects: summary of GAW15 Grou 2007 Group 4 at Genetic Analysis Workshop 15 focused on methods that exploited both linkage and association information to map disease loci. All contributions considered the dichotomous trait of rheumatoid arthritis, using either affected sibpairs and/or unrelated controls. While one contribution investigated linkage and association approaches separately in genome-wide analyses, the remaining others focused on joint linkage and association methods in specific genomic regions. The latter contributions proposed new methods and/or examined existing methods that addressed whether one or more polymorphisms partially or fully explained a linkage signal, particularly the methods proposed by Li et al. that are implemented in the computer program Linkage and Association Modeling in Pedigrees (LAMP). Using simulated SNP data under linkage peaks, several contributions found that existing family-based association approaches such as those of Martin et al. and Lake et al. had power similar to LAMP and to several methods proposed by the contributors for testing that a single nucleotide polymorphism partially explains a linkage peak. In evaluating methods for identifying if a polymorphism or a set of polymorphisms fully accounted for a linkage signal, several contributions found that it was important to understand that these methods may be subject to low power in some situations and thus, a non-significant result was not necessarily indicative of the polymorphism(s) being fully responsible for the linkage signal. Finally, modeling the disease using association evidence conditional on linkage may improve understanding of the etiology of disease.
17575266 The extra domain A of fibronectin stimulates murine mast cells via toll-like receptor 4. 2007 Sep The activation of mast cells by extra domain A of fibronectin (FN-EDA), an endogenous ligand of TLR4, and its contribution to the pathogenesis of rheumatoid arthritis (RA) in vivo were examined. FN-EDA, but no other domain of the fibronectin fragment, III(11) (FN-III(11)) and III(12) (FN-III(12)), stimulated bone marrow-derived murine mast cells (BMMCs) dose-dependently to secret cytokines (TNF-alpha, IL-6, and IL-1beta), similar to the pattern produced by LPS. FN-EDA-induced cytokine production was mediated by TLR4, as cytokine production by FN-EDA was absent in TLR4-deficient (TLR4-/-) BMMCs. We examined the roles of TLR4-mediated mast cell activation by this form of fibronectin fragment in the pathogenesis of RA in vivo. The injection of FN-EDA, but not FN-III(11)and FN-III(12), to joints resulted in joint swelling of mice in vivo. Genetically mast cell-deficient WBB6F(1)-W/W(v) mice exhibited significantly less swelling and cytokine production compared with mast cell-sufficient +/+ mice, suggesting that swelling and inflammatory cytokine production were partially dependent on tissue mast cells. Reduced swelling and cytokine production were recovered by the reconstitution of tissue mast cells by the injection of BMMCs from wild-type mice but not from TLR4-/- mice. Altogether, these results suggest that the TLR4-mediated activation of mast cells by endogenous ligand FN-EDA might contribute to the pathogenesis of RA through proinflammatory cytokine production.
19093117 An unusual central nervous system involvement in rheumatoid arthritis: combination of pach 2009 Sep Severe primary central nervous system (CNS) involvement such as vasculitis and pachymeningitis can rarely occur in rheumatoid arthritis (RA) even in the absence of systemic disease activation. The authors illustrate a female patient with well-controlled RA who presented with headaches, encephalopathy, seizures and relapsing focal neurological deficits. Primary rheumatoid cerebral vasculitis and pachymeningitis were diagnosed based on suggestive brain magnetic resonance (MR) imaging, MR angiography, cerebrospinal fluid analysis and cerebral angiography. MR showed abnormal leptomeningeal enhancement and hyperintense FLAIR signal in the cortical subarachnoid spaces consistent with pachymeningitis. Cerebral angiography findings were consistent with vasculitis. Aggressive treatment resulted in significant clinicoradiological resolution. Cerebral vasculitis is a rare but certain manifestation of RA. This complication can be diagnosed in the presence of suggestive angiographic and CSF findings. The condition may be steroid resistant, and needs to be treated more aggressively.
