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The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA pat

Background: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk., Methods and Results: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P =0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT., Conclusions: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Background: Many patients with rheumatoid arthritis (RA) require a trial of multiple biologic disease-modifying anti-rheumatic drugs (bDMARDs) to control their disease. With the availability of several bDMARD options, the history of bDMARDs may provide an alternative approach to understanding subphenotypes of RA. The objective of this study was to determine whether there exist distinct clusters of RA patients based on bDMARD prescription history to subphenotype RA., Methods: We studied patients from a validated electronic health record-based RA cohort with data from January 1, 2008, through July 31, 2019; all subjects prescribed ≥ 1 bDMARD or targeted synthetic (ts) DMARD were included. To determine whether subjects had similar b/tsDMARD sequences, the sequences were considered as a Markov chain over the state-space of 5 classes of b/tsDMARDs. The maximum likelihood estimator (MLE)-based approach was used to estimate the Markov chain parameters to determine the clusters. The EHR data of study subjects were further linked with a registry containing prospectively collected data for RA disease activity, i.e., clinical disease activity index (CDAI). As a proof of concept, we tested whether the clusters derived from b/tsDMARD sequences correlated with clinical measures, specifically differing trajectories of CDAI., Results: We studied 2172 RA subjects, mean age 52 years, RA duration 3.4 years, and 62% seropositive. We observed 550 unique b/tsDMARD sequences and identified 4 main clusters: (1) TNFi persisters (65.7%), (2) TNFi and abatacept therapy (8.0%), (3) on rituximab or multiple b/tsDMARDs (12.7%), (4) prescribed multiple therapies with tocilizumab predominant (13.6%). Compared to the other groups, TNFi persisters had the most favorable trajectory of CDAI over time., Conclusion: We observed that RA subjects can be clustered based on the sequence of b/tsDMARD prescriptions over time and that the clusters were correlated with differing trajectories of disease activity over time. This study highlights an alternative approach to consider subphenotyping of patients with RA for studies aimed at understanding treatment response., (© 2023. The Author(s).)

T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK + GzmB + CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK + GzmB + T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or T teK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 T teK cells have the potential to drive inflammation.

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.

Objective: We aimed to investigate the musculoskeletal and pulmonary outcomes of patients with osseous sarcoidosis., Methods: We identified 24 patients with osseous sarcoidosis and at least one year of follow-up after diagnosis (baseline). We collected outcome data at 1-year follow-up and last follow-up. We defined a composite outcome measure; worsening considered as worsening in any of the following 4 components compared to baseline: 1) osseous sarcoidosis symptoms, 2) musculoskeletal imaging of affected bone, 3) chest imaging, or 4) pulmonary function testing (PFT)., Results: A minority of patients had a worsening composite outcome at 1-year (9/24, 38%) and last follow-up (5/24, 21%). When only considering musculoskeletal symptoms and imaging, only 25% (6/24) and 13% (3/24) of patients worsened compared to baseline at 1-year and last follow-up, respectively. Patients with a worsening composite overall outcome tended to be older at baseline than those without the outcome for both 1-year (54.3 years vs. 47.5 years, p =0.11) and last follow-up (55.0 years vs. 48.7 years; p =0.23), although these differences were non-significant. Treatment was not associated with worsening composite overall outcome at 1-year follow-up ( p =0.40), but was significantly associated with decreased risk for worsening at last follow-up ( p =0.05)., Conclusions: In this retrospective cohort study of osseous sarcoidosis, most patients had a favorable outcome according to symptoms, musculoskeletal/chest imaging, and PFTs, even though only a minority were treated with glucocorticoids or DMARDs. These results suggest that the natural history of osseous sarcoidosis is often benign, although some patients experience clinical progression.

