Interleukin-1RN gene polymorphisms in elderly patients with rheumatic inflammatory chronic conditions: Association of IL-1RN*2/2 genotype with polymyalgia rheumatica.

The objective of this study was to investigate whether there is an association between IL1RN polymorphism and disease susceptibility for three age-related inflammatory conditions: polymyalgia rheumatica (PMR), giant cell arteritis (GCA), and elderly-onset rheumatoid arthritis (EORA). A tandem-repeat polymorphism within IL1RN intron 2 was analyzed in 139 PMR, 69 GCA, and 156 RA patients (75 with EORA) as well as in 437 healthy subjects, together with the in vitro production of IL-1beta. Our results showed that the IL1RN*2/2 genotype was more frequent in PMR patients compared with controls (p = 0.032, odds ratio = 1.785, 95% confidence interval = 1.047-3.044) and GCA patients (p = 0.008, odds ratio = 4.661, 95% confidence interval = 1.352-16.065). We found no difference in the distribution of genotypes between PMR and EORA or between EORA and controls. However, the frequency of the IL-1RN*2/2 genotype had a tendency to be higher in patients with EORA compared with young onset RA. The presence of IL1RN*1 or IL1RN*2 allele was not associated with severity of the disease in PMR and GCA patients and did not influence the production of IL-1beta. In conclusion, the IL1RN*2 polymorphism in a homozygous state was associated with an increased susceptibility to PMR and may give some clues for a differential therapy with GCA.

[Adult-onset Still's disease with liver failure requiring liver transplantation]. / Enfermedad de Still del adulto con desarrollo de insuficiencia hepática que precisa trasplante hepático.

We present the case of a 23-year-old man with fever of unknown origin, who developed acute liver failure 2 months after symptom onset, requiring an urgent liver transplantation. The diagnosis of adult-onset Still's disease was established after the reappearance of symptoms after transplantation, and high doses of corticosteroids were used to control disease activity. Subsequently, given the impossibility of tapering the steroid dose, interleukin-1 receptor blocking treatment was started with satisfactory outcome. We also review the published literature.

Performance of antinuclear antibody connective tissue disease screen.

Antinuclear antibodies (ANAs) have become routine laboratory parameters in clinical hospitals. However, ANA testing by indirect immunofluorescence (IIF) assays is not an automated laboratory test. Efforts are being made to develop easy and semi- or automated methods to screen for ANAs. We evaluated the clinical performance of a new ELISA developed to screen for connective tissue disease related ANAs. The presence of serum ANA was studied with a commercial ELISA (Varelisa ANA CTD Screen) in 472 patients (202 SLE, 41 Sjögren syndrome, 11 CREST, 59 rheumatoid arthritis, 30 seronegative spondyloarthropaties, 77 inflammatory bowel disease, 13 reactive arthritis, 11 giant cell arteritis, 28 ankylosing spondilitis). A hundred and five sera from healthy subjects were used as controls. Receiver operator characteristics (ROC) analysis was carried out in order to optimize the cutoff. At target specificities of 80/90%, sensitivities of 80.8/ 73.9% were achieved. At the manufacturer's cutoff (ratio >or=1.0) sensitivity/specificity of 71.4/91.2% was found. At that cutoff, a positive likelihood ratio of 8.11 was found. For helping in the diagnosis of connective tissue diseases a test employing a subset of the most prevalent specificities reveals a good compromise as indicated by a high-positive likelihood ratio. However, the presence of ANAs in pathologies other than connective tissue diseases, such as SLE or Sjögren syndrome, may be of clinical significance as well. In these cases an IIF assay test is still mandatory, especially in autoimmune laboratories.

Outcome of late-onset rheumatoid arthritis.

