Rheumatoid Arthritis: Carmona L

Carmona L, Ortiz A, Abad MA. · Unidad de Investigación, Fundación Espanola de Reumatología, Madrid, Spain. · Acta Reumatol Port. · Pubmed #17572650 No free full text.

Abstract: Despite the biological rationale for switching between TNF-antagonists, there is not a definitive answer from a clinical point of view. METHODS: We performed a systematic review. The strategy for the literature search included synonyms for the active drugs, trade names, and different synonyms for biologic therapies, plus the words "switch" or "switching", limited to studies in humans. The time limit was March 1st 2007. From 256 initial hits in Medline and Embase, plus 13 abstracts from rheumatology meetings, we finally included 33 studies. RESULTS AND DISCUSSION: The most frequently died switches are those between etanercept and infliximab. The mean number of patients studied per type of switch was 126. There are, apart from retrospective observational studies and cases series, 5 prospective cohorts from biologic registries, 1 randomised open-label clinical trial and 1 phase IV clinical trial, all seven of which are of moderate to good quality. There results are promising but not excellent. Any switch, especially those between monoclonal antibodies, have an effect size that is usually lower than that of a first biologic. When the switch is due to an adverse event with the first TNF-antagonist, however, the response rate of the second one is high. Perhaps the best alternative when a first TNF-antagonist fails is to start a different type of biologic, and leave the switch to another TNF-antagonist in the case of adverse event to the previous one.

Naredo E, Möller I, Cruz A, Carmona L, Garrido J. · Hospital Severo Ochoa, Madrid, Spain. <> · Arthritis Rheum. · Pubmed #18668537 links to  free full text

Abstract: OBJECTIVE: To evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA). METHODS: Three hundred sixty-seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti-TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. RESULTS: A significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within-subject between-visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time-integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time-integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59). CONCLUSION: These findings indicate that PDUS is a valid method for monitoring response to anti-TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.

Naredo E, Collado P, Cruz A, Palop MJ, Cabero F, Richi P, Carmona L, Crespo M. · Hospital Severo Ochoa, Madrid, Spain. · Arthritis Rheum. · Pubmed #17266071 links to  free full text

Abstract: OBJECTIVE: To evaluate the sensitivity to change of power Doppler ultrasound (PDUS) assessment of joint inflammation and the predictive value of PDUS parameters in disease activity and radiologic outcome in patients with early rheumatoid arthritis (RA). METHODS: Forty-two patients with early RA who started therapy with disease-modifying antirheumatic drugs underwent blinded sequential clinical, laboratory, and ultrasound assessment at baseline, 3 months, 6 months, and 1 year and radiographic assessment at baseline and 1 year. For each patient, 28-joint Disease Activity Score (DAS28) was recorded at each visit. The presence of synovitis was investigated in 28 joints using gray-scale ultrasonography and intraarticular power Doppler signal. Active synovitis was defined as intraarticular synovitis detected with power Doppler signal. The ultrasound joint count for active synovitis and an overall joint index for power Doppler signal were calculated. Sensitivity to change of PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability. RESULTS: The SDD for ultrasound joint count for active synovitis and ultrasound joint index for power Doppler signal was lower than mean changes from baseline to 3 months, 6 months, and 1 year. Time-integrated values of PDUS parameters demonstrated a highly significant correlation with DAS28 after 1 year (r = 0.63, P < 0.001) and a stronger correlation with radiographic progression (r = 0.59-0.66, P < 0.001) than clinical and laboratory parameters (r < 0.5). CONCLUSION: PDUS is a sensitive and reliable method for longitudinal assessment of inflammatory activity in early RA. PDUS findings may have a predictive value in disease activity and radiographic outcome.

Naredo E, Gamero F, Bonilla G, Uson J, Carmona L, Laffon A. · Department of Rheumatology and Research Unit, Hospital de la Princesa, Madrid, Spain. · Clin Exp Rheumatol. · Pubmed #16396709 No free full text.

