Showing papers in "Arthritis & Rheumatism in 2000"

The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.

Abstract: Objective Since modern treatment of rheumatoid arthritis (RA) is shifting toward aggressive antirheumatic therapy in an early phase of the disease, diagnostic tests with high specificity are desirable. A new serologic test (anti–cyclic citrullinated peptide [anti-CCP] enzyme-linked immunosorbent assay [ELISA]) was developed to determine the presence of antibodies directed toward citrullinated peptides, using a synthetic peptide designed for this purpose. Methods A cyclic peptide variant that contains deiminated arginine (citrulline) was designed and used as antigenic substrate in ELISA. Test parameters and diagnostic characteristics of the test were studied in patients with and without RA, in patients with various infectious diseases, and in a group of patients from an early arthritis clinic (EAC). Results Using prevalent RA and non-RA sera, the anti-CCP ELISA proved to be extremely specific (98%), with a reasonable sensitivity (68%). Also, in the EAC study group, the anti-CCP ELISA appeared to be highly specific for RA (96%). In comparison with the IgM rheumatoid factor (IgM-RF) ELISA, the anti-CCP ELISA had a significantly higher specificity (96% for CCP versus 91% for IgM-RF; P = 0.016) at optimal cut-off values. The sensitivity of both tests for RA was moderate: 48% and 54% for the anti-CCP ELISA and the IgM-RF ELISA, respectively (P = 0.36). Combination of the anti-CCP and the IgM-RF ELISAs resulted in a significantly higher positive predictive value of 91% (P = 0.013) and a slightly lower negative predictive value of 78% (P = 0.35) as compared with the use of the IgM-RF ELISA alone. The ability of the 2 tests performed at the first visit to predict erosive disease at 2 years of followup in RA patients was comparable (positive predictive value 91%). Conclusion The anti-CCP ELISA might be very useful for diagnostic and therapeutic strategies in RA of recent onset.

Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins

Abstract: Objective Twin concordance data for rheumatoid arthritis (RA) on their own provide only limited insight into the relative genetic and environmental contribution to the disease. We applied quantitative genetic methods to assess the heritability of RA and to examine for evidence of differences in the genetic contribution according to sex, age, and clinical disease characteristics. Methods Data were analyzed from 2 previously published nationwide studies of twins with RA conducted in Finland and the United Kingdom. Heritability was assessed by variance components analysis. Differences in the genetic contribution by sex, age, age at disease onset, and clinical characteristics were examined by stratification. The power of the twin study design to detect these differences was examined through simulation. Results The heritability of RA was 65% (95% confidence interval [95% CI] 50–77) in the Finnish data and 53% (95% CI 40–65) in the UK data. There was no significant difference in the strength of the genetic contribution according to sex, age, age at onset, or disease severity subgroup. Both study designs had power to detect a contribution of at least 40% from the common family environment, and a difference in the genetic contribution of at least 50% between subgroups. Conclusion Genetic factors have a substantial contribution to RA in the population, accounting for ∼60% of the variation in liability to disease. Although tempered by power considerations, there is no evidence in these twin data that the overall genetic contribution to RA differs by sex, age, age at disease onset, and disease severity.

Severe organ involvement in systemic sclerosis with diffuse scleroderma.

Abstract: Objective To determine the natural history and timing of severe involvement of the kidney, heart, lung, gastrointestinal (GI) tract, and skin in patients with systemic sclerosis (SSc) and diffuse cutaneous involvement. Methods This study used the Pittsburgh Scleroderma Databank and included patients with diffuse scleroderma who were seen between January 1, 1972 and December 31, 1995. Patients had frequent followups, and a 95% accountability for these patients was maintained. Severe organ involvement was defined as the presence of any of the following: 1) in the kidney, scleroderma “renal crisis”; 2) in the heart, cardiomyopathy, symptomatic pericarditis, or an arrhythmia requiring treatment; 3) in the lung, pulmonary fibrosis on chest radiograph and a forced vital capacity of 40. The timing from disease onset to survival for each case of severe organ involvement was determined. Results Of the 953 patients with diffuse scleroderma, kidney involvement developed in 177 (19%), heart involvement in 143 (15%), lung involvement in 151 (16%), GI tract involvement in 74 (8%), and skin involvement in 233 (24%). Severe skin and kidney involvement occurred during the first 3 years in 70% of those who ever developed these problems throughout a mean of 10 years of followup. Severe heart, lung, and GI tract involvement developed during the first 3 years in 45–55% of those who were ever affected. The survival of patients with severe organ involvement was poor. The 9-year cumulative survival rate of all patients with severe organ involvement was 38%, compared with 72% in patients without such involvement (P < 0.0001). Conclusion This study demonstrates that severe organ involvement in SSc patients with diffuse scleroderma most often occurs early in the course of the disease. Survival for patients with severe organ involvement is markedly reduced. Patients should therefore be monitored very closely during the first 3 years of disease for signs and symptoms that may signal the subsequent development of severe organ damage. Potential disease-modifying therapies must be initiated early to modify the natural history of SSc and to improve survival. Patients who survive the first few years without developing severe organ involvement are less likely to develop such life-threatening involvement later in the disease course.

