Rheumatoid Arthritis: Martín-Mola E

Cobo-Ibáñez T, Martín-Mola E. · Hospital Universitario La Paz, Servicio de Reumatología, Paseo de la Castellana 261, 28046 Madrid, Spain. · Expert Opin Pharmacother. · Pubmed #17563271 No free full text.

Abstract: Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.

Orozco G, Pascual-Salcedo D, López-Nevot MA, Cobo T, Cabezón A, Martín-Mola E, Balsa A, Martín J. · Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain. · Rheumatology (Oxford). · Pubmed #18156150 No free full text.

Abstract: OBJECTIVE: To analyse the relationship between the presence of auto-antibodies [rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)], HLA-DRB1 alleles and PTPN22 1858 C/T polymorphism and test the value of their combination as susceptibility markers for rheumatoid arthritis (RA). METHODS: Patients with early arthritis were included. At entry in the cohort or during follow-up, 191 patients fulfilled the criteria for RA and 184 individuals suffered from other arthropathies. RF was measured by nephelometry and anti-CCP antibody by enzyme-linked immunosorbent assay. HLA class II alleles were determined by polymerase chain reaction. Samples were genotyped for PTPN22 1858C/T variants using a TaqMan 5'-allele discrimination assay. RESULTS: The presence of shared epitope (SE) alleles was strongly associated with anti-CCP and RF-positive RA [P = 7.05 x 10(-10), odds ratio (OR) 4.57, 95% confidence interval (CI) 2.76-7.57 and P = 1.68 x 10(-6), OR 2.99, 95% CI 1.89-4.74, respectively). The combination of the PTPN22 1858T variant and anti-CCP antibodies gave a high specificity for the disease, and was significantly associated with RA (P = 8.86 x 10(-5), OR 10.05, 95% CI 1.88-53.73). CONCLUSION: The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA.

Miranda-Carús ME, Benito-Miguel M, Balsa A, Cobo-Ibáñez T, Pérez de Ayala C, Pascual-Salcedo D, Martín-Mola E. · Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain. · Arthritis Rheum. · Pubmed #16575870 links to  free full text

Abstract: OBJECTIVE: To investigate the osteoclastogenic potential of T cells from the peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) on autologous monocytes, and to study the cytokines implicated in this process. METHODS: T cells and monocytes were isolated from the PB of 20 healthy subjects and 20 patients with early RA, and from the SF of 20 patients with established RA. Autologous T cell/monocyte cocultures were established in the absence of exogenous cytokines or growth factors in order to examine spontaneous ex vivo osteoclast differentiation by tartrate-resistant acid phosphatase staining and calcified matrix resorption activity. RESULTS: Surface RANKL was expressed on freshly isolated T cells from the PB of patients with early RA and the SF of patients with established RA. In addition, surface interleukin-15 (IL-15) was detected on freshly isolated T cells and monocytes from the PB of patients with early RA and the SF of patients with established RA. Autologous T cell/monocyte cocultures derived from the SF of patients with established RA and from the PB of patients with early RA, but not from the PB of healthy controls, resulted in osteoclast differentiation that was significantly inhibited by osteoprotegerin (OPG) and by neutralizing monoclonal antibodies to IL-15, IL-17, tumor necrosis factor alpha (TNFalpha), and IL-1beta. OPG, anti-TNFalpha, and anti-IL-1beta demonstrated a cooperative inhibitory effect. At 1-year followup, surface RANKL and IL-15 and ex vivo osteoclastogenesis were no longer observed on PB T cells or monocytes from patients with early RA in whom clinical remission had been achieved with treatment. CONCLUSION: T cells are important contributors to the pathogenesis of bone erosions in RA through interaction with osteoclast precursors of the monocyte/macrophage lineage.

