Benjamín Fernández-Gutiérrez

Combined Treatment of Giant-Cell Arteritis with Methotrexate and Prednisone: A Randomized, Double-Blind, Placebo-Controlled Trial

Giant-cell (temporal) arteritis is a T-celldependent vasculitis in elderly persons that involves large and medium-sized arteries (1). Treatment with high doses of corticosteroids usually suppresses inflammatory activity dramatically, thus improving clinical symptoms and preventing disease-related complications. It is commonly accepted that patients should receive prednisone at an initial dosage of 40 to 60 mg/d, with subsequent tapering to a lower maintenance dose that is given for an average of 2 years (2). However, up to 60% of patients experience disease relapse during corticosteroid tapering (3, 4), and long-term corticosteroid therapy leads to corticosteroid-related adverse events in up to 80% of patients (5-7). Corticosteroid-related side effects are thus a major problem in the management of giant-cell arteritis in already frail patients. Various agents have been used in an attempt to reduce corticosteroid requirements in corticosteroid-resistant giant-cell arteritis (8-11), but only azathioprine has been shown to reduce maintenance doses of corticosteroid in a double-blind, placebo-controlled study lasting 1 year (12). Methotrexate has proven to be useful in the management of several types of systemic vasculitis, such as Wegener granulomatosis, polyarteritis nodosa, and Takayasu disease (13), and various open studies in small series of patients have shown a potential corticosteroid-sparing effect of methotrexate in giant-cell arteritis (14). After a previous open preliminary study (15), we conducted a trial to assess the safety and efficacy of methotrexate in the management of giant-cell arteritis. Methods Patients with newly diagnosed active giant-cell arteritis were consecutively entered into a randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of methotrexate therapy combined with corticosteroids in this condition. Patients were enrolled from May 1993 through August 1997. The study protocol was approved by the Ethics and Research Committees of Hospital Clnico San Carlos, Madrid, Spain. Selection and Randomization All patients with suspected recent-onset giant-cell arteritis were eligible for entry into the trial after giving informed consent. Patients attending Hospital Clnico San Carlos (n =38) and those referred from other hospitals in the metropolitan area of Madrid, Spain (n =12), were invited to participate in the study. Inclusion criteria were a positive result on temporal artery biopsy and less than 2 weeks of treatment with high-dose corticosteroid (prednisone,>10 mg/d, or equivalent) before randomization. Exclusion criteria were contraindications to methotrexate, such as known liver dysfunction or baseline elevation of serum aminotransferase levels to more than twice the normal values; renal failure (baseline serum creatinine concentration>176.8 mol/L [>2 mg/dL]); history of chronic alcohol abuse (consumption of>20 g/d); active chronic infection; history of neoplasm (unless it was treated successfully>5 years before screening) or any other clinical condition that might hinder follow-up; history of poor compliance with other treatment protocols; treatment with low doses of steroids ( 10 mg of prednisone per day or equivalent) for more than 3 months before screening; previous use of other immunosuppressive drugs; or lack of written consent. Patients were randomly assigned in blocks of six and in a 1:1 ratio to receive prednisone plus methotrexate or placebo. The active drug and placebo were identical in terms of physical characteristics. Baseline Studies and Follow-up Baseline and follow-up visits were scheduled weekly during the first month, monthly until completion of the first year of therapy, and quarterly during the second year of follow-up. Each scheduled visit included a detailed clinical assessment; a complete physical examination; routine blood tests (including erythrocyte sedimentation rate, complete blood count, serum chemistry studies, and urinalysis); and a structured questionnaire designed to detect symptoms of giant-cell arteritis, occurrence of adverse events, and use of concomitant medication. Chest radiography was performed at baseline, at 6 months, and at the end of the protocol. Clinical follow-up was performed by the same two physicians. A third physician who had no contact with patients and did not assess outcomes monitored the laboratory tests before each clinical visit. Results of serum liver enzyme tests and mean corpuscular volume were not made available to the physicians involved in clinical follow-up. No physician on the research team was aware of group assignments. Treatment Protocol A single weekly dose of four tablets (each containing 2.5 mg) of oral methotrexate (total weekly dose, 10 mg) or placebo was started on diagnosis, maintained throughout the treatment period, and discontinued after 24 months of follow-up if clinical signs of disease activity were absent. Adherence to therapy was