Abstract: OBJECTIVE: To investigate the validity of reduced joint counts for ultrasonographic (US) assessment of joint inflammatory activity in patients with rheumatoid arthritis (RA). METHODS: Ninety-four patients with RA were included. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels were recorded for each patient. The presence of tenderness, swelling and a subjective swelling score from 0 to 3 were assessed by two rheumatologists who reached consensus in 60 joints examined in each patient. All patients underwent an US examination by a third blinded rheumatologist, using power Doppler (PD). US joint effusion, synovitis and PD signal were graded from 0 to 3 in the 60 joints. A 60-joint count and index for effusion, synovitis and PD signal were recorded. A 6-, 10-, 16-, 18-, and two 12-joint counts and indices for US parameters that included the most frequently US involved joints were calculated for each patient. RESULTS: A 12-joint assessment for effusion, synovitis and PD signal, including bilateral wrist, second and third MCP, second and third PIP of hands and knee joints highly correlated with corresponding 60-joint US counts and indices. This reduced-joint US evaluation showed a similar correlation with clinical and laboratory parameters of disease activity to corresponding 60-joint assessment. CONCLUSION: We propose that a 12-joint evaluation may be a useful tool for US assessment of overall joint inflammatory activity in RA.

González-Alvaro I, Descalzo MA, Carmona L, Anonymous00053. · Rheumatology Service, Hospital Universitario de la Princesa, Madrid, Spain. · Arthritis Res Ther. · Pubmed #19036152 links to  free full text

Abstract: INTRODUCTION: The disease activity in patients with rheumatoid arthritis has improved during the past decade. The availability of new drugs and also a better assessment of the disease have been proposed to be responsible for this improvement. In the present work we estimate the effect of these factors on disease activity and function in patients with rheumatoid arthritis at the beginning of the new century. METHODS: The Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide (EMECAR) cohort was assembled in 2000 from the random sampling of rheumatoid arthritis patients registered in 34 centers. The cohort was composed of 789 patients who underwent a baseline assessment plus four annual follow-up visits in which functional ability (Health Assessment Questionnaire score), the disease activity score obtained from 28-joint count with three parameters (DAS28-3) and radiological progression (Larsen score) were recorded. The effect of the calendar year on the DAS28-3, the Health Assessment Questionnaire score, and the Larsen score was obtained from adjusted models in which all treatments were included as dummy variables. RESULTS: The effect of time as the beta coefficient (95% confidence interval) for 2004, taking 2000 as a reference year, was -0.43 (-0.58 to -0.28) for the DAS28-3, 0.15 (0.07 to 0.22) for the Health Assessment Questionnaire score, and 4.4 (2.68 to 6.12) for the Larsen score. Treatment with new therapies, either leflunomide or TNF antagonists, increased in frequency from 1.1% (n = 8) in 2000 to 30.9% (n = 144) in 2004. Treatment with TNF antagonists (-0.28 (-0.5 to -0.05)) and with gold salts (-0.21 (-0.38 to -0.04)) was independently associated with a decrease in the DAS28-3 over time, whereas cyclosporin A treatment (0.45 (0.13 to 0.76)) was associated with an increase in disease activity. CONCLUSIONS: The mean disease activity of rheumatoid arthritis has improved from 2000 to 2004. An explanation is the introduction of new therapies, but not solely. Other factors related to the calendar year, plausibly a better management of available drugs, show a greater effect on improvement than the drugs used.

Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, Bombardier C, Carmona L, van der Heijde D, Bijlsma JW, Boumpas DT, Canhao H, Edwards CJ, Hamuryudan V, Kvien TK, Leeb BF, Martín-Mola EM, Mielants H, Müller-Ladner U, Murphy G, Østergaard M, Pereira IA, Ramos-Remus C, Valentini G, Zochling J, Dougados M. · Leiden University Medical Center, Department of Rheumatology, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #19033291 links to  free full text

Abstract: 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.

Castrejón I, Ortiz AM, García-Vicuña R, Lopez-Bote JP, Humbría A, Carmona L, Gonzalez-Alvaro I. · Rheumatology Service, Hospital Universitario de la Princesa, Madrid, Spain. · Clin Exp Rheumatol. · Pubmed #19032807 No free full text.

Abstract: A formula for calculating disease activity score with 28 joint counts (DAS28) with C-reactive protein (CRP) instead of the erythrocyte sedimentation rate (ESR) has been proposed. OBJECTIVE: Here we analyze the factors that contribute to the differences in the DAS28 when calculated using either the ESR (DAS28-ESR) or the CRP values (DAS28-CRP). METHODS: We analyzed the data from 587 visits made by 220 patients with early arthritis. The age at the onset of the disease was 51+/-16 years old and 76.3% of the patients were women. The disease evolution at the first visit was 5 months and at each visit information related to several variables was collected, including that necessary to calculate the DAS28-ESR and DAS28-CRP. We defined a new variable DIFDAS=DAS28-ESR-DAS28-CRP to analyze which independent variables account for differences between the two indexes. RESULTS: There was a correlation between the two indexes of 0.91 (p<0.0001), although the DAS28-ESR value obtained was higher than that of DAS28-CRP at approximately 90% of the visits. Significantly, the difference between both indexes was higher than 0.6 in 44% of the visits studied. A multivariate analysis showed that female gender and disease duration were associated with the higher values obtained for DAS28-ESR when compared to those of DAS28-CRP. CONCLUSION: Our data show that DAS28-ESR and DAS28-CRP are not fully equivalent, because the former usually produces higher values. This finding is particularly relevant in females and patients with a long disease duration.