17766219 [Role of fibroblasts in physiologic, reparative and pathologic processes]. 2007 Sep 9 Fibroblast is counted as one of the important cell of the connective tissue. At the present time many phenotypes are known taking part in normal, repair and pathological processes, meanwhile cellular and molecular events occur, where fibroblasts play essential role. Among molecular factors, first of all integrins, growth factors, cytokines and matrix molecules are discussed. The aim of this work is to summarize the morphological, biochemical and functional role of fibroblasts in addition to the physiological process, wound repair and in such pathological processes as Dupuytren's disease, rheumatoid arthritis, Graves' ophthalmopathy and carcinogenesis. It becomes known that fibroblasts participate in dynamic interplay with other cells and with the extracellular matrix. The results of the new investigations clarify better the physiological and pathological processes of the tissue, at the same time give potential help to the therapy of some illnesses. The authors summarise the important data of the subject on the basis of international literature and of their own investigations.
17326817 Patients with early rheumatoid arthritis exhibit elevated autoantibody titers against mild 2007 Rheumatoid arthritis is a chronic inflammatory disease, associated with an excess of cardiovascular morbidity and mortality due to accelerated atherosclerosis. Oxidized low-density lipoprotein (oxLDL), the antibodies against oxLDL and the lipoprotein-associated phospholipase A2 (Lp-PLA2) may play important roles in inflammation and atherosclerosis. We investigated the plasma levels of oxLDL and Lp-PLA2 activity as well as the autoantibody titers against mildly oxLDL in patients with early rheumatoid arthritis (ERA). The long-term effects of immunointervention on these parameters in patients with active disease were also determined. Fifty-eight ERA patients who met the American College of Rheumatology criteria were included in the study. Patients were treated with methotrexate and prednisone. Sixty-three apparently healthy volunteers also participated in the study and served as controls. Three different types of mildly oxLDL were prepared at the end of the lag, propagation and decomposition phases of oxidation. The serum autoantibody titers of the IgG type against all types of oxLDL were determined by an ELISA method. The plasma levels of oxLDL and the Lp-PLA2 activity were determined by an ELISA method and by the trichloroacetic acid precipitation procedure, respectively. At baseline, ERA patients exhibited elevated autoantibody titers against all types of mildly oxLDL as well as low activity of the total plasma Lp-PLA2 and the Lp-PLA2 associated with the high-density lipoprotein, compared with controls. Multivariate regression analysis showed that the elevated autoantibody titers towards oxLDL at the end of the decomposition phase of oxidation and the low plasma Lp-PLA2 activity are independently associated with ERA. After immunointervention autoantibody titers against all types of oxLDL were decreased in parallel to the increase in high-density lipoprotein-cholesterol and high-density lipoprotein-Lp-PLA2 activity. We conclude that elevated autoantibody titers against oxLDL at the end of the decomposition phase of oxidation and low plasma Lp-PLA2 activity are feature characteristics of patients with ERA, suggesting an important role of these parameters in the pathophysiology of ERA as well as in the accelerated atherosclerosis observed in these patients.
16901955 Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with seve 2007 Jan OBJECTIVE: To study antibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor in patients with active, severe extra-articular rheumatoid arthritis (ExRA) compared with controls without ExRA. METHODS: 35 consecutive patients with severe ExRA manifestations according to predefined criteria were studied. 70 patients with rheumatoid arthritis, but no ExRA manifestations, individually matched for age, sex and disease duration, served as controls. Patients were included when ExRA was diagnosed, before any new treatment was started. Anti-CCPs were detected with ELISA, rheumatoid factor was quantified using nephelometry and anti-nuclear antibodies (ANA) were investigated using indirect immune fluorescence. RESULTS: Anti-CCPs were detected in 77% of patients with ExRA versus 56% of controls without ExRA (p = 0.03). Anti-CCP levels also tended to be higher in patients with ExRA (p = 0.09). Rheumatoid factor was detected in 94% v 71% of patients and controls, respectively (p = 0.006), and rheumatoid factor levels were higher in patients with ExRA (median interquartile range (IQR) 245 IU/ml (94-604) v 73 IU/ml (not detected-165); p = 0.001). Levels and occurrence of ANA did not differ between patients with ExRA and controls. Patients with ExRA had higher swollen joint counts and C reactive protein levels, but no correlations were found between anti-CCP or rheumatoid factor levels and these measures within the ExRA group. CONCLUSION: Rheumatoid factor is strongly associated with severe ExRA manifestations in patients with rheumatoid arthritis, and a similar but weaker association exists for anti-CCPs. This suggests a role for rheumatoid factor and anti-CCP in the pathogenesis of ExRA.