High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4 + T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4 + T cells, identified as CD27 - HLA-DR + effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 × 10 -3 ). The frequency of CD27 - HLA-DR + cells was similarly elevated in blood samples from a second RA patient cohort, and CD27 - HLA-DR + cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27 - HLA-DR + cells were associated with RA (meta-analysis P = 2.3 × 10 -4 ). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27 - HLA-DR + cells, which comprised ~10% of synovial CD4 + T cells. CD27 - HLA-DR + cells expressed a distinctive effector memory transcriptomic program with T helper 1 (T H 1)- and cytotoxicity-associated features and produced abundant interferon-γ (IFN-γ) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

CD4 + T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4 + T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1 hi CXCR5 - CD4 + T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1 hi CXCR5 - 'peripheral helper' T (T PH ) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1 hi CXCR5 + T follicular helper cells, T PH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between T PH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in T PH cells. T PH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Background: Potent anti-inflammatory rheumatoid arthritis (RA) treatments are associated with reduced cardiovascular risk as well as increases in low-density lipoprotein (LDL) cholesterol. This apparent paradox may be explained by favorable changes in other lipid measurements. The objective of this study was to determine the longitudinal association between changes in inflammation with advanced lipoprotein measurements and high-density lipoprotein (HDL) cholesterol efflux capacity., Methods and Results: We conducted this study in a longitudinal RA cohort from a large academic center, including subjects with high-sensitivity C-reactive protein (hs-CRP) reduction ≥10 mg/L at 2 time points 1 year apart. Subjects receiving statins during the study period or preceding 6 months were excluded. We compared total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B, and apolipoprotein A1 levels and HDL cholesterol efflux capacity at baseline and 1-year follow-up by using the paired t test. We also assessed the correlations between reductions in hs-CRP with percentage change in lipid parameters. We studied 90 RA subjects (mean age 57 years, 89% female), all of whom were receiving disease-modifying antirheumatic drugs. We observed a 7.2% increase in LDL cholesterol levels (P=0.02) and improvement in efflux capacity by 5.7% (P=0.002) between baseline and follow-up, with a median hs-CRP reduction of 23.5 mg/L. We observed significant correlations between reductions in hs-CRP with increases in apolipoprotein A1 (r=0.27, P=0.01) and HDL cholesterol efflux capacity (r=0.24, P=0.02)., Conclusion: Among RA subjects experiencing reductions in hs-CRP, we observed increased LDL cholesterol levels and concomitant improvements in HDL cholesterol efflux capacity. These findings provide further insight into lipid modulation and the beneficial effect of reduction in inflammation on lipids in vivo., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: Osseous sarcoidosis has been infrequently reported. We aimed to characterize the distribution of lesions, clinical presentation, treatment, and outcomes for osseous sarcoidosis., Methods: Cases of osseous sarcoidosis were identified by directed inquiry to clinicians and electronic query. Cases were defined as having pathologic evidence of non-caseating granulomas on bone biopsy or evidence of osseous lesions on imaging attributable to sarcoidosis in patients with known sarcoidosis. Detailed characteristics were obtained by medical record review., Results: We identified a total of 20 cases of osseous sarcoidosis. Osseous lesions were detected by imaging during the initial sarcoidosis presentation in 60% of cases. In those who had a prior diagnosis of sarcoidosis, the median duration of sarcoidosis before detection of osseous involvement was 4.3 years. Symptoms were present in 50% of cases. All cases had more than one bone involved. The axial skeleton was involved in the majority of cases (90%), primarily the pelvis and the lumbar spine. Most cases required no treatment (55%); a minority of cases (45%) were treated, most often with prednisone, methotrexate, or hydroxychloroquine. Two cases required multiple immunosuppressants, including tumor necrosis factor inhibitors, for refractory symptomatic osseous sarcoidosis. Treated cases were younger than those who were untreated. At last follow-up, most cases (85%) were asymptomatic from osseous lesions., Conclusions: In this case series of osseous sarcoidosis from a single center, most patients had multiple bones affected and had other systemic manifestations of sarcoidosis. A minority required treatment for relief of symptoms, and most cases were asymptomatic at last follow-up., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.