Carbonell J, Cobo T, Balsa A, Descalzo MA, Carmona L, Anonymous00429. · Rheumatology Department, Hospital del Mar, Institut Municipal Atencio Sanitaria, Barcelona. · Rheumatology (Oxford). · Pubmed #18511475 No free full text.

Abstract: OBJECTIVE: To estimate the incidence of early arthritis (EA) and of RA in adults (>16 yrs) in Spain. METHODS: Primary care physicians were instructed in the detection of new cases using a checklist. All cases were evaluated at EA units (EAUs) within 15 days of detection. ACR criteria for the classification of RA were assessed every 6 months thereafter. RESULTS: In an area covering 4,342,378 inhabitants over the age of 16 yrs, 2467 patients were referred to the EAU, of whom 1063 fulfilled EA criteria (43.1%). After 6 months, 362 patients fulfilled RA criteria. The estimated annual incidence of EA was 25/100,000 population (95% CI: 23, 26). The annual incidence of RA was 8.3 cases/100,000 (95% CI: 7.5, 9.2): 11.3/100,000 in women (95% CI: 10.0, 12.8), and 5.2/100,000 in men (95% CI: 4.3, 6.3). The incidence of RA increased with age in both sexes. At the 6 months' assessment, 187 (51.7%) of the patients with RA were RF positive. The presentation of RA was mainly polyarticular (n = 268; 74.0%). There were 701/1063 patients with EA who did not fulfil RA criteria by 6 months after the first rheumatologist visit. If all cases of undifferentiated arthritis (n = 118; 17%) became RA, the incidence would be in the range of 10 cases/100,000 population. CONCLUSIONS: RA incidence in Spain is in the lower range of published data. The incidence of EA is about three times that of RA.

Abásolo L, Júdez E, Descalzo MA, González-Alvaro I, Jover JA, Carmona L, Anonymous00392. · Rheumatology Department, Hospital Clínico San Carlos, Madrid, Spain. · Semin Arthritis Rheum. · Pubmed #17977580 No free full text.

Abstract: OBJECTIVES: To estimate the prevalence, incidence, mortality, and predictors of cancer in patients with rheumatoid arthritis (RA). METHODS: We compared the incidence of cancer and the mortality by cancer in a cohort of 789 randomly selected RA patients (1999-2005) with the expected ones in the general population. We estimated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) by indirect age and sex standardization. Additionally, we analyzed by generalized linear models the association of various predictors with cancer incidence, obtaining incidence rate ratios (IRR) with 95% confidence intervals (CI). RESULTS: The SIR of cancer in RA is 1.23 (95% CI: 0.78-1.85). By cancer type, there is an increased risk of leukemia, non-Hodgkin's lymphoma, and lung cancer in RA compared with the general population of the same sex and age. The SMR of cancer is 1.0 (95% CI: 0.53-1.7). By cancer type, RA patients with lung or kidney cancer have higher mortality than expected. Being male, elderly, with longstanding disease, and having used any cytotoxic drugs apart from methotrexate are confirmed as predictive factors for cancer. Additional independent predictors are increases in blood leukocyte counts (IRR per 3000 u/mm3 increase: 1.88 (95% CI: 1.6 -2.1)) and decreases in serum hemoglobin (IRR per 2 g/l decrease: 1.88 (95% CI: 1.19 -2.94)). CONCLUSIONS: The overall incidence and mortality of cancer in RA is not greater than the expected, although there is an increased risk of hematopoietic and lung cancers in RA patients compared with the general population. Hemoglobin and leukocyte counts may help to identify RA patients at risk for cancer.

Gómez-Reino JJ, Carmona L, Angel Descalzo M, Anonymous00128. · Hospital Clínico Universitario, University of Santiago de Compostela School of Medicine, Santiago, Spain. · Arthritis Rheum. · Pubmed #17530674 links to  free full text

Abstract: OBJECTIVE: To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI). METHODS: Incidence rate of ATB per 100,000 patient-years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available. RESULTS: Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103-285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60-64.69). Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. CONCLUSION: New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.

