Juan Angel Jover

To evaluate long-term use of antimalarial drugs and to analyse all causes of discontinuation. This is a retrospective study of a cohort of rheumatic diseases patients on antimalarials, during a maximum period of 17.5 years. Case was defined as antimalarial treatment discontinuation due to: a) lack of efficacy, b) adverse events, and c) other causes. Survival techniques were used to estimate the incidence rate (IR) per 1,000 patient-years with the 95% Confidence Interval (95% CI) of antimalarial treatment discontinuation. Cox regression models were conducted to evaluate possible associated factors to antimalarial discontinuation. One thousand, two hundred and ninety-one medical records were reviewed, and 778 patients were included. Patients started 869 different courses of treatment, with a total follow-up of 2,263 person-years. The IR of global discontinuation was 204 (95% CI 186-224). Fifty-two per cent of the treatments stopped were related to adverse events, 14% to lack of efficacy; and 34% to other reasons (refusal to take medication, ocular comorbidity, remission, or pregnancy). Adverse events discontinuations were related to non-ophthalmologic reasons in 54.5% (gastrointestinal, neuro-psychiatric, skin problems), and to ophthalmologic adverse events in 45.5%. Nine patients suffered definite presence of antimalarial retinopathy (IR: 3.97 [IC 95%: 2.06-7.62]) and one of them irreversible loss of vision (IR: 0.44 [IC 95%: 0.06-3.12]). Women, increasing age, and chloroquine vs. hydroxychloroquine use, increased the risk of discontinuation due to ophthalmologic adverse events. Results suggest that antimalarials have a good balance between benefit and risk. However, we noted a number of discontinuations due to both inefficacy and adverse events. The potential for an unusual but serious ophthalmologic toxicity emphasises the importance of close ophthalmologic monitoring.

To evaluate the variability in the characteristics and management of rheumatoid arthritis (RA) patients between rheumatology attending physicians and training residents in Spain. A retrospective medical record (MR) review was performed in a probabilistic sample of 1379 RA patients from 46 centres distributed in 16 of the 19 autonomous communities (AC) of Spain. RA patients' sociodemographic and clinical characteristics, healthcare resources use, and their single responsible physician's (defined as an identifiable single physician who attended the patient in more than 75% of visits) characteristics were recorded following a standardized protocol. Multivariate analyses were performed to assess differences in the characteristics and management of RA patients between attending physicians and training residents. A total of 1205 RA patients had a single responsible physician and were analysed (nearly 75% women with rheumatoid factor positive and more than 25% with persistent active disease), 49 of whom were followed by training residents and 1156 by attending physicians. In the multivariate analyses, irrespective of patient and disease characteristics, training residents' patients reported more hospital admissions, laboratory tests, and imaging techniques compared to attending physicians. Training residents also less frequently used combined therapy with disease-modifying antirheumatic drugs (DMARDs). Training residents and attending physicians differ in RA patients' care. More efforts in training programmes are necessary to guarantee proper RA management and to improve the profile of the future rheumatologists.

Objective: To evaluate how an intervention program modifies the clinical course of work disability in musculoskeletal diagnoses.Methods: All patients with temporary work disability related to musculoskeletal disorders (MSDs) in 3 health districts of Madrid, Spain were randomized into standard care (control group) or the intervention group. Intervention consisted of a specific program, run by rheumatologists, following detailed proceedings. Inclusion and followup lasted 12 months each. According to the cause, every temporary work disability episode was classified into 11 syndrome categories. For each we calculated efficacy, as the difference between groups in the number of days on sick leave per temporary work disability episode; relative efficacy, or the percentage of days saved in the intervention group; and time of maximum program effect. Analyses were performed on an intent‐to‐treat basis. Survival techniques were run and results were expressed as the hazard ratio (HR) in the intervention versus control group.Results: A total of 13,077 patients were included, generating 16,297 temporary work disability episodes. The most frequent cause was back pain. Temporary work disability episodes were significantly shorter in the intervention group than in the controls in all syndrome categories except knee pain (excluding osteoarthritis). Program relative efficacy varied from 28–72%. The program was highly efficacious in carpal tunnel syndrome (HR 2.09, 95% confidence interval [95% CI] 1.17–3.75), peripheral osteoarthritis (HR 1.58, 95% CI 1.14–2.19), and inflammatory diseases (HR 1.52, 95% CI 1.09–2.12). The maximum effect of the program always took place within the first 2 months.Conclusion: The implementation of this type of specialist‐run, protocol‐based early intervention program would be very beneficial in the treatment of patients with work disability related to MSDs, except for those with knee pain (excluding osteoarthritis).