assessed by assigning patients an exact number of tablets for each period and checking the empty package during each scheduled visit. All patients received oral prednisone, 60 mg/d, in three divided doses during the first week and once daily during the second week. The daily prednisone dose was then gradually tapered by 10 mg per week until a dosage of 40 mg/d was being given at the end of the first month. Thereafter, a tapering schedule of 5 mg per week was used; by the end of the second month, patients were receiving a daily dose of 20 mg. The daily prednisone dose was then tapered by 2.5 mg every 2 weeks until therapy was completely withdrawn. The rate of prednisone tapering could be decreased if complete response to initial therapy was not achieved; if relapse occurred; or if the patient had clinical findings that could be attributed to relapse until a second, unrelated process was ruled out. The prednisone dose could be tapered more quickly if patients presented with serious prednisone-related complications in the absence of clinical activity of giant-cell arteritis. The dose of methotrexate or placebo could also be decreased in the event of comorbid conditions or adverse events attributable to therapy. If relapse occurred, the dose of prednisone was increased to the minimum amount that controlled symptoms and the dose of methotrexate or placebo was increased by one tablet per week. Tapering of the prednisone regimen was then resumed while the new dose of methotrexate or placebo was maintained. All patients received oral calcium, 1000 mg/d, and oral vitamin D3, 600 IU/d, as a part of the treatment protocol. Patients with a history of tuberculosis or compatible changes on chest radiography received prophylaxis with oral isoniazid, 600 mg/d, during the first 6 months of treatment. Starting in June 1994, the initial protocol was modified so that all patients received oral folic acid, 5 mg/d, in accordance with current recommendations (16-18). Patients could receive any other concomitant medication needed to control adverse events except those specified in the exclusion criteria. Assessment of Disease Activity Initial response to treatment was defined as absence of symptoms of giant-cell arteritis and normalization of laboratory values after initiation of treatment. Relapse was defined as recurrence of symptoms of giant-cell arteritis after definite objective improvement followed by symptom reversal on resumption of or increases in the prednisone dose (5). The research team classified relapses according to their clinical characteristics: presence or absence of cranial symptoms, such as visual or ocular disturbances; jaw claudication; headache; and thickness, tenderness, or ulcers or nodules over the temporal or occipital arteries. Once other causes of symptoms were ruled out, relapses were further classified as definite if the clinical presentation was characteristic of giant-cell arteritis or possible if there were unclear or atypical symptoms or nonspecific manifestations, such as asthenia or general discomfort, that resolved spontaneously in a few days. Definition and Classification of Adverse Events Adverse events were defined as a new diagnosis or incidence of any condition during the treatment protocol. The relationship between adverse events and study drugs was classified as follows: 1) definitely related, if the temporal sequence was compatible, the pattern was consistent with the established toxicity profile, and withdrawal of therapy resolved or improved the adverse event; 2) probably related, if the temporal sequence was compatible, no alternative causes could be established, and withdrawal of therapy resolved or improved the adverse event; 3) possibly related, if the temporal sequence was compatible but the adverse event could have been due to another, equally likely cause; or 4) unrelated, if the temporal sequence was not compatible and there was another, more likely cause of the adverse event. The following criteria were used to define the most commonly reported adverse events associated with corticosteroid or methotrexate therapy: arterial hypertension as blood pressure greater than 140/90 mm Hg measured at three routine visits; symptomatic vertebral fractures as spinal pain accompanied by a 20% height loss in a vertebra compared with previous radiographs; diabetes mellitus as fasting plasma glucose levels greater than 7.77 mmol/L (>140 mg/dL) on three routine analyses; glucose intolerance as fasting plasma glucose levels greater than 6.11 mmol/L (>110 mg/dL) but less than 7.77 mmol/L (<140 mg/dL) on three routine analyses; hypercholesterolemia as fasting plasma cholesterol levels greater than 5.18 mmol/L (>200 mg/dL) on three routine analyses; cataracts as loss of visual acuity that was diagnosed or confirmed by an ophthalmologist; weight gain as a 5% increase in baseline body weight; myopathy as clinically detectable proximal muscle weakness; thrombocytopenia as a platelet count less than 130 109 cells/L; and leukopenia as a l

Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases.