Carmona L, Descalzo MA, Perez-Pampin E, Ruiz-Montesinos D, Erra A, Cobo T, Gómez-Reino JJ, Anonymous00127. · Research Unit, Spanish Foundation of Rheumatology, Madrid, Spain. · Ann Rheum Dis. · Pubmed #17324968 links to  free full text

Abstract: BACKGROUND: Mortality is increased in rheumatoid arthritis (RA), mainly because of cardiovascular (CV) events, cancer and infections. Recent data suggest that treatment with tumour necrosis factor (TNF) antagonists may affect this trend. OBJECTIVE: To assess whether treatment with TNF antagonists is associated with reduction in CV events, cancer and infection rates, and in mortality in patients with RA treated and not treated with TNF antagonists. METHODS: BIOBADASER is a registry for active long-term follow-up of safety of biological treatments in patients with RA. It includes 4459 patients with RA treated with TNF antagonists. EMECAR is an external RA cohort (n = 789) established to define the characteristics of the disease in Spain and to assess comorbidity. The incidence density (ischaemic heart disease) of CV events, cancer and infections was estimated and compared. The standardised mortality ratio was compared with the rate in the general population. A propensity score was used to match cohorts by the probability of being treated. RESULTS: Rates of CV and cancer events are significantly higher in EMECAR than in BIOBADASER (RR 5-7 for different CV events, and RR 2.9 for cancer), whereas the rate of serious infections is significantly higher in BIOBADASER (RR 1.6). Mortality ratio of BIOBADASER by EMECAR is 0.32 (0.20-0.53) for all causes of death, 0.58 (0.24-1.41) for CV events, 0.52 (0.21-1.29) for infection and 0.36 (0.10-1.30) for cancer-related deaths. CONCLUSION: Morbidity, other than infection, and mortality are not higher than expected in patients with RA treated with TNF antagonists.

Ariza-Ariza R, Hernández-Cruz B, Carmona L, Dolores Ruiz-Montesinos M, Ballina J, Navarro-Sarabia F, Anonymous00382. · Rheumatology Service, Hospital Universitario Virgen Macarena, Seville, Spain. · Arthritis Rheum. · Pubmed #17013822 links to  free full text

Abstract: OBJECTIVE: To compare the utility values and quality-adjusted life years (QALYs) obtained by the Time Trade-Off instrument (TTO) and the EuroQol-5D (EQ-5D) in patients with rheumatoid arthritis (RA); to analyze the association between utility values and Disease Activity Score 28 (DAS28) and Health Assessment Questionnaire (HAQ). METHODS: We conducted a longitudinal, prospective, 1-year study of RA patients selected randomly from 10 rheumatology clinics. TTO and EQ-5D were administered at 4 scheduled visits. RESULTS: The study sample comprised 300 RA patients (82% women, mean age 59 years, mean disease duration 10.3 years). A total of 260 patients completed both the TTO and the EQ-5D at baseline, and the mean +/- SD TTO scores were significantly higher than the EQ-5D scores (0.81 +/- 0.22 versus 0.53 +/- 0.35, P < 0.0001). The intraclass correlation coefficient (ICC) for the utility methods was 0.19. Data about changes in both TTO and EQ-5D scores during the study year were available in 163 patients. These changes tended to be larger in the TTO scores than the EQ-5D scores (mean +/- SD 0.05 +/- 0.25 versus -0.005 +/- 0.35, P = 0.054). The ICC for the mean changes in the utility scores was 0.24. Patients obtained a mean +/- SD of 0.04 +/- 0.20 QALYs based on TTO scores and 0.004 +/- 0.27 based on EQ-5D scores (P = 0.12). At baseline, the EQ-5D scores were highly correlated with the HAQ (r = -0.74) and moderately correlated with the DAS28 (r = -0.47), whereas the TTO correlated poorly with both the HAQ and DAS28. Correlation between the mean change in the EQ-5D and in the HAQ was moderate (r = -0.55). CONCLUSION: TTO and EQ-5D do not yield the same utility values. The results suggest that the EQ-5D is more representative of RA status than the TTO, a valuable conclusion when addressing economic evaluations in RA.

