Differences in clinical manifestations and increased severity of systemic lupus erythematosus between two groups of Hispanics: European Caucasians versus Latin American mestizos (data from the RELESSER registry).

BACKGROUND: Systemic lupus erythematosus (SLE) is regarded as a prototype autoimmune disease because it can serve as a means for studying differences between ethnic minorities and sex. Traditionally, all Hispanics have been bracketed within the same ethnic group, but there are differences between Hispanics from Spain and those from Latin America, not to mention other Spanish-speaking populations. OBJECTIVES: This study aimed to determine the demographic and clinical characteristics, severity, activity, damage, mortality and co-morbidity of SLE in Hispanics belonging to the two ethnic groups resident in Spain, and to identify any differences. METHODS: This was an observational, multi-centre, retrospective study. The demographic and clinical variables of patients with SLE from 45 rheumatology units were collected. The study was conducted in accordance with Good Clinical Practice guidelines. Hispanic patients from the registry were divided into two groups: Spaniards or European Caucasians (EC) and Latin American mestizos (LAM). Comparative univariate and multivariate statistical analyses were carried out. RESULTS: A total of 3490 SLE patients were included, 90% of whom were female; 3305 (92%) EC and 185 (5%) LAM. LAM patients experienced their first lupus symptoms four years earlier than EC patients and were diagnosed and included in the registry younger, and their SLE was of a shorter duration. The time in months from the first SLE symptoms to diagnosis was longer in EC patients, as were the follow-up periods. LAM patients exhibited higher prevalence rates of myositis, haemolytic anaemia and nephritis, but there were no differences in histological type or serositis. Anti-Sm, anti-Ro and anti-RNP antibodies were more frequently found in LAM patients. LAM patients also had higher levels of disease activity, severity and hospital admissions. However, there were no differences in damage index, mortality or co-morbidity index. In the multivariate analysis, after adjusting for confounders, in several models the odds ratio (95% confidence interval) for a Katz severity index >3 in LAM patients was 1.45 (1.038-2.026; p = 0.02). This difference did not extend to activity levels (i.e. SLEDAI >3; 0.98 (0.30-1.66)). CONCLUSION: SLE in Hispanic EC patients showed clinical differences compared to Hispanic LAM patients. The latter more frequently suffered nephritis and higher severity indices. This study shows that where lupus is concerned, not all Hispanics are equal.

Differences associated with age at onset in early systemic sclerosis patients: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR) database.

OBJECTIVE: The aim of this study was to analyse differences in clinical presentation in patients with early (< 3 years' duration) systemic sclerosis (SSc), comparing three age groups according to disease subsets. METHOD: Cross-sectional analysis of the prospective EULAR Scleroderma Trials and Research database (EUSTAR) was performed. Patients fulfilling preliminary American College of Rheumatology 1980 classification criteria for SSc, with < 3 years from the first non-Raynaud's SSc symptom at first entry, were selected. Patients with < 3 years from the first SSc symptom, including Raynaud's phenomenon, were also analysed. SSc-related variables, including antibodies, SSc subsets, and organ involvement, were examined. Age was categorized into ≤ 30, 31-59, and ≥ 60 years. We performed descriptive and bivariate analyses. RESULTS: The study included 1027 patients: 90% Caucasian, 80% women, and 40% with diffuse disease. In early stages of SSc, younger patients had significantly more anti-Scl-70 antibodies and diffuse disease. With increasing age, we observed more elevation of estimated pulmonary systolic pressure on echocardiography (5%, 13%, and 30%, respectively, in the three age groups), cardiac conduction blocks (6%, 6%, and 15%), and left ventricular diastolic dysfunction (4%, 12%, and 27%). The results were similar for 650 patients with < 3 years from first SSc symptom, including Raynaud's. CONCLUSION: In early stages of SSc, older patients showed data indicating more severe disease with greater cardiac involvement. The diffuse subset was more frequent in the younger subgroup. The identification of such differences may help in selecting appropriate management for individual patients in clinical practice.

The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population.

OBJECTIVE: Methotrexate (MTX) is the first-choice drug for the treatment of rheumatoid arthritis (RA) patients. However, 30% of RA patients discontinue therapy within 1 year, usually because of adverse effects. Previous studies have reported conflicting results on the association of polymorphisms in the MTHFR gene with the toxicity of MTX in RA. The aim of this study was to assess the involvement of the C677T and A1298C polymorphisms in the MTHFR gene in the toxicity of MTX in a Spanish RA population. METHODS: The study included retrospectively 468 Spanish RA patients treated with MTX. Single nucleotide polymorphism (SNP) genotyping was performed using the oligonucleotide microarray technique. Allele and genotype association analyses with regard to MTX toxicity and a haplotype association test were also performed. RESULTS: Eighty-four out of the 468 patients (18%) had to discontinue therapy due to adverse effects or MTX toxicity. The C677T polymorphism (rs1801133) was associated with increased MTX toxicity [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.01-1.98, p = 0.0428], and the strongest association was shown in the recessive model (OR 1.95, 95% CI 1.08-3.53, p = 0.0246). The A1298C polymorphism (rs1801131) was not associated with increased MTX toxicity (OR 0.94, 95% CI 0.65-1.38, p = 0.761). A borderline significant risk haplotype was found: 677T-1298A (OR 1.40, 95% CI 1.00-1.96, p = 0.0518). CONCLUSION: These results demonstrate that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in a Spanish RA population.

