Javier Ballina

GWAS replication study confirms the association of PDE3A–SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis

AIM The present study was undertaken to replicate the association of candidate genes for anti-TNF response in rheumatoid arthritis. Candidate genes were selected from a recent genome-wide association study on anti-TNF response performed in a population from Denmark. MATERIALS & METHODS Genomic DNA was obtained from 315 Spanish rheumatoid arthritis patients having received an anti-TNF agent as their first biological therapy. SNPs from NR2FR2, MAP2K6, CBLN2 and PDE3A-SLCO1C1 candidate loci were genotyped. RESULTS The PDE3A-SLCO1C1 locus rs3794271 SNP showed a highly significant association with anti-TNF treatment response (p = 1.74 × 10⁻⁵). Combining the statistical evidence from the Spanish and Danish rheumatoid arthritis cohorts, the associated rs3794271 SNP reached a genome-wide significance level of association (p = 3.3 × 10⁻¹⁰). CONCLUSION The present findings establish the PDE3A-SLCO1C1 locus as a strong genetic marker of anti-TNF therapy response.

HLA-C locus alleles may modulate the clinical expression of psoriatic arthritis.

The aim of the present study was to evaluate the relative contribution of human leukocyte antigen (HLA)-C locus alleles in determining the risk and the clinical expression of psoriatic arthritis (PsA). One hundred PsA patients were randomly selected and grouped into three disease subsets: oligoarthritis (n = 40), polyarthritis (n = 25) and spondylitis (n = 35). The HLA-C locus profile of this cohort was studied by methods based on molecular biology and was compared with that of 45 patients with psoriasis vulgaris and 177 healthy blood donors from the same ethnic origin. HLA-Cw*0602 was found associated with both psoriasis (odds ratio (OR) 6.2; 95% confidence interval (CI) 3.1 to 12.5; p < 0.0001) and PsA (OR 6.2; 95% CI 3.6 to 10.8; p < 0.0001); however, this allele was equally found among the PsA subsets. HLA-Cw6-positive patients showed a longer psoriasis-arthritis latency period (p = 0.012). HLA-Cw*0701 was found under-represented in PsA in comparison with controls (OR 0.5; 95% CI 0.3 to 0.9; p = 0.04), as was HLA-Cw*0802 (OR 0.3; 95% CI 0.08 to 1; p = 0.05). A positive association was found between psoriatic spondylitis and HLA-Cw*0702 (OR 5.0; 95% CI 1.4 to 25; p = 0.01). HLA-Cw*0602 seems to confer a general risk for psoriasis, but the presence of other HLA-C locus alleles may explain an additional arthritogenic risk. HLA-C alleles may modulate some aspects of the clinical expression of PsA, but these findings need confirmation.

Clinical expression, but not disease outcome, may vary according to age at disease onset in psoriatic spondylitis.

OBJECTIVES To investigate whether the clinical expression and disease outcome in psoriatic spondylitis (PsS) may vary according to age at disease onset. METHODS This study included 70 patients from a unique outpatient spondylitis clinic followed on a regular basis with a standard protocol. Patients were diagnosed with PsS according to ESSG criteria plus radiographic sacroiliitis (SI). Outcome parameters included: disease activity, functional evaluation, radiological damage, mobility restriction, and enthesitis score. Patients were divided into those with disease onset before 40 years (young-onset PsS) and those with onset over this age (late-onset PsS). Clinical features and outcome parameters were compared between groups. RESULTS There were 44 men and 26 women. Thirty-nine (M:F ratio 1.8) patients had disease onset before 40 years and 31 (M:F ratio 1.6) over this age. HLA-B27 correlated with PsS susceptibility (34% vs 7%, RR 6.4, p<0.0004), but it was found over-represented in young-onset PsS compared to late-onset cases (51% vs 13%, p=0.001). Young-onset cases tended to have a higher frequency of family history (26% vs 13%), bilateral SI (62% vs 29%, p=0.013), isolated axial pattern (31% vs 13%), and enthesitis (54% vs 29%, p=0.09). In late-onset PsS there was a higher frequency of unilateral SI (71% vs 38%, p=0.013), polyarthritis (45% vs 23%, p=0.022), and silent axial disease (32% vs 10%, p=0.022). Outcome parameters were similar between groups. CONCLUSIONS Clinical picture but not outcome parameters, varies according to age at disease onset in PsS. The correlation between HLA-B27 and young-onset PsS supports the notion that disease susceptibility and disease expression are not driven by the same gene in this entity.

Entheseal ultrasound abnormalities in patients with SAPHO syndrome

This study was conducted to investigate the presence and characteristics of the ultrasound lesions that may be found in the entheses of patients with SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome. This cross-sectional study included 15 patients with SAPHO syndrome and 30 healthy controls matched for age, sex and body mass index. Subjects with regular sport activities as well as those with other rheumatic conditions were excluded from the study. Ultrasonography was used in both groups to study 14 entheses of the upper and lower extremities. Different elementary lesions representative of enthesis damage were defined. A total of 210 entheses in the study group and 420 in the control group were evaluated. Only one patient presented clinical enthesitis. In the study group, seven of the 15 patients (47%) showed morpho-structural entheseal alterations, versus only four of the 30 controls (13.3%; p < 0.001). The subjects with SAPHO showed ultrasound alterations in 32/210 entheses (15%), while the controls showed alterations in 20/420 entheses (4.8%), p < 0.001. The entheses with the largest number of morpho-structural alterations were those of the patellar and Achilles tendon. None of the controls showed power Doppler signal at enthesis or perienthesis level. Ultrasound evidence of enthesopathy seems to be a common feature in this series of patients with SAPHO syndrome.

