The Phenotype of Axial Spondyloarthritis: Is It Dependent on HLA-B27 Status?

OBJECTIVE: To describe the radiographic phenotype of axial spondyloarthritis (SpA) according to the presence of HLA-B27. METHODS: An international collaboration compared the radiographic phenotype of axial SpA according to HLA-B27 status. Patients with ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA) were collected. Radiographs were read centrally, blinded to clinical details. The symmetry of the sacroiliac joints and lumbar syndesmophytes and the morphology of syndesmophytes (typical marginal versus atypical chunky), together with the modified Stoke Ankylosing Spondylitis Spine Score and the Psoriatic Arthritis Spondylitis Radiographic Index, were recorded. RESULTS: A total of 244 patients with PsA and 198 patients with AS were included. In PsA, 60 patients (25%) were HLA-B27 positive while in AS, 148 patients (75%) were HLA-B27 positive. Patients with HLA-B27 were younger and more often male and had a longer duration of disease. In multivariable logistic regression, HLA-B27 was significantly associated with syndesmophyte symmetry (odds ratio [OR] 3.02 [95% confidence interval (95% CI) 1.38, 6.61]) and marginal syndesmophytes (OR 1.97 [95% CI 1.16, 3.36]) but not with sacroiliac symmetry. Mean radiographic scores were higher for patients with HLA-B27. CONCLUSION: Patients with axial SpA who are positive for HLA-B27 have more severe radiographic damage, more marginal syndesmophytes, and more frequent syndesmophyte symmetry compared to patients who are negative for HLA-B27.

PDE3A-SLCO1C1 locus is associated with response to anti-tumor necrosis factor therapy in psoriatic arthritis.

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.

Individual telomere length decay in patients with spondyloarthritis.

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.

Standards of care for patients with spondyloarthritis.

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.

Scoring with the Berlin MRI method for assessment of spinal inflammatory activity in patients with ankylosing spondylitis: a calibration exercise among rheumatologists.

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.

Comparison of 2 referral strategies for the diagnosis of axial spondyloarthritis in Spain. The RADAR study.

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.

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Risk variants for psoriasis vulgaris in a large case-control collection and association with clinical subphenotypes.

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.

FCGR2A/CD32A and FCGR3A/CD16A variants and EULAR response to tumor necrosis factor-α blockers in psoriatic arthritis: a longitudinal study with 6 months of followup.

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.

Clinical features of late-onset ankylosing spondylitis: comparison with early-onset disease.

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.

[Prognostic factors in psoriatic arthritis]. / Factores pronóstico en la artritis psoriásica.

Peripheral psoriatic arthritis is an inflammatory and progressive disease; its burden, either at the structural level or the function and quality of life, is similar to other chronic poliarthritidies. In spite of treatment with synthetic or biologic DMARDs, remission is only achieved in about 30% of the patients. From a clinical point of view, persistent joint activity (tender and swollen joints) is a factor leading to joint damage progression. These data indicate the need for a tight follow up and treatment of the patients.

[Consensus statement of the Spanish Society of Rheumatology on risk management of biologic therapy in rheumatic patients]. / Consenso SER sobre la gestión de riesgo del tratamiento con terapias biológicas en pacientes con enfermedades reumáticas.

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.

[Consensus statement of the Spanish Society of Rheumatology on the management of biologic therapies in psoriatic arthritis]. / Documento SER de consenso sobre el uso de terapias biológicas en la artritis psoriásica.

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.

Prevalence of vertebral fractures by semiautomated morphometry in patients with ankylosing spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory disease mainly affecting the axial skeleton and characterized by ossification of the spinal disc, joints, and ligaments leading to progressive ankylosis. Vertebral osteoporosis is a recognized feature of AS. Studies have confirmed a moderate to high prevalence of vertebral fractures with extremely varying ranges in patients with AS. Our objective was to estimate the prevalence of vertebral fractures in a representative Spanish population of patients with AS using a validated semiquantitative method, MorphoXpress(®). METHODS: Patients were randomly selected from the 10 initial participating centers of the Spanish National Registry of Spondyloarthropathies (REGISPONSER) by consecutive sampling. All patients fulfilled the New York modified criteria for AS and had a baseline thoracolumbar radiograph. A prevalent vertebral fracture was defined according to the Genant classification criteria. RESULTS: The estimated prevalence of vertebral fractures was 32.4% (95% CI 25.5%-39.3%). The majority of fractures were localized in the thoracic segment (n = 100; 82.%) and were mild (n = 79; 64.8%). In logistic regression analysis, age (odds ratio per year 1.05, 95% CI 1.03-1.08, p < 0.001), disease duration (OR per year 1.03, 95% CI 1.01-1.06, p = 0.011), Bath Ankylosing Spondylitis Functional Index score (OR per score 1.16, 95% CI 1.03-1.30, p = 0.015), Bath Ankylosing Spondylitis Radiographic Index-TS (OR per score 1.25, 95% CI 1.12-1.39, p < 0.001), and wall-occiput distance (OR per cm 1.15, 95% CI 1.08-1.23, p < 0.001) were all associated with prevalent fracture. CONCLUSION: Semiquantitative methods are needed to improve the diagnosis of vertebral fractures in AS in order to start early treatment and to avoid complications arising from osteoporosis.

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.

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

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.

[Axial psoriatic arthritis]. / Artritis psoriásica axial.

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.

Differing patterns of peripheral blood leukocyte telomere length in rheumatologic diseases.

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.