Rheumatology RSS : Gourt

Permanent RHEUMATOLOGY Job in Southeast Idaho Idaho with Enterprise Medical Service

Southeast Idaho critical care access facility in need of first Rheumatologist due to patient demand. This hospital employed position will split practice 50% Rhuem/50% IM traditional patient. Call shared

Permanent RHEUMATOLOGY Job in Western Coast of Florida Florida with Enterprise Medical Service

Western coast of Florida facility in need of 2nd Rheumatologist due to patient demand. Join female Rheumatologist will also cover Internal Medicine patients until build up to 100% Rheumatology. Financial

Permanent RHEUMATOLOGY Job in Albuquerque, NM Area New Mexico with Enterprise Medical Service

Well respected multi-specialty group in metro New Mexico in need of Rheumatologist due to growth. This position will include attractive salary, production bonuses, full benefits to include malpractice,

Permanent RHEUMATOLOGY Job in Southern Georgia Georgia with Enterprise Medical Service

Southern Georgia community within minutes of Florida state capital in need of 2nd full time 100% Rheumatologist in multi-specialty clinic due to growth. NO CALL. Strictly consultative practice. Office

Permanent RHEUMATOLOGY Job in Within 2 hours of St. Louis Illinois with Enterprise Medical Service

Rheumatology/Internal Medicine need is available in Southern Illinois. This practice will not be 100% Rheumatology; it will be 60/40 or 70/30 with Internal Medicine. Can be either an employed or income

Permanent RHEUMATOLOGY Job in Northeast Pennsylvania H1-B Visa Welcome Pennsylvania with Enterprise Medical Service

Well established multi-specialty group in Northeast Pennsylvania in need of first Rheumatologist due to patient demand. Minimum call from home only. Financial package to include attractive salary, signing

Permanent RHEUMATOLOGY Job in 40 Minutes from Salt Lake City Utah with Enterprise Medical Service

Well respected physician owned multi-specialty group within 40 minutes of Salt Lake City, UT in need of Rheumatologist due to patient demand. Clinic has EMR system linking all 6 clinical locations.

Permanent RHEUMATOLOGY Job in Panhandle Area Florida with Enterprise Medical Service

Large health system in coastal Florida is seeking 2 Rheumatologists. The need is due to growth and demand of the area. This can be an employed position through the hospital OR one can choose to be

Permanent RHEUMATOLOGY Job in Central Florida Facility Seeks Rheumatologist Florida with Enterprise Medical Service

Central Florida facility within minutes of Orlando in need of hiring a full time Rheumatologist due to growth. This position can be set up as solo with income guarantee, marketing, relocation expenses

Permanent RHEUMATOLOGY Job in Central Western Oregon Oregon with Enterprise Medical Service

Well established multi-specialty group in central western Oregon in need of 3rd Rheumatologist due to patient demand. Call 1:3. Will be on staff of 115-bed, Level III trauma center, state-of-the-art

Permanent RHEUMATOLOGY Job in Southeast Tennessee Area Tennessee with Enterprise Medical Service

Southeast Tennessee facility assisting solo Rheumatologist with recruitment of 2nd Rheumatologist due to growth. Hospital also open to setting up specialist in solo practice with shared call 1:3. Patient

Permanent RHEUMATOLOGY Job in NW South Carolina Region South Carolina with Enterprise Medical Service

Rheumatologist needed to join solo in private practice in NW South Carolina due to growth. Patient draw area covers 7 counties in a community recognized as one of the Top 50 Best Towns in America. The

Permanent RHEUMATOLOGY Job in Northeast Georgia Georgia with Enterprise Medical Service

Well established multi-specialty group 40 minutes NE of Atlanta, GA in need of 3rd 100% Rheumatologist due to patient demand. Call 1:3 with very dynamic and female Rheumatologist in group. Financial

Permanent RHEUMATOLOGY Job in Western North Carolina Location North Carolina with Enterprise Medical Service

Western North Carolina facility in need of solo Rheumatologist due to patient demand. This will be hospital sponsored independent practice with first year income guarantee, sign-on bonus, housing assistance,

Permanent RHEUMATOLOGY Job in Within One Hour of the Bronx New York with Enterprise Medical Service

MSG within 1 hour of NYC in need of 1st Rheumatologist due to patient demand, will be busy practice, cover 4 clinics, 50+ physician referral base, new state-of-the-art medical building, financial package

Permanent RHEUMATOLOGY Job in Tampa Bay Area Florida with Enterprise Medical Service

Well established group has over 50 providers and due to continued growth, seeks a third Rheumatologist to practice 100% of this subspecialty. At this point the current providers elect to take their own

Permanent RHEUMATOLOGY Job in Muskogee, OK Oklahoma with Enterprise Medical Service

Multi-specialty group in Muskogee, Oklahoma looking to add a BC/BE Rheumatologist-Job #16518 due to growth and retirement. This clinic offers the highest quality medical care to the citizens of their

Permanent RHEUMATOLOGY Job in 45 minutes from Raleigh North Carolina with Enterprise Medical Service

Seeking BC/BE Rheumatologist to join one other in practice. There will be no medical call. Every other month call for Rheumatology. Competitive 1st year income guarantee. Production base from two

Permanent RHEUMATOLOGY Job in Only 1 hour from NYC New York with Enterprise Medical Service

Join a large MSG in New York. Group has over 120 physicians and over 20 specialties. They currently have one other Rheumatologist in the group looking to recruit another provider. Very little call,

Permanent RHEUMATOLOGY Job in Wichita Falls, TX Area Texas with Enterprise Medical Service

Multi-specialty group of over 55 physicians is seeking a Rheumatologist to join their group. Walk into a ready-made practice with patients and referring physicians waiting your arrival. Join forces

Serum levels of hyaluronic acid and chondroitin sulfate as a non-invasive method to evaluate healing after cartilage repair procedures

MRI remains the only non-invasive method to assess the quality of cartilage repair procedures, but ideally would be complemented by other modalities, particularly blood tests. Pruksakorn et al. investigated serum levels of hyaluronic acid (HA) and chondroitin sulfate (CS) for their correlation with tissue quality after cartilage repair with autologous chondrocytes versus subchondral drilling in a dog model. They reported better tissue quality in animals treated with chondrocyte implantation. Serum levels correlated with the histological score of biopsy samples: CS showed a negative (r= -0.69), and HA a positive correlation (r= +0.46). Many questions remain to be answered before serum markers can provide a reliable, non-invasive tool to assess tissue quality, but these data provide an important foundation for additional research.

Apoptotic cell-mediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T cell increase: a potential cell-based therapy?

IntroductionExperimental streptococcal cell wall (SCW)-induced arthritis is characterized by two successive phases of the disease. The acute phase occurs early and is associated with an inflammatory process and neutrophil infiltration into the synovium. The second chronic phase is related to effector T cell activation and the dysregulation of macrophage function. Creation of an immunomodulatory environment has been attributed to apoptotic cells themselves, apoptotic cell uptake by phagocytes as well as a lesser sensitivity of phagocytes capturing apoptotic bodies to activation. Therefore we evaluated the potential of apoptotic cell injection to influence the course of inflammation in SCW-induced arthritis in rats. Methods: Rat apoptotic thymocytes were injected i.p. (2.10e8) in addition to an arthritogenic dose of systemic SCW in LEW female rats. Control rats received SCW immunization and PBS. Rats were then followed for arthritis occurrence and circulating cytokine detection. At sacrifice, regulatory T cells (Treg) and macrophages were analyzed. Results: Apoptotic cell injection profoundly suppressed joint swelling and destruction typically observed during the acute and chronic phases of SCW-induced arthritis. Synovial inflammatory cell infiltration and bone destruction were also markedly suppressed. Ex vivo experiments revealed reduced levels of tumor necrosis factor (TNF) in cultures of macrophages from rats challenged with SCW in the presence of apoptotic thymocytes as well as reduced macrophage response to lipo-polysaccharide (LPS). Moreover, apoptotic cell injection induced higher Foxp3+ Tregs in the lymphoid organs, especially in the draining lymph nodes. Conclusions: Our data indicate that apoptotic cells modulate macrophage function and result in Treg generation/increase. This may be involved in inhibition of inflammation and amelioration of arthritis. This highlights and confirms previous studies showing that in vivo generation of Tregs using apoptotic cell injection may be a useful tool to prevent and treat inflammatory autoimmune responses.

Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study

IntroductionRadiographic progression in rheumatoid arthritis (RA) has in several studies been shown to be predicted by serological markers widely used in daily clinical practice. The objective of this longitudinal study was to examine if these serological markers also predict hand bone mineral density (BMD) loss in patients with RA of short disease duration. Methods: 163 patients with RA of short disease duration (2.4 years) were included and followed longitudinally. Antibodies to cyclic citrullinated protein (anti-CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed from baseline blood-samples. Hand BMD was measured by digital X-ray radiogrammetry (DXR) based on hand and wrist radiographs obtained at baseline and 1, 2 and 5-year follow-up. Results: During the study period, DXR-BMD decreased by median (inter quartile range) 1.7% (4.1 to 0.4), 2.8% (5.3 to 0.9) and 5.6% (11.7 to 2.3) after 1, 2 and 5 years, respectively. Elevated baseline anti-CCP, RF, ESR and CRP levels were in univariate linear regression analyses consistently associated with DXR-BMD change at all time-points. Anti-CCP and ESR were independently associated with hand DXR-BMD in multivariate linear regression analyses. Elevated anti-CCP levels were consistent and independent predictors of loss in cortical hand bone during the study period, with the odds ratios (95% confidence interval) 2.2 (1.0 to 4.5), 2.6 (1.1-6.2) and 4.9 (1.4-16.7) for the 1, 2, and 5-year follow-up periods, respectively. Conclusions: Anti-CCP and ESR were found to be independent predictors of early localised BMD loss. This finding adds to the understanding of anti-CCP and ESR as important predictors of bone involvement in RA.

Broad-range PCR, cloning and sequencing of the full 16S rRNA gene for detection of bacterial DNA in synovial fluid samples of Tunisian patients with reactive and undifferentiated arthritis

IntroductionBroad-range rDNA polymerase chain reaction (PCR) provides an alternative, cultivation-independent approach for identifying bacterial DNA in reactive and other form of arthritis. The aim of this study was to use broad-range rDNA polymerase chain reaction targeting the 16S rRNA gene in patients with reactive and other forms of arthritis and to screen for the presence of DNA from any given bacterial species in synovial fluid (SF) samples. Methods: We examined the synovial fluid (SF) samples from a total of 27 patients consisting of patients with reactive arthritis (ReA) (n=5), undifferentiated arthritis (UA) (n=9), rheumatoid arthritis (n=7), and osteoarthritis (n=6) of which the latter two were used as controls. Using broad-range bacterial PCR amplifying a 1,400-base-pair fragment from the 16S rRNA gene, we identified and sequenced at least 24 clones from each synovial fluid sample. To identify the corresponding bacteria, DNA sequences were compared to the EMBL (European Molecular Biology Laboratory) database. Results: Bacterial DNA was identified in 20 of the 27 SF samples (74, 10 %). Analysis of a large number of sequences revealed the presence of DNA from more than one single bacterial species in the SF of all patients studied. The nearly complete sequences of the 1,400 bp were obtained for most of the detected species. DNA of bacterial species including Shigella sp, Escherichia sp, and other coli-form bacteria as well as opportunistic pathogens such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans were shared in all arthritis patients. Among pathogens described to trigger ReA, DNA from Shigella sonnei was found in ReA and UA patients. We also detected DNA from rarely occurring human pathogens such as Aranicola sp and Pantoea ananatis. We also found DNA from bacteria so far not described in human infections such as Bacillus niacini, Paenibacillus humicus, Diaphorobacter sp and uncultured bacterium genera incertae sedis OP10. Conclusions: Broad-range PCR followed by cloning and sequencing the entire 16S rDNA, allowed the identification of the bacterial DNA environment in the SF samples of arthritic patients. We found a wide spectrum of bacteria including those known to be involved in ReA and others not previously associated with arthritis.

Increased production of soluble CTLA-4 in patients with spondylarthropathies correlates with disease activity

IntroductionSpondylarthropathies (SpA) are characterized by abnormal immune responses including T cell activation. Cytotoxic T lymphocyte associated molecule-4 (CTLA-4) is involved in down-regulating immune responses. A soluble form of CTLA-4 (sCTLA-4), resulting from an alternative splicing, has been identified and was found increased in several autoimmune diseases. Here, we evaluated circulating levels of sCTLA-4 as a marker of immune dysregulation in SpA. Intracellular CTLA-4 and levels of CTLA-4 transcript expression in peripheral blood lymphocytes (PBL) were also studied. Methods: Sera from 165 patients with SpA were evaluated for sCTLA-4 measurements. Results were compared to those from 71 patients with rheumatoid arthritis (RA) and 88 healthy subjects. In 32 patients with SpA, 22 patients with RA and 15 healthy controls, we analyzed the intracellular CTLA-4 expression in CD4+ T cells, CD8+ T cells, activated (HLA-DR+Foxp3-) CD4+ T cells, CD4+ regulatory (CD25+Foxp3+) T cells and in CD3 negative cells by flow cytometry. Expression of the full length (coding for membrane CTLA-4) and spliced form (coding for sCTLA-4) of CTLA-4 transcripts in PBL were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). Results: High levels of sCTLA-4 were found in the SpA group compared to the RA group and healthy controls (P< 0.0001). Soluble CTLA-4 serum levels strongly correlated with clinical index of disease activity BASDAI (r= 0.42, P< 0.0001) and C-reactive protein (CRP) levels (r= 0.17, P= 0.037). In contrast to RA patients, SpA patients did not exhibit changes in intracellular CTLA-4 expression in the different PBL subsets tested. Finally, the SpA group showed a preferential expression of the spliced CTLA-4 mRNA (P= 0.0014) in PBL. Conclusions: SpA patients exhibit high levels of circulating sCTLA-4 that may result from an alternative splicing of CTLA-4 transcripts. This may influence immune activation and regulation in SpA.

