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Aim: Variation at PDE3A-SLCO1C1 locus has been recently associated with the response to anti-TNF therapy in rheumatoid arthritis. We undertook the present study to determine whether PDE3A-SLCO1C1 is also associated with the response to anti-TNF therapy in psoriatic arthritis. Patients & methods: Genomic DNA was obtained from 81 psoriatic arthritis patients that had been treated with anti-TNF therapy. PDE3A-SLCO1C1 SNP rs3794271 was genotyped using Taqman realt-time PCR. The clinical response to anti-TNF therapy was measured as the change from baseline in the level of disease activity according to the DAS28 score. Results: A significant association between rs3794271 and anti-TNF response in psoriatic arthritis was found (beta = -0.71; p = 0.0036). Conclusion: PDE3A-SLCO1C1 locus is also associated with response to anti-TNF therapy in psoriatic arthritis. Original submitted 12 May 2014; Revision submitted 18 August 2014.

Telomere length was sequentially determined in peripheral blood leukocytes (PBL) from patients with ankylosing spondylitis (AS; n = 44) and psoriatic arthritis (PsA; n = 42) followed through 2.93 ± 0.99 years, using a quantitative PCR (qPCR) assay. The initial telomere size from PsA patients was higher than those with cutaneous psoriasis only (n = 53), possibly due to the inflammatory condition. The qPCR assay was sensitive enough to evidence a significant telomere length shortening in PBL from practically all subjects and PsA patients showed a higher rate of loss of telomere sequence than patients with AS during the follow-up time., (Copyright © 2014 Elsevier B.V. All rights reserved.)

To define and give priory to standards of care in patients with spondyloarthritis (SpA). A systematic literature review on SpA standards of care and a specific search in relevant and related sources was performed. An expert panel was established who developed the standards of care and graded their priority (high, mild, low, or no priority) following qualitative methodology and Delphi process. An electronic survey was sent to a representative sample of 167 rheumatologists all around the country, who also gave priority to the standards of care (same scale). A descriptive analysis is presented. The systematic literature review retrieved no article specifically related to SpA patients. A total of 38 standards of care were obtained-12 related to structure, 20 to process, and 6 to result. Access to care, treatment, and safety standards of care were given a high priority by most of rheumatologists. Standards not directly connected to daily practice were not given such priority, as standards which included a time framework. The standards generated for the performance evaluation (including patient and professionals satisfaction) were not considered especially important in general. This set of standards of care should help improve the quality of care in SpA patients.

Objectives: Improving referral of patients with back pain to rheumatologists could accelerate the diagnosis of axial spondyloarthritis. The RADAR study compared two strategies in the referral of patients with chronic back pain (>3 months) with an onset before the age of 45 years from primary care centers to rheumatology departments, in relation to the diagnosis of axial spondyloarthritis., Patients and Methods: Each primary care center was assigned a referral strategy for its patients: (a) strategy 1, patients who had one of the 3 following criteria: inflammatory back pain, HLA-B27 positivity or sacroiliitis in imaging; or (b) strategy 2, patients who had 2 of the following 6: inflammatory back pain, HLA-B27 positivity, sacroiliitis in imaging, family history of axial spondyloarthritis, extra-articular manifestations or good response to nonsteroidal antiinflammatory drugs. The rheumatologist established the final diagnosis., Results: Eighty-eight Spanish patients (mean age 36.8 years [SD 8.7], 55.7% females and 44.3% males) were referred for evaluation, 60 patients under strategy 1 and 28 under strategy 2. A definitive diagnosis of axial spondyloarthritis was established in 25.4% with strategy 1 and in 28.6% with strategy 2 (p=NS). Inflammatory back pain was the criterion most commonly used for referral, and the agreement rate between the primary care physician and rheumatologist was 75%., Conclusions: A simple referral strategy based on one of three3 criteria proved as effective as a strategy based on two of 6 criteria in diagnosing axial spondyloarthritis. Inflammatory back pain was the criterion most commonly used for patient referral., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Objectives: To test the reliability of the Berlin MRI scoring method and the effect of a calibration exercise on the score's reliability among untrained readers in MRI examinations of patients with established ankylosing spondylitis (AS)., Methods: Eleven rheumatologists read blinded images of 20 AS patients before and after a two-day workshop on the Berlin MRI scoring method. Reliability (intra- and inter-reader) and concordance with the expert (all measured by intraclass correlation coefficient (ICC)) were compared before and after 2 weeks of the training. Feasibility in terms of time and difficulty was also measured., Results: The mean Berlin score increased from (mean ± standard deviation) 5.04 ± 6.41 before to 6.40±7.08 after the calibration exercise (p<0.01). Inter-reader ICC decreased from 0.83 (95% CI: 0.75-0.93) to 0.78 (95% CI: 0.66-0.90), and intra-reader ICC from 0.89 (95% CI: 0.84-0.94) to 0.87 (95% CI: 0.82-0.92). Agreement with an experienced reader improved after the calibration exercise, with ICC = 0.59 (95% CI 0.45-0.76) before vs. ICC = 0.65 (95% CI 0.50-0.80) after training., Conclusions: The Berlin method is a reliable scoring method for assessment of spinal inflammatory activity by using MRI in patients with AS, even in the hands of inexperienced readers. A calibration exercise can improve feasibility and sensitivity of the scoring method.