The role of the chondrocyte in osteoarthritis

Abstract: Osteoarthritis (OA) is a slowly progressive degenerative disease characterized by gradual loss of articular cartilage. Since the OA lesion is often localized to weight-bearing cartilage or to sites of trauma, repetitive mechanical injury has been proposed as the critical signal for the initiation and progression of OA. It is now generally accepted that the chondrocyte is the target of these abnormal biomechanical factors, and that biochemical and genetic factors also contribute to alterations in the normal functional activities of these cells. Although OA has been regarded primarily as a noninflammatory arthropathy, symptoms of local inflammation and synovitis are present in many patients and have been observed in animal models of OA. Even in the absence of classic inflammation, which is characterized by infiltration of neutrophils and macrophages into joint tissues, elevated levels of inflammatory cytokines have been measured in OA synovial fluid. Although the OA cartilage lesion is present at sites remote from the synovium, the fibroblastand macrophage-like synovial cells, as well as the chondrocyte itself, are potential sources of cytokines that could induce chondrocytes to synthesize and secrete cartilagedegrading proteases, cytokines, and other inflammatory mediators. These synoviumand chondrocyte-derived products represent potential targets for the development of therapeutic agents, such as proteinase inhibitors, cytokine antagonists, and cytokine receptor blocking antibodies, which could be used to prevent or retard the progression of the OA articular lesion. This review will focus on evidence that implicates chondrocyte responses to cytokines in the pathogenesis of OA and will discuss the potential therapeutic applications of these findings.

Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor

Abstract: Objective Osteoclast differentiation factor (ODF; also known as osteoprotegerin ligand, receptor activator of nuclear factor κB ligand, and tumor necrosis factor–related activation-induced cytokine) is a recently described cytokine known to be critical in inducing the differentiation of cells of the monocyte/macrophage lineage into osteoclasts. The role of osteoclasts in bone erosion in rheumatoid arthritis (RA) has been demonstrated, but the exact mechanisms involved in the formation and activation of osteoclasts in RA are not known. These studies address the potential role of ODF and the bone and marrow microenvironment in the pathogenesis of osteoclast-mediated bone erosion in RA. Methods Tissue sections from the bone–pannus interface at sites of bone erosion were examined for the presence of osteoclast precursors by the colocalization of messenger RNA (mRNA) for tartrate-resistant acid phosphatase (TRAP) and cathepsin K in mononuclear cells. Reverse transcriptase–polymerase chain reaction (RT-PCR) was used to identify mRNA for ODF in synovial tissues, adherent synovial fibroblasts, and activated T lymphocytes derived from patients with RA. Results Multinucleated cells expressing both TRAP and cathepsin K mRNA were identified in bone resorption lacunae in areas of pannus invasion into bone in RA patients. In addition, mononuclear cells expressing both TRAP and cathepsin K mRNA (preosteoclasts) were identified in bone marrow in and adjacent to areas of pannus invasion in RA erosions. ODF mRNA was detected by RT-PCR in whole synovial tissues from patients with RA but not in normal synovial tissues. In addition, ODF mRNA was detected in cultured adherent synovial fibroblasts and in activated T lymphocytes derived from RA synovial tissue, which were expanded by exposure to anti-CD3. Conclusion TRAP-positive, cathepsin K–positive osteoclast precursor cells are identified in areas of pannus invasion into bone in RA. ODF is expressed by both synovial fibroblasts and by activated T lymphocytes derived from synovial tissues from patients with RA. These synovial cells may contribute directly to the expansion of osteoclast precursors and to the formation and activation of osteoclasts at sites of bone erosion in RA.

Risk factors for the incidence and progression of radiographic knee osteoarthritis.

Abstract: Objective Preventive strategies against knee osteoarthritis (OA) require a knowledge of risk factors that influence the initiation of the disorder and its subsequent progression. This population-based longitudinal study was performed to address this issue. Methods Ninety-nine men and 255 women aged ≥55 years had baseline interviews and weight-bearing knee radiographs in 1990–1991. Repeat radiographs were obtained in 1995–1996 (mean followup duration 5.1 years, median age at followup 75.8 years). Risk factors assessed at baseline were tested for their association with incident and progressive radiographic knee OA by logistic regression. Results Rates of incidence and progression were 2.5% and 3.6% per year, respectively. After adjusting for age and sex, the risk of incident radiographic knee OA was significantly increased among subjects with higher baseline body mass index (odds ratio [OR] 18.3, 95% confidence interval [95% CI] 5.1–65.1, highest versus lowest third), previous knee injury (OR 4.8, 95% CI 1.0–24.1), and a history of regular sports participation (OR 3.2, 95% CI 1.1–9.1). Knee pain at baseline (OR 2.4, 95% CI 0.7–8.0) and Heberden's nodes (OR 2.0, 95% CI 0.7–5.7) were weakly associated with progression. Analyses based on individual radiographic features (osteophyte formation and joint space narrowing) supported differences in risk factors for either feature. Conclusion Most currently recognized risk factors for prevalent knee OA (obesity, knee injury, and physical activity) influence incidence more than radiographic progression. Furthermore, these factors might selectively influence osteophyte formation more than joint space narrowing. These findings are consistent with knee OA being initiated by joint injury, but with progression being a consequence of impaired intrinsic repair capacity.

An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients.

Abstract: Objective To examine the outcome in 155 consecutive patients with Wegener's granulomatosis (WG) followed up for a median of 7 years. Methods Treatment was adapted to the activity and extent of disease, with regular evaluation by an interdisciplinary team accompanied by group education about vasculitis. Results The estimated median survival time was 21.7 years (95% confidence interval [95% CI] 15.60-27.86). Twenty-two patients died; 19 deaths were attributable to WG and/or its treatment. Significant predictors of survival at diagnosis were age >50 years (hazard ratio [HR] 5.45, 95% CI 1.97-15.02), kidney involvement with impaired renal function (HR 5.42, 95% CI 1.76-16.68), and lung involvement (HR 3.75, 95% CI 1.26-11.16). At some stage, 142 patients received prednisone and cyclophosphamide (CYC), usually as daily CYC plus mesna as uroprotection, 50 patients received trimethoprim/sulfamethoxazole, and 45 received methotrexate. Complete remission was achieved in 83 of the 155 patients. One or more relapses occurred in 99 patients after either complete or partial remission. CYC-induced cystitis and myelodysplastic syndrome occurred in 17 and 11 patients, respectively. A cumulative dose of 100 gm or more of CYC resulted in a 2-fold greater risk of CYC-related morbidity than with lower CYC doses. Serious infections occurred in 41 patients. Conclusion An interdisciplinary approach to the care of 155 WG patients resulted in a median survival of >21 years. Kidney or lung involvement at diagnosis was predictive of a >3-fold higher mortality. Although CYC remains essential in the treatment of WG, it was administered as briefly as possible and under close surveillance to avoid permanent CYC-related morbidity, which can lead to serious therapeutic problems in chronic relapsing WG.