Introduction: Rheumatoid arthritis (RA) is associated with hypogalactosylation of immunoglobulin G (IgG). We examined whether a proxy measure for galactosylation of IgG N-glycans could predict response to therapy or was differentially affected by methotrexate (MTX) or TNF blockade., Methods: Using a previously defined normal phase high-performance liquid chromatography approach, we ascertained the galactosylation status of whole serum N-glycans in two well-defined RA clinical cohorts: the Autoimmune Biomarkers Collaborative Network (n = 98) and Nested I (n = 64). The ratio of agalactosylated to monogalactosylated N-glycans in serum (sG0/G1) was determined before and during therapy with MTX or TNF inhibition and correlated with anticitrullinated peptide antibody (ACPA) status and clinical response as assessed by 28-joint Disease Activity Score utilizing C-reactive peptide and European League Against Rheumatism response criteria., Results: RA patients from both cohorts exhibited elevation of sG0/G1 at baseline. Improvement in clinical scores correlated with a reduction in sG0/G1 (Spearman's ρ = 0.31 to 0.37; P < 0.05 for each cohort). However, pretreatment sG0/G1 was not predictive of clinical response. Changes in sG0/G1 were similar in the MTX and TNF inhibitor groups. Corrected for disease activity, ACPA positivity correlated with higher sG0/G1., Conclusions: Baseline serum N-glycan hypogalactosylation, an index previously correlated with hypogalactosylation of IgG N-glycans, did not distinguish patients with rheumatoid arthritis who were likely to experience a favorable clinical response to MTX or TNF blockade. Clinical improvement was associated with partial glycan normalization. ACPA-positive patients demonstrated enhanced N-glycan aberrancy compared with ACPA-negative patients.

Objective: Treatment algorithms in RA include factors associated with poor prognosis; however, many patients remain erosion free despite years of disease. Our objective was to characterize the group of RA patients without erosions and identify its clinical predictors., Methods: Our study was conducted within a prospective observational cohort of RA patients recruited from the outpatient practice of an academic medical centre. We studied patients with bilateral hand radiographs at cohort baseline and 2-year follow-up assessed with Sharp/van der Heijde scores (SHS). The primary outcome was erosion-free status at baseline and 2-year follow-up. We assessed baseline values of the following as potential correlates: age at RA onset, gender, RA duration, BMI, 28-joint DAS (DAS-28), CRP, anti-CCP status, tender and swollen joint counts, functional status [multidimensional HAQ (MDHAQ)], tobacco use and RA treatments. Variables with P ≤ 0.25 in the univariate analyses were assessed using backward selection in multivariable logistic regression models., Results: Of the 271 subjects included, 21% (n = 56) were considered erosion free. Forty-six per cent (n = 26) of this group was anti-CCP positive compared with 56% (n = 121) in subjects with erosions present. Mean RA duration for erosion-free subjects was 3.9 years compared with 4.6 years in erosive subjects. Treatments for RA did not differ between the two groups. In the multivariable-adjusted analysis, significant predictors of erosion-free status were younger age at onset and shorter RA duration., Conclusion: In our cohort, 21% of subjects were erosion free at baseline and 2 years. Few baseline clinical characteristics significantly predicted erosion-free status.

Phospholipase A2 (PLA2) catalyses the release of arachidonic acid for generation of lipid mediators of inflammation and is crucial in diverse inflammatory processes. The functions of the secretory PLA2 enzymes (sPLA2), numbering nine members in humans, are poorly understood, though they have been shown to participate in lipid mediator generation and the associated inflammation. To further understand the roles of sPLA2 in disease, we quantified the expression of these enzymes in the synovial fluid in rheumatoid arthritis and used gene-deleted mice to examine their contribution in a mouse model of autoimmune erosive inflammatory arthritis. Contrary to expectation, we find that the group V sPLA2 isoform plays a novel anti-inflammatory role that opposes the pro-inflammatory activity of group IIA sPLA2. Mechanistically, group V sPLA2 counter-regulation includes promotion of immune complex clearance by regulating cysteinyl leukotriene synthesis. These observations identify a novel anti-inflammatory function for a PLA2 and identify group V sPLA2 as a potential biotherapeutic for treatment of immune-complex-mediated inflammation.

In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles--submicrometer vesicles elaborated by activated platelets--in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.

Objectives: The objective of this study was twofold: (1) to determine how best to measure adherence with time-dependent quality indicators (QIs) related to laboratory monitoring, and (2) to assess the accuracy and efficiency of gathering QI adherence information from an electronic medical record (EMR)., Methods: A random sample of 100 patients were selected who had at least three visits with the diagnosis of rheumatoid arthritis (RA) at Brigham and Women's Hospital Arthritis Center in 2005. Using the EMR, it was determined whether patients had been prescribed a disease-modifying antirheumatic drug (DMARD) (QI #1) and if patients starting therapy received appropriate baseline laboratory testing (QI #2). For patients consistently prescribed a DMARD, adherence with follow-up testing (QI #3) was calculated using three different methods, the Calendar, Interval and Rolling Interval, Method: ., Results: It was found that 97% of patients were prescribed a DMARD (QI #1) and baseline tests were completed in 50% of patients (QI #2). For follow-up testing (QI #3), mean adherence was 60% for the Calendar Method, 35% for the Interval Method, and 48% for the Rolling Interval Method. Using the Rolling Interval Method, adherence rates were similar across drug and laboratory testing type., Conclusions: Results for adherence with laboratory testing QIs for DMARD use differed depending on how the QIs were measured, suggesting that care must be taken in clearly defining methods. While EMRs will provide important opportunities for measuring adherence with QIs, they also present challenges that must be examined before widespread adoption of these data collection methods.