Miranda-Carús ME, Balsa A, Benito-Miguel M, De Ayala CP, Martín-Mola E. · Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain. · Arthritis Rheum. · Pubmed #15457446 links to  free full text

Abstract: OBJECTIVE: To examine fibroblasts grown from the synovial fluid of rheumatoid arthritis (RA) patients for TRAIL-R2 expression, and for susceptibility to apoptosis induced by an agonistic anti-TRAIL-R2 monoclonal antibody (mAb). METHODS: The expression of TRAIL-R2 (DR5) was determined by flow cytometry on fibroblasts grown from the synovial fluid of patients with RA, osteoarthritis (OA), seronegative arthritis, and unclassified monarthritis or oligoarthritis, and on fibroblasts from the synovial membrane of RA and OA patients. Susceptibility to apoptosis mediated by an agonistic anti-TRAIL-R2 mAb was determined by alamar blue bioassay, fluorescence microscopy (annexin V/propidium iodide staining), and caspase activation. RESULTS: Fibroblasts grew from 35 of 50 RA synovial fluid samples, of which 26 were DR5(+) (mean [+/-SD] fluorescence intensity [MFI] 18.74 +/- 2.5). Fibroblasts also grew from 15 of 30 seronegative arthritis synovial fluid samples, 28 of 40 OA synovial fluid samples, and 8 of 20 unclassified monarthritis or oligoarthritis synovial fluid samples; all of these were DR5- (MFI 0.32 +/- 0.02). All 10 of the fibroblast lines from joint replacement surgery or synovectomy specimens of RA patients were DR5(+) (MFI 20.3 +/- 3.2). All fibroblast lines from the synovium of 10 OA patients were DR5-, as were fibroblasts from the skin of 5 healthy subjects. DR5(+) fibroblast cultures underwent apoptosis when treated in vitro with an agonistic anti-DR5 antibody. CONCLUSION: Fibroblasts grown from the synovial fluid and synovial membrane of RA patients express TRAIL-R2 that is functionally active. An agonistic anti-TRAIL-R2 antibody that does not induce hepatocyte toxicity may be an alternative strategy for treatment of RA.

Miranda-Carús ME, Balsa A, Benito-Miguel M, Pérez de Ayala C, Martín-Mola E. · Department of Rheumatology, Hospital Universitario La Paz, Paseo de La Castellana, Madrid, Spain. · J Immunol. · Pubmed #15240743 links to  free full text

Abstract: To characterize the molecules responsible for synovial fibroblast-T lymphocyte (TL) cross-talk in rheumatoid arthritis (RA), synovial fibroblasts from patients with established RA (RASFibs) were cocultured with TLs from peripheral blood of early RA patients (RAPBTL). TLs from peripheral blood of healthy controls and from synovial fluid of RA served as controls. Adhesion molecules and cytokines were determined by flow cytometry, ELISA, and real-time PCR. RAPBTL (n = 20) induced an up-regulation of ICAM-1, intracellular IL-8, IL-6, IL-15, and surface IL-15 in cocultured RASFibs. In turn, RAPBTL showed an up-regulation of TNF-alpha, IFN-gamma, IL-17, CD25, and CD69 expression. Responses seen with TLs from peripheral blood of healthy controls (n = 20) were significantly lower, whereas responses with TLs from synovial fluid of RA (n = 20) were maximal. Blocking Abs to IL-15 and CD54, but not an isotype-control Ab, down-regulated the increased TL cytokine and activation marker expression. Abs to CD69, CD11a, IL-17, TNF-alpha, and IFN-gamma significantly decreased the up-regulation of RASFib cytokine and CD54 expression. Cocultures using 0.4- micro m inserts did not result in up-regulation of surface molecules or cytokines. Methotrexate significantly inhibited RASFib/TL cross-talk signals and decreased adhesion of TL to RASFibs. In summary, RASFib production of IL-15 induces the proinflammatory cytokines TNF-alpha, IFN-gamma, and IL-17 in cocultured TLs through a cell contact-dependent mechanism. In turn, these cytokines stimulate the expression of IL-15, IL-8, and IL-6 in RASFibs, thereby creating a feedback loop that favors persistent synovial inflammation. Methotrexate seems to disrupt this loop by decreasing cell adhesion.