Pathogenesis of tendinopathies: inflammation or degeneration?

The intrinsic mechanisms of tendinopathies are largely unknown and whether inflammation or degeneration have the prominent pathogenetic role is debated.Assuming that there is a continuum from physiology to pathology, overuse may be considered as the initial disease factor; microruptures of tendon fibers occur and several molecules are expressed: some of them promote the healing process, others, including inflammatory-cytokines can act as disease mediators. The neural ingrowth, accompanying the neovessels, explains the occurrence of pain and triggers a neurogenic mediated inflammation.It is conceivable that inflammation and degeneration are not mutually exclusive, but work together in the pathogenesis of tendinopathies.

Molecular therapies for systemic lupus erythematosus: clinical trials and future prospects

The prognosis of patients with systemic lupus erythematosus has greatly improved since treatment regimens combining corticosteroids and immunosuppressive medications have been widely adopted in therapeutic strategies given to these patients. Immune suppression is evidently efficient but also leads to higher susceptibility to infectious and malignant diseases. Toxic effects and sometimes unexpectedly dramatic complications of current therapies have been progressively reported. Identifying novel molecular targets therefore remains an important issue in the treatment of lupus. The aim of this review article is to highlight emerging pharmacological options and new therapeutic avenues for lupus with a particular focus on non-antibody molecular strategies.

Epidemiology, costs, and the economic burden of fibromyalgia

The assumption, that fibromyalgia is associated with a maior impact on the utilization of both healthcare and non-healthcare resources has not been thoroughly supported by many evidence-based data. Despite the differences between health care and sociopolitical systems in various countries, more recent results from epidemiological research now clearly demonstrate the socioeconomic burden of fibromyalgia and its comorbidities. The costs of the disease, calculated in single studies and countries, allow estimates for populations in other countries. The alarming results highlight the urgent need both for more research (including pathophysiology and epidemiology) and for the acceptance of emerging treatment challenges.

Myeloid dendritic cells correlate with clinical response whereas plasmacytoid dendritic cells impact autoantibody development in rheumatoid arthritis patients treated with infliximab

IntroductionThe objective of our study was to identify the significance of the sub-types of dendritic cell (DC), specifically myeloid DC (mDC) and plasmacytoid DC (pDC), in rheumatoid arthritis (RA) pathogenesis through their longitudinal follow-up in patients receiving infliximab. Methods: Circulating mDC and pDC levels were evaluated by flow cytometry in RA patients (n = 61) and healthy volunteers (n = 30). In RA patients, these levels were measured before and during infliximab therapy. Their counts were correlated to RA disease activity markers and anti-nuclear antibodies occurrence. Interferon-a production was measured by ELISA in serum of RA patients and, in vitro, in supernatant of peripheral blood mononuclear cells stimulated by influenza virus in presence or absence of infliximab. Statistical evaluations were based on Mann-Whitney tests or Wilcoxon's signed rank tests. Results: RA patients with active disease were characterized by a baseline decrease in both circulating pDCs and mDCs. Disease activity markers inversely correlated only with mDC level. This level increased in RA patients responsive to infliximab therapy, to reach the level observed in controls. Conversely, anti-nuclear antibodies appearance during infliximab therapy correlated inversely with pDCs level and was associated with increased serum interferon-a level and circulating plasma cells number. In vitro studies revealed that infliximab kept pDCs in an interferon-a secreting state upon viral stimulation allowing differentiation of B cells into anti-nuclear antibody-secreting plasma cells. Conclusions: This study reveals two distinct roles for pDC and mDC in RA. Circulating mDCs mainly contribute to RA activity, whereas pDCs seem to be involved in appearance of anti-nuclear antibodies under infliximab therapy through the ability of this drug to keep pDCs in an interferon-a secreting state.

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

IntroductionRheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods: Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and normal synovia were linked to the biological processes involved in each situation. Results: Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from normal synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions: Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment.

[Editorials] Methotrexate: the gold standard without standardisation

[Reviews] Erectile dysfunction in systemic sclerosis

Erectile dysfunction (ED) is observed in up to 81% of men with systemic sclerosis (SSc) and therefore should be counselled as a common complaint in this disorder. Whereas ED is frequently associated with atherosclerosis in the general population in which it is also a harbinger of cardiovascular events, ED has a different aetiology in SSc. In SSc the penile blood flow is impaired due to both myointimal proliferation of small arteries and corporal fibrosis. Data on the prevention of ED in SSc are not available. On-demand phosphodiesterase type 5 (PDE-5) inhibitors are not effective in improving erectile function, but fixed daily or alternate day regimens of long acting PDE-5 inhibitors provide a measurable, although often limited, clinical benefit. When intracavernous injections of prostaglandin E1 (alprostadil) are ineffective, the implantation of a penile prosthesis may be considered. Complex treatment options may require the involvement of urology.

[Recommendation] Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

Objectives: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. Methods: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007–8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005–7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. Results: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases. Conclusions: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

[Clinical and epidemiological research] Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature

Objectives: To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice recommendations. Methods: A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and American College of Rheumatology/European League Against Rheumatism meeting abstracts, searching for randomised controlled trials evaluating various dosages or routes of administration of methotrexate in RA. Articles that fulfilled predefined inclusion criteria were systematically reviewed and the quality was appraised. Effect sizes and odds ratios for clinical, radiological and toxicity outcomes were calculated and directly or indirectly compared between study groups using methotrexate in different dosages or by different routes. Results: A total of 38 publications out of 1748 identified references was included in the review. Start doses of 25 mg/week or fast escalation with 5 mg/month to 25–30 mg/week were associated with higher clinical effect sizes and more (gastrointestinal) adverse events in comparison with doses of 5–15 mg/week or slow escalation. Starting with 15 mg/week subcutaneous versus oral methotrexate was associated with higher clinical efficacy but more withdrawal due to toxicity in early RA. In longstanding RA, after failure on 15–20 mg/week orally, a switch to 15 mg/week intramuscularly with subsequent dose escalation did not result in increased efficacy. Conclusions: Starting on methotrexate 15 mg/week orally, escalating with 5 mg/month to 25–30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, seems to be the optimal evidence-based dosing and routing recommendation for methotrexate in RA.

[Clinical and epidemiological research] Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research

Objective: To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA). Methods: A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied. Results: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a–2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b–4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b–4). Conclusion: This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.

[Clinical and epidemiological research] Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis

Objective: To evaluate the efficacy and toxicity of methotrexate (MTX) monotherapy compared with MTX combination with non-biological disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis. Method: A systematic review of randomised trials comparing MTX alone and in combination with other non-biological DMARDs was carried out. Trials were identified in Medline, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy. Results: A total of 19 trials (2025 patients) from 6938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (relative risk (RR) = 1.16; 95% CI 0.70 to 1.93). Trials in MTX or non-MTX DMARD inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups (RR = 0.86; 95% CI 0.49 to 1.51 and RR = 0.75; 95% CI 0.41 to 1.35), but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed a better efficacy/toxicity ratio than MTX alone with RR = 0.3 (95% CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effects and liver toxicity. Withdrawals for toxicity were most significant with ciclosporin and azathioprine combinations. Conclusion: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

[Clinical and epidemiological research] Inhibition of radiographic progression with combination etanercept and methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy

Objective: To determine the effect of changing from etanercept or methotrexate monotherapy to etanercept plus methotrexate combination therapy on radiographic progression in rheumatoid arthritis (RA) patients. Methods: Patients enrolled in this 1-year open-label study previously completed a 3-year blinded study in which they received methotrexate or etanercept monotherapy or the combination of both. All patients received the combination of etanercept 25 mg subcutaneously twice weekly plus oral methotrexate up to 20 mg/week. The primary radiographic endpoint was a change in modified total Sharp score (TSS), as assessed by blinded readers. Results: At baseline, patients previously receiving methotrexate monotherapy (etanercept-added, n = 52) or etanercept monotherapy (methotrexate-added, n = 68) had moderate disease activity levels (mean disease activity score (DAS) of 2.6 and 2.5, respectively), whereas patients previously receiving combination therapy (n = 90) had a low disease activity level (mean DAS of 2.0). The addition of etanercept to methotrexate monotherapy resulted in a significant reduction in radiographic progression (p<0.05). Mean TSS changes in the previous year versus the current year were +1.79 versus +0.25 for the etanercept-added group (p<0.05); +0.51 versus –0.18 for the methotrexate-added group (NS) and +0.42 versus +0.24 for the combination group (NS). Conclusion: In these RA patients with on average moderate disease activity despite previous methotrexate monotherapy, combination treatment with etanercept and methotrexate inhibited radiographic progression and improved radiographic outcomes. These data, in conjunction with the previously published clinical data, support the use of combination therapy in RA patients with moderate disease activity.

[Clinical and epidemiological research] Dose-related patterns of glucocorticoid-induced side effects

Objective: To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. Methods: Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5–7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. Results: The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). Conclusion: The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit–risk ratio.

[Clinical and epidemiological research] Deoxyspergualin in relapsing and refractory Wegener's granulomatosis

Objectives: Conventional therapy of Wegener’s granulomatosis with cyclophosphamide and corticosteroids is limited by incomplete remissions and a high relapse rate. The efficacy and safety of an alternative immunosuppressive drug, deoxyspergualin, was evaluated in patients with relapsing or refractory disease. Methods: A prospective, international, multicentre, single-limb, open-label study. Entry required active Wegener’s granulomatosis with a Birmingham vasculitis activity score (BVAS) >=4 and previous therapy with cyclophosphamide or methotrexate. Immunosuppressive drugs were withdrawn at entry and prednisolone doses adjusted according to clinical status. Deoxyspergualin, 0.5 mg/kg per day, was self-administered by subcutaneous injection in six cycles of 21 days with a 7-day washout between cycles. Cycles were stopped early for white blood count less than 4000 cells/mm3. The primary endpoint was complete remission (BVAS 0 for at least 2 months) or partial remission (BVAS <50% of entry score). After the sixth cycle azathioprine was commenced and follow-up continued for 6 months. Results: 42/44 patients (95%) achieved at least partial remission and 20/44 (45%) achieved complete remission. BVAS fell from 12 (4–25), median (range) at baseline to 2 (0–14) at the end of the study (p<0.001). Prednisolone doses were reduced from 20 to 8 mg/day (p<0.001). Relapses occurred in 18 (43%) patients after a median of 170 (44–316) days after achieving remission. Severe or life-threatening (>= grade 3) treatment-related adverse events occurred in 24 (53%) patients mostly due to leucopaenias. Conclusions: Deoxyspergualin achieved a high rate of disease remission and permitted prednisolone reduction in refractory or relapsing Wegener’s granulomatosis. Adverse events were common but rarely led to treatment discontinuation.

[Clinical and epidemiological research] Cardiovascular morbidity in psoriatic arthritis

Background: Increasing evidence for cardiovascular mortality among patients with psoriasis and psoriatic arthritis (PsA) has accumulated, together with evidence for increased prevalence of risk factors for cardiovascular disease (CVD). Objectives: To describe cardiovascular morbidity in PsA, determine its prevalence and identify risk factors for its development. Methods: At the University of Toronto, patients were followed up prospectively according to a standard protocol, including disease-related features and comorbidities. Patients with CVD, including myocardial infarction (MI), angina, hypertension and cerebrovascular accident (CVA), were identified. The prevalence of CVD morbidities in these patients was compared with data from the Canadian Community Health Survey through standardised prevalence ratios (SPRs). Cox relative risk regression analysis was used to analyse risk factors. Results: At the time of analysis, 648 patients were registered in the database. After clinic entry, 122 developed hypertension, 38 had an MI and 5, 21 and 11 had CVA, angina and congestive heart failure (CHF), respectively. 155 patients had at least one of these conditions. The SPRs for MI (2.57; 95% CI 1.73 to 3.80), angina (1.97; 95% CI 1.24 to 3.12) and hypertension (1.90; 95% CI 1.59 to 2.27) were statistically significant, whereas the SPRs for CHF (1.19; 95% CI 0.50 to 2.86) and CVA (0.91; 95% CI 0.34 to 2.43) were not. Factors associated with CVD included diabetes, hyperlipidaemia and high Psoriasis Area and Severity Index scores. Conclusion: Patients with PsA are at increased risk of cardiovascular morbidities compared with the general population. In addition to known risk factors for CVD, severe psoriasis is an important predictor in patients with PsA.

