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Objective: To assess the relationship between the body mass index (BMI) and the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA)., Methods: We conducted a retrospective study in 222 patients with RA followed by 5 centers. The European League Against Rheumatism response was evaluated at 6 months. Univariate and multivariate logistic regressions were performed., Results: No significant association between the BMI and the response to TCZ at 6 months was found after adjustment for potential confounding factors (adjusted OR 0.45, 95% CI 0.16-1.24, p = 0.13 and OR 1.19, 95% CI 0.31-4.48, p = 0.78 for BMI 25-30 kg/m(2) and BMI > 30 kg/m(2), respectively, compared to BMI < 25 kg/m(2))., Conclusion: Response to TCZ in patients with RA is not influenced by the baseline BMI, in contrast to anti-tumor necrosis factor drugs.

Anti-tumor necrosis factor-a (anti-TNF-a) therapy strategies result in significant clinical benefits in patients with rheumatoid arthritis, but with an increased rate of serious infectious diseases. We describe a patient receiving infliximab who developed a primary cutaneous Nocardia otitidiscaviarum infection after a skin injury.

Objective: Double blind studies were conducted with the anti-CD4 monoclonal antibody (Mab) keliximab in patients with active, stable rheumatoid arthritis (RA), to confirm preliminary evidence of efficacy and safety from open. uncontrolled studies., Methods: We enrolled 136 and 186 patients into 2 consecutive, randomized, double blind trials, with similar populations [apart from inclusion of disease modifying antirheumatic drug (DMARD)-naïve patients in Study 2]. Patients received 4 weeks intravenous placebo or keliximab [40, 80, 120, or 140 mg twice weekly (bw), or 240 mg once weekly (ow)]. The primary endpoint was the American College of Rheumatology (ACR) 20 response criteria, one week after the end of treatment., Results: ACR 20 response rates in Study I were 19%, 42%, 51%*, and 69%* (*p < 0.05 compared to placebo), with placebo, 40, 80, or 140 mg keliximab bw, respectively. The response rates in Study 2 were 30%, 39%, 46% and 47% with placebo, 80 or 120 mg bw, or 240 mg keliximab ow, respectively. In the 2 studies, there was a dose dependent increase in peripheral blood CD4+ T cell coating with keliximab, but a different pattern of CD4 depletion was seen. While only 12% of keliximab treated patients in Study I had CD4 counts below 250 cells/mm3 at the end of the treatment period, 47% fell below this level in Study 2. Clinical response was not correlated with CD4 depletion, but was correlated with CD4+ T cell coating with keliximab., Conclusion: Coating of peripheral blood CD4+ T cells with keliximab, but not CD4 depletion, is a determinant of clinical response.

Objective: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug., Methods: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used., Results: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method., Conclusion: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.

Objective: To investigate whether serial anticardiolipin determination contributes to the clinical management of patients with systemic lupus erythematosus (SLE) with no previous sign of the antiphospholipid syndrome (APS)., Methods: In 90 patients with SLE with no previous clinical manifestations of the APS, repeated clinical evaluations were performed, and serial blood samples (obtained over a 30 month period, range 13-53 mo) were screened for antiphospholipid antibodies (aPL). Anticardiolipin antibodies (aCL) were detected using an ELISA and considered positive if the result was >25 GPL on 2 separate occasions. Patients were not required to be on a specific treatment regimen during the study., Results: Thirty-four patients (37%) had at least one positive ELISA and 11 (11/90, 12%) 2 positive ELISA for IgG aCL during the study. Lupus anticoagulant (LAC) was found in 16 patients, and a false positive VDRL in 5. At study completion, the total number of clinical or laboratory events associated with APS was 30. In univariate analysis, aCL was significantly associated only with LAC (p<0.012). Presence of aCL also correlated with hemoglobin level, anti-DNA antibody, leukocyte count, and the SLE Disease Activity Index (SLEDAI). LAC and aCL were significantly associated with each other (OR 5.17; 95% CI 1.5-17.7), but LAC had a better positive predictive value than aCL for arterial thrombosis and neurological events., Conclusion: Among our patients with SLE without previous clinical manifestations of APS, positive aCL did not predict the occurrence of APS within the next 3 years, but was statistically related to the clinical disease activity (SLEDAI).