Bonilla Hernán MG, Cobo Ibáñez T, de Miguel Mendieta E, Martín-Mola E. · Servicio de Reumatología, Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid. · An Med Interna. · Pubmed #15195482 No free full text.

Abstract: Adult Still's disease is a systemic inflammatory disorder of unknown etiology. First-line treatment for Still's disease includes nonsteroidal anti-inflammatory drugs and corticosteroids. In refractory cases o when the dose of corticosteroid is unacceptably high, other disease modifying antirheumatic drugs have been used. But recent study showed the efficacy anti-TNF therapy in adult Sill's disease refractory to conventional therapy. We report a favourable response to infliximab in two patients who has proved resistant to conventional therapy.

Hernanz A, Medina S, de Miguel E, Martín-Mola E. · Servicio de Bioquímica Clínica, Hospital Universitario La Paz, Castellana 261, 28046 Madrid, Spain. · Regul Pept. · Pubmed #12873794 No free full text.

Abstract: In the present study, we have investigated the in vitro effect of calcitonin-related peptide (CGRP), neuropeptide Y (NPY), substance P (SP) and vasoactive intestinal peptide (VIP) at concentrations of 10(-8), 10(-9) and 10(-10) M on the production of different proinflammatory cytokines or chemokines such as IL-1beta, IL-6 and TNFalpha by peripheral whole blood cells from patients with rheumatoid arthritis, as well as from osteoarthritis patients studied as a control group without immunoinflammatory background. We have found that CGRP, NPY, SP and VIP stimulated significantly the production of those cytokines and chemokines in rheumatoid arthritis patients. In general, the stimulation was higher at the 10(-9) M concentration, with SP and VIP, and in rheumatoid arthritis patients compared to osteoarthritis ones. Neuropeptides did not significantly modify the LPS-induced cytokine production by whole blood cells. The results indicate that physiological concentrations of the neuropeptides studied can modulate the inflammatory and immunological response, stimulating significantly the production of inflammatory cytokines by human whole blood cells in rheumatoid arthritis patients, as well as, in a minor way, in osteoarthritis patients.

Richi P, Balsa A, Muñoz-Fernández S, Villaverde V, Fernández-Prada M, Vicario JL, Martín-Mola E. · Rheumatology Unit, La Paz Hospital, Madrid, Spain Transfusions Centre Comunidad Autónoma de Madrid, Spain. · Ann Rheum Dis. · Pubmed #11830438 links to  free full text

Abstract: OBJECTIVE: To determine whether the presence of radiographic erosions at disease onset in patients with early rheumatoid arthritis (RA) is associated with clinical, serological, or genetic factors of poor outcome and whether patients with erosions only in the feet have a different pattern of presentation. METHODS: Sixty one patients with early RA (<6 months of evolution) were studied. Clinical evaluation and serological, radiological, and genetic studies were performed at disease onset and after one year. RESULTS: Forty one (67%) patients showed erosions in their hands or in their feet, or in both. Subjects with erosive RA had a higher number of swollen joints (SJN; 9 (SD 6) v. 6 (3), p=0.008), and rheumatoid factor (RF) positivity was more common (80% v. 50%, p<0.02) than those without erosions. Seven (17%) of the 41 patients in the group with erosions had erosions only in their feet. This group had a longer duration of morning stiffness (120 (60) v. 72 (52) min, p<0.005), better patient's global assessment of general health (34 (22) v. 57 (25), p< 0.05), and lower erythrocyte sedimentation rate (32 (22) v. 60 (30) mm/1st h, p <0.05) than the rest of the subjects with erosions, and none of them was in remission after one year. Remission after one year was related to a lack of cortical damage at onset and RF negativity. CONCLUSIONS: Radiological damage at disease onset is associated with a worse clinical presentation and RF positivity, which are markers of poor outcome. There is a subgroup of patients, with erosions only in their feet, whose clinical presentation is less aggressive. To identify these cases of early erosive RA, radiographs of the feet should be obtained routinely.