The value of sonography in the detection of bone erosions in patients with rheumatoid arthritis: a comparison with conventional radiography.

Abstract: Objective. The ability to make an early, accurate diagnosis of rheumatoid arthritis (RA) has become increasingly important with the availability of new, expensive, and targeted therapies. However, plain radiography, the traditional method of detecting the characteristic bone erosions and an important adjunct in establishing a diagnosis of RA, is known to be insensitive. This study compared sonography, a modern imaging technique, with conventional radiography for the detection of erosions in the metacarpophalangeal (MCP) joints of patients with RA. Methods. One hundred RA patients (including 40 with early disease) underwent posteroanterior radiography and sonography of the MCP joints of the dominant hand. Twenty asymptomatic control subjects also underwent sonography. Erosion sites were recorded and subsequently compared using each modality. Magnetic resonance imaging (MRI) was performed on the second MCP joint in 25 patients with early RA to confirm the pathologic specificity of sonographic erosions. Intraobserver reliability of sonography readings was assessed using video recordings of 55 MCP joint scans of RA patients, and interobserver reliability was assessed by comparing 160 MCP joint scans performed sequentially by 2 independent observers. Results. Sonography detected 127 definite erosions in 56 of 100 RA patients, compared with radiographic detection of 32 erosions (26 [81%] of which coincided with sonographic erosions) in 17 of 100 patients (P < 0.0001). In early disease, sonography detected 6.5-fold more erosions than did radiography, in 7.5-fold the number of patients. In late disease, these differences were 3.4-fold and 2.7-fold, respectively. On MRI, all sonographic erosions not visible on radiography (n = 12) corresponded by site to MRI abnormalities. The Cohen-kappa values for intra- and interobserver reliability of sonography were 0.75 and 0.76, respectively. Conclusion. Sonography is a reliable technique that detects more erosions than radiography, especially in early RA. Sonographic erosions not seen on radiography corresponded to MRI bone abnormalities. This technology has potential in the management of patients with early RA/inflammatory arthritis and is likely to have major implications for the future practice of rheumatology.

The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis.

Abstract: Objective To study the predictive value of anti–cyclic citrullinated peptide antibody (anti-CCP) in patients with recent-onset rheumatoid arthritis (RA). Methods Outcome in terms of physical disability (Health Assessment Questionnaire) and radiologic damage (modified Sharp method) over 3-year and 6-year periods was determined in an inception cohort of 273 RA patients who had had disease symptoms for >1 year at study entry. Anti-CCP titers were determined at baseline and considered positive as recently described. Their prognostic value was studied by means of multiple regression analysis, in which anti-CCP positivity, sex, age at study entry, IgM rheumatoid factor (IgM-RF) status, Disease Activity Score (DAS), HLA–DR4 status, and (in a separate group of patients) shared epitope status were used as independent variables, and radiologic damage and functional disability as dependent variables. Results Patients with anti-CCP had developed significantly more severe radiologic damage after 6 years of followup. In multiple regression analysis, radiologic damage after 6 years followup was significantly predicted by IgM-RF status, radiologic score at entry, and anti-CCP status. Functional disability was significantly predicted by sex, age at entry, IgM-RF status, and DAS. Conclusion Our data show that in almost 70% of RA patients, anti-CCP antibody is present at the early stages of disease. Anti-CCP–positive patients developed significantly more severe radiologic damage than patients who were anti-CCP negative, although in multiple regression analysis the additional predictive value was rather moderate.

Interleukin‐1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c‐jun N‐terminal kinase, and nuclear factor κB: Differential regulation of collagenase 1 and collagenase 3

Abstract: Objective To examine the mechanism of interleukin-1 (IL-1)–induced collagenase 3 (matrix metalloproteinase 13 [MMP-13]) gene expression in cultured chondrocytes for the purpose of better understanding how the gene is induced in these cells, and how it contributes to cartilage degradation in osteoarthritis. Methods The transcriptional and posttranscriptional responses of the MMP-13 gene to IL-1 were assessed first. Then, direct inhibitors of mitogen-activated protein kinase (MAPK) signaling pathways and a constitutive repressor of nuclear factor κB (NF-κB) were used to assess the role of each pathway in IL-1–mediated induction of MMP-13. Results We found that IL-1 induction of MMP-13 requires p38 activity, c-Jun N-terminal kinase (JNK) activity and NF-κB translocation. These results suggest that both NF-κB and activator protein 1 transcription factors are necessary for IL-1 induction of MMP-13. We also compared the signaling pathways necessary for IL-1 to stimulate collagenase 1 (MMP-1) in articular chondrocytes and chondrosarcoma cells and found that IL-1 induction of MMP-1 requires different pathways from those required by MMP-13. In chondrosarcoma cells, MMP-1 induction depends on p38 and MEK (an MAPK kinase of the extracellular signal–regulated kinase pathway) and does not require JNK or NF-κB. In articular chondrocytes, inhibition of MEK had no effect, while inhibition of p38 gave variable results. Conclusion These studies demonstrate, for the first time, that p38, JNK, and NF-κB are required for IL-1 induction of MMP-13. The results also highlight the differential requirements for signaling pathways in the induction of MMP-1 and MMP-13. Additionally, they demonstrate that induction of MMP-1 by IL-1 in chondrocytic cells depends on unique combinations of signaling pathways that are cell type–specific.

Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis

Abstract: Objective To clarify the mechanism by which osteoclasts are formed in culture of rheumatoid synoviocytes by exploring the involvement of receptor activator of nuclear factor κB ligand (RANKL)/osteoclast differentiation factor (ODF). Methods Osteoclast formation was evaluated in cocultures of rheumatoid synovial fibroblasts and peripheral blood mononuclear cells (PBMC) in the presence of macrophage colony stimulating factor and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) utilizing separating membrane filters. RANKL/ODF expression was examined by Northern blotting in synovial tissues from 5 rheumatoid arthritis (RA) patients and tissues from patients with giant cell tumor (GCT), osteosarcoma (OS), and osteoarthritis (OA). RANKL/ODF expression and the ability of synovial fibroblasts to support osteoclastogenesis were investigated in coculture with PBMC in the presence or absence of 1,25(OH)2D3, and soluble RANKL/ODF and osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) were measured by enzyme-linked immunosorbent assay. The effects of OPG/OCIF on the osteoclastogenesis in the primary culture of rheumatoid synoviocytes and the coculture system were determined. Results Synovial fibroblasts did not induce osteoclastogenesis when separately cocultured with PBMC. Northern blotting revealed that RANKL/ODF was highly expressed in all tissues from RA and GCT patients, but not from OA or OS patients. Cultured rheumatoid synovial fibroblasts efficiently induced osteoclastogenesis in the presence of 1,25(OH)2D3, which was accompanied by up-regulated expression of RANKL/ODF and decreased production of OPG/OCIF. Osteoclastogenesis from synoviocytes was dose-dependently inhibited by OPG/OCIF. Conclusion RANKL/ODF expressed on synovial fibroblasts is involved in rheumatoid bone destruction by inducing osteoclastogenesis and would therefore be a good therapeutic target.

Assessment of antibodies to double‐stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor α: Findings in open‐label and randomized placebo‐controlled trials

Abstract: Objective To compare the incidence of anti–double-stranded DNA (anti-dsDNA) antibodies in rheumatoid arthritis (RA) patients receiving either single or multiple doses of a chimeric anti–tumor necrosis factor α (anti-TNFα) antibody or placebo infusions, with or without methotrexate, in open-label, randomized, placebo-controlled trials. Methods Multiple sera obtained from 156 patients before and after treatment with infliximab and from 37 patients treated with placebo infusions were tested for anti-dsDNA antibodies by 3 methods: Crithidia luciliae indirect immunofluorescence test (CLIFT), a commercial Farr assay (Ortho Diagnostics radioimmunoassay [RIA]) in which the antigen source is mammalian DNA, and a Farr assay employing 125I-labeled circular plasmid DNA (Central Laboratory of The Netherlands Red Cross Blood Transfusion Service [CLB] RIA). Patients with positive findings on the CLIFT were also tested for antibodies to histones (H1–H5) and chromatin and for IgM rheumatoid factors (IgM-RFs). Results None of the RA patients had a serum sample that was positive for anti-dsDNA antibodies by the CLIFT prior to infliximab therapy. Of the 22 patients who developed a positive CLIFT result, 11 (7% of 156 exposed to infliximab) also had positive findings on the Ortho RIA at a concentration of >10 units/ml and another 8 (5%) were positive at a concentration of >25 units/ml. In all but 1 patient, the anti-dsDNA antibodies were solely of the IgM isotype. Only 1 patient had detectable anti-dsDNA antibodies by the CLB RIA. All sera containing anti-dsDNA by the CLIFT contained antibodies to chromatin, and sera from 2 patients also contained antibodies to histones. IgM-RF titers showed a significant reduction following infliximab therapy in these 22 patients. One patient developed anti-dsDNA antibodies of IgG, IgA, and IgM isotype and had positive results on both Farr assays (peaking at 22 weeks and resolving by 54 weeks); this was associated with a reversible lupus syndrome. Conclusion Anti-dsDNA antibodies of IgM class are induced by infliximab therapy; the frequency is dependent on the assay method used. Only 1 of the 156 patients who were treated with infliximab developed a self-limiting clinical lupus syndrome; that patient developed high titers of anti-dsDNA antibodies of IgG, IgM, and IgA class, as detected by the CLIFT and by 2 different Farr assays.

Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register.

Abstract: Objective To examine the bone mineral density (BMD), frequency of osteoporosis, and risk factors for BMD reduction in a representative population of female rheumatoid arthritis (RA) patients ages 20–70 years. Methods BMD in the femoral neck, total hip, and spine L2–4 (anterior-posterior view) was measured in 394 RA patients recruited from a validated county RA register (completeness 85%) comprising 721 women ages 20–70 years. BMD was measured with dual-energy x-ray absorptiometry, and age-specific values were compared with pooled values from a European/US population of healthy subjects free from earlier fractures, chronic diseases, and medications influencing bone metabolism. A multiple linear regression model was used to determine individual predictors of BMD. Results No statistically significant differences were found in demographic, disease activity, disease severity, or health status parameters between the RA register patients in whom BMD was measured and the remaining register patients. Femoral neck BMD was significantly reduced by 4.2% in the age group 50–59 years, and by 5.0% in those ages 60–70 years. For BMD in the total hip, the significant reductions were 3.7%, 6.0%, and 8.5% in the age groups 40–49 years, 50–59 years, and 60–70 years, respectively. No significant reduction in spine L2–4 BMD was found. A 2-fold increased frequency of osteoporosis was observed in all 4 age groups of RA patients compared with the reference population, ranging from 0% to 28.6% in the femoral neck, 0% to 29.9% in the total hip, and 1.8% to 31.5% in the spine. Predictors of reduced BMD were as follows: at the femoral neck, older age, low body weight, current use of corticosteroids, greater physical disability (as measured by the modified Health Assessment Questionnaire [M-HAQ]), and presence of rheumatoid factor; at the total hip, older age, low weight, current use of corticosteroids, and higher M-HAQ disability score; and at the lumbar spine, older age, low weight, and current use of corticosteroids. Conclusion Register-based prevalence data on BMD reduction in female RA patients ages 20–70 years are presented for the first time in this report, which demonstrates a 2-fold increase in osteoporosis in this representative population.

