Vicente Rodriguez-Valverde

PERMANENT VISUAL LOSS AND CEREBROVASCULAR ACCIDENTS IN GIANT CELL ARTERITIS Predictors and Response to Treatment

OBJECTIVE To assess the features and therapeutic response of visual manifestations and cerebrovascular accidents (CVA) in giant cell (temporal) arteritis (GCA) and to identify the predictors for permanent visual loss (VL) and CVA in GCA. METHODS Two hundred thirty-nine patients with biopsy-proven GCA were included in a retrospective multicenter study. Data on demographic, clinical, and laboratory features were collected. The predictors were identified by a forward stepwise nonconditional logistic regression analysis. RESULTS Visual involvement was observed in 69 patients, and 34 had permanent VL. The diagnostic delay since the onset of visual symptoms was longer in the 11 patients with bilateral VL. The interval to involvement of the second eye was 5 days. The predictors of permanent VL were transient VL, jaw claudication, normal levels of liver enzymes, and absence of constitutional syndrome. Partial improvement of visual acuity was observed in 8 patients. After adjustment for the treatment regimen (intravenous pulse methylprednisolone versus oral prednisone), early treatment (within the first day of VL) was the only predictor of improvement. CVA, observed in 8 patients, involved the vertebral-basilar territory in 4. CVA was more frequent in patients with visual symptoms, appearing shortly after VL (median 7 days) and despite appropriate therapy. Predictors of CVA were permanent VL and jaw claudication. CONCLUSION In GCA, the risk of permanent VL is increased in patients with transient VL and/or jaw claudication, and decreased in those with elevated liver enzyme levels and/or constitutional syndrome. Partial therapeutic success is more probable if treatment is started within the first day of VL. CVA is more likely in patients with permanent VL and/or jaw claudication, often developing despite appropriate corticosteroid therapy.

A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects

Objective: Open label studies have suggested that tumour necrosis factor (TNF) antagonists led to sustained improvement and corticosteroid sparing effect in patients with giant cell arteritis (GCA). To confirm these observations, we conducted a randomised, double-blind, placebo controlled trial with etanercept in patients with biopsy-proven GCA with side effects secondary to corticosteroids. Methods: We randomly assigned patients with GCA to receive etanercept (n = 8) or placebo (n = 9) over 1 year together with corticosteroids that were reduced according to a predefined schedule. The primary outcome was the ability to withdraw the corticosteroid therapy and control the disease activity at 12 months. Results: Baseline characteristics were similar in the two groups, although patients in the etanercept group showed higher levels of basal glycaemia (p = 0.02) and a higher erythrocyte sedimentation rate (ESR) (p = 0.01). After 12 months, 50% of the patients in the etanercept group and 22.2% in the placebo group were able to control the disease without corticosteroid therapy (p value not significant). Patients in the etanercept group had a significant lower dose of accumulated prednisone during the first year of treatment (p = 0.03). There were no differences in the number and type of adverse events. Conclusion: The limited number of patients included in this study does not allow us to draw definitive conclusions. Etanercept therapy was well tolerated in this aged population. The therapeutic role of etanercept in patients with GCA should be evaluated in studies with a larger number of patients.

CUTANEOUS VASCULITIS IN CHILDREN AND ADULTS : ASSOCIATED DISEASES AND ETIOLOGIC FACTORS IN 303 PATIENTS

Cutaneous vasculitis (CV), a condition characterized by palpable purpura and nonspecific histopathologic findings, presents a diagnostic and therapeutic challenge because it may be a primary disorder or it may be a cutaneous manifestation of another entity, such as systemic necrotizing vasculitis, connective tissue disease, systemic bacterial infection, or malignancy. We studied 303 unselected patients (172 adults and 131 children) with CV to assess the disease associations and etiologic factors, to identify the frequency of primary and secondary CV in different age-groups, and to characterize features that help to distinguish between primary and secondary CV. Of the 131 children, 130 had primary CV: Henoch-Schönlein purpura (HSP) in 116 and hypersensitivity vasculitis (HV) in 14. In contrast, of the 172 adults, only 120 had primary CV: HSP in 39, HV in 70, and essential mixed cryoglobulinemia in 11. CV was a manifestation of systemic necrotizing vasculitis in 23 adults (polyarteritis nodosa in 17, Wegener granulomatosis in 4, and Churg-Strauss syndrome in 2). CV was secondary to other processes in 29 adults: in 20 patients CV was associated with connective tissue disease or another autoimmune or rheumatic disease, in 5 patients CV was a manifestation of severe bacterial infection, especially bacterial endocarditis (4 cases), and in the other 4 patients CV was the presenting symptom of an underlying malignancy. The patients for whom CV was a manifestation of systemic necrotizing vasculitis or secondary to a connective tissue disease, severe bacterial infection, or malignancy had clinical and laboratory data suggestive of the associated disorder. The clinical picture and outcome of primary CV in both children and adults were benign. By contrast, the prognosis of patients with CV in the context of systemic necrotizing vasculitis or secondary to other entities depended on the primary process. Given the different disease association in children and adults, we propose a simple diagnostic workup in children with CV. By contrast the diagnostic approach in adults with CV should be more cautious and the workup more extensive. The early differentiation between primary CV, secondary CV, and CV presenting as a symptom of systemic necrotizing vasculitis, especially in adults, is of paramount importance for an adequate diagnosis and appropriate treatment.

