Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheumatoid arthritis (AGRA): a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients. METHOD: In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3-5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15. RESULTS: By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08-1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups. CONCLUSIONS: Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.

The association of luteinizing hormone and follicle-stimulating hormone with cytokines and markers of disease activity in rheumatoid arthritis: a case-control study.

OBJECTIVES: Disease activity in rheumatoid arthritis (RA) varies substantially during periods when luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels change, for example during pregnancy, postpartum, and menopause. We wanted to investigate whether small fluctuations in these hormones could be associated with similar fluctuations in cytokines and disease activity in RA. METHODS: Disease activity markers, serum LH, FSH, and 24 cytokines were assessed on days 1 and 8 in 20 RA patients (median age 58 years, six males) and 19 controls (median age 56 years, six males). RESULTS: Percentage changes in LH and FSH correlated positively with percentage changes in key proinflammatory cytokines such as tumour necrosis factor (TNF)alpha (LH r = 0.737, p = 0.0007; FSH r = 0.680, p = 0.001) and interleukin (IL)-1beta (LH r = 0.515, p = 0.050; FSH r = 0.749, p = 0.0008). Similar correlations were observed with IL-2, IL-2R, IL-8, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and eotaxin, but not with the anti-inflammatory cytokine IL-10, in RA and not in controls. Percentage changes in LH, FSH, and cytokines were not correlated with percentage changes of several disease activity markers but were correlated positively with cross-sectional levels of disease activity markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Visual Analogue Scale (VAS) pain, VAS global (physician/patient), and the modified Health Assessment Questionnaire (MHAQ)]. CONCLUSIONS: The significant associations between percentage changes in LH and FSH and percentage changes in key cytokines and several cross-sectional markers of disease activity may indicate that LH and FSH influence crucial points of the cytokine cascade in RA. This may help to explain, partially, why disease activity initiates or worsens during periods of increased LH and FSH, such as the postpartum period and the menopause.

Treatment of fibromyalgia at the Maharishi Ayurveda Health Centre in Norway. A six-month follow-up study.

BACKGROUND: Treatments offered at the Maharishi Ayurveda Health Centre in Norway are based on Maharishi Vedic medicine, which is also known as Maharishi Ayurveda. It is a consciousness based revival of the ancient Ayurvedic medicine tradition in India and is established by Maharishi Mahesh Yogi, the founder of the Transcendental Meditation (TM) technique. OBJECTIVE: To conduct a pilot study of the effect of the treatment program at the Health Centre on fibromyalgia patients. METHODS: Thirty-one women with diagnosed fibromyalgia received an individually designed Maharishi Vedic physiological purification therapy. All subjects received personal advice on diet based on Ayurvedic principles, including a novel approach to food into-lerance, and daily routines. In addition they were offered instruction in TM (for stress and pain management and personal development) (four subjects started), and recommended Ayurvedic herbal food products for home treatment. MAIN OUTCOME MEASURES: A modified Fibromyalgia Impact Questionnaire included a visual analogue scale for each of the seven outcomes: working ability, generalised pain, tiredness, stiffness, tiredness on arising, anxiety and depression. Pre-treatment scores were compared with scores at six-month follow-up for levels of statistical significance. RESULTS: Twenty-eight subjects (90%) completed the follow-up. The outcome measures were reduced by 25 to 46% by the study's endpoint: working ability (p<0.002), pain (p<0.001), tiredness (p<0.001), morning tiredness (p<0.001), stiffness (p<0.005), anxiety (p<0.136), and depression (p<0.001). A group of five excellent responders including all four participants who started to practise TM, had almost no symptoms by the endpoint. Compared to the non-meditating control group the TM-subgroup showed statistically significant improvements for all outcome measures except depression. CONCLUSIONS: In this pilot study fibromyalgia patients undergoing treatment at Maharishi Ayurveda Health Centre in Norway showed significant improvements six months post treatment. Because fibromyalgia is considered a treatment-resistant condition, these encouraging results warrant further research.

Spondyloarthritis: a strong predictor of early coronary artery bypass grafting.

OBJECTIVES: The main aim of the study was to examine whether patients with spondyloarthritides underwent their first coronary artery bypass grafting (CABG) at a younger age than those without spondyloarthritides. METHODS: Patients who underwent their first CABG at the Feiring Heart Clinic during 2001-2005 were preoperatively screened for spondyloarthritides, and the cardiological assessment was registered. We compared the characteristics of patients with and without spondyloarthritides. RESULTS: Of the 3852 patients undergoing their first CABG, 30 (0.78%) had spondyloarthritides. No statistically significant differences in traditional cardiovascular risk factors were found. The mean ages of patients with and without spondyloarthritides were 60.1 (SD = 8.7) and 66.9 (SD = 10.1) years, respectively. Spondyloarthritis was found by multivariate analysis to be a stronger independent predictor of early CABG than traditional cardiovascular risk factors [adjusted beta -6.2, p<0.001, 95% confidence interval (CI) -9.5 to -2.8]. Sixty per cent of spondyloarthritis patients and 52% of control patients had already suffered a myocardial infarction (p = 0.4). CONCLUSION: Spondyloarthritis was a stronger predictor of early CABG than most of the registered traditional cardiovascular risk factors. The prevalence of spondyloarthritis seemed to be higher in the CABG population than in the general population. These findings may indicate accelerated coronary artery disease (CAD) in spondyloarthritides.