Successful treatment of active ankylosing spondylitis with the anti–tumor necrosis factor α monoclonal antibody infliximab

Abstract: Objective Tumor necrosis factor α (TNFα) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFα monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). Methods Eleven patients with AS of short duration (median 5 years, range 0.5–13 years) that had been active for at least 3 months (range 3–72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted >1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. Results One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2–6 weeks after the third infusion revealed improvement in 2. Improvement of ≥50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41–94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6–90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0–28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. Conclusion These data suggest that anti-TNFα therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.

Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration.

Abstract: Objective To use individual patient data from rheumatoid arthritis (RA) clinical trials to identify factors that affect the response to treatment as defined by the American College of Rheumatology (ACR) criteria for improvement (the “ACR response”). Methods Primary trial data from 14 diverse, randomized, controlled trials of second-line drugs or devices in RA were analyzed. The trials included 11 methotrexate (MTX) trials (5 placebo controlled and 6 comparative, of which 2 were unpublished), 1 combination trial of cyclosporine plus MTX, 1 induction trial of a combination treatment in early RA (the COBRA trial), and 1 placebo-controlled trial of a new device (Prosorba). Both patient factors and disease activity measures (primarily, items from the ACR core criteria set) were available. Results A total of 1,435 patients (549 in placebo-controlled trials, 886 in comparative trials) were studied. In both active treatment and placebo groups, disease duration had a strong effect on the likelihood of patient response (e.g., with any active treatment, the response rate was 53% for patients with ≤1 year of disease, 43% for 1–2 years' disease duration, 44% for 2–5 years, 38% for 5–10 years, and 35% for >10 years; P = 0.001). Decreasing response with greater disease duration was seen during treatment with most of the individual active drugs, as well as with placebo. Other factors decreasing the rate of response to treatment included any prior use of a disease-modifying antirheumatic drug (DMARD), higher disease functional class (according to the Steinbrocker criteria), low disease activity (according to patient's global assessment), and female sex. Each ACR core set variable exhibited a diminished response to treatment in patients with long-standing disease. The difference between active treatment and placebo response rates was not affected by disease duration nor by other factors associated with the ACR response. Conclusion RA patients with longer disease duration do not respond as well to treatment compared with patients with early disease, and female sex, prior DMARD use, disease functional class, and disease activity also have effects on the likelihood of patient response to treatment. This has implications for trial interpretation and for the clinical expectations of RA patients.

Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis.

Abstract: Objective To define clinically meaningful changes in 2 widely used health-related quality of life (HQL) instruments in studies of patients with rheumatoid arthritis (RA). Methods Patients with RA (n = 693) who were enrolled in 2 double-blind, placebo-controlled clinical trials completed the Short Form 36 (SF-36) modified health survey and the Health Assessment Questionnaire (HAQ) disability index at baseline and 6-week followup assessments. Data on 5 RA severity measures were also collected at baseline and at 6 weeks (patient and physician global assessments, joint swelling and tenderness counts, and global pain assessment). Comparison of changes in the SF-36 scales and HAQ scores was made between groups of patients known to differ in the level of change on each RA severity measure. Results With few exceptions, changes in the SF-36 and HAQ scores were different between patients who differed in the level of change on each RA severity measure. Changes in the SF-36 and HAQ scores were more strongly related to changes in the patient and physician global assessments and patient pain assessment than to changes in the joint swelling and tenderness counts. Conclusion Based on these results, minimally important changes in the SF-36 scales and HAQ disability scores were determined, which will be useful in interpreting HQL results in clinical trials.

Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus

Abstract: Objective To evaluate the safety and clinical efficacy of administering an anti–interleukin-10 (anti–IL-10) monoclonal antibody (mAb) to systemic lupus erythematosus (SLE) patients with active and steroid-dependent disease. In addition, we sought to assess the effects of in vivo IL-10 neutralization on biologic markers of SLE. Methods Treatment consisted of 20 mg/day intravenous administration of an anti–IL-10 murine mAb (B-N10) for 21 consecutive days, with a followup period of 6 months. Six patients were studied. Results Treatment was safe and well tolerated. All patients developed antibodies against B-N10. Cutaneous lesions and joint symptoms improved in all patients beginning during B-N10 administration and continuing to month 6. The SLE Disease Activity Index decreased from a mean ± SEM of 8.83 ± 0.91 on day 1 to 3.67 ± 0.67 on day 21 (P = 0.001), 1.50 ± 0.84 at month 2, and 1.33 ± 0.80 at month 6 (P < 0.001). At the end of followup, the disease was clinically inactive in 5 of the 6 patients. Prednisone administration was decreased from a mean ± SEM of 27.9 ± 5.7 mg/day on day 1 to 9.6 ± 2.0 mg/day at month 6 (P < 0.005). Activity of immune and endothelial cells rapidly decreased, as assessed by the early evolution of several biologic markers. Conclusion This is the first report of IL-10 antagonist administration to humans. The study shows the involvement of IL-10 in the pathogenesis of SLE, and indicates that the use of IL-10 antagonists may be beneficial in the management of refractory SLE.