Validity of enthesis ultrasound assessment in spondyloarthropathy.

OBJECTIVES: To develop an ultrasound enthesis score and to assess its validity in the diagnostic classification of the spondyloarthropathies (SpAs). METHODS: Twenty-five patients with SpA and 29 healthy controls participated in a blinded, gender-matched, cross-sectional study involving ultrasound assessment. The following entheses were explored bilaterally: proximal plantar fascia, distal Achilles tendon, distal and proximal patellar ligament, distal quadriceps and brachial triceps tendons. The ultrasound score evaluated enthesis thickness, structure, calcifications, erosions, bursae and power Doppler signal. The value of each elemental lesion was calculated using a three-model analysis. Validity was analysed by receiver operating characteristic (ROC) curves. Inter-reader and interexplorer intraclass correlation coefficients (ICCs) were calculated. RESULTS: The logistic regression model overestimated the score of three elemental lesions: calcification (0-3), Doppler (0 or 3) and erosion (0 or 3), while scoring tendon structure, tendon thickness and bursa as 0 or 1. ROC curves established an ultrasound score of >or=18 as the best cut-off point for differentiation between cases and controls. This cut-off point was exceeded by 5/29 controls (17%) and by 21/25 patients with SpA (84%). The sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-) were 83.3%, 82.8%, 4.8% and 0.2%, respectively. The inter-reader and interexplorer ICCs were 0.60 and 0.86, respectively. CONCLUSION: The findings suggest that the ultrasound enthesis score could be a valid tool in the diagnosis of SpA.

Relationship between damage and mortality in juvenile-onset systemic lupus erythematosus: Cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER).

OBJECTIVES: To identify patterns (clusters) of damage manifestation within a large cohort of juvenile SLE (jSLE) patients and evaluate their possible association with mortality. METHODS: This is a multicentre, descriptive, cross-sectional study of a cohort of 345 jSLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestation were identified and compared. RESULTS: Mean age (years) ±â€¯S.D. at diagnosis was 14.2 ±â€¯2.89; 88.7% were female and 93.4% were Caucasian. Mean SLICC/ACR DI ±â€¯S.D. was 1.27 ±â€¯1.63. A total of 12 (3.5%) patients died. Three damage clusters were identified: Cluster 1 (72.7% of patients) presented a lower number of individuals with damage (22.3% vs. 100% in Clusters 2 and 3, P < 0.001); Cluster 2 (14.5% of patients) was characterized by renal damage in 60% of patients, significantly more than Clusters 1 and 3 (P < 0.001), in addition to increased more ocular, cardiovascular and gonadal damage; Cluster 3 (12.7%) was the only group with musculoskeletal damage (100%), significantly higher than in Clusters 1 and 2 (P < 0.001). The overall mortality rate in Cluster 2 was 2.2 times higher than that in Cluster 3 and 5 times higher than that in Cluster 1 (P < 0.017 for both comparisons). CONCLUSIONS: In a large cohort of jSLE patients, renal and musculoskeletal damage manifestations were the two dominant forms of damage by which patients were sorted into clinically meaningful clusters. We found two clusters of jSLE with important clinical damage that were associated with higher rates of mortality, especially for the cluster of patients with predominant renal damage. Physicians should be particularly vigilant to the early prevention of damage in this subset of jSLE patients with kidney involvement.

Accuracy of physical examination in subacromial impingement syndrome.