Background: A 60-year-old white woman with a history of breast cancer, autoimmune hemolytic anemia, type 2 diabetes mellitus, peripheral vascular disease, and chronic renal insufficiency presented with stiffness in her arms and legs of 3 months' duration. She had undergone multiple MRI and magnetic resonance angiography examinations with gadolinium-containing contrast media over the last 2 years., Investigations: Complete physical examination including thorough skin examination; laboratory examinations including CBC, urinalysis, serum creatinine, protein electrophoresis and C-reactive protein; antinuclear antibody assay; Westergren erythrocyte sedimentation rate; and an excisional skin biopsy., Diagnosis: Nephrogenic systemic fibrosis (also known as nephrogenic fibrosing dermopathy)., Management: Symptomatic treatment, physical therapy, and a brief trial of imatinib mesylate.

Background: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA)., Objective: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis., Methods: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions., Results: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA., Conclusions: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

Objective: Osteoporosis in patients with rheumatoid arthritis (RA) is increasingly recognized as a major comorbidity. We examined past management patterns for glucocorticoid-induced osteoporosis and attempted to improve care through an educational intervention. The goal was to examine the frequency of osteoporosis management in patients with RA treated at a large academic rheumatology practice., Methods: We performed a structured chart review on randomly selected patients seen during 2004 for RA. Osteoporosis management was defined as a bone mineral density test or receipt of a medication for osteoporosis in the prior 24 months. The frequency of osteoporosis management among our study group was assessed. We also examined how glucocorticoid dosage affected osteoporosis management in adjusted models., Results: We reviewed the records for 193 patients, 99 had not used glucocorticoids in the prior 24 months, and 94 had used them. Of the total study population, 48% had received a bone mineral density test or medication for osteoporosis. Some form of osteoporosis management was present for 64% of patients taking > or =5 mg prednisone for > or =3 months compared with 38% for patients taking none (P = 0.002). Predictors of osteoporosis management included older age, female sex, glucocorticoid dosage, and prior osteoporosis diagnosis or fracture., Conclusion: The frequency of osteoporosis management appears to have increased compared with a prior chart review.

The objective of the current report was to determine the relapse rates and characterize the nature of relapses during the disease course of adult patients with idiopathic inflammatory myopathies (IIM). A retrospective cohort study of 53 medical records of patients with polymyositis (PM), dermatomyositis (DM), connective tissue disease (CTD)-associated myositis, and malignancy-associated myositis at an academic rheumatology center was performed. Medical records were reviewed to determine clinical presentation, initial treatment, and clinical follow-up, with an emphasis on relapses. Relapses were defined as a sustained elevation in serum creatine kinase (CK) levels in the absence of an alternative etiology. Patients were followed for an average of 65+/-43 months. All patients received corticosteroids, and 35 patients received additional immunosuppressive medications as part of their initial treatment. Serum CK levels normalized in 51 patients, and muscle strength normalized in 43 patients. Biochemical relapse was observed in 33 patients (65%). Patients with PM and CTD-associated myositis had a higher relapse rate compared to DM and malignancy-associated myositis patients. Multiple relapses were observed in 17 patients. Relapses tended to occur within the first 2 years after treatment initiation and during the tapering phase of treatment. No risk factors were unequivocally identified, although advanced age and increased duration of symptoms prior to treatment initiation had nonsignificant associations with increased risk of relapse. In conclusion, initial treatment of IIM results in a high rate of normalization of serum CK and muscle weakness. However, physicians should be aware of the high rate of relapse in patients with IIM.