OBJECTIVE The STAT4 gene encodes a transcription factor involved in the signaling pathways of several cytokines, including interleukin-12 (IL-12), the type I interferons, and IL-23. Recently, the association of a STAT4 haplotype marked by rs7574865 with rheumatoid arthritis (RA) and systemic lupus erythematosus was reported. The aim of this study was to investigate the role of this STAT4 tagging polymorphism in other immune-mediated diseases. METHODS The study group comprised 2,776 consecutively recruited Spanish individuals: 575 with RA, 440 with multiple sclerosis, 700 with inflammatory bowel disease, 311 with type 1 diabetes, and 723 ethnically matched healthy control subjects. The STAT4 polymorphism rs7574865 was genotyped using a predesigned TaqMan assay. Allele and genotype frequencies in patients and control subjects were compared by chi-square test. RESULTS The association of STAT4 polymorphism rs7574865 with RA was validated in patients of Spanish origin (for T versus G, P = 1.2 x 10(-6), odds ratio [OR] 1.59, 95% confidence interval [95% CI] 1.31-1.92), and the association was described for the first time in both clinical forms of inflammatory bowel disease, Crohns disease and ulcerative colitis (for T versus G, P = 0.006, OR 1.29, 95% CI 1.07-1.55), and in type 1 diabetes mellitus (for T versus G, P = 0.008, OR 1.36, 95% CI 1.07-1.71). In contrast, the genotypic distribution of this polymorphism showed no difference between patients with multiple sclerosis and healthy control subjects (for T versus G, P = 0.83, OR 1.02, 95% CI 0.82-1.28). CONCLUSION The STAT4 gene is emerging as a novel common risk factor for diverse complex diseases.

A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis

IntroductionThe severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.MethodsIn total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.ResultsNo associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.ConclusionVariants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.

Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis.

OBJECTIVE Previous studies have shown either a lack of effect of IRF5 polymorphisms or an association of the IRF5 gene in only a minor subset of rheumatoid arthritis (RA) patients in whom anti-citrullinated protein antibodies (ACPAs) are absent. The present study was undertaken to investigate the role of genetic variation in IRF5 in susceptibility to RA. METHODS Nine IRF5 single-nucleotide polymorphisms (SNPs) were studied in 1,338 patients with RA and 1,342 control subjects in analyses of exploratory and replication sample collections, with stratification according to sex and by the presence or absence of ACPAs, rheumatoid factor, the shared epitope, the 620W PTPN22 allele, and erosions. A meta-analysis that included results from previous studies was also carried out. RESULTS Our findings together with those from previous studies, in a total of 4,620 RA patients and 3,741 controls, showed a significant association of the rs2004640 IRF5 SNP in RA patients as a whole (odds ratio [OR] 0.88, 95% confidence interval [95% CI] 0.83-0.94; P = 6.5 x 10(-5) versus controls). This association was stronger in ACPA- patients, but was also present in ACPA+ patients (from 3 sample collections). Further analysis of our exploratory sample collection showed that only patients in the ACPA+ and SE- group lacked an association with IRF5 SNPs. All of the remaining RA patients (ACPA- or SE+) showed a strong association with IRF5 SNPs, which followed a complex pattern of opposing effects mediated by independent haplotypes. The susceptibility haplotype showed an OR of 1.8 (95% CI 1.4-2.3; P = 1.2 x 10(-6) versus controls), whereas the protective haplotype showed an OR of 0.76 (95% CI 0.6-0.98; P = 0.046 versus controls). CONCLUSION IRF5 polymorphisms seem to influence RA susceptibility in a large subgroup of patients, following a pattern of association very similar to that described in patients with systemic lupus erythematosus.

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis

IntroductionWe determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA.MethodsSix hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays.ResultsNo significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005).ConclusionsOur results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.