OBJECTIVE: Shoulder pain is a common complaint, frequently caused by subacromial impingement syndrome (SIS). There are a number of physical examination (PE) manoeuvres that explore the subacromial space. MRI provides an accurate anatomic image of the subacromial space, being the current gold standard in the diagnosis of SIS. The aim of this study is to evaluate the accuracy of the PE in the diagnosis of SIS and/or subacromial-subdeltoid bursitis (SSB) confirmed by MRI. METHODS: Consecutive outpatients with an episode of shoulder pain were prospectively included in the study. They were examined by a rheumatologist and, within 3 days, an MRI was done. Sensitivity, specificity, positive and negative predictive values, and accuracy of PE manoeuvres were calculated using a 2 x 2 table. RESULTS: Fourteen males and 16 females were included. All the tests exhibited acceptable sensitivity. As a result Yocum manoeuvre was considered the most sensitive and most accurate for SIS. With regard to SSB, the Gerber test was the most sensitive. The majority of the PE manoeuvres showed low specificity. CONCLUSIONS: Most PE manoeuvres identify reasonably well subacromial impingement of the shoulder, although, in general, they have low specificity. The Yocum test has the best sensitivity and precision. Our data suggest that imaging techniques should be recommended to better define shoulder lesions.

Candida arthritis in adult patients who are not intravenous drug addicts: report of three cases and review of the literature.

Candida species are an uncommon cause of infectious arthritis, although the frequency has increased during recent years. Three cases of septic arthritis caused by Candida species are reported, and the literature is reviewed. The first patient developed a popliteal cyst infected by Candida albicans after multiple intravenous antibiotic treatments. The second patient had acute myelogenous leukemia and experienced knee arthritis after chemotherapy, and the third suffered oligoarthritis after a second heart transplantation. All patients received treatment with a standard dose of intravenous amphotericin B. Responses were achieved only in the first two cases; the third patient died despite therapy. Thirty-six previously reported Candida arthritis cases are reviewed, and epidemiologic, diagnostic, therapeutic, and prognostic features are analyzed. Cases are divided into two categories: direct inoculation of fungus and hematogenously disseminated disease; these two categories are compared in terms of sex, age, pathogen species, treatment, and survival. Arthritis induced through direct inoculation of fungus is seen in older individuals, is more frequently produced by species other than C albicans (Candida parapsilosis especially), and has a better prognosis than arthritis caused by disseminated candidiasis. Arthritis can be resolved even in the persistence of the systemic disease. It is believed that the first case of Baker's cyst infected by C albicans and the first case of Candida arthritis in a heart transplant patient are reported here.

Role of the new azoles in the treatment of fungal osteoarticular infections.

OBJECTIVES: To analyze the usefulness of the new azoles for the treatment of fungal osteoarticular infections, and to report three cases of fungal knee arthritis treated with fluconazole in our unit. METHODS: The medical literature was reviewed for all cases of osteoarticular infection caused by fungi and treated with fluconazole or itraconazole registered in the MedLine Silver Platter database from 1972 to 1997. RESULTS: The total number of patients included in this review was 56; 19 were treated with fluconazole and 37 with itraconazole. The most frequent causative agents implicated were fungi of the genuses Candida and Aspergillus. There were eight therapeutic failures, and there were no statistically different findings among the patients in terms of their health status. Adverse effects were unusual. CONCLUSIONS: Controlled studies are necessary to establish the true role of the new azole drugs in the treatment of fungal osteoarticular infections, but they seem to be a promising therapeutic option.

Treatment with IL2/vaccinia recombinant virus leads to serologic, histologic and phenotypic normalization of autoimmune MRL/lpr-lpr mice.

We have analyzed the effect of IL2 administered in vivo on both the lymphoproliferation and autoimmune disease progression of MRL/lpr mice. Human IL2 was delivered by infecting MRL/lpr mice with vaccinia virus recombinants at different stages of lpr disease. The results reported here showed that treatment of lpr mice with IL2 mediated: (1) restored normal thymic differentiation illustrated by an expansion of the double positive population accompanied by increased numbers of mature thymocytes; (2) depletion of the peripheral CD3+ CD4- CD8- (DN) T-cell population; (3) normalization in the pattern of TcRV beta gene expression displayed by mature T cells; (4) decreased urine-protein levels and immune complex deposition in the kidney, with a resultant absence of glomerulonephritis; and (5) an increased longevity (from 195 to more than 400 days). We speculate that the dramatic reduction in the abnormally expanded CD3+ DN T-cell population following IL2 therapy might be directly related to the amelioration and/or prevention of autoimmune disease in these mice. Collectively, these results suggest that diseases showing a selective expansion of DN cells should be envisaged as possible targets for the treatment described here.

Intra-articular osteoid osteoma at the elbow: report of a case and review of the literature.

Osteoid osteoma is a benign tumor that may occur in almost any part of any bone. Diagnosis can be difficult, particularly when it is intra-articular. In these cases, osteoid osteoma may present initially with symptoms suggestive of inflammatory arthritis, degenerative joint disease, neoplasm, or infection. We report a case of intra-articular osteoid osteoma in a teenager who presented with a monoarthritis of the elbow. The patient did not have a typical pattern of pain, did not have the typical relief with anti-inflammatory agents, and misinterpretation of the radiographs led to a delay in the diagnosis and definitive treatment. Surgical excision confirmed the diagnosis and resulted in resolution of the monoarthritis. Intra-articular osteoid osteoma must be taken into account in cases of unexplained chronic monoarthritis, with a sterile and relatively noninflammatory synovial fluid. A definitive diagnosis depends on surgical excision and histologic confirmation. Ahigh index of suspicion is necessary to make the diagnosis.