Musculoskeletal disorders (MSDs) are a frequent cause of work disability, accounting for productivity losses in industrialized societies equivalent to 1.3% of the U.S. gross national product. To evaluate whether a population-based clinical program offered to patients with recent-onset work disability caused by MSDs is cost-effective. Randomized, controlled intervention study. The inclusion and follow-up periods each lasted 12 months. Three health districts in Madrid, Spain. All patients with MSD-related temporary work disability in 1998 and 1999. The control group received standard primary care management, with referral to specialized care if needed. The intervention group received a specific program, administered by rheumatologists, in which care was delivered during regular visits and included 3 main elements: education, protocol-based clinical management, and administrative duties. Efficacy variables were 1) days of temporary work disability and 2) number of patients with permanent work disability. All analyses were done on an intention-to-treat basis. 1,077 patients were included in the study, 7805 in the control group and 5272 in the intervention group, generating 16,297 episodes of MSD-related temporary work disability. These episodes were shorter in the intervention group than in the control group (mean, 26 days compared with 41 days; P < 0.001), and the groups had similar numbers of episodes per patient. Fewer patients received long-term disability compensation in the intervention group (n = 38 [0.7%]) than in the control group (n = 99 [1.3%]) (P < 0.005). Direct and indirect costs were lower in the intervention group than in the control group. To save 1 day of temporary work disability, 6.00 dollars had to be invested in the program. Each dollar invested generated a benefit of 11.00 dollars. The program's net benefit was in excess of 5 million dollars. The study was unblinded. Implementation of the program, offered to the general population, improves short- and long-term work disability outcomes and is cost-effective.

To determine whether anti-TNF alpha (infliximab) treatment affects B cell activation in patients with rheumatoid arthritis (RA) METHODS: B cell activation was analyzed in fifteen anti-TNF-treated RA patients. CD23 expression was used as a B cell activation marker and was studied before and after three months of infliximab treatment. PBMC were stimulated with anti-CD3 mAb during 18 h and were separated by rosseting into E+ and E-cells. B cells were assessed in E-population by double staining with CD19 and CD23. ELISA assays were used to assess both soluble TNF alpha and circulant immune complexes (CIC) containing TNF alpha. We also used B cells from tonsils to establish the relationship between B cell activation and TNF alpha CIC. The proportion of B cells expressing CD23 was higher before infliximab exposure than after treatment (48.3 +/- 16.7 versus 29.5 +/- 12.5, p = 0.007). T-B cell interactions were assessed by means of blocking antibodies to CD154, CD40, CD69, and CD18; these interactions were not specially affected by infliximab treatment. We could demonstrate CIC containing TNF alpha after infliximab treatment, these CIC, similarly to others IgG-containing immune complexes, were capable to downregulate CD23 on B cells. Infliximab treatment in RA downregulates CD23 expression on T-cell activated B cells. This downregulation is connected with the presence of CIC containing TNF alpha. Presumably, the Fc gamma RIIb1 endows IgG-containing immune complexes, as TNF alpha-anti-TNF alpha, with the capacity to regulate B cells and inflammatory cells.