Carmona L, Gómez-Reino JJ, Anonymous00303. · Research Unit, Spanish Society of Rheumatology, Madrid, Spain Marques de Duero 5, 28001 Madrid, Spain. · Arthritis Res Ther. · Pubmed #16620398 links to  free full text

Abstract: The aim of the present work is to compare drug survival and safety of infliximab, etanercept, and adalimumab (tumor necrosis factor [TNF] antagonists) in spondylarthritis (SpA) with those of rheumatoid arthritis (RA). To this purpose, we analysed the data in BIOBADASER (2000-2005), a drug registry launched in 2000 for long-term follow-up of the safety of these biologics in rheumatic diseases. The rates of drug discontinuation and adverse events (AEs) in SpA (n = 1,524) were estimated and compared with those of RA (n = 4,006). Cox regression analyses were used to adjust for independent factors. Total exposure to TNF antagonists for SpA was 2,430 patient-years and 7,865 for RA. Drug survival in SpA was significantly greater than in RA at 1, 2, and 3 years. The hazard ratio (HR) for discontinuation in SpA compared with RA was 0.66 (95% confidence interval [CI], 0.57-0.76) after adjustment for age, gender, and use of infliximab. The difference remained after controlling for the individual medication and its place in the sequence of treatment. There were fewer SpA patients with AEs (17%) than RA patients (26%; p < 0.001). The HR for AEs in SpA was 0.80 (95% CI, 0.70-0.91) compared with RA after adjustment for age, disease duration, and use of infliximab. In conclusion, due in part to a better safety profile, survival of TNF antagonists in SpA is better than in RA. TNF antagonists are at present a safe and effective therapeutic option for long-term treatment of patients with SpA failing to respond to traditional drugs. Because chronic therapy is necessary, continual review of this issue is necessary.

Gomez-Reino JJ, Carmona L, Anonymous00301. · Rheumatology Service and Department of Medicine, Hospital Clinico Universitario, Medical School, Universidad de Santiago de Compostela, Spain. · Arthritis Res Ther. · Pubmed #16507128 links to  free full text

Abstract: The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34-0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97-2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13-4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications.

Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D, Pascual-Gómez E, Mola EM, Carreño L, Figueroa M, Anonymous00287. · Spanish Society of Rheumatology, Madrid, Spain. · Arthritis Rheum. · Pubmed #15934089 links to  free full text

Abstract: OBJECTIVE: To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists. METHODS: Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years. RESULTS: Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre-OR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6- and 6.2-fold higher than the background and EMECAR populations, respectively. Post-OR, 324 patients with a tuberculin skin test result > or =5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03-0.88; P = 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02-8.2). There were no INH treatment-related hospitalizations or deaths. CONCLUSION: Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.

Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A. · Department of Rhumatology, Hospital de la Princeca, Madrid, Spain. · Ann Rheum Dis. · Pubmed #15708891 links to  free full text

Abstract: OBJECTIVE: To compare the clinical assessment of overall inflammatory activity in patients with rheumatoid arthritis (RA) with grey scale and power Doppler (PD) ultrasonography (US). METHODS: Ninety four consecutive patients with RA were included. Demographic and clinical data, C reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were recorded for each patient. The presence of tenderness, swelling, and a subjective swelling score from 1 to 3 were independently assessed by two rheumatologists, who reached a consensus in 60 joints examined in each patient. All patients underwent a US examination by a third blinded rheumatologist, using PD. US joint effusion, synovitis, and PD signal were graded from 1 to 3 in the 60 joints. Joint count and joint index for effusion, synovitis, and PD signal were recorded. A 28 joint count for clinical and US variables was calculated. Interobserver reliability of the US examination was evaluated by a fourth blinded rheumatologist. RESULTS: US showed significantly more joints with effusion (mean 15.2) and synovitis (mean 14.6) than clinical examination (mean 11.5, p<0.05). A significant correlation was found between joint count and joint index for swelling, US effusion, synovitis, and PD signal. The 28 joint count for effusion, synovitis, and PD signal correlated highly with the corresponding 60 joint counts. US findings correlated better with CRP and ESR than clinical measures. Interobserver reliability was better for US findings than for clinical assessment. CONCLUSION: US is a sensitive method for assessing joint inflammatory activity in RA, complementary to clinical evaluation.

Naranjo A, Carmona L, Gavrila D, Balsa A, Belmonte MA, Tena X, Rodríguez-Lozano C, Sanmartí R, González-Alvaro I, Anonymous00225. · Rheumatology Department, Hospital Dr Negrín, Las Palmas, Spain. · Clin Exp Rheumatol. · Pubmed #15301239 No free full text.