Prediction of relapses in Wegener's granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study.

Abstract: Objective. Prediction of relapses in Wegener's granulomatosis (WG) by measuring levels of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) remains a controversial issue. To assess the value of serial quantification of ANCA by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for monitoring disease activity in patients with WG, a prospective observational study was conducted in patients with WG attending an outpatient clinic in the Netherlands. Methods. One hundred patients with WG (85 with PR3-ANCA, 15 with MPO-ANCA) were studied prospectively from 1996 to 1998. Serum samples were obtained and analyzed every 2 months for ANCA levels. Disease activity was prospectively assessed without knowledge of the ANCA levels. Results. Relapses occurred in 37 of 100 patients (37%). Thirty-four (92%) of the 37 patients showed a rise in the level of ANCA preceding their relapse, as detected by ELISA or IIF. The predictive value of an increase in ANCA titers for relapse was 57% (17 of 30) for cytoplasmic/classic ANCA (cANCA; by IIF), 71% (27 of 38) for PR3-ANCA (by ELISA), and 100% (3 of 3) for MPO-ANCA (by ELISA). The predictive value of a rise in ANCA as measured by ELISA or IIF did not substantially improve following concomitant measurement of the IgG3 subclass of PR3-ANCA. Forty-three percent of patients who showed a rise in cANCA (by IIF) and 29% with a rise in PR3-ANCA (by ELISA) did not subsequently experience a relapse. Conclusion. Serial measurement of ANCA levels is valuable for the early prediction of relapses in patients with WG.

Damage in systemic lupus erythematosus and its association with corticosteroids

Abstract: Objective To evaluate the association between corticosteroid use and organ damage in patients with systemic lupus erythematosus (SLE). Methods The occurrence and date of organ damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were determined for 539 patients enrolled in the Hopkins Lupus Cohort Study. The risk of damage associated with the cumulative prednisone dose, high-dose prednisone (≥60 mg/day for ≥2 months), and pulse methylprednisolone (1,000 mg intravenously for 1–3 days) was estimated using Cox proportional hazards regression analyses, controlling for age, race, and sex. Risk estimates for the cumulative prednisone dose were based on a reference dose of 36.5 gm (e.g., 10 mg of prednisone daily for 10 years [or equivalent]). Results The cumulative prednisone dose was significantly associated with the development of osteoporotic fractures (relative risk [RR] 2.5, 95% confidence interval [95% CI] 1.7, 3.7), symptomatic coronary artery disease (RR 1.7, 95% CI 1.1, 2.5), and cataracts (RR 1.9, 95% CI 1.4, 2.5). Each intravenous pulse was associated with a small increase in the risk of osteoporotic fractures (RR 1.3, 95% CI 1.0, 1.8); however, this result failed to reach statistical significance (P = 0.07). Each 2-month exposure to high-dose prednisone was associated with a 1.2-fold increase in the risk of both avascular necrosis (95% CI 1.1, 1.4) and stroke (95% CI 1.0, 1.5). Conclusion SLE patients receiving long-term prednisone therapy were at significant risk of morbidity due to permanent organ damage. Additional research is required to determine the relative contributions of SLE disease activity and corticosteroids to the pathogenesis of specific types of organ damage. Furthermore, new steroid-sparing therapies are needed in order to treat disease activity and minimize cumulative and high-dose prednisone exposure.

Epidemiology of systemic vasculitis: A ten‐year study in the United Kingdom

Abstract: Objective To describe the epidemiology of the primary systemic vasculitides (PSV; Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, polyarteritis nodosa) in a well-defined population over a 10-year period. Methods An inception cohort of patients from the Norwich Health Authority (NHA) who were >15 years of age and had PSV first diagnosed between January 1, 1988 and December 31, 1997 was collected. Incidence rates were adjusted for age and sex to the 1992 population. The prevalence of PSV in this cohort was estimated on December 31, 1997. Patients were classified according to the American College of Rheumatology 1990 vasculitis criteria and the Chapel Hill Consensus definitions. Results Eighty-two NHA residents fulfilled the inclusion criteria. There were 47 men and 35 women, with a mean age of 62.9 years (median 65.0 years). The overall annual incidence of PSV among NHA residents was 19.8/million (95% confidence interval [95% CI] 15.8–24.6). The point prevalence on December 31, 1997 was 144.5/million (95% CI 110.4–185.3). PSV was more common in males (23.5/million; 95% CI 17.3–31.3) than females (16.4/million; 95% CI 11.4–22.8). The age- and sex-specific incidence showed a clear increase with age, with an overall peak in the 65–74 year age group (60.1/million). Conclusion In our study population, the annual incidence of PSV is slowly increasing with time and the incidence is greatest in the elderly.