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases.

A functional single nucleotide polymorphism, 1858C>T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR=1.41; P=0.04), not previously reported, and a tendency for an association with coeliac disease (OR=1.35; P=0.08). In primary sclerosing cholangitis, no association was observed (OR=0.95; P=0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR=1.58; P=0.001), but could not find support for an association with systemic lupus erythematosus (OR=0.94; P=0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C>T polymorphism in PTPN22.

Superantigen-mediated proliferation and cytotoxicity of T cells isolated from the inflammatory tissues and peripheral blood of arthritis patients.

Superantigens are thought to play a role in acute infections and in the pathogenesis of autoimmune diseases that are believed to have an infectious etiology. The effect of the superantigens staphylococcal enterotoxin A, staphylococcal enterotoxin B, and streptococcal M type 5 protein on T cells derived from inflammatory tissues and peripheral blood (PB) of arthritis patients was studied in seven rheumatoid arthritis (RA), two psoriatic arthritis, two reactive arthritis, and one ankylosing spondylitis patient. Superantigen-reactive T cells and T cell lines derived from the PB, synovial fluid (SF), and synovial membrane (SM) of all 12 arthritis tissues recognized the superantigens in an MHC-unrestricted manner. Heterogeneities in proliferation and superantigen-directed T cell cytotoxicity were observed in E+ T cells and the T cell lines. Four SF-CD4+ mycobacteria heat-shock protein 65-kDa specific T cell clones generated from an RA patient could recognize and lyse each other when pulsed with staphylococcal enterotoxin A and used as targets. From another RA patient, four SF-CD4+ T cell clones that specifically recognize autoantigens were generated with human IgG fragments or collagen type II fragments. Heterogeneities of such superantigen-mediated specific lysis were also demonstrated. The data presented by us suggest a model in which superantigens do not have to be involved in triggering the initial disease because autoreactive T cells elicited by antigen can, in the presence of superantigen, lyse cells that express MHC class II molecules, including activated T cells.

Mycobacteria and human heat shock protein-specific cytotoxic T lymphocytes in rheumatoid synovial inflammation.

OBJECTIVE: To study the cytotoxic capacity of mycobacteria-specific T lymphocyte lines and clones from sites of inflammation in patients with rheumatoid arthritis (RA). We also studied antigen specificity, surface phenotype, expression of T cell receptors (TCR), and HLA restriction. METHODS: Autologous macrophages (M phi) from the synovial membrane (SM), synovial fluid (SF), or peripheral blood (PB) were used as target cells in cytotoxicity assays. RESULTS: All SM and SF cell lines tested thus far have shown specific lysis of the autologous M phi from SM or PB that had been pulsed with BCG (bacillus Calmette-Guerin), but no cytotoxicity when the targets were pulsed with irrelevant antigens such as tetanus toxoid and Chlamydia. Both CD4+ and CD8+ cells were shown to be involved in the specific cytolysis. The majority of the cytotoxic T lymphocyte (CTL) lines were TCR alpha/beta + cells. However, both TCR alpha/beta + and TCR gamma/delta + clones (TCR delta 1+) from one RA patient showed antigen-specific lysis. Antigen-specific recognition by a number of CTL lines and clones generated from SF and SM was restricted by HLA-DR molecules. Two Mycobacterium bovis 65-kd heat shock protein (HSP)-specific TCR alpha/beta + SF T cell clones also lysed M phi that had been pulsed with a recombinant human 65-kd HSP. CONCLUSION: Joint inflammation and destruction might be partly attributable to a cross-reaction of mycobacteria-induced cytotoxic T cells with self HSP.

Shared idiotypes of human peripheral blood B and T lymphocytes.

In a patient with an IgG lambda monoclonal serum component possessing anti-streptolysin O activity, we have demonstrated peripheral blood B and T lymphocytes with shared or similar idiotypes. The idiotypic T lymphocyte membrane structure was capable of binding the specific antigen (SLO). After radioiodination and subsequent detergent solubilization of the same T cell population, immunoprecipitation of the lysate by employing anti-idiotypic antibodies, resulted in the isolation of a polypeptide chain with a m.w. of 70,000 on SDS polyacrylamide gels under reducing conditions. The polypeptide expressed no isotypic immunoglobulin markers. Internal labeling experiments indicated that this membrane structure was actively synthesized by the T lymphocytes.

A study of the variable heavy chain (VH) regions in human polyclonal IgM rheumatoid factors.

Ten IgM polyclonal rheumatoid factor (RF) preparations isolated from sera from various patients with rheumatoid arthritis (RA) were investigated with respect to their variable heavy chain (VH) subgroups. They were tested in a haemagglutination inhibition system using red cells sensitized with myeloma proteins with known chemical VH subgroups and anti-VH subgroup specific antisera. Most of the preparations showed a considerable degree of restriction to one VH subgroup. Seven of the IgM-RF preparations were restricted to the VHIII subgroup, two to the VHI subgroup and one to the VHII subgroup. However, a weak reaction in other VH subgroup systems was seen in several instances. Two normal IgM fractions from healthy persons showed no VH subgroup restriction, and showed a rather similar degree of reaction in all the three subgroup systems.