Abstract: OBJECTIVE: To estimate the prevalence of anterior atlantoaxial subluxation (AAS) in patients with rheumatoid arthritis (RA), and to analyse its association with disease markers. METHODS: Cross-sectional analysis of a cohort of RA patients randomly selected from the clinical registries of 34 centres. AAS, defined as an atlantoaxial displacement in cervical spine X-rays greater than 3 mm on flexion films, was actively searched for. Bivariate and multivariate analysis was performed to examine its association with clinical, functional, and treatment variables. RESULTS: AAS was found in 88 out of 736 patients with available cervical radiographs, (prevalence and 95% confidence interval [CI]: 12% [9.7-14.2]). The presence of AAS was highly associated with a Larsen score (0-150) over 50 (OR and 95% CI: 5.31 [2.68-10.55]), RA duration of more than 10 years (4.48 [2.70-7.44]), disease onset before age 50 (4.15 [2.42-7.12]), eye involvement (3.93 [1.63-9.46]), and previous RA related surgery (3.90 [2.46-6.19]). No association was found with rheumatoid factor. Multivariate analysis showed that a disease onset before the age of 50, the number of previous DMARD, and, above all, a Larsen score greater than 50 were important independent factors associated with AAS. There is a 33% increased risk for AAS every 10 units up in the Larsen score. CONCLUSION: AAS is frequent in RA patients, particularly in those with markers of erosive disease.

Balsa A, Carmona L, González-Alvaro I, Belmonte MA, Tena X, Sanmartí R, Anonymous00163. · Rheumatology Unit, Hospital Universitario La Paz, Madrid, Spain. · J Rheumatol. · Pubmed #14705217 No free full text.

Abstract: OBJECTIVE: To assess the criteria for remission based on Disease Activity Score 28 (DAS28) and DAS28-3 (excluding patients' evaluation of disease activity) compared to American College of Rheumatology (ACR) preliminary criteria in established rheumatoid arthritis (RA), and to examine the value of each ACR criterion individually. METHODS: The EMECAR study was designed to assess the burden of comorbidity and inflammatory activity for RA in Spain. A random sample of 788 patients with RA from 34 Spanish centers was selected. Remission was defined by preliminary ACR criteria applied specifically and the clinical activity assessed by the DAS28 and the DAS28-3. A receiver operating characteristics curve analysis was performed to identify cutoff values with the highest usefulness in defining remission on both DAS indices. RESULTS: Thirty-two patients (4.1%) were in ACR-defined remission, 62 (7.9%) if fatigue was excluded from the criteria. The frequency of any single criterion that patients in remission fulfilled: no fatigue and joint pain by anamnesis in 31 patients (96.9%); morning stiffness < 15 min in 26 (81.3%); no swelling in joints in 21 (65.6%); normal erythrocyte sedimentation rate (ESR) in 29 (90.6%); and no joint tenderness in 21 (65.6%) patients. The positive predictive value for remission of each criterion: normal ESR 6.5%; morning stiffness < 15 min 8.4%; no fatigue 8.7%; no joint tenderness 13%; no swelling in joints 15.8%; and no joint pain by anamnesis 27.7%. The DAS28 cutoff values with higher discriminatory power for remission were 3.14 (sensitivity 87%; specificity 67%) when all the ACR criteria were used, and 2.81 (sensitivity 84%; specificity 81%) when fatigue was omitted. The equivalent cutoffs for the DAS28-3 were 3.52 (sensitivity 84%; specificity 66%) and 2.95 (sensitivity 82%; specificity 83%), respectively. CONCLUSION: DAS28 and DAS28-3 are good tools to define remission in established RA. No joint pain by anamnesis is the criterion with the highest value in defining remission, while normal ESR, an absence of morning stiffness, and fatigue are the least effective.

Carmona L, González-Alvaro I, Balsa A, Angel Belmonte M, Tena X, Sanmartí R. · Rheumatology Department, H Clínico San Carlos, Madrid, Spain. · Ann Rheum Dis. · Pubmed #12922967 links to  free full text

Abstract: OBJECTIVES: To characterise RA in a sample of Spanish patients by estimating mean clinical activity, functional ability, and radiological damage, and current and cumulative prevalence of extra-articular manifestations. METHODS: Cross sectional analysis of a cohort of patients with RA randomly selected from the clinical databases of 34 centres. Standard definitions and measurements were used, and radiographs read centrally. Estimates and confidence intervals were adjusted to sampling. RESULTS: Data were available for 788 patients. Extra-articular RA was present in 285 (36.2%) patients. Cumulative prevalence and 95% confidence intervals of extra-articular manifestations were estimated: nodules 24.5% (21.5 to 27.5), Sjögren's syndrome 17.0% (14.4 to 19.6), atlantoaxial subluxation 12.1% (9.8 to 14.4), carpal tunnel syndrome 10.7% (7.8 to 13.6), interstitial lung disease 3.7% (2.4 to 5.0), serositis 2.5% (1.4 to 3.5), eye disease 2.5% (1.1 to 3.9), vasculitis 1.3% (0.5 to 2.1), amyloidosis 0.6% (0.1 to 1.2), and Felty's syndrome 0.3% (<0.6). Mean (SD) activity/progression indexes were: DAS28-3 3.4 (1.2), HAQ 1.6 (0.4), Larsen score 54.7 (26.4). Less than 5% of the patients were in remission. 205 (72%) patients were receiving disease modifying antirheumatic drugs (DMARDs). CONCLUSION: Spanish patients with RA ever seen by a rheumatologist have, on average, a moderate degree of activity, despite widespread use of DMARDs. Measures of the degree of progression do not show a benign disease. The proportion of extra-articular manifestations in Spanish patients with RA is similar to that found in other Mediterranean populations, and lower than that reported in Anglo Saxon countries.

Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, Anonymous00269. · Hospital Clinico Universitario and Universidad de Santiago de Compostela, Santiago, Spain. · Arthritis Rheum. · Pubmed #12905464 links to  free full text

Abstract: OBJECTIVE: The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs. METHODS: We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment. RESULTS: Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). CONCLUSION: Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

Carmona L, Hernández-García C, Vadillo C, Pato E, Balsa A, González-Alvaro I, Belmonte MA, Tena X, Sanmartí R, Anonymous00297. · Hospital Clínico San Carlos, Madrid, Spain. · J Rheumatol. · Pubmed #12858438 No free full text.

Abstract: OBJECTIVE: To quantify the risk of tuberculosis (TB) in an unselected sample of patients with rheumatoid arthritis (RA) compared to the risk in the general population. METHODS: The incidence of TB in the general population of Spain was obtained from the National Network of Epidemiological Surveillance reports. The incidence of TB was ascertained from a cohort of 788 patients with RA selected randomly from the registries of 34 participating centers throughout Spain. A patient was considered a TB case only if information about disease symptoms, microorganism identification, and TB treatment were confirmed in the clinical records. The relative risk of TB in RA was calculated by dividing the standardized mean incidence of TB from 1990 to 2000 in the RA cohort by the mean incidence of TB in Spain during the same years. RESULTS: The mean incidence of TB in the general population of Spain from 1990 to 2000 was 23 cases per 100,000. Seven cases of TB were identified in the RA cohort, yielding a mean annual incidence (1990-2000) of 134/100,000 patients. The incidence risk ratio of pulmonary TB in patients with RA compared to the general population is 3.68 (95% CI 2.36-5.92). CONCLUSION: We found a 4-fold increased risk of TB infection in patients diagnosed with RA. These results might help to interpret the magnitude of the problem attributable to the introduction of new therapies in RA.

Gonzalez-Alvaro I, Carmona L, Balsa A, Sanmarti R, Belmonte MA, Tena X, Anonymous00148. · Department of Rheumatology, Hospital Universitario de la Princesa, Madrid, Spain. · J Rheumatol. · Pubmed #12672186 No free full text.

Abstract: OBJECTIVE: To determine the adequacy of disease modifying antirheumatic drug (DMARD) prescription to disease activity in patients with rheumatoid arthritis (RA) and to assess whether the reasons for DMARD discontinuation agree with published evidence. METHODS: Cross-sectional analysis of the baseline year of a RA cohort (n = 788) randomly selected from the clinical registries of 34 centers. Data about current and previous DMARD use was collected from medical records and confirmed by the patient. Disease activity score (DAS), Health Assessment Questionnaire (HAQ) and Larsen scores, and other clinical data were obtained during the study visit. RESULTS: At baseline visit, 607 patients (77%) were receiving one or more DMARD. Mean DAS, HAQ, and Larsen scores (+/- SD) were: 3.40 +/- 1.22, 1.6 +/- 0.4, and 54.68 +/- 26.37, respectively. Methotrexate (MTX) was the most frequently prescribed DMARD and parenteral gold salts (GS) showed the highest rate of discontinuation. MTX was used as single therapy in a significantly higher proportion (64.3%) than other DMARD (< 50%) and treatment discontinuation due to inefficacy was significantly less frequent (25.5%) than with other DMARD (> 40%). However, the DAS28 was significantly worse in the group treated with MTX in single therapy than in the group treated with GS alone (4.13 vs 3.43; p = 0.032). CONCLUSION: Despite the high use of DMARD among Spanish patients with RA, a significant number of them still have poor control of the disease. In addition, our data show a different perception of ineffectiveness depending on the DMARD used. A non-systematic use of objective quantitative tools for assessment of RA activity and some non-evidence based decisions on the management of DMARD may account for these findings.