The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial

Objective: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. Methods: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. “Washout” patients discontinued anti-TNF therapy 2 months or longer pre-screening; “direct-switch” patients began abatacept (∼10 mg/kg) at their next scheduled anti-TNF therapy dose. Results: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (⩾1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index ⩾0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). Conclusion: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. Trial registration number: NCT00124982.

A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs

Objective: To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. Methods: 549 patients entered this 5-year, open-label extension study and received etanercept 25 mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs before entry into the double-blind studies. Safety assessments were carried out at regular intervals. Primary efficacy end points were the numbers of painful and swollen joints; secondary variables included American College of Rheumatology (ACR) response rate, Disease Activity Score and acute-phase reactants. Efficacy was analysed using the last-observation-carried-forward approach. Results: Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%) completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis. A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the open-label trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively. Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site reactions. Rates of serious infections and malignancies remained unchanged over the course of the study; there were no reports of patients with central demyelinating disease or serious blood dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%, respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from 5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the 3-year time period. Conclusion: After 3 years of treatment, etanercept showed sustained efficacy and a favourable safety profile.

Clinical Features and Outcome of 95 Patients with Hypersensitivity Vasculitis

PURPOSE To evaluate the clinical features and outcome of patients with isolated hypersensitivity vasculitis (HV). PATIENTS AND METHODS Retrospective study of patients with cutaneous vasculitis followed up at a University Hospital from 1975 to 1994. Patients with vasculitis secondary to collagen vascular diseases, neoplasia, or major infections were excluded. Patients were classified as HV according to the differential criteria proposed by Michel et al (J Rheumatol. 1992;19:721-728). RESULTS Ninety-five patients were classified as HV. The mean age was 42.7 +/- 21.7 years, with similar disease frequency in both sexes. In 43 patients, the precipitating event was drug therapy, either alone or as a treatment for a coexistent infection, usually an upper respiratory tract infection. The most frequent clinical manifestation was palpable purpura followed by joint symptoms. Systemic involvement was infrequent: 7 patients had nephropathy, manifested almost exclusively by microhematuria, and 5 patients had gastrointestinal symptoms. In 54 subjects the vasculitis did not require treatment; 26 patients were treated with NSAIDs, and 14 required corticosteroids (associated to immunosuppressive agents in 2 of them). After a mean follow-up of 15.5 +/- 28.9 months (median 6), only 2 patients had slight renal impairment, whereas the remaining had a complete recovery. CONCLUSION Hypersensitivity vasculitis is usually a benign syndrome, often secondary to drugs or infections, or both. Its main clinical manifestations are skin and joint symptoms. The systemic involvement is scarce and its prognosis is excellent.

Risk Factors and Predictive Models of Giant Cell Arteritis in Polymyalgia Rheumatica

OBJECTIVE To identify in polymyalgia rheumatica the best set of predictors for a positive temporal artery biopsy and to define predictive models with either a high or low probability of giant cell arteritis (GCA). PATIENTS AND METHODS Retrospective study of 227 patients, 137 with polymyalgia rheumatica unassociated with arteritis (group A) and 90 with polymyalgia associated with biopsy-proven giant cell arteritis (group B or training set). Data on demographic features, clinical and laboratory abnormalities were collected. Risk factors for arteritis were estimated by nonlinear logistic regressions. Simple predictive models were constructed with those predictors more related to arteritis by multivariable analysis. These models were then tested in group B and in 89 cases of arteritis without polymyalgia rheumatica (group C or test set). RESULTS The best predictors of arteritis were a new headache odds ratio (OR) 13.6 (95% confidence interval [CI] 4.7 to 39.3); age at onset < 70 years OR 0.11 (CI 0.04 to 0.35); abnormal temporal arteries OR 4.2 (CI 1.3 to 13.7); raised liver enzymes OR 2.9 (CI 1.1 to 7.8), and jaw claudication OR 4.8 (CI 1.0 to 22.7). Amaurosis was only observed in patients with arteritis. Three subsets had a very high risk of arteritis: (1) Patients with recent headache, abnormal arteries, and > or = 70 years at disease onset: sensitivity 44%, positive predictive value (PPV) 93%, likelihood ratio (LR) 20.3; (2) patients with a new headache, jaw claudication, and abnormal arteries: sensitivity 34.4%, PPV 96.9%, LR 47.2; and (3) those, that in addition to the last 3 features, were > or = 70 years of age at disease onset: sensitivity 26.7%, PPV 100%. We could also identify a subset with a very low risk of arteritis constituted by patients < 70 years, without headache, and with clinically normal temporal arteries: sensitivity 1.1%, PPV 1.7%, LR 0.03. In group C or the test set, these four predictive models correctly identified 57.3%, 29.2%, 23.6, and 3.4% of patients, respectively. CONCLUSIONS In polymyalgia rheumatica it is feasible to identify subsets with a very high likelihood of GCA. Although in some of these subsets the diagnosis of arteritis is almost certain, we suggest that even then it should be confirmed by temporal artery biopsy. By contrast, in those patients with polymyalgia < 70 years and without cranial features of giant cell arteritis, the risk of vasculitis is so low that the biopsy could be initially avoided and the patient treated with low-dose corticosteroids.