Increased interleukin‐17 production in patients with systemic sclerosis

Abstract: Objective To determine the role of a novel T cell–derived cytokine, interleukin-17 (IL-17), which activates fibroblasts and endothelial cells, in the pathogenesis of systemic sclerosis (SSc) Methods We examined IL-17 production by lymphocytes from the peripheral blood (PBL) and from fibrotic lesions of the skin and lungs of SSc patients by reverse transcriptase–polymerase chain reaction and enzyme-linked immunosorbent assay We also studied the effect of IL-17 on the proliferation of fibroblasts and on the production of cytokines and the expression of adhesion molecules on endothelial cells in vitro Results IL-17 messenger RNA was expressed in unstimulated PBL and lymphocytes from the skin and lungs of SSc patients, but not in similar samples from patients with systemic lupus erythematosus (SLE) or polymyositis/dermatomyositis or from healthy donors IL-17 levels were also increased in the serum of SSc patients, but not in that of SLE patients or healthy donors IL-17 overproduction was significantly related to the early stage of SSc, but not to other clinical features of SSc Moreover, IL-17 enhanced the proliferation of fibroblasts and induced the expression of adhesion molecules and IL-1 production in endothelial cells in vitro Conclusion IL-17 is overproduced by T cells from the peripheral blood and fibrotic lesions of the skin and lungs in SSc patients These results suggest that IL-17 overproduction plays an important role in the pathogenesis of SSc, especially in the early stages of the disease, by inducing the proliferation of fibroblasts and the production of IL-1 and the expression of adhesion molecules on endothelial cells

A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores.

Abstract: Objective To evaluate radiographic progression and the relationship of radiologic scores obtained by the Genant and Larsen methods in a clinical trial of recombinant human interleukin-1 receptor antagonist (IL-1Ra). Methods Patients with rheumatoid arthritis (RA) were randomized into 4 groups: placebo (n = 121) or IL-1Ra at a daily dosage of 30 mg (n = 119), 75 mg (n = 116), or 150 mg (n = 116). Hand radiographs obtained at baseline, 24 weeks, and 48 weeks were scored using both methods. Results At 24 weeks, by the Genant method, there was significant reduction in the score for progression of joint space narrowing (JSN) and the total score (a combination of erosion and JSN) in all treatment groups. Least-squares mean changes in the Genant erosion score from baseline to 24 weeks were significantly reduced after treatment with IL-1Ra at 30 mg/day and for all IL-1Ra treatment groups combined. The changes corresponded to a reduction of 38% in erosion, 58% in JSN, and 47% in total score. Patients treated with IL-1Ra at 75 mg/day had a significant reduction in the Larsen erosive joint count (LEJC), and all IL-1RA–treated groups combined showed a 45% reduction. Correlations (r) between the Genant total and Larsen scores were 0.84 at baseline, 0.83 at week 24, and 0.83 at week 48 (P < 0.0001); correlations between the Genant erosion score and the LEJC were 0.83 (P < 0.0001) at all visits; correlations between the Genant total and the Larsen scores were 0.32 and 0.49 (P < 0.0001) for progression from baseline to week 24 and from baseline to week 48, respectively; correlations between the Genant erosion score and the LEJC were 0.36 and 0.41 (P < 0.0001) for progression to weeks 24 and 48, respectively. Conclusion IL-1Ra reduced radiologic progression of RA. Scores by the 2 methods correlated strongly for each individual time point, but much less strongly for assessments of disease progression.

Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis.

Abstract: OBJECTIVE: To verify the hypothesis that in rheumatoid arthritis (RA), tumor necrosis factor alpha (TNFalpha) plays a critical role in regulating leukocyte trafficking and chemokine levels METHODS: Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNFalpha monoclonal antibody (cA2) The articular localization of autologous granulocytes, separated in vitro and labeled with 111In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3+ T cells, CD22+ B cells, and CD68+ macrophages Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, Groalpha, and RANTES was also determined Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosorbent assay RESULTS: Anti-TNFalpha therapy in RA significantly reduced 111In-labeled granulocyte migration into affected joints There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells, and CD68+ macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines CONCLUSION: TNFalpha blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints

Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis

Abstract: Objective To analyze which physiologic stimuli induce secretion of myeloid-related protein 8 (MRP8) and MRP14, two S100 proteins expressed in neutrophils and monocytes, and to determine whether serum concentrations of these proteins are reliable parameters for monitoring inflammatory activity in pauciarticular juvenile rheumatoid arthritis (JRA). Methods Secretion of MRP8 and MRP14 was analyzed using a coculture system of endothelial cells and monocytes. Concentrations of MRP8/MRP14 in the serum and synovial fluid of JRA patients or culture medium were determined by enzyme-linked immunosorbent assay. The expression of MRP8 and MRP14 by leukocytes in synovial tissue or fluid was investigated using immunohistochemistry. Results MRP8 and MRP14 were specifically released during interaction of activated monocytes with tumor necrosis factor–stimulated endothelial cells. Secretion was mediated via an increase in intracellular calcium levels in monocytes. In contrast, contact with resting endothelium inhibited protein kinase C–induced secretion of the proteins by monocytes. In JRA patients, MRP8 and MRP14 were strongly expressed in infiltrating neutrophils and monocytes within the inflamed joints and could be found in significantly higher concentrations in synovial fluid (mean 42,800 ng/ml) compared with serum (2,060 ng/ml). Concentrations of MRP8/MRP14 in serum correlated well with those in synovial fluid (r = 0.78) and showed a strong correlation with disease activity (r = 0.62). After intraarticular triamcinolone therapy, the serum concentrations of MRP8/MRP14 decreased significantly in therapy responders, whereas no differences were found in patients who showed no clinical benefit. Conclusion MRP8 and MRP14 are specifically released during the interaction of monocytes with inflammatory activated endothelium, probably at sites of local inflammation. Their serum concentrations represent a useful marker for monitoring local inflammation in JRA.