Lajas C, Abasolo L, Bellajdel B, Hernández-García C, Carmona L, Vargas E, Lázaro P, Jover JA. · Hospital Clínico San Carlos, Madrid, Spain. · Arthritis Rheum. · Pubmed #12579595 links to  free full text

Abstract: OBJECTIVE: To analyze the annual cost of rheumatoid arthritis (RA) and its predictive factors. METHODS: Data were obtained from a 12-month retrospective cohort of 201 RA patients, randomly selected from a rheumatology registry, through a structured interview and records of the Central Information System of the hospital. Results were divided into direct, indirect, and total costs in 2001 US dollars. A sensitivity analysis was performed. Multiple linear regression models for the different types of costs were carried out. RESULTS: The total cost was US dollars 2.2 million per year, with a cost attributable to RA of US dollars 2.07 million per year. The average cost per patient was US dollars 10419 per year (ranging from US dollars 7914 per patient per year in the best scenario to US dollars 12922 per patient per year in the worst case). Direct costs represent nearly 70% of total costs. We found an average increment in total costs of US dollars 11184 per year per unit of Health Assessment Questionnaire (HAQ) score (P < 0.0001) and an average annual increment of US dollars 621 per year of disease (P < 0.0001). After adjustment, the HAQ score, inability to perform housework tasks, and being permanently disabled for work were the only predictors of high costs. CONCLUSION: Our data show a remarkable economic impact of RA over society and link the costs of the disease to its consequences in terms of functional disability, work disability, and housework disability.

Carmona L, Villaverde V, Hernández-García C, Ballina J, Gabriel R, Laffon A, Anonymous00180. · Research Unit, Hospital de la Princesa, Diego de Léon, 62, 28006 Madrid, Spain. · Rheumatology (Oxford). · Pubmed #11792885 links to  free full text

Abstract: OBJECTIVE: To estimate the prevalence of rheumatoid arthritis (RA) in the adult Spanish population and to assess its distribution by basic sociodemographic characteristics. METHODS: Two thousand nine hundred and ninety-eight adults were selected randomly from the censuses of 20 municipalities. Trained rheumatologists administered a structured interview that included a screening questionnaire for RA. Subjects with a positive screening result were examined according to a standardized protocol. Cases were defined by the 1987 American College of Rheumatology (ACR) criteria adapted to epidemiological surveys. RESULTS: One hundred and eighty-six persons (8.5%) had a positive screening result for RA and 11 of these fulfilled the ACR criteria for RA. The estimated prevalence was 0.5% (95% confidence interval 0.25-0.85). The ratios of women to men and of urban to rural were both 4:1. Function and health perception of the cases were significantly impaired, even after controlling for age and sex. CONCLUSION: The prevalence of RA in Spain is comparable to that in other Mediterranean countries. RA may be less frequent in rural settings, a finding that merits further research. A significant proportion of RA cases in the community remain undiagnosed despite impaired functional status.

Carmona L, Ballina J, Gabriel R, Laffon A, Anonymous00280. · Research Unit, Hospital Universitario de La Princesa, Madrid, Spain. · Ann Rheum Dis. · Pubmed #11602475 links to  free full text

Abstract: OBJECTIVE: The objective of the EPISER study was to estimate the prevalence of rheumatoid arthritis (RA), low back pain, hand and knee osteoarthritis (OA), and fibromyalgia in the adult Spanish population, and to assess the impact of these diseases on function and quality of life, and use of health and social resources. METHODS: 2998 subjects aged 20 years or above were randomly selected by stratified multistage cluster sampling from the censuses of 20 municipalities. Trained rheumatologists carried out structured visits at which subjects were asked about rheumatic symptoms and sociodemographic characteristics, completed validated instruments for measuring function (HAQ) and quality of life (SF-12), and underwent a standardised physical examination. Cases were defined by previously validated criteria. RESULTS: The estimated prevalences with 95% confidence intervals were as follows: RA lifetime cumulative: 0.5% (0.3 to 0.9); low back pain: 14.8% (12.2 to 17.4); symptomatic knee OA: 10.2% (8.5 to 11.9); hand OA: 6.2% (5.9 to 6.5); fibromyalgia: 2.4% (1.5 to 3.2). Most conditions significantly impaired function and quality of life. CONCLUSIONS: The EPISER study has internal and external validity for application of the results to the adult Spanish population. The diseases studied affect a significant proportion of the population, with various degrees of impact on disability and quality of life resulting in a significant number of physician visits, work disability, and medication use.