[Fibromyalgia and its diagnosis]. / La fibromialgia y su diagnóstico.

Fibromyalgia or fibromyalgic syndrome (FMS) is a clinical picture of unknown origin that is characterized by generalized, incapacitating and chronic pain together with the demonstration in the physical examination of previously defined points in which moderate pressure causes pain, called fibromyalgia tender points (FTP). FMS lacks objective, analytic imaging or pathological data, so that its diagnosis is based exclusively on subjective data, such as that the pain reported by the patient and the pain caused by the FTP pressure. Although the fibromyalgia classification criteria of the American College of Rheumatology are not diagnostic criteria, they have been extensively used to diagnose FMS in patients with chronic diffuse arthromyalgias. Fibromyalgia diagnosis reduces the patient's anxiety, avoiding complementary expensive and unnecessary tests and it allows the patient to share his/her fears, illnesses and expectations with other human beings who suffer the same problem.

Selective expansion of T cells bearing the gamma/delta receptor and expressing an unusual repertoire in the synovial membrane of patients with rheumatoid arthritis.

In a study of 7 patients with rheumatoid arthritis (RA), we characterized the T cell population present in the synovial membrane, thought to be the location where T cells trigger the disease. Synovial membrane lymphocytes from the RA patients were found to have a selective expansion of gamma/delta T cells (8.8% in synovial membrane versus 4% in peripheral blood). Expansion of the gamma/delta T cell subset was not found in the synovial membrane of patients with osteoarthritis. We characterized the gamma/delta T cell repertoire using monoclonal antibodies Ti gamma A, BB3, and delta TCS1, which recognize the gene products encoded by V gamma 9, V delta 2, and V delta 1-J delta 1, respectively. The majority of the synovial gamma/delta T cells did not express the repertoire encoded by these genes, which is found in nearly 100% of the peripheral blood gamma/delta T cells of healthy volunteer donors and in the thymus at early stages of development. We conclude that the synovial membrane of patients with RA displays a selective expansion of a specific population of gamma/delta T cells expressing a clonotypic receptor not yet serologically defined, which might be implicated in the development of the disease.

Cytomegalovirus esophagitis as a treatable complication of systemic sclerosis.

We report the case of a 51-year-old woman with a connective tissue disease of 8 years duration. She had been taking corticosteroids at a dose of 1 mg/kg/day and azathioprine at a dose of 3 mg/kg/day for 1 month. Given the clinical suspicion of systemic sclerosis (limited form of scleroderma), she was studied according to a protocol including endoscopy to assess the degree to which the underlying disease had affected the gastrointestinal tract. Endoscopy revealed a asymptomatic severe esophagitis and a subsequent biopsy disclosed the presence of cytomegalovirus. Cytomegalovirus pneumonia was also detected. Both processes were successfully managed with intravenous ganciclovir (5 mg/kg/12 hr) for 21 days. This report is a case of cytomegalovirus involving the esophagus in association with systemic sclerosis in a patient immunosuppressed because of drugs that she had been taking. This complication can be asymptomatic and is amenable to treatment.

Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus.

Interleukin-2 (IL-2) is a T-cell derived molecule implicated in the clonal expansion of antigen-activated T cells and in T-cell development. IL-2 is also implicated in autoimmune disease, although its role is still controversial. Murine systemic lupus erythematosus (SLE) is a good model for human SLE as most of the immunological abnormalities in the human disease also seem to be operative in the mouse. Among SLE mice, the MRL/lpr strain develops early in life autoimmune diseases such as immune complex-mediated glomerulonephritis, arthritis and arteritis. Lymphoid abnormalities associated with those diseases in this strain are thymic atrophy and abnormal proliferation of CD3+ CD4- CD8- 'double-negative' T cells, resulting in massive generalized lymph node enlargement. We have therefore now examined the effects of IL-2 on the disease progression in MRL/lpr mice using live vaccinia recombinant viruses expressing the human IL-2 gene. Vaccinated mice showed prolonged survival, decreased autoantibody and rheumatoid factor titres, marked attenuation of kidney interstitial infiltration and intraglomerular proliferation, as well as clearance of synovial mononuclear infiltrates. Inoculation with the IL-2/vaccinia recombinant virus led, in addition, to drastic reduction of the double-negative T-cell population, improved thymic differentiation and restoration of normal values of mature cells in peripheral lymphoid organs.