The objective of this study was to determine possible differences in the outcome of patients with rheumatoid arthritis (RA) with disease onset early and late in life. As part of a broader outcome study of RA which included patients seen in the division of Rheumatology of Hospital Universitario Marqués de Valdecilla of Santander, Cantabria (Northern Spain) with disease duration between 2 and 7 years, we selected patients with an age at disease onset of or=65 years. The medical records of all eligible patients were reviewed for relevant clinical and laboratory variables; the patients were then further evaluated for disease activity using biological tests and joint indices such as joint counts and Thompson's Index, functional capacity using the American College of Rheumatology (ACR) functional classification (ACR-FC) and the modified Health Assessment Questionnaire (M-HAQ), and anatomical damage using the number of joint damage (NJD) and radiographs read by the Sharp's scoring method for joint erosion (JE), joint narrowing (JN), and overall. Patients in both subsets were then compared. For the multivariable analyses all patients in the original larger cohort were included, so that age could be used as a continuous variable and the power of the analyses could increase; 31 younger (mean age+/-SD: 36+/-7 years) and 35 older (73+/-6 years) patients were available for assessment. No differences in disease duration and gender distribution were observed. Likewise, both subsets had similar levels of disease activity, both articular indices, and biological markers. In contrast, elderly patients showed more functional limitations as per the M-HAQ [median (interquartile range): 0.4 (0.13-1.2) vs 0.13 (0-0.6), p=0.007] and greater anatomical damage as per the NJD [median (interquartile range): 2 (0-4) and 0 (0-2), respectively, p=0.04] and the JE, JN, and total Sharp Index score (p=0.001, 0.02, and 0.001, respectively). Although older patients took fewer disease-modifying antirheumatic drugs (DMARD) and combined DMARD treatments (2.5+/-1.4 vs 1.9+/-1.3, p=0.05 and 0.8+/-1.1 vs 0.3+/-0.6, p=0.01, respectively), multivariable analysis demonstrated an independent association between age at disease onset and the number of DMARD and functional and anatomical decline. Late-onset RA does not present a better prognosis than the early-onset form of the disease. At the very least the disease is comparable between both patient groups. However, disease compounded by age-associated factors may in fact have a worse prognosis late than early in life.

Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic-pituitary-adrenal axis.

A growing body of evidence indicates that ageing brings a progressive disruption in the immune and endocrine systems. However, very few reports have correlated the changes in the immune system with the endocrine function in the elderly. The aim of the present study was to investigate the changes occurring in the peripheral blood lymphocyte subpopulations with age and correlate them with the hypothalamic-pituitary-adrenal (HPA) function. We determined the peripheral blood lymphocyte phenotype and the T cell receptor usage by flow cytometry analysis. The HPA function was evaluated by the basal serum levels of adrenal steroids and the response to stimulation with a low-dose ACTH. In the elderly, we observed a decrease of major T subsets together with an increase of NK cells and activated T cells. With regard to the HPA function, the most significant decline was found in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS). A close correlation between immune changes with ageing and DHEA response to ACTH stimulation was found. The present study showed an inverse correlation of lymphocyte changes with the plasma levels of steroids, especially DHEA and its metabolite, DHEAS. This association was not found for other steroids and points for the possibility of using DHEA to correct the immunological decline associated with ageing.

Hypothalamic-pituitary-adrenocortical axis function in patients with polymyalgia rheumatica and giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are 2 closely related syndromes affecting elderly people. One of the most striking features of these conditions is the development of the disease in an almost exclusive manner in people older than 50 years. Despite this close association with age, the pathogenic mechanisms that could explain this age-related predisposition are unknown. Aging is accompanied by a number of quantitative and qualitative changes in the endocrine system that may predispose to several pathologic conditions that occur in the elderly. OBJECTIVE: To explore the hypothalamic-pituitary-adrenal axis in PMR and GCA. METHODS: Basal levels of adrenal hormones as well as the response to low-dose adrenocorticotropin hormone (ACTH) were investigated in 20 patients with active untreated disease and compared with levels in 16 healthy age-matched controls. RESULTS: Male patients with active disease had low basal levels of androstenedione compared to the controls. After low-dose ACTH challenge, cortisol and dehydroepiandrosterone reached higher levels in patients than in healthy subjects, indicating that the adrenal gland function was not suppressed. Furthermore, the authors did not find a clear relationship between the levels of acute phase reactants and adrenal hormones in the patient population. CONCLUSIONS: The authors' findings are probably more compatible with the hypothesis that the abnormalities found in the patient group are the consequences of chronic illness rather than a crucial factor contributing to the pathogenesis of the disease.

HLA-DRB1 allele distribution in polymyalgia rheumatica and giant cell arteritis: influence on clinical subgroups and prognosis.