Recent genome-wide association studies (GWASs) have identified >20 new loci associated with the susceptibility to psoriasis vulgaris (PsV) risk. We investigated the association of PsV and its main clinical subphenotypes with 32 loci having previous genome-wide evidence of association with PsV (P < 5e-8) or strong GWAS evidence (P < 5e-5 in discovery and P < 0.05 in replication sample) in a large cohort of PsV patients (n = 2005) and controls (n = 1497). We provide the first independent replication for COG6 (P = 0.00079) and SERPINB8 (P = 0.048) loci with PsV. In those patients having developed psoriatic arthritis (n = 955), we found, for the first time, a strong association with IFIH1 (P = 0.013). Analyses of clinically relevant PsV subtypes yielded a significant association of severity of cutaneous disease with variation at LCE3D locus (P = 0.0005) in PsV and nail involvement with IL1RN in purely cutaneous psoriasis (PsC, P = 0.007). In an exploratory analysis of epistasis, we replicated the previously described HLA-C-ERAP1 interaction with PsC. Our findings show that common genetic variants associated with a complex phenotype like PsV influence different subphenotypes of high clinical relevance.

Objective: Ankylosing spondylitis (AS) is generally observed in young patients but can occur later in life or in persons ≥ 50 years of age. Our objective was to characterize the clinical features of late-onset AS in a large multicenter national cohort., Methods: We studied late-onset AS in the National Registry of Spondyloarthritis of the Spanish Society of Rheumatology (REGISPONSER database) cohort (n = 1257), of whom 3.5% had onset at age ≥ 50 years versus a control group with onset at < 50 years., Results: There were no differences between late-onset and early-onset AS according to sex and family history of spondyloarthropathies. Patients in the late-onset group more often showed involvement of the cervical spine (22.7% vs 9.7%; p = 0.03) and arthritis of the upper (13.6% vs 3.0%; p = 0.002) and lower limbs (27.3% vs 15.2%; p = 0.03) as first manifestations than did patients in the early-onset group. A higher percentage of mixed forms (axial and peripheral joint disease) during the course of the disease was also recorded in the late-onset group (50% vs 24%; p = 0.0001)., Conclusion: Our study suggests that age at onset of AS affects the patients' presenting clinical form. Arthritis of the upper limbs requires a differential diagnosis with other conditions frequent in patients over 50 years of age, such as rheumatoid arthritis or crystal-induced arthropathy.

Objective: The efficacy of antibody-based biological therapies currently used in psoriatic arthritis (PsA) depends not only on their blocking effect on the targeted molecule but also on their binding affinity to genetically defined variants of cell-surface Fc-γ receptors. Our objective was to assess the potential influence of functionally relevant FCGR2A/CD32A (H131R) and FCGR3A/CD16A (V158F) genetic polymorphisms on the EULAR response to tumor necrosis factor-α (TNF-α) blocker therapy in PsA., Methods: In total 103 patients with PsA starting anti-TNF-α therapy were included. The efficacy of therapy was evaluated according to EULAR response criteria at 3 and 6 months. FCGR2A-R131H and FCGR3A-F158V polymorphisms were genotyped. Potential correlations between clinical response and the FCGR2A-R131H and FCGR3A-F158V polymorphisms were evaluated., Results: EULAR response (moderate plus good) was 85.4% at 3 months and 87.4% at 6 months, while good EULAR response was 61.2% and 62.1%, respectively. More patients with high-affinity FCGR2A genotypes (homozygous or heterozygous combinations) achieved a EULAR response at 6 months compared to patients with the low-affinity genotype (RR; p = 0.034, adjusted comparison error rate < 0.025). This association was due mainly to the group of patients treated with etanercept. No correlation was found for the FCGR3A polymorphism. Similarly, no effect of C-reactive protein levels was observed., Conclusion: Our data indicate that FCGR2A polymorphism may influence the response to TNF-α blockers (namely etanercept) in PsA in a direction opposite to that previously found in patients with rheumatoid arthritis.

Introduction: Psoriatic arthritis (PsA) is an autoantibody-negative immune-mediated disease in which synovial lymphoid neogenesis (LN) occurs. We determined whether LN is associated with specific patterns of inflammatory cytokine expression in paired synovial tissue (ST) and fluid (SF) samples and their potential correlation with the clinical characteristics of PsA., Methods: ST and paired SF samples were obtained from the inflamed knee of PsA patients. ST samples were immunostained with CD3 (T cell), CD20 (B cell), and MECA-79 (high endothelial vessels). Total ST mRNA was extracted, and the gene expression of 21 T-cell-derived and proinflammatory cytokines were measured with quantitative real-time PCR. SF concentrations of Th1, Th2, Th17, and proinflammatory cytokines were determined with the Quantibody Human Th17 Array. Clinical and biologic data were collected at inclusion and after a median of 27 months of follow-up., Results: Twenty (43.5%) of 46 patients had LN. Only two genes showed differences (Wilcoxon test, P < 0.06) in ST between LN-positive and LN-negative patients: interleukin-23A (IL-23A) (P = 0.058) and transforming growth factor-beta (TGF-β1) (P = 0.050). IL-23A expression was higher, and TGF-β1 expression was lower in LN-positive patients. ST IL-15 mRNA showed a nonsignificant trend toward higher expression in LN-positive patients, and SF IL-15 protein levels were significantly higher in LN-positive patients (P = 0.002). In all PsA patients, IL-23A mRNA expression correlated with C-reactive protein (CRP) (r = 0.471; P = 0.001) and swollen-joint count (SJC) (r = 0.350; P = 0.018), whereas SF levels of IL-6 and CC chemokine-ligand 20 (CCL-20) correlated with CRP levels (r = 0.377; P = 0.014 and r = 0.501; P < 0.0001, respectively)., Conclusions: These findings suggest differences in the cytokine profile of PsA patients with LN, with a higher expression of IL-23A and IL-15 and a lower expression of TGF-β1. In the entire group of patients, IL-23 ST expression and CCL20 SF levels strongly correlated with markers of disease activity. This cytokine pattern was not accompanied by gross clinical or biologic differences between LN-positive and -negative patients. Taken together, these results suggest a role of the IL-17/IL-23 cytokine axis in synovial LN in PsA.