Objective: The 65 kDa heat shock protein (HSP) chaperonin is a highly conserved intracellular protein. HSP are involved in the pathogenesis of arthritis, but are not able to induce experimental arthritis. T cell clones recognizing the 180-188 amino acid sequence of 65 kDa HSP are present in inflamed synovium of both adjuvant arthritis and rheumatoid arthritis (RA). Oral administration of bovine collagen II or co-chaperonin 10 kDa HSP has been shown to induce an immune tolerance state to collagen induced arthritis (CIA). We investigate the effect of oral gavage with 65 kDa HSP on CIA., Methods: We immunized 6-8-week-old DBA1 male mice with bovine type II collagen. A group of 25 mice were given oral recombinant mycobacterial 65 kDa HSP before immunization (30 microg in 200 microl phosphate buffered saline (PBS) at Days -7, -5, -2) while PBS alone was administered in 27 controls. A 3rd group was fed 65 kDa HSP according to the same protocol but was not immunized with collagen II (n = 8). The clinical arthritis score was recorded 3 times/week until Day 60. Antibodies to collagen II were determined by ELISA., Results: The incidence of arthritis was comparable in the 2 groups (72 vs 70%). The onset of arthritis was not delayed in mice fed HSP. However, the severity of arthritis was lower 10 days after arthritis onset in animals fed 65 kDa HSP (clinical score 1.83 +/- 0.79 vs 2.74 +/- 1.1; p < 0.0001). No animals in Group 3 had arthritis. Serum IgG anti-type II collagen levels were decreased in HSP treated mice (optical density 0.33 +/- 0.21 vs 0.46 +/- 0.21; p < 0.0001). However, the ratio of IgG1/IgG2a antitype II collagen antibody response remained unchanged in the mice fed 65 kDa HSP., Conclusion: These results suggest that oral administration of 65 kDa HSP may diminish collagen induced arthritis.

Objective: To assess the feasibility of gene therapy in rheumatoid arthritis (RA) and determine the appropriate vector., Methods: Human rheumatoid synovial tissue from 6 patients with RA was transduced ex vivo with a recombinant retroviral vector (pMFG.nlsLacZ) containing the Escherichia coli beta-galactosidase (beta-gal) gene in a coculture assay in the presence of 20 ng/ml tumor necrosis factor alpha (TNF-alpha) for promoting cell division. We also conducted in vitro infection experiments using an adenoviral vector (AdCMVSpl.LacZ) containing the beta-gal gene. After gene transduction, the synovial tissue was engrafted subcutaneously in 8-week-old severe combined immunodeficiency (SCID) CB17 mice. Beta-gal expression was then monitored as a function of time (up to 21 days) and of virus dose [up to 50 colony forming units (cfu)/cell]. The efficacy of direct in vivo gene transfer was also tested by injection of 10(6) cfu of pMFG.nlsLacZ into rheumatoid synovial tissue engrafted in SCID mice., Results: When recombinant retroviral vector was used, 30 +/- 5% of ex vivo infected synovial cells were positive for staining. In synovial tissue implanted in SCID mice, beta-gal expression declined to 5% after one week, but persisted for at least 21 days. Direct injection of pMFG.nlsLacZ vector into the rheumatoid synovial tissue implanted in SCID mice allowed efficient and stable in vivo infection of the synovial tissue. Ex vivo gene transfer with adenoviral vector resulted in a 98% infection rate of the synovial lining cells. However, beta-gal activity declined 7 days after subcutaneous implantation., Conclusion: Highly efficient gene transfer in rheumatoid synovial tissue is achievable with both adenoviral and retroviral vectors, but the results were transient. Exogenous gene transfer through retroviral vectors required stimulation with TNF-alpha for synovial cell division and proviral integration. Direct in vivo gene transfer with recombinant retrovirus was shown to be efficient. Transduction of human synovial tissue engrafted in SCID mice is a potent tool for developing preclinical models of gene therapy in RA.