OBJECTIVE: To evaluate HLA-DRB1 associations in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in the Spanish population, especially those alleles that include the disease-linked sequence motif DRYF (positions 28 to 31 of the HVR2). METHODS: We performed a PCR based HLA-DRB1 genotyping in 89 PMR patients, 44 GCA patients, and 99 unrelated healthy controls from the same geographic area. RESULTS: We did not find any significant difference between the whole group of PMR/GCA patients (n = 133) compared with the healthy controls with the exception of a lower frequency of HLA-DRB1*0405 in the patient group (odds ratio [OR], 0.1 [CI0.02 to 1.2]; P =.04). The distribution of DRB1 alleles was very similar between PMR patients and controls. However, DRB1*0401 (OR, 3.1 [1.1 to 8.6]; P =.02) and DRB1*0404 (OR, 3.5 [0.97 to 12.9]; P =.04) were overrepresented in patients with GCA compared with the control group. DRB1*04 (OR, 1.9 [0.96 to 3.8]; P =.06), especially *0401 (OR, 2.8 [1 to 7.7]; P =.04), and DRB1*07 (OR, 2.3 [1.2 to 4.6]; P =.01) were more frequent in GCA than in PMR. Frequency of the DRYF 28-31 motif was similar among GCA (79.5%), PMR (89.9%), and controls (87.9%) and did not confer any significant risk of the development of systemic vasculitis. We also compared the DRB1 allele distribution in patients with classic PMR (n = 58) and those with an erythrocyte sedimentation rate (ESR) <40 mm/hour (n = 31). Patients with classic PMR expressed DRB1*07 less frequently (OR, 0.4 [0.1 to 1]; P =.04) and had a higher frequency of the DRYF 28-31 motif (94.8% vs 80.6%; P =.03) than patients with ESR < 40. Within the GCA group, DRB1 alleles were not predictive for the development of severe ischemic complications. However, the development of relapses in patients with PMR was associated with a higher frequency of DRB1*09 (5.6% vs 0%; P =.04). CONCLUSIONS: Our data suggest that the HLA-DRB1 alleles associated with susceptibility for developing PMR and GCA are different. Whether PMR with low ESR represents a different clinical subset of the disease should be clarified in a larger sample of patients. HLA-DRB1 genes might predict the presence of relapses in PMR, but they do not seem to be indicators of severe disease in GCA patients.

Health-related quality of life in psoriatic arthritis patients in Spain.

PURPOSE: To describe the demographic and clinical characteristics, including health-related quality-of-life (HRQL), in patients with psoriatic arthritis (PsA). METHODS: 287 patients from 18 Spanish centres were assessed. PsA severity was measured using the following criteria: (1) Psoriasis Area and Severity Index (PASI score 0-72, from low to high severity); (2) number of swollen and tender joints; and (3) Health Assessment Questionnaire (HAQ score 0-3 from low to high impairment in daily activities). HRQL assessment was performed using the following criteria: (a) EuroQol-5D (EQ-5D scores 1-3, with a higher score representing a worse HRQL), Visual Analogue Scale (VAS score 0-100, with a higher score representing a better HQRL) and (b) Short Form-36 (SF-36 score 0-100, with a higher score representing a better HRQL). RESULTS: 24.7% of patients were treated with infliximab. In the two groups, 55.7% of the patients were male with a mean age of 52.40±12.53 years. The average number of swollen joints was higher in patients not receiving biological therapy than in those receiving treatment (2.98 vs. 1.54). The mean PASI score was 3.73±5.83, and there was no difference between groups. HAQ scores were higher in patients receiving infliximab than in those not receiving treatment (0.93 vs. 0.70). The mean EQ-5D scores in the two groups indicated a poorer status based on pain and inability to perform usual/daily activities. HRQL measured by VAS score mean was 60.41 ± 20.08, and there was no difference between the groups. The domains in the SF-36 suggesting poorer functioning in the two groups were the physical role (50.76 ± 43.43), physical pain (49.35 ± 25.69) and the overall physical component (37.88 ± 10.87). CONCLUSIONS: PsA is associated with an impaired HRQL characterised by physical pain and poorer functioning in daily activities.

[Update of the Consensus Statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis]. / Actualización del Documento de Consenso de la Sociedad Española de Reumatología sobre el uso de terapias biológicas en la artritis reumatoide.

OBJECTIVE: To provide a reference to rheumatologists and to those involved in the treatment of RA who are using, or about to use biologic therapy. METHODS: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and grade of recommendation were classified according to the model proposed by the Center for Evidence Based Medicine at Oxford. The level of agreement was established through Delphi technique. RESULTS: We have produced recommendations on the use of the seven biologic agents available for RA in our country. The objective of treatment is to achieve the remission of the disease as quickly as possible. Indications and nuances regarding the use of biologic therapy were reviewed as well as the evaluation that should be performed prior to administration and the follow up of patients undergoing this therapy. CONCLUSIONS: We present an update on the SER recommendations for the use of biologic therapy in patients with RA.

Cloxacillin-based therapy in severe septic bursitis: retrospective study of 82 cases.