Objectives: Etanercept 50 mg a week is approved in the treatment of AS. Increasing the etanercept dose to 100 mg/week improves efficacy in cutaneous psoriasis, a clinical manifestation related to the spondylarthritis family, while maintaining its safety profile. The purpose of this study was to evaluate the efficacy and safety of etanercept 100 vs 50 mg/week in patients with AS., Methods: Adult patients with AS were randomized to receive etanercept 50 mg twice a week (biw), or etanercept 50 mg once a week (qw) for 12 weeks. The primary efficacy endpoint was Ankylosing Spondylitis Assessment Study (ASAS20) response at Week 12; secondary endpoints included ASAS40, ASAS50, ASAS70 and ASAS5/6 responses, partial remission and quality of life. Safety was assessed until 15 days after the last visit., Results: A total of 108 patients were randomly selected and treated, 54 in each arm. At 12 weeks, ASAS20 response was achieved by 34 (71%) out of 48 patients of the etanercept 50 mg biw group and by 37 (76%) out of 49 patients of the etanercept 50 mg qw group (not statistically significant differences). Other efficacy variables improved significantly over time, but not between treatment groups. Fifty-six patients experienced at least one adverse event (generally, infections and infestations, gastrointestinal disorders and injection site reactions), most of them mild or moderate., Conclusions: High-dose (100 mg/week) etanercept in the treatment of AS for 12 weeks is as safe as the standard dose (50 mg/week). However, it does not significantly increase its efficacy. Trial Registration. Clinicaltrials.gov, http://clinicaltrials.gov/, NCT00873730.

Objective: Due to the increasing use of biologic therapy in rheumatic diseases and the importance of its risk management, the Spanish Society of Rheumatology (SER) has promoted the development of recommendations based on the best evidence available. These recommendations should be a reference to rheumatologists and those involved in the treatment of patients who are using, or about to use biologic therapy irrespectively of the rheumatic disease., Methods: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and degree 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 a Delphi technique. Evidence from previous consensus and clinical guidelines was used., Results: We have produced recommendations on risk management of biologic therapy in rheumatic patients. These recommendations include indication risk management, risk management before the use of biologic therapy, risk management during follow-up, attitude to adverse events, and attitude to special situations., Conclusions: We present the SER recommendations related to biologic therapy risk management., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Objective: The LCE3C&#95;LCE3B-del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C&#95;LCE3B-del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta-analysis including the previous case-control studies., Methods: We genotyped LCE3C&#95;LCE3B-del and its tag single-nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta-analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed., Results: We observed a significant association between PsA and the LCE3C&#95;LCE3B-del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14-1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta-analysis including data from all previous published studies confirmed an association of PsA with the LCE3C&#95;LCE3B-del tag SNP., Conclusion: LCE3C&#95;LCE3B-del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Due to the amount and quality variability regarding the use of biologic therapy (BT) in psoriatic arthritis (PsA) patients, the Spanish Society of Rheumatology (SER) has promoted the generation of recommendations based on the best evidence available. These recommendations should serve as reference to rheumatologists and those involved in the treatment of patients with PsA, who are using, or about to use BT., Methods: Recommendations were developed following a nominal group methodology and based on systematic reviews. The level of evidence and degree of recommendation was 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 for the use of TB currently available for PsA in our country. These recommendations include disease assessment, treatment objectives, therapeutic scheme and switching., Conclusions: We present an update on the SER recommendations for the use of BT in patients with PsA., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Objective: To investigate the response to therapy of entheseal abnormalities assessed with power Doppler (PD) ultrasound (US) in spondyloarthropathies (SpA)., Methods: A total of 327 patients with active SpA who were starting anti-tumor necrosis factor (TNF) therapy were prospectively recruited at 35 Spanish centers. A PDUS examination of 14 peripheral entheses was performed by the same investigator in each center at baseline and at 6 months. The following elementary lesions were assessed at each enthesis (presence/absence): morphologic abnormalities (hypoechogenicity and/or thickening), entheseal calcific deposits, cortical abnormalities (bone erosion and/or proliferation), adjacent bursitis and intraenthesis and perienthesis (tendon body and/or bursa) PD signal. Response to therapy of each elementary lesion was assessed by calculating change in the cumulative presence from baseline to 6 months. Intraobserver reliability of PDUS was evaluated by blindly assessing the stored baseline images 3 months after the real-time examination., Results: Complete data were obtained on 197 patients who received anti-TNF therapy for 6 months. In 91.4% of the patients there were gray-scale or PD elementary lesions at baseline and at 6 months. Cumulative entheseal morphologic abnormalities, intraenthesis PD, perienthesis PD, and bursitis showed a significant decrease from baseline to 6 months (p < 0.05). There was high intraobserver reliability for all elementary lesions (interclass correlation coefficient > 0.90, p < 0.0005)., Conclusion: Entheseal morphologic abnormalities, PD signal, and bursitis were US abnormalities that were responsive to anti-TNF therapy in SpA. PDUS can be a reproducible method for multicenter monitoring of therapeutic response in enthesitis of SpA.

Spinal involvement in PsA is a controversial issue. Currently, in spite of clinical recognition of axial involvement in axial PsA, there is a lack of consensus that impedes elaborating a definition for axial Psa. Recent advances in classification, clinical features, outcome measures and therapeutics are reviewed in this paper., (Copyright © 2009 Elsevier España, S.L. All rights reserved.)

