José Luis Fernández-Sueiro

The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis

Objectives: Recent results have shown that the IL23R gene, coding for a subunit of the interleukin-23 receptor, is strongly associated with autoimmunity. The aim of the current study was to investigate, for the first time, the possible involvement of the IL23R gene in genetic susceptibility to ankylosing spondylitis (AS). Methods: We carried out a case–control association study in which 365 patients with AS and 500 blood bank donors were included. Eight single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected as genetic markers for our association study and were genotyped using a Taqman 5′ allelic discrimination assay. Results: Interestingly, we observed association of two of eight IL23R genotyped SNPs. The strongest effect was conferred by the non-synonymous rs11209026 (Arg381Gln) SNP (odds ratio 0.46 95% confidence interval 0.2 to 0.7 p = 0.001). Similarly, the IL23R rs1343151 SNP showed association with AS genetic susceptibility (odds ratio 0.68 95% confidence interval 0.55 to 0.83 p = 0.0002). After a conditional case–control test we observed that the effect of these two genetic variants was independent of linkage disequilibrium. Conclusions: These results suggest that the IL23R gene seems to be involved in AS genetic predisposition.

Power Doppler Ultrasonography Assessment of Entheses in Spondyloarthropathies: Response to Therapy of Entheseal Abnormalities

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.

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

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

Patient Global Assessment in Psoriatic Arthritis: A Multicenter GRAPPA and OMERACT Study

Objective. During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0–100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). Methods. In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. Results. Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). Conclusion. PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.

Evaluation of ankylosing spondylitis spinal mobility measurements in the assessment of spinal involvement in psoriatic arthritis

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.

Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features

IntroductionPsoriatic 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.MethodsST 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.ResultsTwenty (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).ConclusionsThese 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.

Work Disability in Patients with Ankylosing Spondylitis

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 R2 = 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.

High-dose etanercept in ankylosing spondylitis: results of a 12-week randomized, double blind, controlled multicentre study (LOADET study)

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.

Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: a study in Spanish and Italian populations and meta-analysis.

OBJECTIVE The LCE3C_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_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_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_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_LCE3B-del tag SNP. CONCLUSION LCE3C_LCE3B-del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders.

Validity of the bath ankylosing spondylitis disease activity index for the evaluation of disease activity in axial psoriatic arthritis

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).