OBJECTIVE: The purpose of this retrospective study was to describe a tertiary care center experience with different antibiotic strategies that include cloxacillin (C) in patients with severe septic bursitis (SB). METHODS: A severe SB was considered when the patient needed hospitalization and/or intravenous (i.v.) antibiotics. Patients were treated with bursal aspiration and one of these antibiotic options: C, 2 g/4 h per day i.v. until improvement, and afterwards 1 g/6 h per day v.o. until resolution; (C+G), gentamicin i.v. was added to C for 5 to 7 days (initial dose 240 mg/d); (C+R), rifampicin was added at a dose of 600 mg/d v.o. RESULTS: The study comprised 82 patients with severe SB. The mean delay to diagnosis was 6.1+/-6.9 days, and the most frequent location was the prepatellar bursa. In 67%, the bursal fluid culture yield a positive result, being Staphylococcus aureus the most frequent bacteria isolated (94.4%). At admission, fever and extensive cellulites were more frequent in the C+G group. Patients in the C+G had a longer duration of i.v. antibiotics compared with the C group (p=0.008), although the total duration of antibiotics was not different. There was a tendency in the C+R group to need more surgery. All patients except one had a complete resolution and there were no differences in side effects. CONCLUSION: In patients with severe SB without extensive cellulites i.v., C alone may be sufficient. In patients with a more severe presentation, C plus gentamicin seems to be an appropriate option in the majority of them.

Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial.

OBJECTIVE: To evaluate the efficacy, including radiographic changes, and safety of etanercept and methotrexate (MTX), used in combination and alone, in patients with rheumatoid arthritis (RA) in whom previous treatment with a disease-modifying antirheumatic drug other than MTX had failed. METHODS: Patients with RA were treated with etanercept (25 mg subcutaneously twice weekly), oral MTX (up to 20 mg weekly), or combination therapy with etanercept plus MTX through a second year, in a double-blinded manner. Clinical response was assessed using American College of Rheumatology (ACR) criteria and the Disease Activity Score (DAS), in a modified intent-to-treat analysis with the last observation carried forward (LOCF) and in a population of completers. Radiographs of the hands, wrists, and forefeet were scored for erosions and joint space narrowing at annual intervals. RESULTS: A total of 503 of 686 patients continued into year 2 of the study. During the 2 years, significantly fewer patients receiving combination therapy withdrew from the study (29% of the combination therapy group, 39% of the etanercept group, and 48% of the MTX group). Both the LOCF and the completer analyses yielded similar results. The ACR 20% improvement (ACR20), ACR50, and ACR70 responses and the remission rates (based on a DAS of <1.6) were significantly higher with combination therapy than with either monotherapy (P<0.01). Similarly, improvement in disability (based on the Health Assessment Questionnaire) was greater with combination therapy (P<0.01). The combination therapy group showed significantly less radiographic progression than did either group receiving monotherapy (P<0.05); moreover, radiographic progression was significantly lower in the etanercept group compared with the MTX group (P<0.05). For the second consecutive year, overall disease progression in the combination therapy group was negative, with the 95% confidence interval less than zero. Adverse events were similar in the 3 treatment groups. CONCLUSION: Etanercept in combination with MTX reduced disease activity, slowed radiographic progression, and improved function more effectively than did either monotherapy over a 2-year period. No increase in toxicity was associated with combination treatment with etanercept plus MTX.

Presentation and analysis of data on radiographic outcome in clinical trials: experience from the TEMPO study.

OBJECTIVE: To evaluate different methods of presentation and analysis of radiographic data in a rheumatoid arthritis (RA) randomized controlled trial. METHODS: A double-blind randomized controlled trial including 682 patients with active RA who were treated with methotrexate, etanercept, or a combination of the 2 drugs was used for this study. Probability plots of the change from baseline to year 1 were produced to visualize progression, and were compared with usual descriptive statistics. The primary analysis of the trial (based on annualized actual mean change from baseline in total Sharp score at 1 year, using linear imputation) was challenged using various ways of handling missing information with alternative imputation methods, and by various statistical analyses including analysis of covariance (ANCOVA) and mixed model analysis on both raw and log-transformed data. RESULTS: Probability plots provided detailed insight into the differentiated treatment effects between the 3 arms of this study. As adjuncts to formal hypothesis testing, these plots were more useful for presenting data than were summary descriptive statistics or use of preset cutoff points to define lack of progression. Additional analyses presented here support the results obtained with the per-protocol analysis that showed an advantage of the combination treatment compared with the monotherapy arms and for etanercept versus methotrexate alone. Various ways of handling missing information confirmed the robustness of the results. In addition, both ANCOVA and mixed model analyses on raw and on log-transformed data produced similar results. CONCLUSION: We suggest a panel of alternative analysis methods and alternative ways of handling missing information to verify that the radiographic results reported in an randomized controlled trial are not influenced by technical factors, such as interpolation, handling of missing data, and choice of statistical tests.

Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists.

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.