16404562 Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabol 2006 Aug To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.
17498267 No association in frequency of KIR receptors in patients with rheumatoid arthritis from No 2007 Jun The frequency of inhibiting and activating killer cell immunoglobulin-like receptors was similar in 331 patients with rheumatoid arthritis and in 354 controls. Patients and controls came from a relatively homogeneous Caucasian population from Northern Ireland, thus limiting population stratification. Furthermore, no differences were found when the patients were sub-divided according to gender or shared epitope and when the presence of the human leucocyte antigen ligand was taken into account.
18587229 [Minimal change nephrotic syndrome developing in a rheumatoid arthritis patient under etan 2008 Jun A 67-year-old female patient with rheumatoid arthritis (RA) developed minimal change nephrotic syndrome (MCNS) while under treatment with etanercept (ETN). Histopathological examination of renal biopsy specimens showed minimal-change nephropathy. Almost complete resolution of the MCNS was achieved by discontinuation of ETN and initiation of steroid therapy. There have been no reports from Japan of the occurrence of MCNS caused by ETN administration in RA patients, and only very few cases have been reported from around the world. Therefore, this case was considered to be very uncommon and worthy of reporting, and herein is a report of our patient.
18163520 Expression of mucin 3 and mucin 5AC in arthritic synovial tissue. 2008 Jan OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by hypertrophy of the synovial tissue, leukocyte infiltration, angiogenesis, and ultimately joint destruction. Mucins (MUCs) are a family of heavily glycosylated proteins that protect epithelial membranes and are used as ligands for cell adhesion. MUC gene expression has been found to be altered in many cancers and inflammatory states. This study was undertaken to examine its expression in synovial tissue (ST) and role in arthritis. METHODS: We performed immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction to determine expression patterns of MUC1, MUC2, MUC3, and MUC5AC in RA, osteoarthritic (OA), and normal human ST. RESULTS: MUC3 was expressed in synovial lining cells, macrophages, and fibroblasts. Significantly more RA (n=12) and OA (n=13) synovial lining cells expressed MUC3 than did normal synovial lining cells (n=7) (22% and 24% versus 0.4%, respectively; P<0.05). Additionally, macrophages in RA and OA ST expressed significantly more MUC3 than did macrophages in normal ST (50% and 51% versus 10%, respectively; P<0.05). MUC5AC was expressed at low levels in synovial lining cells, macrophages, and endothelial cells in RA and OA ST, and was barely expressed in normal ST. MUC1 and MUC2 proteins were not detected in ST. Messenger RNA (mRNA) for MUC3 and MUC5AC was detected in ST, and mRNA for MUC3 was detected in cultured ST fibroblasts. CONCLUSION: These data demonstrate up-regulated MUC expression by ST cells and suggest a novel role of MUC3 and MUC5AC in the pathogenesis of arthritis.
18378920 The results of two-stage re-implantation for infected shoulder replacement. 2008 Apr While frequently discussed as a standard treatment for the management of an infected shoulder replacement, there is little information on the outcome of two-stage re-implantation. We examined the outcome of 17 consecutive patients (19 shoulders) who were treated between 1995 and 2004 with a two-stage re-implantation for the treatment of a deep-infection after shoulder replacement. All 19 shoulders were followed for a minimum of two years or until the time of further revision surgery. The mean clinical follow-up was for 35 months (24 to 80). The mean radiological follow-up was 27 months (7 to 80). There were two excellent results, four satisfactory and 13 unsatisfactory. In 12 of the 19 shoulders (63%) infection was considered to be eradicated. The mean pain score improved from 4.2 (3 to 5 (out of 5)) to 1.8 (1 to 4). The mean elevation improved from 42 degrees (0 degrees to 140 degrees ) to 89 degrees (0 degrees to 165 degrees ), mean external rotation from 30 degrees (0 degrees to 90 degrees ) to 43 degrees (0 degrees to 90 degrees ), and mean internal rotation from the sacrum to L5. There were 14 complications. Our study suggests that two-stage re-implantation for an infected shoulder replacement is associated with a high rate of unsatisfactory results, marginal success at eradicating infection and a high complication rate.