Objective: To assess the validity of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for the evaluation and definition of disease activity of axial psoriatic arthritis (PsA)., Methods: Fifty-four peripheral PsA, 46 axial PsA, and 103 primary ankylosing spondylitis (AS) patients were assessed. Patients were classified as having axial PsA if they had grade 2 or higher unilateral sacroiliitis in the presence of spinal symptoms. The 3 groups of patients were evaluated using several measurements for AS. Assessments of acceptability, data quality, internal consistency, construct validity, and responsiveness of the BASDAI were undertaken. Disease activity of the disease was assessed in peripheral PsA and axial PsA patients using the BASDAI, and compared with those with AS., Results: For peripheral PsA patients, the Cronbach's alpha for the BASDAI was 0.783, for axial PSA patients it was 0.647, and for AS patients it was 0.786. The analysis of convergent validity showed that in peripheral PsA and axial PsA patients, the BASDAI was significantly correlated with other subjective disease activity parameters. For responsiveness, no association was found between changes in the BASDAI and changes in disease activity either in peripheral PsA or in axial PsA. BASDAI scores were similar in axial PsA and AS. Axial PsA patients with a BASDAI score >4 cm showed significant differences with peripheral PsA in terms of disease activity and were very similar to patients with AS., Conclusion: The BASDAI performed similarly in evaluating disease activity in both axial and peripheral PsA. The BASDAI does not seem to be a good index for evaluating disease activity in axial PsA.

Telomeres progressively shorten with repeated somatic tissue cell division, their length being an indicator of cellular ageing. Telomeric dysfunction may be implicated in a variety of diseases. We measured mean telomere length in peripheral blood leukocytes (PBL) from patients with various rheumatologic diseases. Mean PBL telomere length was measured using real-time quantitative polymerase chain reaction (Q-PCR) assay in a control population (n=130; age range: 3-94 years) and in subjects diagnosed with rheumatoid arthritis (RA; n=86; age range: 31-82 years), psoriatic arthritis (PA; n=56; age range: 26-79 years) and ankylosing spondylitis (AS; n=59; age range: 21-75 years). These diseases are associated with chronic systemic inflammatory activity. Telomere length was also quantified in subjects with osteoarthritis (OA; n=34; age range: 43-82 years) and osteoporosis (OP; n=35; age range: 59-95 years), diseases without a chronic systemic inflammatory component. Telomere length in OA showed no differences from age-matched controls (p=0.234), but was significantly shorter in OP (p=0.001). Telomere length was significantly longer than controls in RA (p=0.015), PA (p<0.001) and AS (p<0.001). Different patterns in telomere length from PBL are evidenced in rheumatologic pathologies, possibly dependent on the presence or absence of chronic systemic inflammation.

Background: Psoriatic arthritis (PsA) has been inconsistently associated with common NOD2 gene variants, although some of these studies did not include patient stratification by clinical phenotype., Objectives: To analyse the association between the three common NOD2 variants (R702W, G908R and L1007fs) and clinical phenotypes of PsA, particularly with surrogate markers of severe joint destruction., Patients and Methods: A total of 183 unrelated PsA patients and 187 controls were included. Demographic, clinical, biological and immunological characteristics were collected. Genotypes for the three common NOD2 gene variants were obtained by PCR and direct sequencing., Results: NOD2 variants in PsA patients (7.6%) are just as prevalent as in healthy controls (7.5%). 18.5% of PsA patients carrying at least one NOD2 variant underwent joint surgery compared with 4.5% of those without these variants (p=0.019). Multivariate analysis confirmed this finding (OR 8.82, CI 1.7-46.3). There was no requirement for early surgery in patients carrying the NOD2 variants but there was an increased possibility of requiring surgery at similar times of disease duration. No other association with clinical features and NOD2 status carrier was found., Conclusions: Common NOD2 gene variants are not associated with PsA, but might increase the risk of undergoing joint replacement surgery, suggesting that this autoinflammatory-associated gene could act as a phenotypic modifier gene in PsA patients by increasing the risk of joint destruction. Given the small number of PsA patients with joint surgery included, we consider our findings a new hypothesis that will need further testing.

Objective: To determine the prevalence of work disability in Spanish patients with ankylosing spondylitis (AS) and to identify factors related to it., Methods: A cross-sectional study based on data from Regisponser (National Spanish Registry of Patients with Spondyloarthropathy). Demographic and disease-related variables were collected. AS patients were classified as work-disabled according to the Spanish Social Security System criteria. Variables that discriminated between AS patients with and those without work disability were identified using chi-square test or unpaired t test when appropriate. Multiple logistic regression was performed., Results: In total 699 AS patients, age 48.7 +/- SD 12.7 years and with disease duration 14.1 +/- 10.1 years, were analyzed; 179 patients (25.6%) had permanent work disability. Several variables had significantly different values in patients with compared to those without work disability. In the regression model (pseudo R(2) = 0.26, p < 0.0001), age (p = 0.001), sex (p = 0.04), disease duration (p = 0.006), total Bath AS Radiological Index (p = 0.007), Bath AS Functional Index (BASFI; p = 0.007), and chest expansion (p = 0.03) retained an independent association with work disability. When BASFI was excluded from the model the independent association with sex did not remain, and a significant association with finger to floor distance was found (p = 0.040)., Conclusion: The prevalence of permanent work disability in Spanish patients with AS is significant, and the main factors related to it are age, disease duration, structural damage, and physical functioning. Longitudinal studies are needed to confirm these results.