Actualización en la patogenia de la artritis psoriásica

Psoriasis and psoriatic arthritis are autoimmune diseases that share common pathogenic mechanisms. The cause and the pathogenesis of these diseases are unknown; however, there is increasing evidence which suggest that cytotoxic CD8T cells, Th1 and Th17 may be involved in the pathogenesis of these diseases. Cytokines produced as the result of Th1 and Th17 responses, such as TNF-α and IL-17, play a key role in the chronic inflammatory response observed in the joints of psoriatic arthritis patients. It is conceivable that unraveling of the pathogenesis of this disease may lead to the development of new therapeutic approaches and may improve the prognosis of patients.

A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis

Objective To identify genomic variants in the 19q13 chromosome region associated with ankylosing spondylitis (AS) in human leucocyte antigen (HLA)-B27-positive populations. Methods High-throughput genotyping of 1536 haplotype-tag single nucleotide polymorphisms (SNPs) was performed in 249 patients with AS and 302 healthy controls. Some of the identified associations were validated by genotyping four SNPs in two additional cohorts consisting of 412 cases/301 controls and 144 cases/203 controls. All individuals selected (both cases and controls) were HLA-B27-positive. Results Two markers in two different genes (CNOT3 and LAIR2) showed significant association (p<10−3) with AS. In addition, sliding windows analysis showed association of groups of adjacent SNPs in regions located around CNOT3 (Chr19: 59347459-59356564, p=2.43×10−4 to 6.54×10−4). The associations were validated by genotyping four SNPs from regions located near LAIR2 and CNOT3 genes (rs1055234, rs8111398, rs2287828 and rs4591276) in two additional cohorts. The CNOT3 polymorphism (rs1055234) remained associated with AS (combined p=9.73×10−6). One SNP, located downstream of KIR3DL1, was detected which, tested in combination with HLA-Bw4I80, was associated with AS. Conclusion A novel significant association was detected between SNP rs1055234 and AS susceptibility.

HLA-DR17 is associated with enthesitis in psoriatic arthritis

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 6 mai 2011

Comparación de 2 estrategias de derivación en el diagnóstico de la espondiloartritis axial en España. Estudio RADAR

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.

Recomendaciones sobre el uso de metrotexato parenteral en enfermedades reumáticas

OBJECTIVE To develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience. METHODS A group of 21 experts on parenteral MTX use was selected. The coordinator formulated 13 questions about parenteral MTX (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (involving Medline, EMBASE and the Cochrane Library). Three different reviewers selected the articles. Evidence tables were created. Abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) were evaluated. Based on this evidence, the coordinator proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Center for Evidence-Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). RESULTS Most of the evidence involved rheumatoid arthritis. A total of 13 preliminary recommendations on the use of parenteral MTX were proposed; 11 of them were accepted. Two of the 13 were not voted and are commented on in the main text. CONCLUSIONS The manuscript aims to solve frequent questions and help in decision-making strategies when treating patients with parenteral MTX.

Eficacia y seguridad de golimumab añadido a fármacos antirreumáticos modificadores de la enfermedad en artritis reumatoide. Resultados del estudio GO-MORE en España

OBJECTIVES To assess the efficacy and safety of golimumab in the 140 patients included in Spain as the first part of the GO-MORE trial, a multinational study involving patients with active rheumatoid arthritis (RA) despite treatment with different disease-modifying antirheumatic drugs (DMARDs). PATIENTS AND METHODS The patients received subcutaneous golimumab 50mg once a month during 6 months. The primary endpoint was the percentage of individuals with a good or moderate EULAR DAS28-ESR response after 6 months of treatment. RESULTS A total of 140 patients were included. Of these, 76.4% had very active disease (DAS28-ESR>5.1). 76.4% were taking methotrexate, 40.0% other DMARDs in monotherapy or combined, and 65.0% received corticosteroids. After 6 months, 82.9% of the patients showed a good or moderate EULAR response, 41.4% had low disease activity, and 30.7% were in remission. The percentage of responders one month after the first dose was 69.3%. The efficacy was similar in patients treated with methotrexate or other DMARDs, with different methotrexate doses, with or without corticosteroids, or in subjects who had failed one or more DMARDs. The response to golimumab was observed from the first dose. Golimumab was well tolerated and its safety profile was consistent with the findings of previous studies. Serious adverse events were reported in 11 patients (7.9%). CONCLUSION The addition of subcutaneous golimumab 50 mg once a month to different DMARDs in patients with active RA yielded a moderate or good response after 6 months in 82.9% of the cases. The response was observed early, from the start of the second month, after a single dose of golimumab.