16402112 Glucocorticoids: exemplars of multi-tasking. 2006 Jan Well over 80 years ago Philip Smith described the beneficial clinical effects of adrenocortical extracts in animal models of adrenal insufficiency. In the ensuing years, scientists across the globe have sought to understand the mechanisms by which adrenal hormones and their synthetic analogues produce their complex and varied actions. Particular attention has focused on the glucocorticoids, partly because they have a vital place in the treatment of inflammatory and autoimmune disorders but also because dysregulation of the secretion and/or activity of endogenous glucocorticoids is increasingly implicated in a number of common disorders that pose a growing clinical burden, such as obesity, type II diabetes, the metabolic syndrome, hypertension and depression. This review considers some of the key advances that have been made in our understanding of the physiology, pathology and pharmacology of the glucocorticoids. Emphasis is placed on the molecular mechanisms of glucocorticoid signalling and the complex mechanisms that regulate the access of steroids in the systemic circulation to their receptors in their various target cells and tissues. In addition, consideration is given to the irreversible 'organisational' actions of glucocorticoids in perinatal life and to the potential role of the steroids in the aetiology of disease.
18415767 Hand function tests are important and sensitive tools for assessment of treatment response 2008 Mar OBJECTIVES: To assess the usefulness of hand function measurements in a study of treatment effects of tumour necrosis factor (TNF) blockers and to define the relationship between different hand function tests and also relate hand function to general disability and disease activity. METHODS: The study group consisted of 49 patients with established rheumatoid arthritis (RA) who were followed for 1 year while on TNF inhibitors. Evaluation of hand function included Signals of Functional Impairment (SOFI), grip and pinch grip force, and the Grip Ability Test (GAT). General disability was assessed by the Health Assessment Questionnaire (HAQ) and disease activity by the 28-joint Disease Activity Score (DAS28). The standardized mean response (SMR) method was used to evaluate sensitivity to change for all hand tests using DAS28 and HAQ as external indicators of change. RESULTS: HAQ, DAS28, grip and pinch grip force, and GAT showed a highly significant improvement over time (p<0.001). The improvement in SOFI was also significant (p<0.01). The correlations between the different hand tests varied between 0.45 and 0.72. All hand function tests were significantly related to HAQ but showed only weak correlations to DAS28. SOFI, grip force, and pinch grip force showed large sensitivity for improvement in DAS28 and HAQ (SMR = 0.8-0.9). GAT showed modest sensitivity (SMR = 0.6-0.7). CONCLUSIONS: Patients with advanced RA attained considerable improvement in hand function that was only partly reflected by measures of general disability and disease activity. Focused assessment of hand function is therefore important for optimal evaluation of treatment response.
17984581 [RANKL inhibition as therapy for joint damage]. 2007 Oct RANK ligand (RANKL) is a key mediator of osteoclast formation, function, and survival. Therefore, RANKL is thought to be responsible for osteoclast-mediated bone resorption in a broad range of disorders such as postmenopausal osteoporosis and cancer-induced bone disease. Moreover, RANKL has been implicated as a primary mediator of bone erosions, a hallmark of rheumatoid arthritis (RA). Denosumab is a fully human monoclonal antibody. This antibody binds to RANKL with high affinity and specificity, and inhibits RANKL-RANK interaction, mimicking the endogenous effects of osteoprotegerin (OPG), a soluble RANKL decoy receptor. Clinical trial data support the continued development of denosumab for the inhibition of bone erosions in RA.
18355471 [Demyelinating neuropathy during anti-TNF alpha treatment with a review of the literature] 2007 Dec INTRODUCTION: Tumor necrosis factor- (TNF) blockers are efficient in the treatment of autoimmune disorders such as inflammatory bowel disease and rheumatoid arthritis, but can induce CNS adverse effects including retrobulbar optic neuritis or aggravation of multiple sclerosis. OBSERVATION: We report a case of progressive demyelinating polyneuropathy after initiation of Adalimumab (Humira). Corticosteroid and intravenous immunoglobulins were ineffective but the neuropathy improved within six months after adalimunab discontinuation. DISCUSSION: This case, and other reports recently published suggest that anti-TNF alpha drugs can induce demyelinating neuropathy. CONCLUSION: Clinicians should be on the lookout for signs evocating neuropathy in patients given anti TNF alpha.
18982160 Evidence that cytokines play a role in rheumatoid arthritis. 2008 Nov A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-alpha blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1, IL-6, IL-23, and IL-2 families.