EYE INVOLVEMENT IN THE SPONDYLOARTHROPATHIES

Eye inflammation, especially uveitis, is a prominent feature of spondyloarthropathies. Uveitis associated with ankylosing spondylitis and Reiters syndrome usually is a unilateral acute anterior uveitis with a high tendency to recur sometimes in the contralateral eye. Uveitis associated with undifferentiated spondyloarthropathy, inflammatory bowel disease, and psoriasis may be less characteristic in its presentation, with a higher tendency to posterior pole involvement, bilaterality, and chronicity. Although acute anterior uveitis is grouped into the spectrum of human leukocyte antigen B27-related disease, other genetic and environmental factors including infections by gram-negative bacteria and gut inflammation can play a role in its pathogenesis. The prognosis of uveitis usually is excellent with topical treatment, and only those with posterior pole involvement or a high tendency to recur or to chronicity might benefit from immunosuppressive therapy.

NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis

INTRODUCTION Rheumatoid arthritis (RA) is an inflammatory disease associated with increased cardiovascular (CV) mortality. A recent study has disclosed association between NFKB1-94ATTG ins/del polymorphism and higher risk of coronary heart disease in healthy Caucasians. Because of that, we assessed the influence of this polymorphism in the risk of CV disease in RA patients. MATERIAL AND METHODS 1437 Spanish patients with RA were genotyped for the NFKB1-94ATTG ins/del polymorphism. Two hundred and seventy-one of them (18.8%) had experienced CV events. RESULTS After adjusting for sex, age at RA diagnosis and traditional CV risk factors RA patients carrying the NFKB1 del/del genotype had higher risk of CV events than those with ins/ins genotype (Hazard ratio [HR] = 1.76, 95% CI: 1.05-2.97, p = 0.03), while heterozygous patients had an intermediate (but non-significant) risk (HR = 1.31, 95% CI: 0.90-1.92, p = 0.16). CONCLUSION Our results suggest that NFKB1-94ATTG ins/del polymorphism is associated with CV disease in patients with RA.

Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction

Objective: To determine whether the human herpes viruses, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6), are detectable in serum and peripheral blood mononuclear cells (PBMCs) of patients with rheumatoid arthritis (RA). Methods: 133 PBMC samples (61 RA, 72 healthy donors) and 136 serum samples (59 RA, 77 healthy donors) were analysed by quantitative real time polymerase chain reaction for DNA prevalence and viral load of HHV-6, EBV, and CMV. Results: For PBMC samples significant differences were found for EBV in DNA prevalence (56% in RA v 33% in controls, p = 0.009) and viral load (copies/μg DNA 0–592.3 for RA v 0–40.4 for controls, p = 0.001). For serum samples a significant difference was found for HHV-6 DNA prevalence (10% in RA v 0% in controls, p = 0.006) and viral load (copies/μg DNA 0–529.1 for RA v 0 for controls, p = 0.007). Conclusions: Herpes viruses may have a role in RA, although alternative explanations are possible: (a) defects in cellular immunity in patients with RA may result in a relatively high viral load; (b) patients with RA may be more prone to infection/reactivation. The usefulness of monitoring the DNA viral load in patients with RA is questioned by these data.

A Health System Program To Reduce Work Disability Related to Musculoskeletal Disorders