Objective: To determine the relationship between anthropometric measurements and disease activity, functional capacity, quality of life and radiology in Spanish patients with ankylosing spondylitis (AS)., Patients and Methods: A cross-sectional study was made of 842 patients with definite ankylosing spondylitis (REGISPONSER). Sociodemographic data, spinal mobility measurements, Bath AS disease activity index (BASDAI), nocturnal pain, Bath AS radiology index (BASRI), Bath AS functional index (BASFI), the Short-Format 12 (SF-12) and the AS specific quality of life (ASQoL) questionnaire were applied. Pearson correlation coefficient analysis and regression models were constructed., Results: There was moderate correlation between fingertip-to-floor distance and lateral cervical rotation with the BASFI (p<0.01). Good correlation was evident between wall-occiput distance and lateral cervical rotation with the BASRI (p<0.01). Moderate correlation was found between chest expansion, the Schober modified test and fingertip-to-floor distance with the total BASRI (p<0.01). The anthropometric measurement with the lowest correlation value was lateral lumbar flexion. Significant association was found between the Schober modified test and BASFI, BASDAI and BASRI (R(2) = 0.37; p<0.001); chest expansion and BASFI, BASDAI and BASRI (R(2) = 0.25; p<0.001); wall-occiput distance and BASFI, BASRI and ASQoL (R(2) = 0.44; p<0.001); fingertip-to-floor distance and BASFI and BASRI (R(2) = 0.30; p<0.001); and lateral cervical rotation and BASFI and BASRI (R(2) = 0.34; p<0.001)., Conclusion: In our study, wall-occiput distance and lateral cervical rotation showed the strongest correlation to BASRI. Similarly, fingertip-to-floor distance and lateral cervical rotation exhibited the closest correlation to BASFI.

Objective: To determine the clinical usefulness of spinal mobility measurements used for ankylosing spondylitis (AS) to assess spinal involvement in patients with psoriatic arthritis (PsA)., Methods: We assessed 100 patients with PsA and 103 patients with AS. Patients were classified as having axial PsA if they had grade 2 or higher unilateral sacroiliitis in the presence of spinal symptoms. All PsA patients, without taking the degree of joint involvement into consideration, were evaluated using several measurements for AS. Spinal measurements were compared with axial and peripheral forms of PsA, and the ability of the techniques to discriminate between the 2 forms of PsA was analyzed using the Mann-Whitney U test and the area under the receiver operating characteristic (ROC) curve. A logistic regression model was used to determine the best measurements for evaluating axial PsA. Finally, the results of measurements for axial PsA were compared with those for AS., Results: Of the 100 PsA patients, 46 met the classification criteria for axial PsA, which presented more severe spinal measurement assessments compared with peripheral PsA. Modified Schober test, lumbar side flexion, chest expansion, and cervical rotation measurements performed best under the ROC curve. Modified Schober test, lumbar side flexion, and cervical rotation were the more suitable measurements for assessing axial PsA. There were only minor differences between axial PsA and AS., Conclusion: The spinal measurements used to evaluate AS performed well to assess spinal involvement in PsA. These measurements, notably the modified Schober test, lumbar side flexion, and cervical rotation, should be used in daily clinical practice to assess PsA patients with spinal involvement.

Objective: The national registry of spondyloarthropathies (REGISPONSER) is launched to classify patients with this group of diseases treated in Spanish rheumatology clinics. This manuscript describes the methodological and organizational background as well as characteristics of patients finally included, and provides a comparative analysis between characteristics of both ankylosing spondylitis and undifferentiated spondyloarthropathy groups of patients., Patients and Methods: Twelve members of the GRESSER group have participated in the registry, for a one-year recruitment period. All consecutively registered adult patients treated in their clinics met the classification criteria of the European Spondyloarthropathies Study Group (ESSG). Data collected reflect the socio-demographic characteristics, as well as disease activity and functional status, clinical form at onset, treatment used and quality of life; all measured by standard instruments., Results: Throughout 1 yr, 1385 patients have been included in the registry: 939 males (68%) and 440 females (32%), with an average age of 47 +/- 13 years (mean +/- s.d.), and an average disease duration of 12 +/- 9 years. Diagnoses of the included patients were: AS (n = 842, 61%), PsA (n = 290, 21%), u-SpA (n = 205, 15%), reactive arthritis (n = 16, 1.2%), inflammatory bowel disease arthritis (n = 13, 0.9%) and JCA-spondyloathropathy (n = 13, 0.9%). Regarding clinical form, 54% had axial disease, 20% peripheral disease, 24% mixed disease and 0.6% isolated enthesitic form. Low-back pain was the first symptom reported in 53% of the patients, and most common extra-articular disease manifestations were psoriasis (25%), anterior uveitis (16%) and intestinal inflammatory disease (4%). Some kind of work disability was reported by 353 patients (25.5%)., Conclusions: Such databases are very useful to obtain information about characteristics of SpA patients treated in a certain location or following a specific treatment practice, and provide a tool for assessing the impact of the disease. Data collected in this registry provide an appropriate clinical and demographic profile of patients suffering from SpA in Spain.

Parosteal lipoma is a benign adipose tissue tumor situated directly in the bone cortex. All cases previously reported in the literature were described as solitary lesions. We describe a patient who presented with polyarthritis associated with multiple parosteal lipomatous involvement. A tissue sample from the distal portion of the forearm confirmed the presence of cumulative fat tissue with nodes of esteatonecrosis. To the best of our knowledge this is the first case of multiple parosteal lipoma associated to polyarthritis.

Enthesis is a structure frequently involved in spondyloarthritides. According to a recent hypothesis, it may play a key role in the pathogenesis of these entities. The present review discusses the most important aspects of current knowledge of enthesis, such as its anatomy and the extracellular matrix components present within it. Clinical evaluation and the new imaging techniques (magnetic resonance imaging and ultrasound) that complement its evaluation will be briefly described. Immunohistological studies as well as animal models developed with enthesis molecules underline the importance of enthesis in the pathogenesis of spondyloarthritides. Finally, the latest research assessing the T cell response to enthesis components in patients with ankylosing spondylitis will be reviewed., (Copyright © 2006 Elsevier España S.L. Barcelona. Published by Elsevier Espana. All rights reserved.)