Objective: To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha (TNF-alpha) blocker-naäve active rheumatoid arthritis (RA)., Methods: Seventy-seven patients with RA were randomized in an unequal allocation (2:1) in a blinded fashion to receive either 50 mg (51 patients) or 25 mg (26 patients) of etanercept twice a week for 24 weeks., Results: The primary outcome measure, the ACR-N AUC at 24 weeks, showed no difference between the 2 dose groups. In addition, there was no difference in ACR 20, 50, and 70 responses or in EULAR response criteria by Week 24. There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event. The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg (26% vs 4%, p = 0.027)., Conclusion: Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the standard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients.

Objective: To investigate the pattern of use of infliximab with an emphasis on treatment escalation and the durability of infliximab use in the management of rheumatoid arthritis (RA) in an academic setting., Methods: We conducted a retrospective review of pharmacy and medical records of 183 patients with RA who received at least 1 infliximab infusion at the infusion centers of the Brigham and Women's Hospital. Treatment escalation was defined as an increase in the dosage of infliximab to >3 mg/kg and/or a decrease in the dosing interval to <7 weeks between infusions., Results: A total of 183 patients with RA received infliximab infusions for a mean +/- SD duration of 58.2 +/- 56.6 weeks. Infliximab was discontinued in 48% of the patients during the first year of therapy and in 67% of the patients overall. A total of 126 patients had a treatment escalation, including 25 patients with a dose increase, 35 patients with a decrease in the interval, and 66 patients with both. Infliximab treatment was associated with a decrease in corticosteroid and methotrexate doses. Patients who had a treatment escalation were more likely to continue infliximab infusions compared with patients without a treatment escalation (odds ratio 2.0, 95% confidence interval 1.0-4.1)., Conclusion: The use of infliximab may be an effective treatment for RA; however, a substantial number of patients will discontinue its use. Treatment escalation is commonly used in the management of RA with infliximab and is associated with longer duration of infliximab use.

Rheumatoid arthritis, a chronic inflammatory polyarthritis that destroys synovial joints, is associated with systemic as well as local inflammation and with an increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors. Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and high-risk populations. Not all of this protective benefit appears to be mediated by lowered cholesterol levels. Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis. Recent studies show that statins may provide mild anti-inflammatory benefit in rheumatoid arthritis, in addition to reducing cardiovascular risk.

Objective: To assess the effectiveness of a multifaceted intervention to improve the management of glucocorticoid-induced osteoporosis (GIOP)., Methods: Of 21 rheumatologists, 11 were randomly assigned to a 3-part intervention consisting of a lecture and discussion regarding optimal management of GIOP, a confidential doctor-specific audit regarding management of GIOP, and a reminder mailing including concise pharmacologic recommendations. The remaining 10 rheumatologists received no special education. Patients with rheumatoid arthritis (RA) taking oral glucocorticoids seen in the 2 months after the intervention were followed for 6 months. Medical records were assessed to determine the proportion undergoing bone mineral density testing or receiving pharmacologic interventions for GIOP during the 6 months before and 6 months after the intervention., Results: There were 373 patients with RA taking oral glucocorticoids whose records were assessed. Patients in both arms of the trial were similar with respect to age, sex, menopausal status, glucocorticoid dosage and duration, duration of RA, disease-modifying antirheumatic drug use, and the proportion with comorbid conditions. At baseline, there was no significant difference between the patients with respect to osteoporosis medication use (intervention 32% versus control 34%) or bone densitometry use (intervention 9% versus control 5%). After the intervention and a 6-month followup period, there were no differences in treatment (intervention 33% versus control 38%) or bone densitometry use (intervention 8% versus control 8%). Adjusting for patient and physician characteristics did not significantly change these results., Conclusion: A multifaceted intervention for GIOP, including doctor education, practice audit, and treatment suggestions, had no significant benefit on testing or treatment by rheumatologists over a 6-month followup period. Other intervention approaches need to be tested.

Objective: Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose-6-phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti-GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population-matched healthy control subjects., Methods: Anti-GPI antibodies were assayed in 811 individual serum samples by enzyme-linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting., Results: Several patients had significantly elevated anti-GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti-GPI antibodies (range 12-29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti-GPI antibodies at similar frequencies (12-25%). Similar titers were detected in a proportion (5-10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus., Conclusion: No disease-specific pattern of antibody positivity to GPI was apparent. While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients.