To analyze the mechanisms involved in the characteristic hyperexpression of CD23 on peripheral blood B cells from patients with rheumatoid arthritis (RA). Peripheral blood mononuclear cells (PBMC) were obtained from patients with active disease and activated during 18 h with an anti-CD3 monoclonal antibody in the presence or absence of blocking antibodies to CD154 or CD40. PBMC were further purified by rosetting and CD23 expression was assessed on B cells by flow cytometry after double staining (CD19/CD23). Lymphocytes were also isolated from synovial fluid (SF). CD154 expression was analyzed on PB or SF CD4+ T cells after double staining (CD4/CD154) by flow cytometry at basal conditions and after different stimuli [anti-CD3 or phorbol myristic acetate (PMA) plus ionomycin]. Co-culture experiments between SF and PB cells were performed to analyze the involvement of the CD40-CD154 interaction on CD23 expression. CD154 and CD23 expression was also analyzed on synovial membrane by immunohistochemical techniques. A high proportion of activated CD23 B cells was detected in patients with RA. Blocking experiments with both anti-CD40 and anti-CD154 Mab showed a significant reduction in the proportion of PB B cells expressing CD23. Following activation with anti-CD3 Mab or PMA plus ionomycin, CD154 expression was mainly induced on PB CD4+ T cells. In co-culture experiments, SF T cells were more efficient than PB T cells in inducing CD40 dependent CD23 expression on PB B cells. In addition, CD4+ T cells from synovial membrane clearly expressed CD154. Our results establish a link between CD154-CD40 pathway and CD23 expression on PB B cells from patients with RA. T cells from the synovial microenvironment were active participants in this CD23 expression, presumably in the context of cell recirculation.

To study demographic and clinical variables associated with a longer delay in disease modifying antirheumatic drug (DMARD) therapy initiation in a cohort of patients with rheumatoid arthritis (RA). We studied 527 new RA patients (74.3% female, median age at symptom onset 55 yrs) in a hospital setting who fulfilled the ACR criteria for the diagnosis of RA. Demographic, clinical, laboratory, and treatment variables were collected longitudinally into a computerized research database. Risk factors for delay in use of DMARD therapy and first evaluation by a rheumatologist were analyzed using a Cox regression model. The median lag time between symptom onset and first rheumatologist encounter was 17 months and between onset of symptoms and first DMARD therapy 19 months. Variables associated with longer delay to DMARD therapy were the lag time between symptom onset and first rheumatologist visit (RR 0.73, 95% CI 0.71-0.76) and years of education. Variables associated with longer delay in first visit with rheumatologist were swollen/tender joint count, age at symptom onset, home support, labor force status, marital status, and years of education. Awareness of factors associated with a longer delay in access to rheumatology care and DMARD therapy may help break down barriers that prevent their early access, irrespective of patient age, socioeconomic status, initial symptoms, or need for treatment.

To investigate patients with formerly undiagnosed underlying spondyloarthropathy (SpA) in a series of anterior uveitis (AU) cases and to describe the rheumatologic and ophthalmologic characteristics of these patients. Patients with anterior uveitis referred to the Uveitis Clinic between January 1992 and December 1998 who had a final diagnosis of SpA were included in the study group. The diagnosis of SpA was based on current diagnostic criteria. Patients were classified into 2 groups: formerly diagnosed, or undiagnosed SpA before attendance at the uveitis clinic. Demographic features, clinical symptoms, ophthalmologic characteristics, and laboratory tests were collected prospectively in each patient. A regression logistic model was applied. We evaluated 514 patients with anterior uveitis; 117 (22.7%) had some type of SpA. Ankylosing spondylitis was the most frequent diagnosis (64.1%). More than half the patients (53%) were diagnosed with SpA after an episode of uveitis; the percentage was up to 90.9% in undifferentiated SpA. Clinically, the formerly diagnosed and undiagnosed groups were quite similar, inflammatory low back pain being the most frequent symptom in both groups. Radiological sacroiliitis was less common and with a lower grade in the formerly undiagnosed group. Acute recurrent unilateral anterior uveitis was the most frequent clinical pattern in the group as a whole (68.3%), observed in all subgroups, except for inflammatory bowel disease related SpA, which presented panuveitis as the most frequent pattern. SpA was the most frequent systemic disease related to anterior uveitis, seen in more than 50% of our SpA cases diagnosed after an episode of uveitis. The undiagnosed SpA patient is generally an atypical case, with a shorter clinical evolution and less radiological damage.