The objective of this study was to evaluate the use of cultured porcine chondrocyte xenotransplantation for the repair of human chondral defects. Two-millimeter-diameter defects were drilled into explants of femoral cartilage from healthy adult donors. No cells were implanted in the chondral defects of the control group, while pig chondrocytes from normal femoral cartilage were deposited into the treated chondral defects. Cartilage explants were cultured for 4, 8, and 12 weeks. Tissue sections were processed for standard histologic staining and immunostaining with monoclonal antibodies against types I and II collagen, chondroitin-4-sulfate, chondroitin-6-sulfate, keratan sulfate, and integrin subunit beta1. The porcine origin of chondrocytes was confirmed using a specific pig monoclonal anti-CD46. Repair was only observed in the cell-treated defects. Mono- or bilayers of cells were detected after 4 culture weeks on the bottom of the defects, while after 8-12 weeks a repair tissue filled near 30-40 percent of the defect. At 8 weeks, the newly synthesized tissue was composed of a fibrous mesh including some cells. However, at 12 weeks it showed a hypercellular hyaline-like region. This hypercellular region showed excellent bonding with the native cartilage, cells were located in numerous lacunae, and a high content of proteoglycans as indicated by an intense toluidine blue stain was observed. The repaired tissue showed positive immunostaining for both type I and II collagen, as well as chondroitin-4-sulfate, chondroitin-6-sulfate, keratan sulfate, and integrin subunit beta1. Positive staining for porcine anti-CD46 was localized exclusively in the neo-synthesized tissue. We conclude that xenotransplantation of pig chondrocytes can repair, in an in vitro model, defects in human articular cartilage.

Objective: To assess the prevalence of HLA-B27 and its subtypes in both the normal population and in patients with Ankylosing Spondylitis (AS) in Galicia, Northwest Spain., Methods: The prevalence of HLA-B27 in the normal population was determined by checking the number of HLA-B27 positive samples in 308 subjects from different areas of Galicia who had donated organs over a period of 4 years. A total of 106 patients with the diagnosis of AS, according to the modified New York clinical criteria for definitive ankylosing spondylitis, were collected from three very representative areas of Galicia. HLA-B27 was determined by PCR using the primers E91s and E136as, while 11 subtypes of HLA-B27 were analyzed using a commercial kit., Results: The prevalence of HLA-B27 in organ donors was 9.34%. HLA-B27 was present in 94.3% of patients with AS. Subtypes B*2701, B*2709 and B*2710 were not found. The subtypes found in the normal population were; B*2705 (79.5%), B*2702 (18%) and B*2708 (2.5%). The subtypes associated with AS were B*2705 (88%) and B*2702 (12%)., Conclusion: The prevalence of HLA-B27 in Galicia was 9.34%, which is higher than previously published in Spain. The frequency of the subtypes associated with AS was similar to that reported for other Spanish regions.

Objectives: The intra-articular injection of hyaluronan (HA) was originally used in the treatment of osteoarthritis (OA) to increase the viscosity of synovial fluid. However, some findings suggest that the activity of HA cannot be solely explained by its biomechanical properties. The aim of this study was to analyze the in vitro biological effects of HA on human OA chondrocytes and the impact of its molecular weight (MW) on those effects., Methods: Cells were isolated from cartilage obtained during joint replacement surgery in OA patients. The chondrocytes were cultured for 24 hours to detect prostaglandin E2 (PGE2) and for 48 hours to measure nitric oxide (NO), after which they were pre-incubated with HA and stimulated with interleukin-1 (IL-1) at 5 ng/ml. Two commercial HA preparations with different MWs were used: Hyalgan (500-730 kDa, HA, Bioibérica S.A.) and Synvisc (hylan of 6,000 kDa, Biomatrix Inc). NO was detected by the Greiss reaction and PGE2 was quantified by a commercial EIA in the supernatant. Apoptosis was induced by an NO donor (sodium nitroprusside, SNP) and the effect of HA on apoptosis was quantified by flow cytometry., Results: Neither HA preparation studied had any effect on the basal production of NO or PGE2. However, the 500-730 kDa HA at 200 microg/ml reduced the synthesis of both IL-1-induced NO and PGE2 by 70% and 45% respectively. Furthermore both HA preparations at 200 microg/ml decreased the apoptosis induced by SNP, 500-730 kDa to 40% and 6,000 kDa to 36%., Conclusion: HA may induce biological effects in addition to acting as a viscoelastic substance. This study suggests that HA preparations are different due to differences in biological activity resulting from MW.

Articular cartilage has only a limited ability to regenerate. The transplantation of autologous chondrocytes is currently used to treat focal defects in human articular cartilage, although use of organs, tissues, or cells from different species is being investigated as an alternative treatment. The object of this study was to use xeno-transplantation of cultured pig chondrocytes for the repair of rabbit chondral defects, and to analyze the significance of tissue rejection in this animal model. Partial chondral defects, including removal of cartilage tissue and a part of the subchondral bone, were created in the lateral femoral condyles of 30 adult New Zealand White rabbits. A periosteal flap was sutured to the native cartilage with the cambium layer facing the defect. As a control, culture medium was injected into the defect void of one group of rabbits while in a treatment group, chondrocytes, isolated from normal femoral pig cartilage, were injected into the defect void. All rabbits were killed by 24 weeks. Macroscopic changes of the cartilage were analyzed using Mankin's score. The distal femoral portion was studied histologically using hematoxylin and eosin, alcian blue, toluidine blue, and Mason's trichrome. Pig cells and pig genetic material were detected in the neo-synthesized tissue by immunohistochemical detection of SLA-II-DQ and polymerase chain reaction analysis of the gene SLA-II-DQB. The synovial membrane was studied histologically by hematoxylin and eosin staining. In the control group, on average, less than 25 percent of the chondral defect was filled. The repair tissue had an irregular surface with few cells similar to chondrocytes or fibroblasts and a minimal formation of extracellular matrix. In the treatment group, the chondral defect was approximately 90 percent filled with good integration between the neo-synthesized cartilage and the native cartilage. The repair tissue had a smooth surface with cells similar to chondrocytes and a hyaline-like extracellular matrix. The neo-synthesized cartilage was morphologically similar to hyaline cartilage. Importantly, there were no signs of graft-vs.-host rejections or infiltration by immune cells. In the neo-synthesized tissue, pig genetic material was detected in 27 +/- 5 percent of all cells. These cells containing pig genetic material were distributed throughout the neo-synthesized cartilage. We conclude that the xeno-transplantation of chondrocytes could be an alternative method for the repair of articular cartilage defects.