[Clinical and epidemiological research] The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events

Objective: To evaluate the safety of biological treatments for rheumatoid arthritis (RA) using results from randomised controlled trials (RCT). Methods: The literature was searched to December 2007 for RCT evaluating inhibitors of tumour necrosis factor alpha (anti-TNF) for RA. Safety data were abstracted and risk estimates were calculated using three approaches, meta-analysis with and without adjustment for exposure and simple exposure-adjusted pooling. Results: Eighteen randomised trials involving 8808 RA subjects were included. Treatment with recommended doses of anti-TNF found no increase in the odds of death (odds ratio (OR) 1.39; 95% CI 0.74 to 2.62), serious adverse events (OR 1.11; 95% CI 0.94 to 1.32), serious infection (OR 1.21; 95% CI 0.89 to 1.63), lymphoma (OR 1.26; 95% CI 0.52 to 3.06), non-melanoma skin cancers (OR 1.27; 95% CI 0.67 to 2.42) or the composite endpoint of non-cutaneous cancers plus melanomas (OR 1.31; 95% CI 0.69 to 2.48) when evaluated using the unadjusted meta-analytic method. Risk estimates were similar with the other methods. For subjects who received two to three times the recommended doses of anti-TNF the risk of serious infection was increased with the unadjusted meta-analytic and pooled analysis, (OR 2.07; 95% CI 1.31 to 3.26) and (risk ratio (RR) 1.83; 95% CI 1.18 to 2.85), respectively, but not increased in the exposure-adjusted meta-analysis (RR 1.99; 95% CI 0.90 to 4.37). Meta-regression identified that the risk of serious infection with anti-TNF therapy decreases with increasing trial duration (p = 0.035). Conclusion: Meta-analytic and exposure-adjusted pooled analyses on over 8800 RA subjects in RCT treated over an average of 0.8 years did not identify an increased risk of serious adverse events with recommended doses. High-dose anti-TNF therapy was associated with a twofold increase in the risk of serious infections.

[Clinical and epidemiological research] Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study

Objective: To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy. Methods: Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2–3 g/day) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with active RA despite sulfasalazine therapy. Efficacy was assessed using the American College of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO). Results: Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS 5.1, 5.2 and 5.1 for etanercept (n = 103), etanercept plus sulfasalazine (n = 101) and sulfasalazine (n = 50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS 2.8, 2.5 versus 4.5, respectively (p<0.05); ACR 20 response was achieved by 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar pattern; a clinically significant improvement in health assessment questionnaire was achieved by 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01). Conclusion: Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine.

[Clinical and epidemiological research] Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis

Objectives: To compare the clinical and radiological efficacy of initial vs delayed treatment with methotrexate (MTX) and infliximab (IFX) in patients with recent onset rheumatoid arthritis (RA). Methods: In a post hoc analysis of the BeSt study (for Behandel Stratagieen, Dutch for treatment strategies), 117 patients who started initial MTX+IFX were compared with 67 patients who started MTX+IFX treatment after failing (disease activity score (DAS)>2.4; median delay to IFX: 13 months) on >=3 traditional DMARDs. If the DAS remained >2.4, the protocol dictated IFX dose increases to 6, 7.5 and 10 mg/kg. In case of a DAS <=2.4 for >=6 months, IFX was tapered and finally stopped. We aimed to correct for allocation bias using propensity scores. Functional ability was measured by the Health Assessment Questionnaire (HAQ), radiological progression by Sharp/van der Heijde scoring (SHS). Results: Baseline differences between the initial and delayed groups were no longer significant after propensity score adjustment. At 3 years after baseline, patients treated with initial MTX+IFX experienced more improvement in HAQ over time and were less likely to have SHS progression than patients treated with delayed MTX+IFX (p = 0.034). At 2 years after IFX initiation, more patients in the initial group compared with the delayed group could discontinue IFX after a good response (56% vs 29%, p = 0.008). Conclusions: The results of this post hoc analysis suggest that using MTX+IFX as initial treatment for patients with recent onset RA is more effective than reserving MTX+IFX for patients who failed on traditional DMARDs, with more HAQ improvement over time, more IFX discontinuation and less progression of joint damage.

[Clinical and epidemiological research] Perinatal characteristics, early life infections and later risk of rheumatoid arthritis and juvenile idiopathic arthritis

Objectives: To investigate the importance of birth characteristics and early life infections on the risk of later rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Methods: A nationwide register-based case–control study was performed based on prospectively recorded data on individuals born in 1973 or later. Using the Swedish inpatient register and the early arthritis register, cases with RA aged 16 years or above (n = 333) and JIA (n = 3334) were identified. From the Swedish medical birth register (MBR), four controls per case, matched by sex, year and delivery unit were randomly selected. Through linkage to the MBR and to the Swedish inpatient register information on maternal, pregnancy and birth characteristics and infections during the first year of life was identified. Univariate and multivariate odds ratios (OR) were calculated using conditional logistic regression. Results: Overall, infections during the first year of life were associated with increased risks for seronegative (OR 2.6, 95% CI 1.0 to 7.0) but not seropositive (OR 1.2) RA and for JIA (OR 1.9, 95% CI 1.7 to 2.1). Low birth weight (OR 0.7) and being small for gestational age (OR 0.5) were associated with reduced risks of RA of borderline statistical significance. Preterm birth (gestational age <=258 days) was associated with a non-significantly decreased risk of RA (OR 0.6). Large for gestational age (OR 1.6) and having more than three older siblings (OR 1.4) were non-significantly associated with the risk of RA. Conclusion: Infections during the first year of life, and possibly also factors related to fetal growth and timing of birth, may be important in the aetiologies of adult RA and JIA.

[Clinical and epidemiological research] Reproductive history, hormonal factors and the incidence of hip and knee replacement for osteoarthritis in middle-aged women

Objectives: To examine the effect of reproductive history and use of hormonal therapies on the risk of hip and knee joint replacement for osteoarthritis. Methods: A prospective study of 1.3 million women aged on average 56 years at recruitment and followed-up through linkage to routinely collected hospital admission records was conducted. The adjusted relative risk (RR) of hip and knee replacement for osteoarthritis was examined in relation to parity, age at menarche, menopausal status, age at menopause and use of hormonal therapies. Results: Over a mean of 6.1 person-years of follow-up, 12 124 women had a hip replacement and 9977 a knee replacement. The risk of joint replacement increased with increasing parity and the effect was greater for the knee than the hip: increase in RR of 2% (95% CI 1 to 4%) per birth for hip replacement and 8% (95% CI 6 to 10%) for knee replacement. An early age at menarche slightly increased the risk of hip and knee replacement (relative risk for menarche <=11 years versus 12 years, 1.09 (95% CI 1.03 to 1.16) and 1.15 (95% CI 1.08 to 1.22), respectively). Menopausal status and age at menopause were not clearly associated with risk. Current use of postmenopausal hormone therapy was associated with a significant increase in the incidence of hip and knee replacement (RR 1.38 (95% CI 1.30 to 1.46) and RR 1.58 (95% CI 1.48 to 1.69), respectively) while previous use of oral contraceptives was not (RR 1.02 (95% CI 0.98 to 1.06) and RR 1.00 (95% CI 0.96 to 1.04) for hip and knee, respectively). Conclusions: Hormonal and reproductive factors affect the risk of hip and knee replacement, more so for the knee than the hip. The reasons for this are unclear.

[Miscellaneous] RETRACTION

[Clinical and epidemiological research] Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: explorative analyses from the PREMIER study

Objective: The effect of adalimumab on hand osteoporosis was examined and related to radiographic joint damage in the three treatment arms of the PREMIER study: adalimumab plus methotrexate, adalimumab and methotrexate monotherapy. Predictors of hand bone loss were also searched for. Methods: 768 patients (537 fulfilled 2 years) with rheumatoid arthritis (RA) for less than 3 years, never treated with methotrexate, were included. Hand bone loss was assessed by digital x ray radiogrammetry (DXR) on the same hand radiographs scored with modified Sharp score at baseline, 26, 52 and 104 weeks. For DXR, metacarpal cortical index (MCI) was the primary bone measure. Results: At all time points the rate of percentage DXR–MCI loss was lowest in the combination group (–1.15; –2.16; –3.03) and greatest in the methotrexate monotherapy group (–1.42; –2.87; –4.62), with figures in between for the adalimumab monotherapy group (–1.33; –2.45; –4.03). Significant differences between the combination group and the methotrexate group were seen at 52 (p = 0.009) and 104 weeks (p<0.001). The order of hand bone loss across the three treatment arms was similar to the order of radiographic progression. Older age, elevated C-reactive protein and non-use of adalimumab were predictors of hand bone loss. Conclusion: This study supports a similar pathogenic mechanism for hand bone loss and erosions in RA. The combination of adalimumab and methotrexate seems to arrest hand bone loss less effectively than radiographic joint damage. Quantitative measures of osteoporosis may thus be a more sensitive tool for assessment of inflammatory bone involvement in RA.

[Clinical and epidemiological research] Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials

Purpose: Tumour necrosis factor (TNF) plays an important role in inflammation and may affect tumour growth control. To assess the risk of malignancy with etanercept, a fusion protein that inhibits TNF action, a meta-analysis was performed using individual patient data from randomised controlled trials (RCT) in patients with rheumatoid arthritis (RA). Methods: A search was conducted of bibliographic databases, abstracts from annual meetings and any unpublished studies on file with manufacturers of etanercept to December 2006. Only RCT of etanercept used for 12 weeks or more in patients with RA were included. Nine trials met the inclusion criteria. To adjudicate endpoints, the case narratives of potential cases were reviewed. Patient-level data were extracted from the clinical trials databases. Results: The nine trials included 3316 patients, 2244 who received etanercept (contributing 2484 person-years of follow-up) and 1072 who received control therapy (1051 person-years). Malignancies were diagnosed in 26 patients in the etanercept group (incidence rate (IR) 10.47/1000 person-years) and seven patients in the control group (IR 6.66/1000 person-years). A Cox’s proportional hazards, fixed-effect model stratified by trial yielded a hazard ratio of 1.84 (95% CI 0.79 to 4.28) for the etanercept group compared with the control group. Conclusions: In this analysis, the point estimate of malignancy risk was higher in etanercept-treated patients, although the results were not statistically significant. The approach of obtaining individual patient data of RCT in cooperation with trial sponsors allowed important insights into the methodological advantages and challenges of sparse adverse event data meta-analysis.

[Clinical and epidemiological research] Sensitivity and specificity of the American College of Rheumatology 1987 criteria for the diagnosis of rheumatoid arthritis according to disease duration: a systematic literature review and meta-analysis

Objective: To evaluate the ability of the widely used ACR set of criteria (both list and tree format) to diagnose RA compared with expert opinion according to disease duration. Methods: A systematic literature review was conducted in PubMed and Embase databases. All articles reporting the prevalence of RA according to ACR criteria and expert opinion in cohorts of early (<1 year duration) or established (>1 year) arthritis were analysed to calculate the sensitivity and specificity of ACR 1987 criteria against the "gold standard" (expert opinion). A meta-analysis using a summary receiver operating characteristic (SROC) curve was performed and pooled sensitivity and specificity were calculated with confidence intervals. Results: Of 138 publications initially identified, 19 were analysable (total 7438 patients, 3883 RA). In early arthritis, pooled sensitivity and specificity of the ACR set of criteria were 77% (68% to 84%) and 77% (68% to 84%) in the list format versus 80% (72% to 88%) and 33% (24% to 43%) in the tree format. In established arthritis, sensitivity and specificity were respectively 79% (71% to 85%) and 90% (84% to 94%) versus 80% (71% to 85%) and 93% (86% to 97%). The SROC meta-analysis confirmed the statistically significant differences, suggesting that diagnostic performances of ACR list criteria are better in established arthritis. Conclusion: The specificity of ACR 1987 criteria in early RA is low, and these criteria should not be used as diagnostic tools. Sensitivity and specificity in established RA are higher, which reflects their use as classification criteria gold standard.

[Clinical and epidemiological research] Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences

Objective: To estimate the prevalence of polymyositis and dermatomyositis using population-based administrative data, the sensitivity of case ascertainment approaches and patient demographics and these parameters. Methods: Cases were ascertained from Quebec physician billing and hospitalisation databases (approximately 7.5 million beneficiaries). Three different case definition algorithms were compared, and statistical methods were also used that account for imperfect case ascertainment, to generate estimates of disease prevalence and case ascertainment sensitivity. A hierarchical Bayesian latent class regression model was developed to assess patient characteristics with respect to these parameter estimates. Results: Using methods that account for the imperfect nature of both billing and hospitalisation databases, the 2003 prevalence of polymyositis and dermatomyositis was estimated to be 21.5/100 000 (95% credible interval (CrI) 19.4 to 23.9). Prevalence was higher for women and for older individuals, with a tendency for higher prevalence in urban areas. Prevalence estimates were lowest in young rural men (2.7/100 000, 95% CrI 1.6 to 4.1) and highest in older urban women (70/100 000, 95% CrI 61.3 to 79.3). Sensitivity of case ascertainment tended to be lower for older versus younger individuals, particularly for rheumatology billing data. Billing data appeared more sensitive in ascertaining cases in urban (vs rural) regions, whereas hospitalisation data seemed most useful in rural areas. Conclusions: Marked variations were found in the prevalence of polymyositis and dermatomyositis according to age, sex and region. These methods allow adjustment for the imperfect nature of multiple data sources and estimation of the sensitivity of different case ascertainment approaches.

[Clinical and epidemiological research] Effects of infliximab therapy on biological markers of synovium activity and cartilage breakdown in patients with rheumatoid arthritis

Background: Defining the remission criteria of rheumatoid arthritis (RA) remains a critical issue. Markers of synovium activity, urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) and of cartilage destruction, urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II) have been shown to reflect disease activity and joint damage progression in RA. Methods: The prospective study cohort comprised 66 RA patients treated with infliximab and methotrexate and 76 healthy controls. Measurements of urinary Glc-Gal-PYD and CTX-II were performed at baseline and at 1 year of infliximab therapy. Results: At baseline, urinary Glc-Gal-PYD and CTX-II levels were increased in patients with RA and correlated with modified Sharp scores and progression of joint damage. Patients with more progressive joint destruction had higher Glc-Gly-PYD and CTX-II baseline levels. Conclusion: These markers reflected bone erosion evolution and might be useful for treatment monitoring and evaluation of RA. Markers remained high even in clinical responders after infliximab, suggesting persistence of synovitis.