Muñoz-Fernández S, Martín J, Martín-Mola E, García-Rodriguez MC, Cantalejo M, Fontán G, Ferreira A. · Rheumatology Unit, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain. · Rheumatology (Oxford). · Pubmed #11752506 links to  free full text

Abstract: OBJECTIVES: To investigate the presence of soluble HLA class I (s-HLA) antigens in serum and synovial fluid (SF) from a large cohort of rheumatic patients. METHODS: We studied clinical and analytical data and serum samples from 300 patients [122 patients with rheumatoid arthritis (RA), 38 with osteoarthritis or osteoporosis, 29 with seronegative spondyloarthropathies, 45 patients with other rheumatic diseases] and 66 healthy controls. In addition, we studied 25 paired samples of serum and SF from these groups of subjects. In RA patients, we examined whether the levels of s-HLA in serum and SF were related to the activity of the disease. RESULTS: The mean concentrations of s-HLA molecules in serum were slightly higher in RA patients (1.2 microg/ml) than in the other four groups (1.08, 1.01, 1.09 and 0.94 microg/ml respectively). We found no correlation between serum s-HLA levels and any variable of inflammatory disease activity in RA patients. s-HLA molecules were found in SF and at levels that correlated with those found in serum (P=0.04; r=0.4). Furthermore, s-HLA levels were higher in SF from patients with RA (1.3 microg/ml) or crystal-induced arthritis (0.98 microg/ml) than in SF from those with osteoarthritis (0.38 microg/ml) (P<0.05 and P<0.005 respectively), and these levels were correlated inversely and significantly with the score on the visual analogue scale of pain (P=0.02), the number of painful joints (P=0.05) and the level of C-reactive protein (P=0.03) in RA patients. CONCLUSIONS: This is the first report to demonstrate the presence of s-HLA molecules in SF at levels that correlate with serum levels. The mean levels of s-HLA molecules were significantly higher in SF from patients with RA and crystal-induced arthritis than in SF from cases of osteoarthritis, and correlated inversely with certain variables of disease activity in RA patients.

Villaverde V, Balsa A, Cantalejo M, Fernández-Prada M, Madero MR, Muñoz-Fernández S, Gijón-Baños J, Martín-Mola E. · Rheumatology Unit, Hospital Universitario La Paz, Madrid, Spain. · J Rheumatol. · Pubmed #11093436 No free full text.

Abstract: OBJECTIVE: To determine which activity indices better correlate with assessor's (AGA) and patient's (PGA) global assessment of disease activity and to compare the improvement with American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria and their association with PGA and AGA of overall improvement. METHODS: Seventy-five patients with rheumatoid arthritis (RA) were studied. Swollen and tender joints, morning stiffness, grip strength, pain, AGA, PGA, Health Assessment Questionnaire (HAQ) score, erythrocyte sedimentation rate (ESR), C-reactive protein (CPR), and hemoglobin were determined before and 6 months after treatment. Several activity indices were calculated: Disease Activity Score (DAS), DAS 3, DAS 28, DAS '28,' ACR > or = 20%, Mallya, Riel, IDA, and a modification of the Stoke index. RESULTS: All indices correlated with PGA and AGA before and after treatment (r > 0.38, p < 0.01), but better results were obtained with AGA than PGA. DAS, DAS 3, DAS 28, and modified Stoke had the best correlation with AGA (r > or = 0.77, p < 0.01). The indices that better detected the differences after treatment for AGA were DAS, DAS 3, DAS 28, and modified Stoke (r > or = -0.42, p < 0.01). The level of agreement between EULAR and ACR improvement classifications with both reduced and extensive joint counts was comparable and its association with PGA and AGA overall improvement was significant (p < 0.01). CONCLUSION: All activity indices correlated with PGA and AGA, although the best results were obtained with AGA. Although indices' correlations were similar, the DAS group and the modified Stoke seemed to be the most useful indices to measure disease activity in RA. The discriminating potential between ACR and EULAR improvement classification was comparable, as was the association with PGA and AGA overall improvement.