Context Nonoccupational musculoskeletal disorders account for a large proportion of work disability and represent a major financial burden on society. Contribution A voluntary, randomized, controlled intervention study consisted of avoidance of bed rest, early mobilization, avoidance of splints, stretching exercises, ergonomic training, provision of educational booklets, and suggestions for optimal levels of physical activity. Although return to work was never forced, temporary work disability, long-term disability, and costs were significantly decreased in the intervention group. Implications The personal and financial impact of work disability due to musculoskeletal disorders (not related to work injury) may be mitigated by a voluntary program of education and rehabilitation. The Editors Musculoskeletal disorders (MSDs) are prevalent and potentially disabling conditions (1) that consume a large proportion of health care resources (2-4) and together are the leading cause of functional loss in adults (3-8). The social costs of MSDs are enormous, often overshadowing those of other chronic conditions (9, 10). In industrialized societies, MSDs are one of the most common causes of temporary work disability and the chief cause of permanent work disability (11), accounting for productivity losses equivalent to 1.3% of the U.S. gross national product (12). Work disability related to MSDs is a challenge to employability, business productivity, and the capacity of health and social security systems. Various strategies for addressing MSD-related work disability have been promoted in the field of occupational health, including strategies involving legislation, risk management, ergonomics, prevention, education, and social work (13). However, the role of health systems remains ill-defined in this field. The purpose of this study was to evaluate whether an intervention program, integrated into the health system and offered to the working population, could reduce the impact of recent-onset MSD-related temporary work disability. Methods Setting Of the 5.5 million persons in Madrid, Spain, 98% receive health coverage from the Instituto Madrileo de Salud. Care is organized into 11 health districts. Patients have direct access to primary care physicians, who refer patients to specialized care if needed. Disability compensation payments are made by the Instituto Nacional de la Seguridad Social (INSS), a division of the Ministry of Work. Any worker who requires sick leave is given a temporary work disability initiation form that states the diagnosis made by the primary care physician and entitles the worker to receive INSS compensation payments. The form is renewed weekly by the primary care physician until the worker 1) recovers and receives an ending form, 2) reaches a maximum of 18 months of temporary work disability, or 3) receives a proposal for evaluation for permanent work disability. Proposals for permanent work disability are evaluated by the INSS, which determines the need for and type of long-term compensation. Inspection services in each health district oversee all administrative aspects of these processes. Design We did a randomized, controlled study, unblinded for both patients and physicians, to test whether a clinical intervention could improve the outcome of patients with recent-onset MSD-related temporary work disability. The study began in March 1998 in health district 7 and in March 1999 in health districts 4 and 9. Selection and randomization of patients was done during the first year of the study in each district. Follow-up lasted for another year. Patients and Selection Criteria Health districts 4, 7, and 9 were chosen. Health district 4 had a total population of 508249 persons and an active working population of 192939 persons; health district 7 had a total population of 522742 persons and an active working population of 179155 persons; and health district 9 had a total population of 371294 persons and an active working population of 135475 persons (14). The inclusion criterion was the issue of a common diseases temporary work disability initiation form, with an MSD-related cause reported by the primary care physician, within the inclusion period. The MSD-related causes included all arthropathies, connective tissue disorders, back disorders, soft-tissue rheumatisms, bone and cartilage disorders, musculoskeletal pain not caused by cancer, and nerve entrapment syndromes. Patients were excluded if they had a common diseases temporary work disability form with an MSD-related cause resulting from trauma or surgery. They were also excluded if they had work accidents or professional diseases noted on the temporary work disability initiation form. Work accidents are primarily sudden, external, violent causes of disease occurring at work or during travel to work, and they represent less than 27% of cases of temporary work disability. Professional diseases include silicosis, asbestos-related mesothelioma, and noise-induced hearing loss, and they represent less than 1% of cases of temporary work disability. Randomization All temporary work disability initiation forms meeting the selection criteria were collected daily by a study rheumatologist and coded. The patients associated with the forms were randomly assigned to either the intervention group, which received a specific care program, or the control group, which received standard care (Figure 1). Computer-generated lists of pseudorandom numbers were produced for each district. Group assignments were randomly done in blocks of 50 patients with intervention:control ratios of 1:1 in district 7 and 2:3 in districts 4 and 9. This was done so that similar numbers of patients would be seen by the rheumatologists in all areas. The ratios were based on the number of episodes of MSD-related temporary work disability registered in previous years. Patients maintained their group assignments in successive episodes of MSD-related temporary work disability during follow-up. Figure 1. Flow diagram of the study. Care in the Intervention Group A secretary contacted all patients assigned to the intervention group by telephone or mail as soon as possible after the initiation form was issued, offering them an appointment in the program. Patients who voluntarily decided to enter the program were attended by 2 rheumatologists in each district who worked full-time for the study. Patients were seen as often as necessary until the episode of temporary work disability was resolved or recovery was deemed unrealistic. Patients who were assigned to the intervention group but were unable or unwilling to participate, were already working, or could not be located were considered to be assigned to the intervention group throughout the study for statistical purposes. Within the intervention program, care was delivered in regular visits and included education, clinical management, and administrative duties. Education At the first 45-minute visit, patients received a specific diagnosis, reassurance that no serious disease was present, instructions on self-management, instructions on taking medications on a fixed schedule, and information on indications for return to work before complete symptom remission. Return to work was negotiated with patients and was never forced on them. Instructions on self-management included instructions to avoid bed rest, instructions to promote early mobilization of the painful regions, restrictions on the use of splint and neck collars, training in stretching and strengthening exercises (15-18), teaching of ergonomic care (19), delivery of booklets in instances of back or neck pain (19), and information on optimal levels of physical activity (20). Patients with higher degrees of disability or abnormal pain behavior received immediate extra reassurance, information on pain-relieving positions, and a telephone call or second visit within 72 hours. Specific protocols were created for low-back (21), neck, shoulder, arm and hand, knee, and foot pain (19, 22-25) and included the 3-level clinical-management system described later. Moving a patient from the lower to the upper levels of the system implied the need for further diagnostic or therapeutic procedures and was indicated 1) after a patient spent a predefined period at the lower level without return to work or substantial clinical improvement or 2) by the clinical judgment of the rheumatologist. At the first level of the system, patients received the clinical management started at the first visit, including a diagnosis based on clinical criteria, pharmacologic treatment of pain and inflammation, pharmacologic treatment of anxiety and depression, peripheral intra- and periarticular injections (26), and education. Time spent at the first level averaged 2 to 6 weeks. At the second level, patients received maintenance of therapy plus referral for formal rehabilitation and laboratory tests, radiography, computerized tomography, magnetic resonance imaging, and electromyography. After 4 to 8 weeks with no improvement at the second level, patients were moved to the third level and received further diagnostic procedures or referral for surgical or other specialized care. Red flags were defined, including age older than 50 years for patients with axial pain, previous trauma, cancer, serious medical illness, inflammatory pain, night pain, drug abuse, corticosteroid use, fever, weight loss, progressively deteriorating function, and progressive neurologic deficit. The presence of a red flag precluded the use of the level system, and the patient in question was managed according to clinical criteria, with a focus on excluding serious illness. Treatment Failures Patients who did not respond to interventions at the second level of the system were examined for the presence of yellow flags, which included psychiatric illness, family problems, sociolabor conflicts, unemployment, and occupational causes of disability. The presence of a yell