Occupational physical activities and osteoarthritis of the knee

Abstract: Objective: to assess the risk of knee osteoarthritis (OA) associated with kneeling, squatting, and other occupational activities. Methods: we compared 518 patients who were listed for surgical treatment of knee OA and an equal number of control subjects from the same communities who were matched for sex and age. Histories of knee injury and occupational activities were ascertained at interview, height and weight were measured, and the hands were examined for Heberden's nodes. Data were analyzed by conditional logistic regression. Results: after adjustment for body mass index (BMI), history of knee injury, and the presence of Heberden's nodes, risk was elevated in subjects who reported prolonged kneeling or squatting (odds ratio [OR] 1.9; 95% confidence interval [95% CI] 1.3-2.8), walking >2 miles/day (OR 1.9; 95% CI 1.4-2.8), and regularly lifting weights of at least 25 kg (OR 1.7; 95% CI 1.2-2.6) in the course of their work. The risks associated with kneeling and squatting were higher in subjects who also reported occupational lifting, and appeared to interact multiplicatively with the risk conferred by obesity. People with a BMI of 30 kg/m2 whose work had entailed prolonged kneeling or squatting had an OR of 14.7 (95% CI 7.2-30.2), compared with subjects with a BMI Conclusion: there is now strong evidence for an occupational hazard of knee OA resulting from prolonged kneeling and squatting. One approach to reducing this risk may lie in the avoidance of obesity in people who perform this sort of work.

Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis.

Abstract: Objective To investigate whether stress- and mitogen-activated protein kinases (SAPK/MAPK), such as extracellular signal–regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, are significantly activated in rheumatoid arthritis (RA) synovial tissue compared with their activation in degenerative joint disease; to assess the localization of SAPK/MAPK activation in rheumatoid synovial tissue; and to search for the factors leading to stress kinase activation in human synovial cells. Methods Immunoblotting and immunohistology by antibodies specific for the activated forms of SAPK/MAPK were performed on synovial tissue samples from patients with RA and osteoarthritis (OA). In addition, untreated and cytokine-treated human synovial cells were assessed for SAPK/MAPK activation and downstream signaling by various techniques. Results ERK, JNK, and p38 MAPK activation were almost exclusively found in synovial tissue from RA, but not OA, patients. ERK activation was localized around synovial microvessels, JNK activation was localized around and within mononuclear cell infiltrates, and p38 MAPK activation was observed in the synovial lining layer and in synovial endothelial cells. Tumor necrosis factor α, interleukin-1 (IL-1), and IL-6 were the major inducers of ERK, JNK, and p38 MAPK activation in cultured human synovial cells. Conclusion Signaling through SAPK/MAPK pathways is a typical feature of chronic synovitis in RA, but not in degenerative joint disease. SAPK/MAPK signaling is found at distinct sites in the synovial tissue, is induced by proinflammatory cytokines, and could lead to the design of highly targeted therapies.

Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial

Abstract: Objective This randomized, double-blind study tested the hypothesis that rofecoxib, a drug that specifically inhibits cyclooxygenase 2, would cause fewer gastroduodenal ulcers than ibuprofen (in a multicenter trial), and its side effects would be equivalent to those of placebo (in a prespecified analysis combining the results with another trial of identical design). Methods Seven hundred seventy-five patients with osteoarthritis were randomized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily, ibuprofen 800 mg 3 times daily, or placebo. Gastroduodenal ulceration was assessed by endoscopy at 6, 12, and (for active treatment) 24 weeks. The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks, respectively. Results Ulcers were significantly less common (P < 0.001) following treatment with rofecoxib (25 mg or 50 mg) than with ibuprofen after 12 weeks (5.3% and 8.8% versus 29.2%, respectively) or 24 weeks (9.9% and 12.4% versus 46.8%, respectively). In the combined analysis, the 12-week ulcer incidence with 25 mg rofecoxib (4.7%) and with placebo (7.3%) satisfied prespecified criteria for equivalence. Conclusion At 2–4 times the therapeutically effective dose, rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen. Rofecoxib at a dose of 25 mg (the highest dose recommended for osteoarthritis) satisfied prespecified criteria for equivalence to placebo.

The mechanism of the effect of obesity in knee osteoarthritis: the mediating role of malalignment.

Abstract: Objective Obesity is most strongly linked to osteoarthritis (OA) at the knee. Varus malalignment was examined as a possible local mediator that may increase the impact of body weight at the knee, versus the hip or ankle. Compartment load distribution is more equitable in valgus than in varus knees, and valgus knees may better tolerate obesity. We therefore tested whether 1) body mass index (BMI) is correlated with OA severity in varus knees, 2) the BMI–OA severity correlation is weaker in valgus than in varus knees, 3) BMI is correlated with the severity of varus malalignment, and 4) the BMI–medial tibiofemoral OA severity relationship is reduced after controlling for varus malalignment. Methods In 300 community-recruited patients with knee OA, 2 groups (varus and valgus) were identified based on dominant knee alignment on a full-limb radiograph, i.e., the angle formed by the intersection of the femoral and tibial mechanical axes. Severity of knee OA was assessed by measurement of the narrowest joint space width on radiographs of knees in a fluoroscopy-confirmed semiflexed position. Results Alignment direction was symmetric (or neutral in 1 limb) in 87% of patients. One hundred fifty-four patients had varus knees and 115 had valgus knees. BMI correlated with OA severity in the varus group (r = –0.29, P = 0.0009) but not in the valgus group (r = –0.13, P = 0.17). BMI correlated with malalignment in those with varus knees (r = 0.26) but not in those with valgus knees (r = 0.16). The partial correlation of BMI and OA severity, controlling for sex, was reduced from 0.24 (P = 0.002) to 0.04 (P = 0.42) when varus malalignment was added to the model. Conclusion BMI was related to OA severity in those with varus knees but not in those with valgus knees. Much of the effect of BMI on the severity of medial tibiofemoral OA was explained by varus malalignment, after controlling for sex. Whether it precedes or follows the onset of disease, varus malalignment is one local factor that may contribute to rendering the knee most vulnerable to the effects of obesity.