Objectives: There is little established information regarding the safety of antitumor necrosis factor therapies used outside the setting of clinical trials. This study evaluated the long-term safety and tolerability of open-label use of etanercept when used to treat patients with a variety of systemic rheumatic diseases. Reduction of concomitant corticosteroid and disease-modifying antirheumatic drug was also assessed., Methods: Retrospective medical record review of 180 patients who were started on etanercept between December 1998 and April 2000 at an academic medical center., Results: Most patients (81%) remained on therapy for longer than 6 months, and a significant number (43%) of patients for longer than 12 months. Etanercept was prescribed for rheumatoid arthritis (RA) in 144 patients and for diseases other than RA, including ankylosing spondylitis, psoriatic arthritis, and polymyositis, in 36 patients. Fifty-six percent of patients taking corticosteroids were able to reduce their dose and 51% of patients were able to taper their methotrexate dosages. Forty-three patients (26%) discontinued etanercept. Reasons for discontinuing therapy included serious adverse events (2.9%), of which infection was most common. These included a psoas abscess secondary to Mycobacterium avium-intracellulare, septic wrist, bacteremia, and septic total hip replacement. Two deaths associated with infection were seen., Conclusions: The majority of the studied patients tolerated etanercept for longer than 6 months. Many of these patients were able to subsequently taper or even discontinue corticosteroid and methotrexate therapy. Serious infections occurred in this patient population. Our results underscore the value of long-term observation under the conditions of clinical practice beyond controlled clinical trials.

Objective: To determine the frequency of weight loss in patients treated with leflunomide for rheumatoid arthritis at an arthritis referral center., Methods: We queried 35 rheumatologists at the Robert Breck Brigham Arthritis Center to determine if weight loss had occurred as an adverse event in patients treated with leflunomide between November 1998 and January 2000. Five such patients were identified and their clinical course was reviewed., Results: Five of 70 patients who had begun leflunomide therapy had significant weight loss that could not be linked to other identifiable etiologies. The amount of weight loss was substantial in this group of patients, ranging from 19 pounds to 53 pounds. All patients had normal levels of thyroid-stimulating hormone and no other gastrointestinal complaints; evaluation revealed no other cause for the weight loss. Despite the significant weight loss, 4 of the 5 patients continued to take the drug due to its efficacy., Conclusion: Significant weight loss is a potential adverse event in patients with rheumatoid arthritis treated with leflunomide. Awareness of this may obviate the need for extensive medical evaluations.

We describe a consecutive series of patients with hydroxychloroquine (HCQ) retinopathy. Their clinical features illustrate that with normal renal function there is no threshold for total dosage for HCQ toxicity; that color vision testing is important; that almost all patients complain of altered central vision as their first symptom; and that a normal optic fundus does not exclude the diagnosis. Finally, HCQ retinopathy may progress even when the agent is stopped.

Objective: To examine the safety and pharmacokinetics of and clinical response to leflunomide, a de novo pyrimidine synthesis inhibitor, when administered to patients with active rheumatoid arthritis (RA) who have been receiving long-term methotrexate therapy., Methods: This was an open-label, 52-week study in which 30 patients with RA that remained active despite therapy with methotrexate at 17+/-4 mg/week (mean +/- SD) for > or =6 months were given leflunomide, 10-20 mg/day. Patients were assessed for adverse effects, pharmacokinetic measurements of leflunomide and methotrexate, and clinical response by American College of Rheumatology (ACR) 20% response criteria., Results: Twenty-three patients completed 1 year of treatment. No significant pharmacokinetic interactions between leflunomide and methotrexate were noted. This combination therapy was generally well tolerated clinically, with the exception of elevations of liver enzyme levels. Seven patients withdrew from the treatment regimen: 2 withdrawals were voluntary, 3 were due to persistent elevation of plasma transaminase levels, and 2 were due to lack of efficacy. Of the patients, 16 (53%) met ACR 20% response criteria. Two met ACR criteria for remission after 1 year., Conclusion: The combination of methotrexate and leflunomide has therapeutic potential in RA.