Recommendations for the management of cardiovascular risk in patients with rheumatoid arthritis: Scientific evidence and expert opinion

OBJECTIVES Last recommendations regarding cardiovascular risk (CVR) in rheumatoid arthritis (RA) patients were developed by the EULAR group in 2010. The aim is to update evidence-based recommendations about this worrying health problem. METHODS We assembled a multidisciplinary workgroup (rheumatologists, endocrinologist, cardiologist, and epidemiologist) and a panel of 28 expert rheumatologists. The study was carried out in two big phases: identifying key areas in the prevention and management of CVR and developing a set of recommendations based on a review of the available scientific evidence and use of the Delphi consensus technique. All this has been developed according to an updating process of evidence-based recommendations. RESULTS Overall, 25 recommendations were made addressing three complementary areas: CVR assessment tools, patient eligibility for assessment, and treatment strategies for control of CVR. The grade of the recommendations was not substantially modified compared to the original EULAR recommendations, except in two of them, which were upgraded from C to B. These two recommendations are the ones related to the use of corticosteroids and smoking cessation. The new developed recommendations address these two areas: CVR assessment and treatment strategies for control of CVR. CONCLUSIONS There are substantial gaps in the current knowledge that do not allow classifying properly RA patients based on their actual CVR and to accurately identify those patients who would benefit from CVR assessment. Consequently, studies designed to determine the causal effects of RA disease characteristics on cardiovascular morbidity/mortality and to identify patients at high risk of cardiovascular disease are still needed.