III Actualización del Consenso de la Sociedad Española de Reumatología sobre terapia biológica en la artritis reumatoide

como en el caso de los antagonistas del factor de necrosis tumoral (TNF), en los pacientes con AR de inicio reciente. Es evidente que la disponibilidad cada vez mayor de agentes biológicos ha mejorado sensiblemente nuestra capacidad de inducir remisión en muchos pacientes con AR y de modificar significativamente su evolución en otros. No obstante, por su alto coste y la todavía limitada información sobre sus posibles efectos secundarios a largo plazo, es necesario evitar su uso indiscriminado. Por ello es aconsejable integrar su uso dentro de una estrategia terapéutica de la enfermedad en general. El presente Documento de Consenso de la Sociedad Española de Reumatología (SER) es una actualización del último documento elaborado con los mismos fines en 20044. Estas recomendaciones deben servir de referencia tanto para los reumatólogos como para todos quienes, desde otras posiciones, tengan interés en el tratamiento de la AR.

Giant cell arteritis with an erythrocyte sedimentation rate lower than 50.

Abstract: A high erythrocyte sedimentation rate (ESR) is considered to be a hallmark of giant cell arteritis (GCA) and one of the 1990 American College of Rheumatology classification criteria. We studied 248 patients with GCA to assess the frequency and clinical features of patients with GCA and an ESR <50 mm/h. Ten patients had a low ESR (43.1 ± 4.9 mm/h) and in the remaining 238, the ESR was ≥50 mm/h (96.4 ± 23.6). None of the patients with an ESR less than 50 had a completely normal ESR. The spectrum of the disease in both groups was very similar. Both groups required similar corticosteroid therapy and had a similar outcome. The ESR, analysed as a continuous variable, showed a significant positive correlation with other parameters reflecting the acute-phase response such as presence of anaemia, weight loss and fever. We suggest that in patients with a clinical picture compatible with GCA, the use of an ESR ≥30 mm/h as the main laboratory parameter to consider the possibility of GCA would be enough to arise the suspicion and prevent cases of GCA being missed.

Insufficiency fractures of the tibia and fibula

OBJECTIVE Insufficiency fractures (IF) occur when normal or physiological muscular activity stresses a bone that is deficient in mineral or elastic resistance. IF of the tibia and fibula are probably less common than IF of the ribs, vertebrae, hip, pelvis, and distal ulna, and therefore they are frequently underrecognized and mistaken for other conditions. Our aim was to analyze the main features and outcome of IF of the tibia and fibula in patients attending our Rheumatology Service. METHODS IF was considered when occurring spontaneously or with minimal trauma. Between January 1984 and July 1997, 25 patients were diagnosed as having IF of the tibia and fibula. The main predisposing factors, clinical features, therapy, and outcome were retrospectively reviewed. RESULTS All the patients except four were women (mean age, 66+/-12 years). Three cases were diagnosed between 1984 and 1990 (0.42 cases/year) and 22 between 1991 and 1997 (three cases/year). Eighteen patients had an underlying condition: rheumatoid arthritis (RA, 13 cases), psoriatic arthritis (2), systemic lupus erythematosus (SLE) (1), kidney transplant (1), and Crohns disease (1). Eleven patients had osteoporotic fractures in other locations. Risk factors for osteoporosis were corticosteroids (13 cases), prolonged immobilization (10), early menopause (2), and methotrexate therapy (10). All patients had pain on weight bearing and marked functional impairment, 16 had local inflammatory signs, and 10 had deformity. In only five patients the diagnosis of IF was considered at the first examination. The diagnostic delay was 76+/-117 days (median, 21). The initial radiograph was diagnostic in 20 patients, and in the remaining the diagnosis was made by computed tomography (CT) scan (three cases), magnetic resonance imaging (MRI) (1), and bone scan (1). IF were located as follows: tibia (10 cases), fibula (seven), tibia and fibula (eight). Nineteen patients were treated with conservative management, four received no specific treatment, and two required surgery. Sixteen patients were hospitalized for a mean period of 12+/-8 days. Most patients had complete recovery. The high frequency of IF seen in RA patients is probably due to the severe disease in patients treated by our Service and that such patients have a higher risk for osteoporosis and its complications. CONCLUSIONS IF of the tibia and fibula are probably more common than previously thought. They usually occur in patients with underlying rheumatic diseases, mainly RA, and are frequently mistaken for other joint and bone conditions. Despite a frequent delay in diagnosis, they have a good prognosis with conservative management. Nonetheless, a higher index of suspicion may avoid unnecessary investigations and treatments.