Objective: Osteoarthritis (OA) is a degenerative rheumatic disease that is associated with extracellular matrix degradation and chondrocyte apoptosis in the articular cartilage. The role of mitochondria in degenerative diseases is widely recognized. We undertook this study to evaluate mitochondrial function in normal and OA chondrocytes and to examine age-related changes in mitochondria., Methods: Mitochondrial function was evaluated by analyzing respiratory chain enzyme complexes and citrate synthase (CS) activities as well as changes in mitochondrial membrane potential (Delta Psi m). The activities of mitochondrial respiratory chain complexes (complex I: rotenone-sensitive NADH-coenzyme Q(1) reductase; complex II: succinate dehydrogenase; complex III: antimycin-sensitive ubiquinol cytochrome c reductase; and complex IV: cytochrome c oxidase) and CS were measured in human articular chondrocytes isolated from OA and normal cartilage. Delta Psi m was measured by JC-1 using flow cytometry. Statistical analysis was performed using the Mann-Whitney U test and Student's t-test as well as several models of multiple linear regression., Results: OA articular chondrocytes had reduced activities of complexes II and III compared with cells from normal cartilage. However, the mitochondrial mass was increased in OA. Cultures of OA chondrocytes contained a higher proportion of cells with de-energized mitochondria. We found no relationship between mitochondrial function and donor age either in normal or in OA chondrocytes., Conclusion: These findings suggest the involvement of mitochondrial function in the pathophysiology of OA. Cartilage degradation by OA and cartilage aging may be two different processes.

Objective: Interleukin 1 receptor antagonist (IL-1Ra) may play an important role in cartilage degradation by inhibiting IL-1 activity and therefore blocking IL-1 stimulation of prostaglandin E2 (PGE2) synthesis. Nitric oxide (NO) formation is increased during inflammation. High concentrations of NO exert negative effects on chondrocyte functions. We investigated the possible effects of 3 different nonsteroidal antiinflammatory drugs (NSAID; aceclofenac, piroxicam, aspirin) on IL-1Ra and NO production in human articular chondrocytes., Methods: Normal and osteoarthritic (OA) cartilage samples were obtained from autopsy and prosthetic joint surgery, respectively. Chondrocytes were isolated and stimulated with 4 different stimuli: IL-1, tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), and insulin-like growth factor (IGF). The 3 NSAID were added simultaneously to each different concentration of stimulus. IL-1Ra was measured in supernatant by ELISA; nitrites were quantified by the Griess reaction; PGE2 level was measured by enzyme immunoassay., Results: OA samples spontaneously produced higher levels of IL-1Ra than normal samples (130+/-2.3 vs 30+/-3.1 pg/mI). IL-1, TNF-alpha, and LPS produced dose dependent increases in synthesis of IL-1Ra. In their presence, IL-1Ra was detected in supernatant at 48 h, but its highest level was measured at 144 h. The most potent stimulus was IL-1, followed by TNF-alpha. Fetal bovine serum and IGF in turn did not modify the basal levels of IL-1Ra. In contrast to piroxicam and aspirin, aceclofenac 10 microg/ml and TNF-alpha 10 ng/ml increased almost 46 times the basal amount of IL-1Ra produced by OA chondrocytes. Additionally, aceclofenac and aspirin inhibited NO synthesis. Finally, the 3 NSAID reduced the levels of PGE2 detected after stimulation with IL-1., Conclusion: Proinflammatory stimuli induce IL-IRa synthesis in human articular chondrocytes. Aceclofenac may modulate PGE2 production by increasing IL-IRa production and decreasing NO synthesis. Some NSAID exert diverse prostaglandin independent effects.

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.

Objective: To assess the frequency and clinical features of an acute febrile toxic reaction (AFTR) in patients with refractory rheumatoid arthritis (RA) receiving combined therapy with methotrexate (MTX) and azathioprine (AZA)., Methods: A cohort of 43 RA patients being treated with MTX/AZA combination therapy were studied. In all of them, RA had been refractory to single-therapy disease-modifying antirheumatic drugs. We analyzed the frequency and clinical features of AFTR, which consisted mainly of the development of fever, leukocytosis, and cutaneous leukocytoclastic vasculitis when AZA was added to the MTX regimen., Results: Four of the 43 patients (9.3%) who had been receiving long-term, well-tolerated treatment with MTX (mean +/- SD 375.5 +/- 159.5 days, range 227-561 days) developed AFTR shortly (mean +/- SD 25.7 +/- 13.6 days, range 17-46 days) after the addition of AZA to the regimen. The AFTR resolved rapidly (3 +/- 1.4 days) after discontinuation of AZA and MTX. In 2 cases, rechallenge with AZA and MTX was linked to a new flare of AFTR., Conclusion: The knowledge of this side effect is particularly important because it mimics a severe infectious complication related to immunosuppressive therapy, and because rechallenge can produce severe toxicity. Most of the new combined therapies for RA do not seem to be more toxic than single-drug treatment. Nevertheless, clinicians should be aware of a possible increase in side effects due to drug interactions or some other unidentified mechanism.