[Basic and translational research] Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance

Background: Earlier publications have suggested a possible role for the efflux transporter breast cancer resistance protein (BCRP) in acquired resistance to disease-modifying antirheumatic drugs (DMARDs) such as leflunomide and its metabolite A771726 (teriflunomide). However, there is no direct evidence that BCRP interacts with these drugs. Objectives: To characterise the interaction between BCRP transporter and leflunomide and its active metabolite A771726, with emphasis on the nature of the interaction (substrate or inhibitor) and the kinetic characterisation of the interactions. Methods: Different in vitro membrane-based methods (ATPase and vesicular transport assay) using BCRP-HAM-Sf9 membrane preparations and cellular assays (Hoechst assay and cytotoxicity assay) were performed on PLB985-BCRP and HEK293-BCRP cell lines overexpressing BCRP. Results: In all assays used, an interaction between the investigated drugs and BCRP was detected. In the vesicular transport assay, both leflunomide and its metabolite inhibited BCRP-mediated methotrexate transport. Both compounds are likely substrates of BCRP as shown by the vanadate-sensitive ATPase assay. In line with the membrane assays, leflunomide and A771726 inhibited BCRP-mediated Hoechst efflux from PLB985-BCRP cells. In the cytotoxicity assay, overexpression of BCRP conferred 20.6-fold and 7.5-fold resistance to HEK293 cells against leflunomide and A771726, respectively. The resistance could be reversed by Ko134, a specific inhibitor of BCRP. Conclusion: Based on these results, BCRP could play an important role in the resistance to leflunomide and A771726 via interactions with these drugs. BCRP may also mediate drug-drug interactions when leflunomide is administered with other BCRP substrate drugs such as methotrexate.

[Basic and translational research] Quantitative assessment of antibodies to ribonucleoproteins in primary Sjogren syndrome: correlation with B-cell biomarkers and disease activity

Objectives: To assess the added value of using a radioligand assay (RLA) compared with ELISA to detect antibodies to SSA, SSB and RNP, and to analyse the correlation between autoantibody levels, B-cell biomarkers and disease activity. Patients and methods: Antibodies to SSA, SSB and RNP were assessed in 127 patients with primary Sjögren syndrome (pSS) using an RLA and ELISA. In parallel, measures of B-cell activation were determined including serum levels of B-cell-activating factor of the tumour necrosis factor family or BLyS (BAFF). Results: RLA was more sensitive than ELISA for the detection of antibodies to SSB (54% of positive samples versus 37%, respectively) and antibodies to RNP (9% vs 3%). No difference was seen for the sensitivity of detection of antibodies to SSA. Anti-SSA and anti-SSB levels were correlated with both techniques. Mean levels of antibodies to SSA were significantly higher in patients presenting antibodies to both SSA and SSB than in those exhibiting antibodies to SSA only (RLA: mean (SEM) anti-SSA levels 2343 (158) cpm vs 1348 (286) cpm, respectively, p = 0.02; ELISA: 6.8 (0.8) vs 3.8 (0.4), respectively, p = 0.003). Levels of antibodies to SSA and SSB significantly correlated with those of circulating BAFF (r = 0.4, p = 0.004 and r = 0.6, p<0.001, respectively) and with B-cell biomarkers, including levels of gammaglobulins, β2 microglobulin and rheumatoid factor. Conclusion: RLA allowed a quantitative and more sensitive detection of antibodies to SSB and RNP in pSS. Quantitative assessment of autoantibodies might disclose a biomarker of disease activity and enable further insight into the pathogenesis of the spreading of the autoantibody response.

[Basic and translational research] The cyclic GMP-dependent protein kinase II gene associates with gout disease: identified by genome-wide analysis and case-control study

Objective: To identify the position of a gout susceptibility gene. Methods: A genome-wide scan was performed using 382 random polymorphic microsatellite markers spread across 22 autosomes in a Taiwanese family with gout to screen for the gout susceptibility genetic marker. Its association with gout by 33 single nucleotide polymorphisms (SNP) in 148 matched case–control subjects was confirmed. The family with gout comprised eight patients with gout and 10 gout-free subjects; case–control subjects were 74 male patients with gout and 74 healthy controls matched by age. Results: Analysis of the genome-wide scan results by a non-parametric linkage method found that chromosome 4q21 contains a locus significantly linked with gout (D4S3243 at 81 289 553 bp; p = 0.004; LOD score = 5.13). In SNP genotyping analysis at the neighbourhood regions of marker D4S3243 for the case–control subjects, the polymorphisms rs7688672 and rs6837293, located on the cGMP-dependent protein kinase II (cGK II) gene, were found to relate significantly to gout disease in a recessive model after adjustment of hyperuricaemia (OR = 2.89, 95% CI 1.19 to 7.02 and OR = 2.72, 95% CI 1.13 to 6.54, respectively). Conclusions: This study suggests that the cGK II gene on chromosome 4q21 is most likely to harbour gout disease independently of hyperuricaemia and is inherited recessively.

[Basic and translational research] Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study

Objectives: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNF) blocking therapy. Methods: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. Results: Sixteen patients (13 women) were studied; all had previously failed TNF-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFN of –52% (95% CI –73 to –15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE–MRI showed a reduction of 15–40% in MRI parameters. Conclusion: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

[Letters] When and how to stop etanercept after successful treatment of patients with juvenile idiopathic arthritis

[Letters] IL23R and IL12B genes: susceptibility analysis in rheumatoid arthritis

[Letters] Thrombin-activatable fibrinolysis inhibitor and its relation with inflammation in rheumatoid arthritis

[Letters] Bilateral parotid gland involvement in Wegener granulomatosis

[Letters] Different effects of local cryogel and cold air physical therapy in wrist rheumatoid arthritis visualised by power Doppler ultrasound

[Letters] Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment

Clinical and immunogenetic prognostic factors for radiographic severity in ankylosing spondylitis

To improve prognostic ability in ankylosing spondylitis (AS), we sought to identify demographic, clinical, and immunogenetic characteristics associated with radiographic severity in a large cohort of patients.Patients with AS for [ge]20 years were enrolled in a cross-sectional study (n = 398). Pelvic and spinal radiographs were scored using the Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s), and radiographic severity was measured as the BASRI-s/duration of AS. Clinical factors and HLA-B, DR, DQ, and DP alleles associated with the highest quartile of the distribution of radiographic severity were identified by first using random forests and then using multivariable logistic regression modeling. Similar procedures were used to identify factors associated with the lowest quartile of radiographic severity.Radiographic severity (being in the top quartile of BASRI-s/duration of AS) was associated with older age at onset of AS (odds ratio [OR] 1.10 per year), male sex (OR 1.90), current smoker (OR 4.72), and the presence of HLA-B*4100 (OR 11.73), DRB1*0804 (OR 12.32), DQA1*0401 (OR 5.24), DQB1*0603 (OR 3.42), and DPB1*0202 (OR 23.36), whereas the presence of DRB1*0801 was strongly negatively associated (OR 0.03). Being in the lowest quartile of BASRI-s/duration of AS was also less likely among those with an older age at onset of AS (OR 0.94 per year), men (OR 0.28), and current smokers (OR 0.29).The accuracy of the prognosis of radiographic severity in AS is improved by knowing the age at disease onset, sex, smoking history, and the presence of HLA-B*4100, DRB1*0804, DQA1*0401, DQB1*0603, DRB1*0801, and DPB1*0202 alleles.

Mail-delivered arthritis self-management tool kit: A randomized trial and longitudinal followup

To determine the effectiveness of an intervention Tool Kit of arthritis self-management materials to be sent once through the mail, and to describe the populations reached.Spanish speakers (n = 335), non-Hispanic English-speaking African Americans (n = 156), and other non-Hispanic English speakers (n = 404) were recruited separately and randomized within each of the 3 ethnic/racial categories to immediately receive the intervention Tool Kit (n = 458) or to a 4-month wait-list control status (n = 463). At the end of 4 months, controls were sent the Tool Kit. All subjects were followed in a longitudinal study for 9 months. Self-administered measures included health status, health behavior, arthritis self-efficacy, medical care utilization, and demographic variables. Using analyses of covariance and t-tests, analyses were conducted for all participants and for Spanish- and English-language groups.At 4 months, comparing all intervention subjects with randomized wait-list controls, there were significant (P < 0.01) benefits in all outcomes except medical care utilization and self-rated health. The results were maintained at 9 months compared with baseline. On average, the Tool Kit reached persons ages 50-56 years with 12-15 years of schooling. There were few differences between English- and Spanish-language participants in either the effectiveness or reach variables.A mailed Arthritis Self-Management Tool Kit proved effective in improving health status, health behavior, and self-efficacy variables for up to 9 months. It also reached younger persons in both English- and Spanish-language groups and Spanish speakers with higher education levels than previous studies of the small-group Arthritis Self-Management Program.

Comparison of two methods of conducting the fit and strong! program

Fit and Strong! is an award winning, evidence-based, multiple-component physical activity/behavior change intervention. It is a group- and facility-based program that meets for 90 minutes 3 times per week for 8 weeks (24 sessions total). We originally tested Fit and Strong! using physical therapists (PTs) as instructors but have transitioned to using nationally certified exercise instructors (CEIs) as part of an effort to translate Fit and Strong! into community-based settings, and have tested the impact of this shift in instruction type on participant outcomes.We used a 2-group design. The first 161 participants to sequentially enroll received instruction from PTs. The next 190 sequential enrollees received instruction from CEIs. All participants were assessed at baseline, at the conclusion of the 8-week Fit and Strong! program, and at the 6-month followup.We saw no significant differences by group on outcomes at 8 weeks or 6 months. Participants in both groups improved significantly with respect to lower-extremity strength, aerobic capacity, pain, stiffness, and physical function. Significant differences favoring the PT-led classes were seen on 2 of 5 mediators, self-efficacy for exercise and barriers adherence efficacy. Participant evaluations rated both types of instruction equally highly, attendance was identical, and no untoward health events were observed or reported under either instruction mode.Outcomes under the 2 types of instruction are remarkably stable. These findings justify the use of CEIs in the future to extend the reach of the Fit and Strong! program.

Hyperuricemia and risk of stroke: A systematic review and meta-analysis

To assess the association between hyperuricemia and risk of stroke incidence and mortality because hyperuricemia is hypothesized to be a risk factor for stroke and other cardiovascular disease, but, to date, results from observational studies are conflicting.A systematic review and meta-analysis were conducted. Studies were identified by searching major electronic databases using the Medical Subject Headings and keywords without restriction in languages. Prospective cohort studies were included only if they contained data on stroke incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the association of stroke incidence and mortality with serum uric acid levels were calculated.A total of 16 studies including 238,449 adults were eligible and abstracted. Hyperuricemia was associated with a significantly higher risk of both stroke incidence (6 studies; RR 1.41, 95% confidence interval [95% CI] 1.05, 1.76) and mortality (6 studies; RR 1.36, 95% CI 1.03, 1.69) in our meta-analyses of unadjusted study estimates. Subgroup analyses of studies adjusting for known risk factors such as age, hypertension, diabetes mellitus, and cholesterol still showed that hyperuricemia was significantly associated with both stroke incidence (4 studies; RR 1.47, 95% CI 1.19, 1.76) and mortality (6 studies; RR 1.26, 95% CI 1.12, 1.39). The pooled estimate of multivariate RRs did not differ significantly by sex.Hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future research is needed to determine whether lowering uric acid level has any beneficial effects on stroke.

Validation of whole-body against conventional magnetic resonance imaging for scoring acute inflammatory lesions in the sacroiliac joints of patients with spondylarthritis

To compare the performance of whole-body magnetic resonance imaging (MRI) versus conventional MRI in assessing acute inflammatory lesions of the sacroiliac (SI) joints in patients with established and active spondylarthritis (SpA) using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index. This study is validating whole-body MRI against the current MRI standard for assessing active inflammatory lesions of the SI joints in patients with SpA.Thirty-two SpA patients with clinically active disease (Bath Ankylosing Spondylitis Disease Activity Index score [ge]4) fulfilling the modified New York criteria were scanned by whole-body and conventional MRI of the SI joints. The MRIs were scored independently in random order by 3 readers blinded to patient identity. Active inflammatory lesions of the SI joints were recorded on a Web-based SPARCC index. Pearson's correlation coefficients were used to compare scores for whole-body and conventional MRI for each reader, whereas intraclass correlation coefficients (ICCs) were used to compare interobserver reliability.The Pearson's correlation coefficients between whole-body and conventional MRI per rater were 0.94, 0.87, and 0.93. The mean sum scores for conventional versus whole-body MRI were statistically significantly higher for all 3 readers, although all patients showing inflammatory lesions on conventional MRI also demonstrated them on whole-body MRI. The ICCs(2,1) were 0.69, 0.78, and 0.95 for conventional MRI, and 0.79, 0.85, and 0.96 for whole-body MRI for the 3 possible reader pairs.Whole-body and conventional MRI scores show a strong correlation and comparable reliability for the detection of inflammatory lesions of the SI joints.

Sensitivity and specificity of spinal inflammatory lesions assessed by whole-body magnetic resonance imaging in patients with ankylosing spondylitis or recent-onset inflammatory back pain

To determine the diagnostic utility of different spinal inflammatory lesions assessed by whole-body magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS) or with recent-onset inflammatory back pain (IBP) compared with healthy controls.We scanned 35 consecutive patients with AS fulfilling the modified New York criteria, 25 patients with IBP of 2 CIL.Diagnostic utility of STIR MRI for AS is optimal when [ge]2 CIL are present. A single CIL can be found in up to 26% of healthy individuals.