Objective: Integrin-adressin binding is a critical step in lymphocyte attachment to target tissues. The lymphocyte function associated antigen (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) pathway has been shown to be involved in the homing of lymphocytes to arthritic joints in animal models. The mucosal recognition system [alpha E beta 7/E-cadherin, alpha 4 beta 7/mucosal vascular adressin cellular adhesion molecule 1 (MADCAM-1)] has been implicated in the autoimmune process of nonobese diabetic mice and in rheumatoid arthritis (RA). We developed a model for in vivo study of radiolabelled lymphocyte circulation and attachment to human engrafted rheumatoid synovium, and studied the involvement of LFA-1 and alpha E beta 7 integrin., Methods: We engrafted human RA or osteoarthritis (OA) synovium subcutaneously in 6-week-old SCID/CB17 mice. Three weeks later, we injected intraperitoneally 20 x 10(6) human peripheral blood lymphocytes (PBL) labelled with 3 mCi 99mtechnetium hexamethyl propylenamine oxime. A mouse total body scintigraphy was obtained 20 h postinjection. The same protocol was performed after pretreatment of the PBL with monoclonal antibodies (Mab) against CD11a (25-3) or against alpha E beta 7 human mucosyl lymphocyte marker 1., Results: PBL migrated in the rheumatoid synovial graft 20 h postinjection (activity in the region of interest of the graft: 7699 +/- 4383 cpm/200 pixel or 4.43 +/- 2.65% of initial activity) versus OA engrafted synovial tissue (1453 +/- 1137 or 0.74 +/- 0.6% of initial activity), p = 0.007. The homing to the engrafted rheumatoid synovial tissue of PBL from healthy subjects was not significantly different from the migration of PBL from patients with RA. A Mab against alpha E beta 7 significantly decreased lymphocyte attachment to rheumatoid synovial tissue (3094 +/- 3808 cpm/200 pixel or 2.65 +/- 2.4% of injected activity), p < 0.03. The same results were obtained with Mab against CD11a (5007 +/- 4190 cpm/200 pixel or 2.27 +/- 1.2%), p < 0.01. Our results show increased blood lymphocytes homing to rheumatoid synovial tissue engrafted in SCID mice versus OA tissue., Conclusion: The data suggest that both LFA-1 and mucosal recognition integrin alpha E beta 7 are involved in lymphocyte binding to target tissues in RA.

Objective: To study the dynamic response of the hypothalamo-pituitary- adrenal axis and of prolactin (PRL) pituitary secretion in rheumatoid arthritis (RA)., Methods: We performed a cortisol releasing hormone (CRH) provocation test followed by determination of adrenocorticotropin hormone (ACTH), beta-endorphin, and cortisol concentration, and then a thyrotropin releasing hormone (TRH) provocation test followed by assessment of PRL pituitary secretion in 10 patients with RA and 5 control subjects. All were women under 40 years of age. Hormone concentrations were assessed by radioimmunoassay., Results: Basal PRL cortisol, and ACTH concentrations were similar in patients with RA and controls. We observed a dissociation between the pituitary secretion of beta-endorphin and of ACTH in response to CRH in RA. The ACTH peak and total ACTH production (area under the curve, AUC) were similar in the 2 groups. In contrast, basal beta-endorphin was increased in RA (12.6 +/- 1.41 vs 8.29 +/- 0.144 pg/ml), and the response upregulated (AUC: 83,080 +/- 12,000 vs 54,200 +/- 2400) after CRH compared to controls (p < 0.05). Cortisol adrenal response curve was blunted, but did not reach statistical significance. In contrast, the PRL response to TRH was increased at 120 and 150 min (3461 +/- 303 vs 1897 +/- 520 muIU/ml)(p < 0.01) in patients with RA, independent of disease activity., Conclusion: We observed upregulated pituitary PRL secretion in RA, and a dissociation of ACTH stress. The implication concerning the neuroendocrine system in the chronic immune response in RA is discussed.

