Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

BACKGROUND

Tumor necrosis factor (TNF) plays an important role in host defense and tumor growth control. Therefore, anti-TNF antibody therapies may increase the risk of serious infections and malignancies.

OBJECTIVE

To assess the extent to which anti-TNF antibody therapies may increase the risk of serious infections and malignancies in patients with rheumatoid arthritis by performing a meta-analysis to derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapy.

METHODS

A systematic literature search of EMBASE, MEDLINE, Cochrane Library, and electronic abstract databases of the annual scientific meetings of both the European League Against Rheumatism and the American College of Rheumatology was conducted through December 2005. This search was complemented with interviews of the manufacturers of the 2 licensed anti-TNF antibodies.

METHODS

We included randomized, placebo-controlled trials of the 2 licensed anti-TNF antibodies (infliximab and adalimumab) used for 12 weeks or more in patients with rheumatoid arthritis. Nine trials met our inclusion criteria, including 3493 patients who received anti-TNF antibody treatment and 1512 patients who received placebo.

METHODS

Data on study characteristics to assess study quality and intention-to-treat data for serious infections and malignancies were abstracted. Published information from the trials was supplemented by direct contact between principal investigators and industry sponsors.

RESULTS

We calculated a pooled odds ratio (Mantel-Haenszel methods with a continuity correction designed for sparse data) for malignancies and serious infections (infection that requires antimicrobial therapy and/or hospitalization) in anti-TNF-treated patients vs placebo patients. We estimated effects for high and low doses separately. The pooled odds ratio for malignancy was 3.3 (95% confidence interval [CI], 1.2-9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of anti-TNF antibodies. For patients treated with anti-TNF antibodies in the included trials, the number needed to harm was 154 (95% CI, 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (95% CI, 39-125) within a treatment period of 3 to 12 months.

CONCLUSIONS

There is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy. The formal meta-analysis with pooled sparse adverse events data from randomized controlled trials serves as a tool to assess harmful drug effects.

Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

OBJECTIVE

Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.

METHODS

Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.

RESULTS

The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.

CONCLUSIONS

We present a definition of improvement which we hope will be used widely in RA trials.

BACKGROUND

Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown.

OBJECTIVE

To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs.

METHODS

The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000.

METHODS

Three hundred eighty-six clinical sites in the United States and Canada.

METHODS

A total of 8059 patients >>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months.

METHODS

Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted.

METHODS

Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period.

RESULTS

For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use.

CONCLUSIONS

In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255

BACKGROUND

Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.

METHODS

In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for>> or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.

RESULTS

At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.

CONCLUSIONS

During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

OBJECTIVE

To evaluate the prevalence and predictive value of anti-cyclic citrullinated peptide (anti-CCP) antibodies in individuals who subsequently developed rheumatoid arthritis (RA) and to determine the relationship to rheumatoid factor (RF) of any isotype.

METHODS

A case-control study was nested within the Northern Sweden Health and Disease Study and the Maternity cohorts of Northern Sweden. Patients with RA were identified among blood donors whose samples had been taken years before the onset of symptoms. Control subjects matched for age, sex, date of sampling, and residential area were selected randomly from the same cohorts. Anti-CCP antibody and RFs were determined using enzyme immunoassays.

RESULTS

Eighty-three individuals with RA were identified as having donated blood before presenting with any symptoms of joint disease (median 2.5 years [interquartile range 1.1-4.7] before RA). In samples obtained before the onset of RA, the prevalence of autoantibodies was 33.7% for anti-CCP, 16.9% for IgG-RF, 19.3% for IgM-RF, and 33.7% for IgA-RF (all highly significant compared with controls). The sensitivities for detecting these autoantibodies >1.5 years and </=1.5 years before the appearance of any RA symptoms were 25% and 52% for anti-CCP, 15% and 30% for IgM-RF, 12% and 27% for IgG-RF, and 29% and 39% for IgA-RF. In conditional logistic regression models, anti-CCP antibody and IgA-RF were found to be significant predictors of RA.

CONCLUSIONS

Anti-CCP antibody and RFs of all isotypes predated the onset of RA by several years. The presence of anti-CCP and IgA-RF predicted the development of RA, with anti-CCP antibody having the highest predictive value. This indicates that citrullination and the production of anti-CCP and RF autoantibodies are early processes in RA.

Health status measures are being used with increasing frequency in clinical research. Up to now the emphasis has been on the reliability and validity of these measures. Less attention has been given to the sensitivity of these measures for detecting clinical change. As health status measures are applied more frequently in the clinical setting, we need a useful way to estimate and communicate whether particular changes in health status are clinically relevant. This report considers effect sizes as a useful way to interpret changes in health status. Effect sizes are defined as the mean change found in a variable divided by the standard deviation of that variable. Effect sizes are used to translate "the before and after changes" in a "one group" situation into a standard unit of measurement that will provide a clearer understanding of health status results. The utility of effect sizes is demonstrated from four different perspectives using three health status data sets derived from arthritis populations administered the Arthritis Impact Measurement Scales (AIMS). The first perspective shows how general and instrument-specific benchmarks can be developed and how they can be used to translate the meaning of clinical change. The second perspective shows how effect sizes can be used to compare traditional clinical measures with health status measures in a standard clinical drug trial. The third application demonstrates the use of effect sizes when comparing two drugs tested in separate drug trials and shows how they can facilitate this type of comparison. Finally, our health status results show how effect sizes can supplement standard statistical testing to give a more complete and clinically relevant picture of health status change. We conclude that effect sizes are an important tool that will facilitate the use and interpretation of health status measures in clinical research in arthritis and other chronic diseases.