Balsa A, Minaur NJ, Pascual-Salcedo D, McCabe C, Balas A, Fiddament B, Vicario JL, Cox NL, Martín-Mola E, Hall ND. · Rheumatology and Immunology Units, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Spain. · Rheumatology (Oxford). · Pubmed #10952737 links to  free full text

Abstract: OBJECTIVE: A number of studies have indicated that rheumatoid arthritis (RA) is a less severe disease in Mediterranean countries than in Northern Europe. We investigated whether differences in the frequency of class II MHC antigens might contribute to this variation in disease severity. METHODS: Typing at HLA-DR and -DQ loci was carried out at low and high resolutions by polymerase chain reaction amplification in patients with early RA of less than 6 months' duration (68 patients in Madrid and 68 in Bath) and in control subjects (929 in Madrid and 226 in Bath). Only ethnic Spanish and British individuals were included as patients and controls. RESULTS: Shared epitope (SE) alleles represented 19.8 and 28.9% of the total number of class II MHC alleles in controls from Madrid and Bath respectively (P: = 0.00001), this difference being largely due to increased numbers of DRB1*0401 individuals in the British subjects (P: = 0.0000001). Analysis of the patients showed the expected increase in SE alleles when compared with their respective control groups (Madrid, 31.6 vs 19.8%; Bath, 42.6 vs 28. 9%). In Bath the SE was mainly encoded by HLA-DR4 alleles (74.1%), while in Madrid it was encoded almost equally by DR4 (51.1%) and DR1 (44.7%) alleles. The risk of developing RA in carriers of SE alleles was similar in the two cities (Bath, odds ratio 1.83, 95% confidence interval 1.23-2.78; Madrid, odds ratio 1.87, 95% confidence interval 1.25-2.77), and was largely accounted for by HLA-DRB1*0401 alleles. CONCLUSION: We conclude that rheumatoid patients in Bath differ from their Spanish counterparts in class II antigen expression and allele frequency. This may be explained partly by genetic differences between the control populations in the two centres, and may help to explain the greater incidence of more severe rheumatoid disease expression seen in RA patients in the UK.

Hernanz A, Plaza A, Martín-Mola E, De Miguel E. · Department of Biochemistry, Hospital Universitario La Paz, Madrid, Spain. · Clin Biochem. · Pubmed #10074894 No free full text.

Abstract: OBJECTIVES: Since moderate hyperhomocysteinemia is an independent risk factor for vascular disease and physiological thiol compounds mediate Cu2+- and Fe3+-dependent low-density lipoprotein (LDL) oxidation, we have studied the total plasma concentrations of thiol compounds including methionine as precursor of homocysteine in rheumatoid arthritis patients, in which the high mortality found is associated with cardiovascular disease. DESIGN AND METHODS: Thirty-eight women with rheumatoid arthritis and 25 age-matched control women were studied. Plasma was used to measure thiol compounds and amino acids by HPLC. RESULTS: Rheumatoid arthritis patients showed significantly higher levels than healthy controls of total plasma homocysteine (17.3 +/- 7.8 vs. 7.6 +/- 1.9; p <0.001), cysteine (293 +/- 61 vs. 201 +/- 45; p < 0.001), cysteinglycine (32.7 +/- 8.3 vs. 22.3 +/- 4.7; p < 0.001) and methionine (25 +/- 9 vs. 18 +/- 3; p < 0.01), whereas total glutathione levels were not increased (4.7 +/- 2.0 vs. 4.1 +/- 1.6). CONCLUSIONS: The increased levels of thiol compounds found in rheumatoid. arthritis patients may be implicated in the increased incidence of cardiovascular disease found in these patients by means of the toxic effect of homocysteine on endothelium and the increased susceptibility of LDL to oxidation by increased plasma amounts of thiol compounds such as cysteine.