Feasibility of second-generation ultrasound contrast media in the detection of active sacroiliitis

To determine whether a recently available contrast-enhanced ultrasound (CEUS) technique using second-generation microbubbles allows for the detection of active sacroiliitis, and to measure CEUS enhancement depth at the dorsocaudal part of the sacroiliac (SI) joints in healthy volunteers compared with patients with sacroiliitis.Forty-two consecutive patients (84 SI joints) presenting with a clinical diagnosis of sacroiliitis in 50 SI joints and 21 controls (42 SI joints) were investigated by CEUS using a standardized low mechanical index ultrasound protocol. Detected vascularity was used to retrospectively measure the enhancement depth in the dorsocaudal part of the SI joints.CEUS detected enhancement in all clinically active SI joints, showing an enhancement depth into the dorsal SI joint cleft of 18.5 mm (range 16-22.1), which was significantly higher compared with both inactive joints of patients (3.6 mm, range 0-12; P < 0.001) and healthy controls (3.1 mm, range 0-7.8; P < 0.001). All inactive joints were correctly classified based on a lack of deep enhancement in patients with sacroiliitis and controls (42 of 42, 100% sensitivity, 100% specificity; Cohen's [kappa] = 1).CEUS allowed the differentiation of active sacroiliitis from inactive SI joints, and proved to be a feasible method for the detection of vascularity in clinically active sacroiliitis by showing deep contrast enhancement into the SI joints not detectable in inactive joints of patients or controls. If this technique might add information to the earlier detection of sacroiliitis, it should be addressed in further studies.

Does the use of ordered values of subregional change in cartilage thickness improve the detection of disease progression in longitudinal studies of osteoarthritis?

To propose a novel strategy for more efficiently measuring changes in cartilage thickness in osteoarthritis (OA) using magnetic resonance imaging, and to hypothesize that determining the magnitude of thickness change independent of the anatomic location provides improved discrimination between healthy subjects and OA participants longitudinally.A total of 148 women were imaged; 90 were Kellgren/Lawrence (K/L) grade 0, 30 were K/L grade 2, and 28 were K/L grade 3. Magnetic resonance images (3T) were acquired at baseline and at 24 months. Changes in femorotibial cartilage thickness were determined in 5 tibial and 3 femoral medial and lateral subregions, respectively (conventional approach). The new strategy provided ordered values of subregional change in each compartment, ranked according to the direction and magnitude of change.Using the new ordered values approach, the minimal P value for the differences in 2-year change in medial cartilage thickness of K/L grade 3 and K/L grade 0 participants was 0.001 (Wilcoxon test), with 4 ordered medial subregions differing significantly between both groups. With the conventional approach, only 1 medial subregion differed significantly between K/L grade 3 and K/L grade 0 (P = 0.037). Cartilage thickening was significantly greater in K/L grade 2 versus K/L grade 0 participants in 1 medial subregion using the conventional approach (P = 0.016), and in 2 medial subregions (minimal P = 0.007) using the ordered values approach.The novel ordered values approach is more sensitive in detecting cartilage thinning in K/L grade 3 and cartilage thickening in K/L grade 2 versus K/L grade 0 participants. The new method may be particularly useful in the context of other comparisons, e.g., a group treated with a disease-modifying OA drug versus one treated with a placebo.

Variables associated with the progression of hip osteoarthritis: A systematic review

As populations age and the prevalence of hip osteoarthritis (OA) increases, health care providers must manage increasing demands for services. Evidence regarding the progression of hip OA can assist health care practitioners in determining expected patient prognosis and planning care. This systematic review of prospective cohort studies examines prognostic variables in patients with hip OA.Articles were selected following a comprehensive search of Medline, EMBase, CINAHL, and Allied and Complementary Medicine from database inception to October 2008 and hand searches of the reference lists of retrieved articles. Inclusion criteria involved 1) estimates of the association between prognostic variables and progression of OA, 2) prospective cohort design, 3) patients diagnosed with hip OA based on established criteria, 4) at least 1 year of followup, and 5) access to the full published text. Two independent reviewers assessed the methodologic quality of each study and the association between prognostic variables and OA progression.Eighteen articles met the inclusion criteria; 17 were considered to be of high quality. Strong evidence of progression was associated with age, joint space width at entry, femoral head migration, femoral osteophytes, bony sclerosis, Kellgren/Lawrence hip grade 3, baseline hip pain, and Lequesne index score [ge]10. Strong evidence of no association with progression was associated with acetabular osteophytes. Evidence was weak or inconclusive regarding associations between various other radiographic or clinical variables, molecular biomarkers, or use of nonsteroidal inflammatory drugs.Overall, few variables were found to be strongly associated with the progression of hip OA, and a variety of other variables were weakly predictive of outcome.

Being careful: A grounded theory of emergent chronic knee problems

To gain insight into the prediagnostic stages of knee osteoarthritis (OA) and identify the process whereby people recognize and address emergent chronic knee problems.Twenty-six people (15 women, mean age 53.2 ± 7.4 years) participated in a grounded theory study. Ten participants had a recent diagnosis of knee OA, and 16 had no diagnosis. The undiagnosed participants self-reported their symptoms, which had lasted at least 6 months and were consistent with knee OA. During semistructured, one-on-one interviews, participants reflected on the development and impact of their chronic knee problems. A constant comparative approach was used for analysis.Participants described uncertainty in understanding the meaning of intermittent knee symptoms for several years before becoming aware of the emergence of chronic knee problems. Once aware, participants engaged in a circular process of interpreting the meaning of knee symptoms and being careful. Being careful referred to the cycle of perceptions, intentions, and behaviors aimed at avoiding knee damage during physical activity. This cycle continued until participants experienced a disruption that challenged their participation in meaningful activities, at which time they decided to access health care.As a new construct, being careful unifies the complex set of experiences and behaviors that describe how participants protected their knee during physical activity. Participants interpret the experiences associated with emerging knee problems through interactions with others. These interactions enhance the participants' self-management, despite not having the benefits associated with diagnosis, such as justification for symptoms and formal assistance.

Factors associated with depression and suicidal ideation among individuals with arthritis or rheumatism: Findings from a representative community survey

To investigate factors associated with depression and suicidal ideation among individuals with arthritis or rheumatism.The nationally representative Canadian Community Health Survey 2000-2001 included 130,880 respondents (response rate 84.7%). Respondents were diagnosed as depressed using a subset of items from the Composite International Diagnostic Interview. There were 23,405 respondents age [ge]20 years who reported that they had been diagnosed with arthritis or rheumatism by a health professional. Logistic regression analyses were conducted to investigate depression and suicidal ideation.One in 10 Canadians with arthritis had clinically relevant levels of major depression. The age- and sex-adjusted odds ratios (ORs) of major depression (OR 2.24, 95% confidence interval [95% CI] 2.11-2.38) and suicidal ideation (OR 2.01, 95% CI 1.75-2.31) among those with arthritis were approximately twice that of those without arthritis. The adjusted ORs of major depression among those with arthritis were significantly higher among women, the unmarried, younger, and poorer individuals. Individuals in pain, with limitations in activities of daily living, with limitations in instrumental activities of daily living, and with greater numbers of chronic conditions had higher odds of major depression. Less than half of those with major depression had consulted a mental health professional. One in 5 individuals with arthritis and major depression had been suicidal in the past year.The majority of individuals with arthritis and major depression were not receiving adequate treatment for major depression. Clients should be screened for major depression and suicidal ideation, particularly if they fall into the identified vulnerable groups.

Effect of baseline quadriceps activation on changes in quadriceps strength after exercise therapy in subjects with knee osteoarthritis

To examine whether pretreatment magnitude of quadriceps activation (QA) helps predict changes in quadriceps strength after exercise therapy in subjects with knee osteoarthritis (OA). We hypothesized that subjects with lower magnitudes of QA (greater failure of muscle activation) would have smaller gains in strength compared with those with higher magnitudes of QA following exercise therapy.One hundred eleven subjects with knee OA (70 women) participated. Baseline measures included demographic information, quadriceps muscle strength, and QA using a burst-superimposition isometric torque test. Following baseline testing, subjects underwent a 6-week supervised exercise program designed to improve strength, range of motion, balance and agility, and physical function. On completion of the program, quadriceps strength and QA were reassessed. Multiple regression analysis was used to determine whether baseline QA predicted quadriceps strength scores at the 2-month followup.Bivariate correlations demonstrated that baseline QA was significantly associated with quadriceps strength at baseline ([rho] = 0.30, P < 0.01) and 2-month followup ([rho] = 0.23, P = 0.01). Greater magnitude of baseline QA correlated with higher strength. While controlling for baseline quadriceps strength and type of exercise therapy, the level of QA did not predict quadriceps strength at the 2-month followup ([beta] = -0.04, P = 0.18).Baseline QA did not predict changes in quadriceps strength following exercise therapy. Measurement of QA using the central activation ratio method does not appear to be helpful in identifying subjects with knee OA who will have difficulty improving quadriceps strength with exercise therapy.

Anti-U11/U12 RNP antibodies in systemic sclerosis: A new serologic marker associated with pulmonary fibrosis

To characterize a new serum autoantibody in patients with systemic sclerosis (SSc) directed against U11/U12 RNP and to identify the clinical features associated with this autoantibody.We identified autoantibodies directed against the U11/U12 RNP complex in sera of patients with SSc and confirmed antibody specificity by immunoprecipitation, reverse transcriptase-polymerase chain reaction, and Southern blotting. We determined the prevalence of these antibodies in SSc and their specificity for SSc. We compared anti-U11/U12 RNP autoantibody-positive and negative SSc patients on demographic, disease classification, clinical variables, and survival.We identified 33 patients with anti-U11/U12 RNP antibodies. In 2 consecutive series of SSc patients first seen at 10-year intervals (1994-1995 and 2004-2005), the prevalence of anti-U11/U12 RNP antibody-positive patients was 15 of 462 (3.2%). Seventeen (52%) of these 33 patients had limited cutaneous involvement. All patients had Raynaud's phenomenon and 82% had gastrointestinal (GI) involvement. None had "intrinsic" pulmonary arterial hypertension. The most significant clinical difference between anti-U11/U12 antibody-positive and negative cohorts was the prevalence of lung fibrosis, which occurred in 79% of the anti-U11/U12 RNP antibody-positive patients versus 37% of the anti-U11/U12 RNP antibody-negative patients (P < 0.0001). GI involvement was also significantly increased in the anti-U11/U12 RNP antibody-positive group. Patients with anti-U11/U12 RNP antibodies and pulmonary fibrosis had a 2.25-fold greater risk of death than anti-U11/U12 RNP negative patients with pulmonary fibrosis.Anti-U11/U12 RNP antibodies are present in the sera of approximately 3% of patients with SSc and are a marker for lung fibrosis, which is often severe.

Sociodemographic, disease, and symptom correlates of fatigue in systemic sclerosis: Evidence from a sample of 659 Canadian Scleroderma Research Group Registry patients

To assess fatigue levels and demographic, socioeconomic, disease, and psychosocial correlates of fatigue in patients with systemic sclerosis (SSc).We conducted a cross-sectional, multicenter study of 659 patients with SSc from the Canadian Scleroderma Research Group Registry. Fatigue was assessed during annual Registry visits with the Short Form 36 (SF-36) health survey vitality subscale. Patients completed measures of depressive symptoms and pain and underwent clinical histories and medical examinations. Kendall's tau was used to assess bivariate association of sociodemographic, medical, and psychosocial variables with fatigue. Multivariable associations of demographic (step 1), socioeconomic (step 2), global disease (step 3), specific disease and lifestyle (step 4), and psychosocial (step 5) factors with fatigue were assessed using hierarchical multiple linear regression.The mean ± SD score of the patients on the SF-36 vitality subscale was 45.6 ± 10.8, substantially lower (indicating more fatigue) than the mean ± SD score for the Canadian general population (65.8 ± 18.0). In multivariate analysis, higher fatigue was significantly associated with the number of medical comorbidities (standardized [beta] = -0.11, P = 0.004), breathing problems (standardized [beta] = -0.23, P < 0.001), the number of gastrointestinal (GI) symptoms (standardized [beta] = -0.27, P < 0.001), and current smoking (standardized [beta] = -0.08, P = 0.018). As a group, specific symptom and lifestyle variables predicted the most incremental variance in fatigue ([utri]R2 = 21.6%, P < 0.001), despite being added to the model after demographic, socioeconomic, and global disease duration/severity indicators. Symptoms of depression ([beta] = -0.42) and pain ([beta] = -0.21) were also independently associated with fatigue (P < 0.001).High levels of fatigue are common in patients with SSc and are independently associated with clinical variables, including number of comorbidities, breathing problems, GI symptoms, and smoking.

Efficacy of intraarticular infliximab in patients with chronic or recurrent gonarthritis: A clinical randomized trial

To evaluate the efficacy and safety of intraarticular infliximab compared with intraarticular methylprednisolone in patients with gonarthritis.In 23 patients with recurrent gonarthritis despite previous intraarticular corticosteroid therapy, a total of 41 intraarticular injections (20 infliximab and 21 methylprednisolone) were performed in 28 knees. Initial therapy was randomly assigned, and crossover therapy was eligible within 3 months. The clinical effect was assessed during 6 months of followup. The primary outcome was event-free survival, defined as the time after treatment until local retreatment was performed and/or nonimprovement of the knee joint score. Adverse effects were recorded during followup.All patients treated with intraarticular infliximab had an insufficient response. In contrast, 8 of the 21 intraarticular methylprednisolone injections were effective (P = 0.004). Between groups, no differences in the patients' age, disease duration, number of disease-modifying antirheumatic drugs, or previous intraarticular methylprednisolone were observed. Reported adverse effects were not related to therapy.Treatment with intraarticular infliximab injection was not effective in patients with a chronically inflamed knee joint. Intraarticular injection with methylprednisolone was superior despite previous intraarticular corticosteroid therapy. Further investigation is needed to provide these patients with a better alternative.

Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate

To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA).In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks.After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups.Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.

Development of a structured interview tool to help patients identify and solve rheumatic condition-related work barriers

To develop a comprehensive and efficient assessment tool for rheumatic condition-related work barriers and explore its use by physical and occupational therapists.Literature on arthritis work barriers was examined, followed by the collection of qualitative data on work barriers from patients with rheumatic conditions. A tool called the Work Experience Survey-Rheumatic Conditions (WES-RC), which identifies barriers and facilitates the formation of solutions for barriers, was developed using this data. Ten physical and occupational therapists reviewed the initial version of the tool and provided qualitative data and the relevance of its use by therapists. Using this data, the WES-RC was revised. The therapists then administered the WES-RC to 20 patients. Quantitative data, qualitative data, and results of the administrative experience were collected from therapists after each administration. Relevant data were used to further revise the WES-RC. Qualitative data were coded and themes developed by 2 readers and compared. Means and frequencies were used to describe the quantitative data.The WES-RC addressed patients' work barriers quite well with a mean score of 8.7, on a scale of 1-10 where 10 = barriers completely covered, and administration time was reported as "about right" in 18 (90%) of 20 administrations. Eighty percent of the therapists' administration experiences were positive. Therapists reported barrier identification as easy, while solution formation was difficult in 45% of the administrations and judged insufficient in 35%.The WES-RC appears to be feasible for rheumatology patients and for use by physical and occupational therapists. Further study is needed to enhance effective solution formation.

Submissions invited for themed issue of Arthritis Care & Research: Drug safety in the rheumatic diseases

No abstract.

Effectiveness of an early cognitive-behavioral treatment in patients with work disability due to musculoskeletal disorders

To evaluate whether an early cognitive-behavioral treatment complementary to a rheumatologic care program, for patients with recent-onset temporary work disability caused by musculoskeletal disorders (MSDs) is effective.Patients with an MSD-related temporary work disability episode from 3-8 weeks' duration who were in a rheumatologic care program were randomized into a control group (rheumatologic care program) or an intervention group (rheumatologic care program plus cognitive-behavioral treatment). Enrollment lasted 24 months and followup lasted 6-24 months. Efficacy variables included duration of temporary work disability episodes, total number of work days saved, relative efficacy, and relative rate to return to work. An economic evaluation was also performed.One hundred eighty-one patients were included (66 control and 115 intervention patients), generating 222 episodes of MSD-related temporary work disability. Episodes tended to be shorter in the intervention group than in the control group (mean 98 versus 127 days; P = 0.053), with a relative efficacy of 22.9%. There were no differences in duration of the first episode between groups (mean 105 versus 110 days; P = 0.79), but relapse episodes were significantly shorter in the intervention group (mean 63 days versus 197 days; P = 0.0002). Costs were also lower in the intervention group. To save 1 day of temporary work disability, $13.50 had to be invested in the program. Each dollar invested generated a benefit of $4.08. The program had a net benefit of $172,607.Early cognitive-behavioral treatment complementary to a rheumatologic care program is cost-effective, adds >20% efficacy to the rheumatologic care program, and reduces the duration of relapses.

Targeted ultrasound of the fifth metatarsophalangeal joint in an early inflammatory arthritis cohort

To determine whether targeted ultrasonographic (US) imaging of the fifth metatarsophalangeal (MTP) joint, compared with radiographs, could aid in the early diagnosis of rheumatoid arthritis (RA) by identifying erosions sooner in early inflammatory arthritis. Radiographic erosion in RA is a late indication of poor prognosis. The earlier detection of erosion may facilitate the timely initiation of disease-modifying antirheumatic drug therapy, particularly in patients with undifferentiated synovitis.Patients presenting with synovitis for the first time were invited to participate. Each patient underwent laboratory tests, radiographs of the hands and feet, and US imaging of both fifth MTP joints.Thirty patients (22 women) took part in the study. Seventeen patients (57%) had RA, and 13 (43%) had undifferentiated arthritis (UA). The mean ± SD time taken to scan both fifth MTP joints was 10.9 ± 4.4 minutes. Ten patients (33%) had US evidence of synovitis associated with a positive power Doppler (PD) signal (P = 0.04). Seven patients (23%) had radiographic erosions of the fifth MTP joint, and 17 patients (57%) had US evidence of fifth MTP joint erosions (P = 0.01). A positive PD signal at the fifth MTP joint was seen in 9 of 17 patients with RA and 1 of 13 patients with UA (P = 0.02). Patients with a definite diagnosis of RA were more likely to have fifth MTP joint erosions (11 [65%] of 17) compared with UA (6 [46%] of 13).Targeted US is a rapid and useful tool in detecting erosive disease in early inflammatory arthritis. It gives a better indication of disease severity and prognosis compared with routinely available laboratory tests, even in the absence of a definite diagnosis.

Erratum

No abstract.

ARHP announcements

No abstract.

In this issue

No abstract.

Fibroblast growth factor 2: A new key player in osteoarthritis

No abstract.

B lymphocyte cytokines and rheumatic autoimmune disease

No abstract.

International rheumatology networking: The 2008 american college of rheumatology/european league against rheumatism exchange program

No abstract.

Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective french research axed on tolerance of biotherapies registry

Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence.We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects.We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7-15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4-25.8] and SIR 29.3 [95% CI 20.3-42.4] versus SIR 1.8 [95% CI 0.7-4.3], respectively). In the case-control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6-69.0] and OR 17.1 [95% CI 3.6-80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area.The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo

To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response.Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks.By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms.Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.

Adipocytokines are associated with radiographic joint damage in rheumatoid arthritis

Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA.We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor [alpha] [TNF[alpha]]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNF[alpha], IL-6, and CRP).Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32-4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI ([rho] = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17-0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42-1.73], P = 0.67).Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: A clinical and imaging comparative study

For patients with rheumatoid arthritis (RA) in remission who are receiving disease-modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging-detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging-detected synovitis.One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1-5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity.In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission.In RA patients with disease in remission, imaging-detected synovitis persists, with power Doppler activity seen in [ge]48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging-detected synovitis.

Anti-cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

It has been suggested that anti-citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement.Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.

Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis

To investigate the molecular mechanisms of CCL13/monocyte chemoattractant protein 4 (MCP-4) chemokine expression through proinflammatory cytokines in different primary human fibroblasts and the contribution of CCL13 to monocyte migration.Using RNase protection assays and enzyme-linked immunosorbent assays, we quantified the expression of CCL13 compared with that of CCL2/MCP-1 in primary human fibroblasts. Boyden chamber assays were performed to determine the importance of CCL13 for migration of primary monocytes. Pharmacologic inhibitors as well as small interfering RNA knockdown approaches were used to investigate the signaling pathways regulating CCL13 expression.The interleukin-6 (IL-6)-type cytokine oncostatin M (OSM) was a powerful inducer of CCL13 expression in primary synovial fibroblasts from patients with rheumatoid arthritis (RA) as well as those from healthy control subjects but not in other types of fibroblasts. Neither IL-6 nor tumor necrosis factor [alpha] could stimulate the expression of CCL13 in synovial fibroblasts; IL-1[beta] was a very weak inducer. Synovial fibroblasts from patients with RA constitutively produced low amounts of CCL13, which was partially dependent on constitutive production of OSM. By investigating the underlying molecular mechanism, we identified STAT-5, ERK-1/2, and p38 as critical factors involved in OSM-dependent transcription and messenger RNA stabilization of CCL13.In contrast to other prominent cytokines involved in the pathogenesis of RA, OSM can strongly up-regulate the expression of CCL13, a chemokine recently identified in the synovial fluid of patients with RA. Despite potent OSM-induced signal transduction in all types of fibroblasts analyzed, only synovial fibroblasts secreted CCL13, which might be indicative of tissue-specific imprinting of different fibroblasts during development.

Alterations of the synovial T cell repertoire in anti-citrullinated protein antibody-positive rheumatoid arthritis

The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA+ versus ACPA- RA patients.Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA+ RA patients, 7 ACPA- RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.ACPA+ and ACPA- RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA+ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA- synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis.The T cell repertoire is specifically restricted in RA patients with ACPA+ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPA-seropositive RA.

Role of osteopontin in induction of monocyte chemoattractant protein 1 and macrophage inflammatory protein 1[beta] through the NF-[kappa]B and MAPK pathways in rheumatoid arthritis

Osteopontin (OPN) is a proinflammatory protein with a critical role in leukocyte migration. Although OPN has been implicated in rheumatoid arthritis (RA), its underlying mechanism remains unknown. In this study, we investigated the role and molecular mechanism of OPN in the induction of 2 key chemokines, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1[beta] (MIP-1[beta]), in RA.Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction were used to determine chemokine expression. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation.The effect of OPN on inflammatory cell migration was mediated through its unique property of inducing the expression of MCP-1 and MIP-1[beta] in CD14+ monocytes. The concentration of OPN was significantly elevated in RA patients and appeared to correlate with the serum levels of inflammation markers and increased expression of MCP-1 or MIP-1[beta] in monocytes in RA patients. Endogenous production of OPN in RA synovial fluid was attributable to increased production of MCP-1 or MIP-1[beta], and this effect could be blocked by an anti-OPN antibody. Furthermore, the structural motif responsible for this property resided within residues 50-83 of human OPN, sparing the known RGD or SVVYGLR sequences. It was evident that the effect of OPN on chemokine expression was mediated through both the NF-[kappa]B and MAPK pathways, involving the activation of IKK[beta], p38, and JNK.These results support a unique role of OPN in leukocyte migration, in the context of perpetuation of rheumatoid synovitis through the induction of MCP-1 and MIP-1[beta].

PAN-DR-Binding Hsp60 self epitopes induce an interleukin-10-mediated immune response in rheumatoid arthritis

Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan-DR-binding Hsp60-derived epitopes as possible modulators of autoimmune inflammation in RA.Lymphocyte proliferation assays (using 3H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls.A disease (RA)-specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor [alpha] (TNF[alpha]), interleukin-1[beta] (IL-1[beta]), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4+ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5-10-fold higher IL-10:TNF[alpha] ratio, compared with that of the microbial peptides.These results suggest a disease-specific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan-DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy.

Spondylarthritis in HLA-B27/human [beta]2-microglobulin-transgenic rats is not prevented by lack of CD8

HLA-B27 predisposes to spondylarthritis by an unknown mechanism. A logical candidate mechanism is through recognition of B27 by CD8+ T cells. The purpose of this study was to examine the effects of a lack of CD8 on the spondylarthritis that develops in B27/human [beta]2-microglobulin (Hu[beta]2m)-transgenic rats.A missense mutation in the CD8a gene that causes a loss of CD8[alpha] expression was identified in offspring of a male Sprague-Dawley rat that had been treated with the mutagen N-ethyl-N-nitrosourea. The mutation was crossed into B27/Hu[beta]2m-transgenic lines on the Lewis background. CD8a-/- and CD8a+/- progeny were compared on a mixed SD-LEW background as well as after at least 10 backcrosses to LEW rats. CD8 function was assessed by generating cytolytic T lymphocytes (CTLs) against allogeneic DA strain antigens.Homozygous mutant rats showed normal CD8a and CD8b messenger RNA levels but no detectable expression of either protein and an almost complete abrogation of the allogeneic CTL response. Two disease phenotypes previously observed in different B27/Hu[beta]2m-transgenic lines also occurred in the respective CD8a-/--transgenic rat lines. There was no significant difference in disease prevalence or severity between CD8a-/- rats and CD8a+/- rats.All of the previously described disease manifestations in HLA-B27/Hu[beta]2m-transgenic rats arise in the absence of any functional CD8+ T cells. It thus seems unlikely that classic T cell recognition of HLA-B27 is of primary importance in this animal model. The possibility of a secondary role of a CD8-dependent mechanism cannot be entirely excluded.

Enthesis inflammation in recurrent acute anterior uveitis without spondylarthritis

To investigate whether patients with idiopathic recurrent acute anterior uveitis (AAU) have enthesis alterations comparable with those in patients with spondylarthritis (SpA).A blinded, controlled study of enthesis evident on ultrasound (US) examination was performed in 100 patients and controls classified into 5 groups, as follows: patients with confirmed SpA (group 1), patients with recurrent AAU who were positive for HLA-B27 and did not have SpA (group 2), patients with recurrent AAU who were negative for HLA-B27 and did not have SpA (group 3), patients with forms of uveitis other than those related to SpA (group 4), and healthy controls (group 5). In total, 12 enthesis locations were explored in each patient and control subject by 2 ultrasonographers who were blinded with regard to the diagnosis. A newly developed US method, the Madrid Sonography Enthesitis Index (MASEI), in which the diagnosis of SpA is determined as a cutoff score of 18 points, was used.A total of 1,200 entheses were explored by US in 100 patients and controls. The MASEI cutoff limit was met or exceeded by 81%, 55.6%, 40%, 10%, and 19% of the subjects in the 5 groups, respectively. The MASEI score was significantly higher in groups 1 and 2 than in groups 4 and 5. The differences between groups 1 and 3 were also found to be significant.Our findings indicate that a high percentage of HLA-B27-positive patients with idiopathic recurrent AAU without features of SpA have enthesis lesions comparable with those seen in patients with SpA. These data suggest that patients with recurrent AAU, especially those who are HLA-B27 positive, have an abortive or incomplete form of SpA.

