Raimon Sanmartí

The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population.

Objective: Methotrexate (MTX) is the first-choice drug for the treatment of rheumatoid arthritis (RA) patients. However, 30% of RA patients discontinue therapy within 1 year, usually because of adverse effects. Previous studies have reported conflicting results on the association of polymorphisms in the MTHFR gene with the toxicity of MTX in RA. The aim of this study was to assess the involvement of the C677T and A1298C polymorphisms in the MTHFR gene in the toxicity of MTX in a Spanish RA population. Methods: The study included retrospectively 468 Spanish RA patients treated with MTX. Single nucleotide polymorphism (SNP) genotyping was performed using the oligonucleotide microarray technique. Allele and genotype association analyses with regard to MTX toxicity and a haplotype association test were also performed. Results: Eighty-four out of the 468 patients (18%) had to discontinue therapy due to adverse effects or MTX toxicity. The C677T polymorphism (rs1801133) was associated with increased MTX toxicity [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.01–1.98, p = 0.0428], and the strongest association was shown in the recessive model (OR 1.95, 95% CI 1.08–3.53, p = 0.0246). The A1298C polymorphism (rs1801131) was not associated with increased MTX toxicity (OR 0.94, 95% CI 0.65–1.38, p = 0.761). A borderline significant risk haplotype was found: 677T-1298A (OR 1.40, 95% CI 1.00–1.96, p = 0.0518). Conclusion: These results demonstrate that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in a Spanish RA population.

Actualización del Consenso de la Sociedad Española de Reumatología sobre el uso de antagonistas del TNFα en las espondiloartritis, incluida la artritis psoriásica

.Hay poca evidencia cientifica de que los denominadosfarmacos modificadores de enfermedad (FAME),como el metotrexato, la sulfasalazina, la leflunomida,las sales de oro, los antimalaricos, etc., sean eficaces enla EA. La sulfasalazina se ha demostrado efectiva enestudios controlados, aunque de forma modesta, en lasmanifestaciones perifericas de la EA

Prediction of functional impairment and remission in rheumatoid arthritis patients by biochemical variables and genetic polymorphisms

OBJECTIVEnTo develop a model to predict RA outcome based on biochemical variables and single nucleotide polymorphisms (SNPs).nnnMETHODSnWe collected baseline data from RA patients. SNP genotyping was performed using an oligonucleotide microarray. Remission and severe disability were investigated as outcomes of the study. Logistic regression models and receiver operating characteristic (ROC) curves were used to determine sensitivity (S), specificity (Sp) and likelihood ratio (LR).nnnRESULTSnSix hundred and thirty-two patients (375 in the study and 257 in the validation) were included. Twenty-two out of 152, and 19 out of 208 patients had an HAQ > 2. The model obtained to predict disability included levels of the anti-cyclic citrullinated peptide (anti-CCP) antibodies, ESR and SNP rs2070874 in the IL-4 gene. Homozygous and heterozygous carriers of the IL-4 33T allele had a decreased risk of severe disability. The discriminative power had an area under the curve (AUC) of 0.792 (95% CI 0.694, 0.889), with S 41%, Sp 95% and LR +7.6. Twenty-one out of 268 and 17 out of 211 patients were in remission in the study and validation cohorts, respectively. The model included absence of anti-CCP antibodies and the SNP rs2476601 on the PTPN22 gene. Homozygous and heterozygous carriers of the PTPN22 1858T allele had a decreased probability of remission. The discriminative power had an AUC of 0.842 (95% CI 0.756, 0.928), with S 76%, Sp 86% and LR + 5.4. Predictive ability was confirmed on the validation cohort.nnnCONCLUSIONSnWe have developed two models based on laboratory variables that are associated with relevant outcomes for RA patients at disease onset.