Objective: To conclude observations of efficacy of longterm methotrexate (MTX) treatment of rheumatoid arthritis (RA)., Methods: Twenty-six patients with RA entered a prospective study of MTX in 1983. The study was completed after 132 months of therapy., Results: Significant improvement (p < 0.001) was noted in the number of painful joints, swollen joints, and physician and patient global assessments. There was 50% improvement in the joint pain index and joint swelling index in > 65% of the patients. A significant reduction in prednisone dose was achieved. Sixteen patients withdrew from the study. Toxicity led to 3 drug related withdrawals of study patients (alopecia 1; pneumonitis 2). At 132 months, 10 patients (38%) had completed the study; 3 patients (11%) discontinued due to MTX toxicity., Conclusion: MTX was an effective treatment for RA in this 132 month prospective study.

Objective: To evaluate the biologic response, tolerability, and potential clinical effect of a humanized antilymphocyte monoclonal antibody, CAMPATH-1H, in patients with rheumatoid arthritis (RA)., Methods: Forty adult patients with active, refractory RA were treated with CAMPATH-1H, given intravenously, in a multicenter, open, single-dose-escalation study. Patients were assigned to dose groups of 1, 3, 10, 30, 60, and 100 mg CAMPATH-1H., Results: There was a profound, immediate, and sustained reduction of the peripheral lymphocyte count; the most susceptible were the levels of CD4+ and CD8+ cells, which remained depressed during the study period. Sixty-three percent of patients developed antibodies to CAMPATH-1H. Side effects occurred frequently throughout the first 24 hours following infusion, and included fever, headache, nausea, vomiting, and hypotension. All of the immediate drug toxicities resolved within the initial 24-hour postdosing period. One patient developed a reactivation of Mycobacterium xenopi infection 10 weeks following infusion. Sixty-five percent of patients developed a clinical response; the mean duration of response was 2 weeks., Conclusion: CAMPATH-1H is a lymphocyte-depleting antibody that is biologically potent even after single-dose therapy. There was no correlation between biologic effect and clinical response. Sustained lymphocyte suppression was observed. Acute infusion toxicities were observed in most patients. The role of depleting monoclonal antibodies in the treatment of RA should be reevaluated.

Objective: To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy., Methods: In this randomized, placebo-controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 micrograms/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks., Results: A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events., Conclusion: A renal-protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.

Bronchiectasis as a feature of rheumatoid arthritis is considered rare and, in most series, has preceded rheumatoid arthritis. We identified 23 patients with rheumatoid arthritis and bronchiectasis at the Brigham and Women's Hospital followed between 1984 and 1991, 18 of whom had arthritis preceding lung disease. The 18 patients with rheumatoid arthritis and subsequent bronchiectasis had a mean age of 63.8 years. Fourteen were women and 4 were men, with a mean arthritis duration of 24.7 years before bronchiectasis developed. Most patients had seropositive and nodular disease. All but 1 had advanced radiographic changes of rheumatoid arthritis, and many had received joint replacement surgery. In addition to standard treatment regimens, 17 patients had received corticosteroids. Productive cough, hemoptysis, and dyspnea were the most common respiratory symptoms and were present for an average of 4.3 years prior to bronchiectasis diagnosis. The most common radiographic abnormalities were bibasilar diffusely increased interstitial markings and focal infiltrates, although nodules, bullae, cysts, and air-fluid levels were found. Common pulmonary-function abnormalities were obstructive and/or restrictive abnormalities. Three patients died of complications relating to bronchiectasis. Five patients with rheumatoid arthritis had antecedent bronchiectasis. Compared with patients with rheumatoid arthritis and subsequent bronchiectasis, those with antecedent lung disease had milder arthritis (stage I or II radiographic changes, p < 0.001), a lower frequency of rheumatoid nodules (p < 0.05) and a lower comorbidity score (5.8 versus 9.4, p < 0.01). They also had received fewer disease-modifying agents for the treatment of their rheumatoid arthritis. Bronchiectasis can be a feature of rheumatoid arthritis and is often found in patients with severe, long-standing nodular disease. Recurrent pulmonary infections and respiratory failure occur and may be fatal.

Objective: To determine if simultaneously administered low dose leucovorin interferes with the efficacy of methotrexate (MTX)., Methods: An 8-week double blind placebo controlled study of leucovorin (1 mg) in 16 patients with rheumatoid arthritis receiving chronic MTX was performed at a single academic center., Results: A flare of disease activity was not observed. Clinical variables of arthritis activity did not change in the leucovorin treated population., Conclusions: Low dose leucovorin when taken simultaneously with MTX did not interfere with the efficacy of MTX in a short term 8 week trial.