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

Interferon regulatory factor 5 is a transcription factor involved in type I interferon (IFN) secretion. This study was undertaken to investigate whether a 5-bp (CGGGG insertion/deletion) promoter polymorphism is involved in genetic predisposition to primary Sjögren's syndrome (SS) and to assess the functional consequences of this polymorphism.The exploratory cohort consisted of 185 patients with primary SS and 157 healthy controls, and the replication cohort consisted of 200 patients with primary SS and 282 healthy controls. Levels of IRF5 messenger RNA (mRNA) were assessed at baseline and after in vitro infection with reovirus in peripheral blood mononuclear cells (PBMCs) from 30 patients with primary SS and from salivary gland epithelial cells that had been cultured for 4 weeks from patients with primary SS or sicca symptoms.Carriage of the IRF5 4R CGGGG allele was associated with a greatly increased risk of primary SS in both cohorts (odds ratio 2.00 [95% confidence interval 1.5-2.7], P = 6.6 × 10-6). The CGGGG insertion/deletion polymorphism alone was sufficient to explain the association of primary SS with IRF5. The level of IRF5 mRNA in PBMCs depended significantly on genotype (P = 0.002) and was correlated with the levels of mRNA for the IFN-induced genes MX1 and IFITM1. Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026).Our findings indicate an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS. Patients carrying the 4R CGGGG IRF5 allele had a high level of mRNA for IRF5 in PBMCs and salivary gland epithelial cells, mainly after in vitro viral infection. Patients with high levels of mRNA for IRF5 also had high levels of mRNA for type I IFN-induced genes in PBMCs.

Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum-induced arthritis in vivo

Endogenous glucocorticoids (GCs) modulate numerous biologic systems involved in the initiation and maintenance of arthritis. Bone cells play a critical role in the progression of arthritis, and some of the effects of GCs on inflammation may be mediated via these cells. The aim of this study was to investigate the impact of osteoblast-targeted disruption of GC signaling on joint inflammation, cartilage damage, and bone metabolism in the K/BxN mouse serum transfer model of autoimmune arthritis.Intracellular GC signaling was disrupted in osteoblasts through transgenic overexpression of 11[beta]-hydroxysteroid dehydrogenase type 2 under the control of a type I collagen promoter. Arthritis was induced in 5-week-old male transgenic mice and their wild-type (WT) littermates, and paw swelling was assessed daily until the mice were killed. The mice were examined by histology, histomorphometry, and microfocal computed tomography, and serum was analyzed for cytokines, adrenocorticotropic hormone, and corticosterone.Acute arthritis developed in both transgenic and WT mice treated with K/BxN mouse serum. However, the arthritis and local inflammatory activity were significantly attenuated in transgenic mice, as judged by clinical and histologic indices of inflammation and cartilage damage. Bone turnover and bone volume remained unchanged in arthritic transgenic mice, while WT mice exhibited stimulated bone resorption, suppressed osteoblast activity, and significantly reduced bone volume, compatible with the known effects of active inflammation on bone. Circulating levels of proinflammatory cytokines tended to be lower in arthritic transgenic mice than in control transgenic mice.Disruption of GC signaling in osteoblasts significantly attenuates K/BxN mouse serum-induced autoimmune arthritis in mice. These data suggest that osteoblasts modulate the immune-mediated inflammatory response via a GC-dependent pathway.

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.A number of non-hydroxamic acid-containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1[alpha]- and oncostatin M-induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean ± SEM damage score 1.3 ± 0.3, versus 2.2 ± 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity.The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs.

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis

We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1-driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage.Basal characteristics of the articular cartilage of Fgf2-/- and Fgf2+/+ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase-polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2-/- and Fgf2+/+ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2-/- mice.Fgf2-/- mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2-/- mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2-/- mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2-/- mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase.These data identify FGF-2 as a novel endogenous chondroprotective agent in articular cartilage.

Changes in proximal femoral mineral geometry precede the onset of radiographic hip osteoarthritis: The study of osteoporotic fractures

Radiographic hip osteoarthritis (RHOA) is associated with increased hip areal bone mineral density (aBMD). This study was undertaken to examine whether femoral geometry is associated with RHOA independent of aBMD.Participants in the Study of Osteoporotic Fractures in whom pelvic radiographs had been obtained at visits 1 and 5 (mean 8.3 years apart) and hip dual x-ray absorptiometry (DXA) had been performed (2 years after baseline) were included. Prevalent and incident RHOA phenotypes were defined as composite (osteophytes and joint space narrowing [JSN]), atrophic (JSN without osteophytes), or osteophytic (femoral osteophytes without JSN). Analogous definitions of progression were based on minimum joint space and total osteophyte score. Hip DXA scans were assessed using the Hip Structural Analysis program to derive geometric measures, including femoral neck length, width, and centroid position. Relative risks and 95% confidence intervals for prevalent, incident, and progressive RHOA per SD increase in geometric measure were estimated in a hip-based analysis using multinomial logistic regression with adjustment for age, body mass index, knee height, and total hip aBMD.In 5,245 women (mean age 72.6 years), a wider femoral neck with a more medial centroid position was associated with prevalent and incident osteophytic and composite RHOA phenotypes (P < 0.05). Increased neck width and centroid position were associated with osteophyte progression (both P < 0.05). No significant geometric associations with atrophic RHOA were found.Differences in proximal femoral bone geometry and spatial distribution of bone mass occur early in hip OA and predict prevalent, incident, and progressive osteophytic and composite phenotypes, but not the atrophic phenotype. These bone differences may reflect responses to loading occurring early in the natural history of RHOA.

Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford study

There is a great need for identification of biomarkers that could improve the prediction of early osteoarthritis (OA). We undertook this study to determine whether circulating levels of interleukin-6 (IL-6), tumor necrosis factor [alpha] (TNF[alpha]), and C-reactive protein (CRP) can serve as useful markers of radiographic knee OA (RKOA) in a normal human population.RKOA data were obtained from the cohort of the Chingford Study, a prospective population-based study of healthy, middle-aged British women. The RKOA-affected status of the subjects was assessed using the Kellgren/Lawrence (K/L) grade as determined on radiographs obtained at baseline (n = 908) and at 10 years and 15 years thereafter. Serum levels of CRP, IL-6, and TNF[alpha] were assayed at 5, 8, and 15 years, using high-sensitivity commercial assays. A K/L grade of [ge]2 in either knee was used as the outcome measure. Statistical analyses included analysis of variance for repeated measurements and logistic regression models, together with longitudinal modeling of dichotomous responses.During 15 years of followup, the prevalence of RKOA (K/L grade [ge]2) increased from 14.7% to 48.7% (P < 0.00001 versus baseline). The body mass index (BMI) and circulating levels of CRP and IL-6 were consistently and significantly higher in subjects diagnosed as having RKOA. When multiple logistic regression was applied to the data, the variables of older age (P = 3.93 × 10-5), higher BMI at baseline (P = 0.0003), and increased levels of IL-6 at year 5 (P = 0.0129) were determined to be independent predictors of the appearance of RKOA at year 10. The results were fully confirmed using longitudinal modeling of repeated measurements of the data obtained at 3 visits. The odds ratio for RKOA in subjects whose IL-6 levels were in the fourth quartile of increasing levels (versus the first quartile) was 2.74 (95% confidence interval 1.94-3.87).This followup study showed that individuals were more likely to be diagnosed as having RKOA if they had a higher BMI and increased circulating levels of IL-6. These results should stimulate more work on IL-6 as a potential therapeutic target.

Variation at the ANP32A gene is associated with risk of hip osteoarthritis in women

The ANP32A gene encodes a tumor suppressor molecule that plays a regulatory role in apoptosis and interferes with canonical Wnt signaling in vitro. We undertook this study to test whether genetic variation at ANP32A was associated with osteoarthritis (OA) in women.Single-nucleotide polymorphisms (SNPs) in the ANP32A gene were genotyped in 438 control women, 425 women with total knee replacements (TKRs), and 537 women with total hip replacements (THRs) from the Nottingham case-control study as well as in 820 women from the population-based Chingford Study cohort for whom hip and knee radiographs were available. The most highly associated SNP was further tested in women from the Rotterdam Study (131 with THRs, 633 with knee OA, and 1,567 controls) and the TwinsUK Study cohort (67 with THRs, 43 with TKRs, and 358 controls), for a total of 2,170 patients with OA and 2,849 controls.The ANP32A transcript was abundantly expressed in normal and OA articular cartilage. Three SNPs in the ANP32A gene were significantly associated in Nottingham patients with hip OA, but not knee OA. One of these (rs7164503) was associated with hip and knee OA in the Chingford Study cohort and with THR in the TwinsUK Study cohort, but the association was not statistically significant in the Rotterdam Study. When we combined hip data from all 4 cohorts, we found that the minor allele of rs7164503 was associated with a significantly lower risk of hip OA (Mantel-Haenszel odds ratio 0.67 [95% confidence interval 0.53-0.84], P < 3.8 × 10-4) and that a similar trend was observed for knee OA (Mantel-Haenszel odds ratio 0.87 [95% confidence interval 0.73-1.01], P < 0.055).Our results provide evidence suggesting that ANP32A is involved in the pathogenesis of OA of the hip.

Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism

Single-nucleotide polymorphism (SNP) rs143383 (T to C) in the 5[prime]-untranslated region (5[prime]-UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk-associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis-acting GDF5 regulatory polymorphisms.Tissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383.We observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint-wide. We identified a second polymorphism, located in the 3[prime]-UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) to the 2 alleles of rs143383.These findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis-acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF-1 is a trans-acting factor that merits further investigation as a potential tool for modulating GDF5 expression.

The small ubiquitin-like modifier mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against fas-induced apoptosis

To study the expression of small ubiquitin-like modifier 1 (SUMO-1) in aseptic loosening of prosthesis implants and to investigate its role in regulating the susceptibility of prosthesis-loosening fibroblast-like synoviocytes (FLS) to Fas-induced apoptosis.Specimens of aseptically loosened tissue were obtained at revision surgery, and the expression of SUMO-1 was analyzed by in situ hybridization. SUMO-1 levels in FLS were determined by quantitative polymerase chain reaction and Western blot analysis. Immunohistochemistry and confocal microscopy were used to study the subcellular localization of SUMO-1. The functional role of SUMO-1 in Fas-induced apoptosis of prosthesis-loosening FLS was investigated by small interfering RNA-mediated knockdown of SUMO-1 and by gene transfer of the nuclear SUMO-specific protease SENP1.SUMO-1 was expressed strongly in aseptically loosened tissue and was found prominently at sites adjacent to bone. Prosthesis-loosening FLS expressed levels of SUMO-1 similar to the levels expressed by rheumatoid arthritis (RA) FLS, with SUMO-1 being found mainly in promyelocytic leukemia protein nuclear bodies. Knockdown of SUMO-1 had no effect on spontaneous apoptosis but significantly increased the susceptibility of prosthesis-loosening FLS to Fas-induced apoptosis. Gene transfer of the nuclear SUMO-specific protease SENP1 reverted the apoptosis-inhibiting effects of SUMO-1.These data suggest that SUMO-1 is involved in the activation of both RA FLS and prosthesis-loosening FLS by preventing these cells from undergoing apoptosis. Modification of nuclear proteins by SUMO-1 contributes to the antiapoptotic effects of SUMO-1 in prosthesis-loosening FLS, providing evidence for the specific activation of sumoylation during their differentiation. Therefore, SUMO-1 may be an interesting target for novel strategies to prevent aseptic prosthesis loosening.

Anti-DNA antibody induction of protein kinase C phosphorylation and fibronectin synthesis in human and murine lupus and the effect of mycophenolic acid

To examine fibronectin (FN) expression in human lupus nephritis and the effect of anti-DNA antibodies on transforming growth factor [beta]1 (TGF[beta]1) and FN synthesis in cultured human mesangial cells. The effects of mycophenolic acid (MPA) on this pathway, and the effects of mycophenolate mofetil (MMF) treatment in (NZB × NZW)F1/J mice were also studied.Immunohistochemical analyses of renal biopsy samples from patients with active diffuse proliferative lupus nephritis were performed. Cultured human mesangial cells were incubated with human polyclonal anti-DNA antibodies, with or without MPA. (NZB × NZW)F1/J mice with active nephritis were randomized to receive either MMF (100 mg/kg/day) or vehicle treatment for 12 weeks.Glomerular FN expression was increased in patients with lupus nephritis, and it colocalized with IgG deposition. Anti-DNA antibodies induced protein kinase C[alpha] (PKC[alpha]), PKC[beta]I, and PKC[beta]II activation, increased levels of bioactive TGF[beta]1, and increased FN synthesis in human mesangial cells (P < 0.001 for each comparison versus control conditions). Pretreatment of anti-DNA antibodies with exogenous DNA reduced their cellular binding and abrogated their induction of TGF[beta]1 and FN synthesis. Inhibition of PKC activation in human mesangial cells prior to anti-DNA antibody stimulation had no effect on cell proliferation, but resulted in significantly reduced antibody-mediated TGF[beta]1 secretion and FN synthesis. MPA treatment down-regulated PKC[alpha], PKC[beta]I, and PKC[beta]II phosphorylation, reduced levels of TGF[beta]1 bioactivation, and decreased FN synthesis and deposition into the extracellular matrix. MMF treatment in (NZB × NZW)F1/J mice resulted in a reduction in glomerular IgG deposition, PKC activation, and FN expression, as well as an amelioration of proteinuria.Human polyclonal anti-DNA antibodies induce TGF[beta]1 and FN synthesis in human mesangial cells through PKC activation, which is inhibited by MPA.