Rats transgenic for the human MHC class I gene HLA-B27 are susceptible to a spontaneous multisystem inflammatory disease that resembles human B27-associated disease. This disease requires a high level of expression of the B27 transgene product in cells of hemopoietic origin and can be adoptively transferred to B27 transgenic or nontransgenic rats by transplantation of bone marrow (BM) or fetal liver (FL) cells. To investigate the role played by T cells and the thymus in the disease process, we produced congenitally athymic rnu/rnu F344 rats carrying the disease-prone B27 transgenic locus of the 33-3 line. Transgenic nude rats were protected from disease manifestations. This protection was abated by reconstitution with T cells from euthymic donors of the 33-3 line, with CD4 T cells being more efficient than CD8 T cells in transferring disease. Lethally irradiated, adult-thymectomized (ATX), nontransgenic recipients reconstituted with intact BM, T cell-depleted BM, FL, or nude BM from syngeneic disease-prone lines all developed disease. Pretreatment of the ATX nontransgenic recipients to deplete T cells enhanced the subsequent transferred disease. The inflammatory disease of B27 transgenic rats is thus T cell-dependent. The relevant T cells do not need to encounter B27 in the thymus, and residual radioresistant and/or extrathymically derived host T cells are sufficient to mediate the adoptively transferred disease. The data are most consistent with a model of B27-mediated disease arising from a failure of tolerance and requiring a population of CD4 T cells.

Background: The aim of the present was to study the clinical features of a wide series of patients with giant cell arteritis (GCA) diagnosed with accurate criteria and to evaluate the sensitivity of the criteria proposed by the ACR for classification of GCA., Methods: A retrospective analysis of 191 patients with GCA, 184 of whom were diagnosed by biopsy and 7 due to their clinical manifestations was carried out., Results: The age was 73 +/- 7 years with the most frequent symptoms being headache (87%), abnormalities in the temporal arteries (75%), general malaise (60%), rheumatic polymyalgia (49%) and mandibular claudication (40%). The frequency of GCA was equal in both genders although the most complex syndrome was observed in women with a greater frequency of polymyalgia (p < 0.005), jaw claudication (p < 0.01) and anemia (p < 0.01). The patients with polymyalgia were characterized by a predominance of the polymyalgic syndrome in the initial phases and a higher frequency of amaurosis. Out of 47 patients with amaurosis, 23 remained with permanent unit or bilateral blindness. Unilateral biopsy of the temporal artery was diagnosed in 91% of the cases (CI 95%; 86 to 95%) increasing to 96.3% (CI 95%; 92 to 98%) on biopsy of both arteries. Ninety-eight percent of the patients (CI 95%; 95 to 99%) had 3 or more GCA criteria for classification as GCA., Conclusions: The clinical manifestations of giant cell arteritis in Spain, with the exception of an equal frequency in both sexes, are similar to that described in other series of patients selected with strict criteria. The present data confirm the sensitivity of the criteria proposed by the ACR for the classification of giant cell arteritis although its application does not avoid the need for temporal artery biopsy for diagnosis. Unilateral biopsy is usually suffice in most of the cases.

A number of inflammatory disease states occur with greatly increased frequency in individuals inheriting the human major histocompatibility complex class I allele HLA-B27. In a minority of cases, namely those with B27-associated reactive arthritis, there is good evidence that the disease state is triggered by infection with an enteric or genitourinary bacterial pathogen. For the majority of B27-associated disease, no definite pathogenetic role for bacteria has been established. However, in these latter cases intestinal inflammation can often be demonstrated, and it sometimes occupies a major part of the clinical picture. Rats transgenic for B27 are known to develop a disorder resembling B27-associated human disease, with prominent intestinal, joint, skin, and male genital inflammatory lesions. We report here that B27 transgenic rats raised in a germfree environment do not develop inflammatory intestinal or peripheral joint disease, whereas the skin and genital inflammatory lesions are unaffected by the germfree state. These findings support the concept that gut and joint inflammation are pathogenetically closely related, and they provide direct evidence that the commensal gut flora play an important role in the pathogenesis of B27-associated gut and joint inflammation.

The association of systemic lupus erythematosus (SLE) and autoimmune thyroiditis has been previously described. We report a woman with negative antinuclear antibodies (ANA) and criteria for the diagnosis of SLE. The patient was also diagnosed with autoimmune thyroiditis. We review the clinical characteristics and the association of both entities. We also remark in this case the association of autoimmune thyroiditis with seronegative SLE.

A patient who consulted because of diarrhea was diagnosed of thyroid medullar carcinoma (TMC) associated to pheochromocytoma. All members of his family were studied for a possible family variety of TMC with a genetic origin. In the 21 family members studied basal and calcium-pentagastrin stimulated calcitonin levels were determined and parathyroid and adrenal gland function were explored to rule out pheochromocytoma. Elevated levels of calcitonin agreed with pathological findings of TMC. Pheochromocytoma carriers had altered catecholamines and an abnormal abdominal CT scan. The clinical, analytical and radiologic findings in the four affected family members are described. The histopathological study revealed a pheochromocytoma in one case and bilateral TMC in two cases. The cytology of aspiration biopsy samples was positive for TMC in three cases. The importance of calcitonin determinations is emphasized as well as the obligatory determination of catecholamines and adrenal CT scan in order to rule out the coexistance of pheochromocytoma. The reasons for not utilizing gammagraphy with meta-iodine benzyl guanidine in these four cases are also explained.