Prevalence of Comorbidities in Rheumatoid Arthritis and Evaluation of Their Monitoring in Clinical Practice: The Spanish Cohort of the COMORA Study

OBJECTIVESnTo describe the prevalence of comorbidities in patients with RA in Spain and discuss their management and implications using data from the Spanish cohort of the multinational study on COMOrbidities in Rheumatoid Arthritis (COMORA).nnnMETHODSnThis is a national sub-analysis of the COMORA study. We studied the demographics and disease characteristics of 200 adults patients diagnosed with RA (1987 ACR), and routine practices for screening and preventing the following selected comorbidities: cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and depression.nnnRESULTSnPatients had a mean age of 58 years and a mean RA duration of 10 years. Mean DAS28 score was 3.3 and approximately 25% of patients were in remission (DAS28 <2.6). Forty-four (22%) patients had ≥1 comorbidity, the most frequent being depression (27%) and obesity (26%). A history of myocardial infarction or stroke was observed in 5% and 1% of patients, respectively, and any solid tumor in 6%. Having a Framingham Risk Score >20% (51%), hypercholesterolemia (46%) or hypertension (41%) and smoking (25%) were the most common CV risk factors. For prostate, colon and skin cancers, only 9%, 10% and 18% of patients, respectively, were optimally monitored. Infections were also inadequately managed, with 7% and 17% of patients vaccinated against influenza and pneumococcal, respectively, as was osteoporosis, with 47% of patients supplemented with vitamin D and 56% with a bone densitometry performed.nnnCONCLUSIONSnIn Spain, the prevalence of comorbidities and CV risk factors in RA patients with established and advanced disease is relatively high, and their management in clinical daily practice remains suboptimal.

Recomendaciones sobre el uso de metrotexato parenteral en enfermedades reumáticas

OBJECTIVEnTo develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience.nnnMETHODSnA 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).nnnRESULTSnMost 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.nnnCONCLUSIONSnThe manuscript aims to solve frequent questions and help in decision-making strategies when treating patients with parenteral MTX.

Indicador compuesto para evaluar la calidad asistencial en el manejo de los pacientes con artritis reumatoide en las consultas externas de Reumatología

OBJECTIVEnThe current guidelines in the treatment of rheumatoid arthritis (RA) include the early diagnosis and early use of disease modifying drugs to achieve remission or low disease activity level, known as Treat to Target (T2T). The objective of this study is to develop a composite indicator (CI) to evaluate the quality of care in the management of patients with RA, according to the T2T strategy and other general recommendations concerning the management of these patients.nnnMATERIAL AND METHODnThe phases of the construction of the CI were: 1) selection of quality criteria through expert judgment; 2) prioritization of the criteria, according to relevance and feasibility, applying the Delphi methodology (two rounds) involving 20 experts; 3) design of quality indicators; and 4) calculation of the weighted CI, using the mean value in relevance and feasibility granted by the experts. The source of information for the calculation of the CI are the medical records of patients with RA.nnnRESULTSnTwelve criteria out of 37 required a second Delphi round. Thirty-one criteria were prioritized. These criteria presented a median in relevance and feasibility greater than or equal to 7.5, with an interquartile range of less than 3.5, and a level of agreement (score greater than or equal to 8) greater than or equal to 80%.nnnCONCLUSIONSnThe constructed CI allows us to evaluate the quality of care of patients with RA following the T2T strategy in the rheumatology units of Spanish hospitals, offering a valid and easily interpretable summary measure.

Recomendaciones de experto sobre el bloqueo de la interleucina 6 en pacientes con artritis reumatoide

OBJECTIVEnTo draft recommendations on interleukin 6 (IL-6) blockade in rheumatoid arthritis (RA), based on best evidence and experience.nnnMETHODSnA group of 10 experts on IL-6 blockade in RA was selected. The 2 coordinators formulated 23 questions about IL-6 blockade (indications, efficacy, safety, etc.). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (Medline, EMBASE and the Cochrane Library were searched). Two different reviewers selected the articles. Evidence tables were created. At the same time, European League Against Rheumatism and American College of Rheumatology abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted on in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Centre 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).nnnRESULTSnThe 8 preliminary recommendations were accepted after the Delphi process. They covered aspects such as the use of these therapies in monotherapy, in combination, in patients with refractory disease or intolerant patients, response evaluation, optimization and risk management.nnnCONCLUSIONSnThe manuscript aims to solve frequently asked questions and aid in decision making strategies when treating RA patients with IL-6 blockade.