The effects of zileuton, a new 5-lipoxygenase inhibitor, on leukotriene generation and clinical response in rheumatoid arthritis (RA) was studied in a 4-week randomized double blind placebo controlled study at 2 academic rheumatology centers. Zileuton decreased the mean (+/- SEM) ionophore induced synthesis of leukotriene B4 at Week 1 by 70% from 191.2 +/- 28.5 to 57.5 +/- 17.0 ng/ml. A parallel suppression of all major 5-lipoxygenase pathway products was observed. An improvement in clinical variables was observed in the zileuton and placebo treated population. No unique toxicity was identified in this study. Zileuton inhibited 5-lipoxygenase in RA with a suggestion of clinical response with limited toxicity.

Objective: To compare the cumulative effects of oral methotrexate (MTX) therapy (after 6-8 weeks) with the acute effects (24 hours after a dose) on arachidonic acid metabolism by the 5-lipoxygenase (5-LO) pathway in neutrophils from patients with active rheumatoid arthritis (RA) who were beginning therapy with MTX., Methods: Neutrophils and monocytes were isolated from whole blood from 7 patients with RA, immediately before and 24 hours after their first weekly dose of 7.5 mg of MTX, and again after their dose at 6-8 weeks., Results: Total immunoreactive leukotriene B4 (LTB4) formation in neutrophils activated ex vivo with calcium ionophore A23187 was significantly suppressed (by 33%) before the 6-8-week dose, compared with the level before the first dose (mean +/- SEM 8.29 +/- 1.24 ng/10(6) cells at predose 6-8 weeks versus 12.29 +/- 2.13 ng/10(6) cells at predose 1; P = 0.03). Reductions were also observed after the first dose (27%; P = 0.07) and after the 6-8-week dose (43%; P = 0.05) compared with the respective predose levels. MTX treatment produced significant reductions in the total generation of 5-LO pathway products (5-hydroxyeicosatetraenoic acid + 6-trans-LTB4 + LTB4 + omega-oxidation products of LTB4) by calcium ionophore-activated neutrophils, as quantitated by integrated optical density after resolution on reverse-phase high-performance liquid chromatography. Decreases were observed after the first dose (26%; P = 0.025), immediately before the 6-8-week dose (23%; P = 0.05), and after the 6-8-week dose (47%; P = 0.0033) compared with levels before the first dose, and after the 6-8-week dose compared with the level before it (32%; P = 0.04). The generation of LTB4 by calcium ionophore-activated monocytes was not significantly affected by MTX therapy., Conclusion: The significant decreases in the formation of omega-oxidation products of LTB4 and in the total generation of neutrophil 5-LO pathway products in the absence of a significant change in the release of 3H-arachidonic acid or the generation of platelet-activating factor suggest that the activity of the 5-LO enzyme in neutrophils is inhibited. We conclude that weekly oral MTX therapy in patients with active RA inhibits neutrophil 5-LO pathway product generation in a pattern consistent with inhibition of the activity of the 5-LO enzyme; an effect is observed after the first dose. The inhibition of 5-LO is cell-selective and cumulative, with a superimposed incremental inhibition observed after the weekly MTX dose.

Objective: To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA)., Methods: Eighty-four-month open prospective trial at a single academic rheumatology center., Results: Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity., Conclusion: The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.

We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity.

Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Twelve patients with active rheumatoid arthritis supplemented their usual diet with 20 gm of Max-EPA fish oil, daily, for 6 weeks. Following this supplementation, the ratio of arachidonic acid to eicosapentaenoic acid in the patients' neutrophil cellular lipids decreased from 81:1 to 2.7:1, and the mean generation of leukotriene B4 (with calcium ionophore stimulation) significantly declined by 33%. The mean neutrophil chemotaxis to both leukotriene B4 and FMLP significantly increased toward the normal range at week 6. The generation of 5-lipoxygenase products by calcium ionophore-stimulated monocytes was not significantly suppressed, but a significant decline (37%) in platelet-activating factor generation was noted at week 6. The modulation of these measures of leukocyte inflammatory potential suggests that fish oil supplementation may have an antiinflammatory effect.