BACKGROUND

Human adipose tissue expresses and releases the proinflammatory cytokine interleukin 6, potentially inducing low-grade systemic inflammation in persons with excess body fat.

OBJECTIVE

To test whether overweight and obesity are associated with low-grade systemic inflammation as measured by serum C-reactive protein (CRP) level.

METHODS

The Third National Health and Nutrition Examination Survey, representative of the US population from 1988 to 1994.

METHODS

A total of 16616 men and nonpregnant women aged 17 years or older.

METHODS

Elevated CRP level of 0.22 mg/dL or more and a more stringent clinically raised CRP level of more than 1.00 mg/dL.

RESULTS

Elevated CRP levels and clinically raised CRP levels were present in 27.6% and 6.7% of the population, respectively. Both overweight (body mass index [BMI], 25-29.9 kg/m2) and obese (BMI,>> or =30 kg/m2) persons were more likely to have elevated CRP levels than their normal-weight counterparts (BMI, <25 kg/m2). After adjustment for potential confounders, including smoking and health status, the odds ratio (OR) for elevated CRP was 2.13 (95% confidence interval [CI], 1.56-2.91) for obese men and 6.21 (95% CI, 4.94-7.81) for obese women. In addition, BMI was associated with clinically raised CRP levels in women, with an OR of 4.76 (95% CI, 3.42-6.61) for obese women. Waist-to-hip ratio was positively associated with both elevated and clinically raised CRP levels, independent of BMI. Restricting the analyses to young adults (aged 17-39 years) and excluding smokers, persons with inflammatory disease, cardiovascular disease, or diabetes mellitus and estrogen users did not change the main findings.

CONCLUSIONS

Higher BMI is associated with higher CRP concentrations, even among young adults aged 17 to 39 years. These findings suggest a state of low-grade systemic inflammation in overweight and obese persons.

Immunoglobulin G (IgG) mediates pro- and anti-inflammatory activities through the engagement of its Fc fragment (Fc) with distinct Fcg receptors (FcgRs). One class of Fc-FcgR interactions generates pro-inflammatory effects of immune complexes and cytotoxic antibodies. In contrast, therapeutic intravenous gamma globulin and its Fc fragments are anti-inflammatory. We show here that these distinct properties of the IgG Fc result from differential sialylation of the Fc core polysaccharide. IgG acquires anti-inflammatory properties upon Fc sialylation, which is reduced upon the induction of an antigen-specific immune response. This differential sialylation may provide a switch from innate anti-inflammatory activity in the steady state to generating adaptive pro-inflammatory effects upon antigenic challenge.

IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.

BACKGROUND

Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).

OBJECTIVE

/st> To develop recommendations for achieving optimal therapeutic outcomes in RA.

METHODS

A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived.

RESULTS

The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations >> or =9/10).

CONCLUSIONS

The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P=6.6 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.

OBJECTIVE

Autoantibodies have been demonstrated in single serum samples from healthy subjects up to 10 years before they developed rheumatoid arthritis (RA). However, the time course for the development of antibodies before onset of clinical RA is unknown, nor is it known which antibody, or combinations of antibodies, might be most sensitive or specific for predicting future development of the disease. The present study was undertaken to investigate this.

METHODS

Patients with RA who had been blood donors before the onset of disease symptoms were enrolled. Frozen serum samples from each donor were retrieved, together with 2 serum samples from controls matched for age, sex, and date of donation. All samples were tested for IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies.

RESULTS

Seventy-nine patients with RA (62% female; mean age at onset of symptoms 51 years) were included. A median of 13 samples (range 1-51) per patient were available; the earliest samples had been collected a median of 7.5 years (range 0.1-14.5) before the onset of symptoms. Thirty-nine patients (49%) were positive for IgM-RF and/or anti-CCP on at least one occasion before the development of RA symptoms, a median of 4.5 years (range 0.1-13.8) before symptom onset. Of the 2,138 control samples, 1.1% were positive for IgM-RF, and 0.6% were positive for anti-CCP.

CONCLUSIONS

Approximately half of patients with RA have specific serologic abnormalities several years before the onset of symptoms. A finding of an elevated serum level of IgM-RF or anti-CCP in a healthy individual implies a high risk for the development of RA. We conclude that IgM-RF and anti-CCP testing with appropriately high specificity may assist in the early detection of RA in high-risk populations.

Considerable progress has been made in identifying the transcription factors involved in the early specification of the B-lymphocyte lineage. However, little is known about factors that control the transition of mature activated B cells to antibody-secreting plasma cells. Here we report that the transcription factor XBP-1 is required for the generation of plasma cells. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium. When introduced into B-lineage cells, XBP-1 initiated plasma-cell differentiation. Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres. However, they secreted very little immunoglobulin of any isotype and failed to control infection with the B-cell-dependent polyoma virus, because plasma cells were markedly absent. XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.

Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis. The possibility was tested that interleukin-8 (IL-8), which is a cytokine that is chemotactic for lymphocytes and neutrophils, is also angiogenic. Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells. Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha. An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity. These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis, tumor growth, and wound repair.

BACKGROUND

Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate.

METHODS

In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks.

RESULTS

The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept.

CONCLUSIONS

In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.