Eficacia y seguridad de la terapia combinada con fármacos modificadores de la enfermedad sintéticos en la artritis reumatoide: revisión sistemática de la literatura

OBJECTIVEn1) To systematically and critically review the evidence of combined therapy with synthetic disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA); 2) To design practical recommendations on their use.nnnMETHODSnA systematic literature review (SLR) was performed with a sensitive bibliographic search strategy in Medline, EMBASE and Cochrane Library. We selected randomized clinical trials that analyzed the efficacy and/or safety of 1) combined therapy of synthetic compared with sequential therapy of synthetic DMARD in early RA; and 2) combination of methotrexate+leflunomide or triple therapy with synthetic DMARD in established RA refractory to synthetic DMARD. Two reviewers made the first selection by title and abstract and 11 performed the selection after detailed review of the articles and data collection. The quality of the studies was evaluated with the Jadad scale. Based on the results, related recommendations were agreed upon in a nominal group meeting.nnnRESULTSnUltimately, no articles were included in the SLR. The analysis of the reviewed articles demonstrated the effectiveness of the treatment with synthetic DMARD following a treat to target strategy in early RA patients, and of combination therapy of synthetic DMARD in established RA refractory to synthetic DMARD. This resulted in 6 recommendations concerning combination therapy with synthetic DMARD.nnnCONCLUSIONSnThese recommendations aim to facilitate decision-making with the use of combined therapy with DMARD in RA.

Clinical, Patient-Reported, and Ultrasound Outcomes from an Open-Label, 12-week Observational Study of Certolizumab Pegol in Spanish Patients with Rheumatoid Arthritis with or without Prior Anti-TNF Exposure

OBJECTIVESnTo assess the effectiveness and safety of certolizumab pegol (CZP) in Spanish patients with RA.nnnMATERIALS AND METHODSnSONAR (NCT01526434), a 12-week, open-label, prospective, observational, multicenter study. Patients with active RA for ≥3 months, according to ACR criteria, were treated with CZP (400mg at Weeks 0, 2 and 4, then 200mg every 2 weeks). The primary effectiveness endpoint was change from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12. Other assessments included DAS28(ESR), patients assessment of arthritis pain (PtAAP-VAS) and Short Form 36-item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS). Joint inflammation was investigated using Power Doppler (PD) ultrasound (US), to detect effusion, synovial hypertrophy and synovial PD signal. PDUS outcomes assessed CFB to Week 12 in synovial hypertrophy, effusion and PD signal indices.nnnRESULTSnA total of 77/80 enrolled patients received ≥1 dose of CZP. The 12-week mean reduction from baseline (SD) was -0.6 (0.6) for HAQ-DI and -2.2 (1.5) for DAS28(ESR). PtAAP-VAS was reduced from baseline (mean [SD]: -36.8 [26.8]) and improvements in SF-36 PCS and SF-36 MCS were reported. Synovial hypertrophy, effusion and PD signal indices were reduced from baseline to Week 12. One death was reported during the study.nnnCONCLUSIONSnSpanish patients with RA demonstrated improvements in clinical, PDUS and patient-reported outcomes over 12 weeks of CZP treatment. No new safety signals were identified, and the safety profile was in line with previous CZP studies. These results support previous clinical trial findings investigating CZP treatment for active RA.

Eficacia y seguridad de los glucocorticoides en la artritis reumatoide: revisión sistemática de la literatura

OBJECTIVESn1) To systematically and critically review the evidence on the characteristics, efficacy and safety of glucocorticoids (CS) in rheumatoid arthritis (RA); 2) to generate practical recommendations.nnnMETHODSnA systematic literature review was performed through a sensitive bibliographic search strategy in Medline, Embase and the Cochrane Library. We selected randomized clinical trials that analyzed the efficacy and/or safety of CS in patients with RA. Two reviewers performed the first selection by title and abstract. Then 10 reviewers selected the studies after a detailed review of the articles and data collection. The quality of the studies was evaluated with the Jadad scale. In a nominal group meeting, based on the results of the systematic literature review, related recommendations were reached by consensus.nnnRESULTSnA total of 47 articles were finally included. CS in combination with disease-modifying antirheumatic drugs help control disease activity and inhibit radiographic progression, especially in the short-to-medium term and in early RA. CS can also improve function and relieve pain. Different types and routes of administration are effective, but there is no standardized scheme (initial dose, tapering and duration of treatment) that is superior to others. Adverse events when using CS are very frequent and are dose-dependent and variable severity, although most are mild. Seven recommendations were generated on the use and risk management of CS.nnnCONCLUSIONSnThese recommendations aim to resolve some common clinical questions and aid in decision-making for CS use in RA.