Systemic activation of the immune system induces aberrant BAFF and APRIL expression in B cells in patients with systemic lupus erythematosus

Elevated levels of BAFF and APRIL are characteristic of patients with systemic lupus erythematosus (SLE). The reasons for enhanced cytokine production are not well understood. This study was undertaken to identify the cells responsible for the overproduction of these cytokines.BAFF expression was analyzed on peripheral blood mononuclear cells by multiparameter flow cytometry and in tissue samples by immunofluorescence staining. The levels of BAFF and APRIL mRNA were quantified in sorted B cells. In vitro cultures were used to analyze whether B cell survival and differentiation was supported by autocrine BAFF and/or APRIL.Aberrant activation of B cells in patients with SLE was associated with a significant up-regulation of BAFF expression in naive, memory, and plasma cells. Furthermore, strong expression of BAFF and APRIL was found in plasma cells from the lymph node, bone marrow, and kidney. The levels of BAFF and APRIL mRNA in CD19+ B cells correlated both with the titer of anti-double stranded DNA antibodies and with the SLE Disease Activity Index. In vitro experiments demonstrated that B cells released functional BAFF/APRIL upon activation.Our data show that B cells contribute to the enhanced levels of circulating BAFF and APRIL. The aberrant up-regulation of these cytokines may initiate a vicious circle in which enhanced levels of BAFF and APRIL act in an autocrine manner to reinforce the systemic activation of the humoral immune system.

Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus

A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects.Levels of uPA, tPA, and PAI-1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non-NPSLE group]) and from 53 age-matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing.In the group of patients with NPSLE, intrathecal PAI-1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI-1 correlated significantly with CSF levels of interleukin-6 (IL-6) (r = 0.34, P < 0.001) and IL-8 (r = 0.33, P < 0.001). Importantly, increased PAI-1 and D-dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF.Intrathecal release of PAI-1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.

Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis

To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents.Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0).A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well.Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.

Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets

To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures.Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization.Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor [beta]-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets.Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.

Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis

Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors.Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.

Intravenous immunoglobulin and salicylate differentially modulate pathogenic processes leading to vascular damage in a model of Kawasaki disease

Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development.Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor [alpha] (TNF[alpha]) production, and real-time polymerase chain reaction to examine TNF[alpha]-mediated expression of matrix metalloproteinase 9 (MMP-9).At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNF[alpha] expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNF[alpha] production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNF[alpha]. TNF[alpha] activity was a prerequisite for local expression of MMP-9 at the coronary artery.Therapeutic concentrations of IVIG and salicylate differentially modulate the expression of TNF[alpha] and its downstream effects. Further dissection of the biologic effects of aspirin in acute KD is necessary for the rational design of therapy.

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen

Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor [beta] (TGF[beta]) and is a mediator of some profibrotic effects of TGF[beta] in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I [alpha]2) in this mouse model and in human pulmonary fibroblasts.Transgenic mice that were carrying luciferase and [beta]-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts.In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by [sim]25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycin-treated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling.Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation of Col1a2. Blocking strategies revealed the signaling mechanisms involved. These findings show CTGF to be a rational target for therapy in fibrotic diseases such as SSc.

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis

B cell depletion with rituximab has allowed remissions in relapsing or refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in small studies. The aim of this study was to determine the efficacy and safety of rituximab for ANCA-associated vasculitis in a larger multicenter cohort. This permitted comparison of rituximab dosing regimens, the value of continuing immunosuppression, and investigation of ANCA and B cell levels as re-treatment biomarkers.Retrospective, standardized data collection from 65 sequential patients receiving rituximab for refractory ANCA-associated vasculitis at 4 centers in the UK was used.All patients achieved B cell depletion. Complete remission occurred in 49 of the 65 patients (75%), partial remission in 15 (23%), and no response in 1 (2%). The prednisolone dosage was reduced from 12.5 mg/day (median) to 9.0 mg/day at 6 months (P = 0.0006). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). Twenty-eight of 49 patients who achieved full remission (57%) experienced relapse (median 11.5 months). B cell return preceded relapse in 14 of 27 patients (52%). Although ANCA levels fell after rituximab therapy, relapse was not associated with ANCA positivity or a rise in ANCA levels. Neither the initial rituximab regimen (4 infusions of 375 mg/m2 each given 1 week apart or 2 infusions of 1 gm each given 2 weeks apart) nor withdrawal of immunosuppressive therapy (37 of 60 patients [62%]) influenced the timing of relapse. Thirty-eight patients received [ge]2 courses of rituximab, and complete remission was induced or maintained in 32 of them (84%). IgM levels fell, although IgG levels remained stable. Forty-six serious adverse events occurred, including 2 episodes of late-onset neutropenia, which were attributed to rituximab.Rituximab was effective remission induction therapy for refractory ANCA-associated vasculitis in this study. There was no difference in efficacy between the 2 main treatment regimens. Continuing immunosuppression did not reduce relapses. Relapses occurred, but re-treatment was effective and safe. There was no clear influence of rituximab on the frequency of serious adverse events. ANCA and B cell levels lacked sufficient sensitivity to guide the timing of re-treatment.

Clinical image: Cerebral amyloid angiopathy

No abstract.

Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains

Fibromyalgia (FM) patients have signs of relentless sympathetic hyperactivity associated with hyporeactivity to stress. Adrenergic receptors (ARs) are parts of the sympathetic nervous system that are fundamental for maintenance of homeostasis. We undertook this study to correlate [alpha]-AR and [beta]-AR gene polymorphisms with the presence of FM and with different domains of the FM syndrome as measured by the Fibromyalgia Impact Questionnaire (FIQ).We studied 78 Mexican FM patients and 48 age-matched controls as well as 78 Spanish FM patients and 71 controls. All subjects studied were women. Single-nucleotide polymorphisms (SNPs) of [alpha]1A-AR (rs574584, rs1383914, rs1048101, and rs573542), [beta]2-AR (rs1042713 and rs1042714), and [beta]3-AR (rs4994) were analyzed by 5[prime] exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis.The [beta]2-AR AC haplotype was a risk factor for the presence of FM. This haplotype had an increased frequency in Mexican patients compared with Mexican controls (42.1% versus 30.5%; P = 0.04). Similarly, 50.4% of Spanish patients had this haplotype compared with 40.0% of Spanish controls (P = 0.05). In Spanish patients, the [alpha]1A-AR SNP rs1383914 was associated with the presence of FM (P = 0.01), and the [alpha]1A-AR SNP rs1048101 was linked with FIQ disability (P = 0.02). Mexican patients with the rs574584 GG genotype presented the highest FIQ score compared with Mexican patients with other genotypes (P = 0.01), and in Mexicans SNP rs574584 was associated with FIQ morning stiffness (P = 0.04) and with FIQ tiredness upon awakening (P = 0.02).AR gene polymorphisms are related to the risk of developing FM and are also linked to different domains of the FM syndrome.

Analysis of Borrelia burgdorferi genotypes in patients with lyme arthritis: High frequency of ribosomal RNA intergenic spacer type 1 strains in antibiotic-refractory arthritis

Most of the Borrelia burgdorferi genotypes have been isolated from erythema migrans (EM) skin lesions in patients with Lyme disease. OspC type K strains, which are 16S-23S ribosomal RNA intergenic spacer type 2 (RST2) strains, are most commonly recovered, but a higher percentage of OspC type A strains (RST1), the next most commonly recovered type, is detectable in blood. The goal of this study was to determine the B burgdorferi genotypes in the joints of patients with Lyme arthritis.Joint fluid samples from 124 patients seen over a 30-year period were analyzed for OspC types by semi-nested polymerase chain reaction (PCR) and sequencing, and for RSTs by nested PCR and restriction fragment length polymorphism analysis. These results were correlated with clinical outcome.OspC and RST genotypes were identified in 49 of the 124 joint fluid samples (40%). In these 49 samples, OspC type K strains (RST2) were identified in 21 samples (43%), OspC type A strains (RST1) were identified in 11 samples (22%), and 8 other OspC types and all 3 RSTs were identified among the remaining 17 samples (35%). However, among the 17 patients who had been treated with antibiotics according to current guidelines, all 7 patients who were infected with RST1 strains had antibiotic-refractory arthritis, compared with 4 of 6 patients infected with RST2 strains and only 1 of 4 infected with RST3 strains (P = 0.03).Most of the B burgdorferi genotypes, particularly OspC type K (RST2), were identified in the joint fluid of patients with Lyme arthritis, and the genotype frequencies found in joints reflected those in EM skin lesions. However, RST1 strains were most frequent in patients with antibiotic-refractory arthritis. Our results help to further the understanding of the differential pathogenicity of strains of B burgdorferi.

Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease

Using a combination of clinical, radiographic, functional, and serum protein biomarker assessments, this study was aimed at defining the prevalence and clinical characteristics of interstitial lung disease (ILD) in a large cohort of patients with anti-Jo-1 antibodies.A review of clinical records, pulmonary function test results, and findings on imaging studies determined the existence of ILD in anti-Jo-1 antibody-positive individuals whose data were accumulated in the University of Pittsburgh Myositis Database from 1982 to 2007. Multiplex enzyme-linked immunosorbent assays (ELISAs) for serum inflammation markers, cytokines, chemokines, and matrix metalloproteinases in different patient subgroups were performed to assess the serum proteins associated with anti-Jo-1 antibody-positive ILD.Among the 90 anti-Jo-1 antibody-positive individuals with sufficient clinical, radiographic, and/or pulmonary function data, 77 (86%) met the criteria for ILD. While computed tomography scans revealed a variety of patterns suggestive of underlying usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia, a review of the histopathologic abnormalities in a subset of patients undergoing open lung biopsy or transplantation or whose lung tissue was obtained at autopsy (n = 22) demonstrated a preponderance of UIP and diffuse alveolar damage. Analysis by multiplex ELISA yielded statistically significant associations between anti-Jo-1 antibody-positive ILD and elevated serum levels of C-reactive protein (CRP), CXCL9, and CXCL10, which distinguished this disease entity from idiopathic pulmonary fibrosis and anti-signal recognition particle antibody-positive myositis. Recursive partitioning further demonstrated that combinations of these and other serum protein biomarkers can distinguish these disease subgroups at high levels of sensitivity and specificity.In this large cohort of anti-Jo-1 antibody-positive individuals, the incidence of ILD approached 90%. Multiplex ELISA demonstrated disease-specific associations between anti-Jo-1 antibody-positive ILD and serum levels of CRP as well as the interferon-[gamma]-inducible chemokines CXCL9 and CXCL10, highlighting the potential of this approach to define biologically active molecules contributing to the pathogenesis of myositis-associated ILD.

RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease

To identify the autoantigen recognized by the autoantibody that is associated with clinically amyopathic dermatomyositis (C-ADM) and rapidly progressive interstitial lung disease (ILD).An anti-CADM-140 antibody-positive prototype serum sample was used to screen a HeLa cell-derived complementary DNA (cDNA) library. Selected cDNA clones were further evaluated by immunoprecipitation of their in vitro-transcribed and in vitro-translated products using anti-CADM-140 antibody-positive and anti-CADM-140 antibody-negative sera. The lysates of COS-7 cells transfected with the putative antigen were similarly tested. An enzyme-linked immunosorbent assay (ELISA) to detect the anti-CADM-140 antibody was established using a recombinant CADM-140 antigen, and its specificity and sensitivity for C-ADM and rapidly progressive ILD were assessed in 294 patients with various connective tissue diseases.By cDNA library screening and immunoprecipitation of in vitro-transcribed and in vitro-translated products, we obtained a cDNA clone encoding melanoma differentiation-associated gene 5 (MDA-5). The anti-CADM-140 antibodies in patients' sera specifically reacted with MDA-5 protein expressed in cells transfected with full-length MDA-5 cDNA, confirming the identity of MDA-5 as the CADM-140 autoantigen. The ELISA, using recombinant MDA-5 protein as the antigen, showed an analytical sensitivity of 85% and analytical specificity of 100%, in comparison with the "gold standard" immunoprecipitation assay, and was useful for identifying patients with C-ADM and/or rapidly progressive ILD.Given that RNA helicase encoded by MDA-5 is a critical molecule involved in the innate immune defense against viruses, viral infection may play an important role in the pathogenesis of C-ADM and rapidly progressive ILD. Moreover, our ELISA using recombinant MDA-5 protein makes detection of the anti-CADM-140 antibody routinely available.

Severe gouty arthritis and mild neurologic symptoms due to F199C, a newly identified variant of the hypoxanthine guanine phosphoribosyltransferase

A deficiency in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity leads to overproduction of uric acid. According to the degree of enzymatic deficiency, a large spectrum of neurologic features can also be observed, ranging from mild or no neurologic involvement to complete Lesch-Nyhan disease. Herein, we describe a patient with hyperuricemia, juvenile-onset gouty arthritis, nephrolithiasis, and mild neurologic symptoms, attributed to a newly identified variant of the hprt gene, c.596T>G, resulting in the amino acid change p.F199C. Residual HPRT activity (8%) protected against severe neurologic involvement in this patient. Modeling of the mutated protein was used to predict the mechanisms that led to partial enzymatic activity. Careful neurologic examination is warranted in juvenile and middle-aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency.

Reply to letter by Nardelli and Schell commenting on the pathogenesis of lyme arthritis

No abstract.

Mortality in rheumatoid arthritis patients with heart failure: Comment on the article by Davis et al

No abstract.

Reply

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Challenges in mapping non-HLA-DRB1 major histocompatibility genes in rheumatoid arthritis: Comment on the article by Vignal et al

No abstract.

Reply

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The clinical relevance of a prediction rule for disease outcome in patients with undifferentiated arthritis: Comment on the article by van der Helm-van Mil et al

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Reply

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Erratum

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ACR announcements

No abstract.