Objective: In rheumatoid arthritis (RA) joint erosion is accompanied by T cell infiltration of the synovial tissue. The resulting T cell receptor (TCR) repertoire is a combination of antigen driven shaping, nonspecific selection by endothelial cell-T cell interactions, and cytokine mediated chemoattraction. Considering the conflicting results of molecular biology studies of the TCR repertoire in RA, we attempted to obtain new data to clarify the situation through microscopic distribution analysis of TCR beta chain diversity in synovium follicular CD4/CD8 subsets., Methods: We used dual color fluorescence confocal microscopy with CD4/CD8 monoclonal antibodies (Mab) and a panel of new anti-V beta Mab. The analysis focussed on lymphocyte rich, follicle-like areas of synovial tissue from 4 patients with RA., Results: The expression of individual TCR beta families varied between areas within the T cell follicles, and between patients. Normal absolute levels of some beta chains can be completely skewed towards one subset, indicating that overall TCR evaluation is insufficient., Conclusion: Confocal microscopy analysis of localized TCR diversity in RA synovium offers novel insight into overall V beta gene usage, which appears to be the accumulation of several localized microexpansions.

Objective: Human mucosyl lymphocyte marker (HML-1) antigen is an activation antigen and adhesion molecule of the beta 7 integrin family, which is generally restricted to T cells found in the intestinal epithelium. Expression of the membrane antigen as defined by the monoclonal antibody HML-1 was studied on peripheral blood (PB) lymphocytes and synovial fluid (SF) lymphocytes in 10 patients with rheumatoid arthritis (RA) and in a control group of patients with osteoarthritis (OA)., Methods: Double fluorescence activated flow cytometry was used to assess HML-1 expression with T cell subtype antigens (CD3, CD4, CD8) or activation markers interleukin 2 receptor (IL-2R) (CD25), HLA-DR, and lymphocyte function associated antigen (LFA-1) (CD11a) were assessed by flow cytometry., Results: HML-1 antigen expression in PB lymphocytes of patients with RA (7.3%) was found to be comparable to the control group (6.4%). In contrast, 25.4% (range 14-43%) of SF lymphocytes expressed HML-1 antigen, compared to 13.6% of SF lymphocytes in patients with OA (p < 0.001). In RA, 62% of HML-1 positive cells from SF lymphocytes were the CD8 subtype, compared to 10.6% of PB lymphocytes (p < 0.003), and 18% of control SF lymphocytes (p < 0.05). Furthermore, HML-1 antigen and HLA-DR antigen were coexpressed in 75% of RA SF lymphocytes compared to 29.6% of control SF lymphocytes (p < 0.01). In contrast, coexpression of LFA-1 and the Il-2R did not differ from that of control., Conclusion: We describe overexpression of the adhesion molecule HML-1 in SF lymphocytes of patients with RA, preferentially in the CD8 subset. These results suggest a similarity between the expression of activation antigens in SF lymphocytes of patients with RA and T lymphocytes present in the intestinal epithelium.

Objective: To evaluate the influence of methotrexate (MTX) on the frequency of postoperative complications in patients with rheumatoid arthritis (RA)., Methods: We conducted a randomized unblinded prospective study in 64 patients with RA treated with MTX and who underwent orthopedic surgery. Two groups of patients were constituted: in Group A (32 patients), MTX was interrupted 7 days before the surgery; in Group B (32 patients), MTX was not discontinued., Results: Fifty surgical procedures were performed in Group A and 39 procedures in Group B. No postoperative infection was observed in any group. A prolonged wound healing was noticed in 6 cases in Group A and in 4 cases in Group B (not significant)., Conclusion: We suggest that the interruption of MTX is not required in patients with RA when an orthopedic surgical treatment is planned. However a large prospective study is needed to make a definitive conclusion.

We describe 7 Achilles tendinitis occurring during fluoroquinolone treatment. Antibiotic agents used were pefloxacin and ofloxacin. In 3 cases the course was complicated by rupture of the tendon, one of which is histologically documented. The toxic effects of quinolones on tendon is discussed.