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Cobo-Ibanez T.,Hospital Universitario Infanta Sofia | Loza-Santamaria E.,Institute for Musculoskeletal Health | Pego-Reigosa J.M.,Institute Investigacion Biomedica Of Vigo Ibiv | Marques A.O.,Hospital Universitario Germans Trias i Pujol | And 5 more authors.
Seminars in Arthritis and Rheumatism | Year: 2015

Objective: To analyse the efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus (SLE). Methods: We systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials up to June 2013. The following were the selection criteria: (1) adult patients with SLE, (2) rituximab treatment, (3) placebo or active comparator, (4) outcome measures assessing efficacy and/or (5) safety. Meta-analysis, systematic literature reviews, randomised control trials (RCT), open clinical trials and cohort studies were included.Independent extraction of articles by 2 authors using predefined data fields was performed. The quality of each study was graded using the Oxford Levels of Evidence and Jadad's scale. Results: A total of 26 articles met our inclusion criteria: one RCT and its exploratory analysis, 2 open studies and 22 cohort studies, which analysed 1,231 patients. Overall, patients had active disease refractory to steroids and/or immunosuppressant drugs. Acceptable evidence suggested improvements in disease activity, arthritis, thrombocytopaenia, complement and anti-dsDNA, with a steroid-sparing effect. But relapses of disease were demonstrated too. Weak evidence suggested a response in anaemia, cutaneous and neuropsychiatric manifestations. Available evidence revealed few major adverse events. Studies had medium methodological quality and in general were applicable to current practice. Conclusion: Rituximab has been shown to be safe and effective in the treatment of non-renal SLE, especially in terms of disease activity, immunologic parameters and steroid-sparing effect. However, it can only be recommended for organ-specific manifestations such as arthritis and thrombocytopaenia. High-quality studies are needed in order to consider the long-term effects of re-treatment on different organ-specific manifestations. © 2014 Elsevier Inc.


Amengual O.,Hokkaido University | Fujita D.,Osaka Medical College | Carmona L.,Institute for Musculoskeletal Health | Oku K.,Hokkaido University | And 2 more authors.
Lupus | Year: 2015

Objective Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. Methods Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I2 statistic. All analyses were conducted using Review Manager 5.3. Results Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. Conclusion This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy. © 2015 Author(s).


PubMed | Nagoya City University, Institute for Musculoskeletal Health, Osaka Medical College and Hokkaido University
Type: Journal Article | Journal: Lupus | Year: 2015

Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death.Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I(2) statistic. All analyses were conducted using Review Manager 5.3.Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers.This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy.


Silva-Fernandez L.,Hospital Universitario Of Guadalajara | Loza E.,Institute for Musculoskeletal Health | Martinez-Taboada V.M.,University of Cantabria | Blanco R.,University of Cantabria | And 3 more authors.
Seminars in Arthritis and Rheumatism | Year: 2014

Objective: Relapses and failure are frequent in systemic vasculitis (SV) patients. Biological agents have been prescribed as rescue therapies. The aim of this systematic review is to analyze the current evidence on the therapeutic use of biological agents for SV. Methods: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched up to the end of April 2013. Systematic reviews and meta-analysis, clinical trials, cohort studies, and case series with >3 patients were included. Independent article review and study quality assessment was done by 2 investigators with consensus resolution of discrepancies. Results: Of 3447 citations, abstracts, and hand-searched studies screened, 90 were included. Most of the studies included ANCA-associated vasculitis (AAV) patients and only a few included large vessel vasculitis (LVV) patients. Rituximab was the most used agent, having demonstrated efficacy for remission induction in patients with AAV. A number of studies used different anti-TNFα agents with contrasting results. A few uncontrolled studies on the use of abatacept, alemtuzumab, mepolizumab, and tocilizumab were found. Conclusion: Current evidence on the use of biological therapies for SV is mainly based on uncontrolled, observational data. Rituximab is not inferior to cyclophosphamide for remission induction in AAV and might be superior in relapsing disease. Infliximab and adalimumab are effective as steroid-sparing agents. Etanercept is not effective to maintain remission in patients with granulomatosis with polyangiitis, and serious adverse events have been reported. For LVV, both infliximab and etanercept had a role as steroid-sparing agents, and tocilizumab might be effective also for remission induction in LVV. © 2014 Elsevier Inc.


Fernandez-Espartero C.,Hospital Universitario Of Mostoles | De Miguel E.,Hospital Universitario La Paz | Loza E.,Institute for Musculoskeletal Health | Tomero E.,Hospital Universitario Of La Princesa | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives To evaluate the validity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) in early spondyloarthritis (SpA) in comparison with conventional clinical measures of disease activity. Methods Six hundred and seventy-six incident cases of early SpA from the Esperanza programme were included. Patients were categorised into high and low disease activity states based on patient and physician global assessment scores and on the physician's decision to start treatment with a disease-modifying antirheumatic drug or tumour necrosis factor blocker. The discriminant ability of ASDAS-C-reactive protein (CRP) and ASDASerythrocyte sedimentation rate (ESR) was tested using standardised mean differences between patients with high and low disease activity. Convergent validity was tested by Pearson correlation between ASDAS versions and other measures of disease activity. Results ASDAS-ESR and ASDAS-CRP showed good correlation with BASDAI (r=0.79 and 0.74, respectively). Both indices correlated well with the patient global assessment (r=0.70 in both indices) and moderately with the physician global score (r=0.46 and 0.47, respectively). CRP and ESR showed poor correlation with patient- And physician-derived measures. ASDAS performed similarly across the global SpA sample, ankylosing spondylitis (AS), non-radiographic axial SpA and peripheral SpA. Conclusions ASDAS performed as a valid activity score even being slightly better than the Bath Ankylosing Spondylitis Disease Activity Index in its ability to discriminate between high and low disease activity in early SpA. ASDAS performed similarly in AS, early forms of SpA, non-radiographic axial SpA and peripheral SpA.


Cobo-Ibanez T.,Hospital Universitario Infanta Sofia | Descalzo M.A.,Research Unit | Loza-Santamaria E.,Institute for Musculoskeletal Health | Carmona L.,Institute for Musculoskeletal Health | And 2 more authors.
Rheumatology International | Year: 2014

Data on infections in patients exposed to biologic therapies are mainly focused on rheumatoid arthritis (RA). Little is known about the safety profile in other immune-mediated connective tissue diseases (ICTD). The purpose of this study was to describe and to compare the risk of serious infections (SI) in patients with RA and other ICTD on anti-TNF or rituximab and to identify predictors of SI. We analyzed RA or other ICTD patients on anti-TNF or rituximab included in the Spanish registry BIOBADASER 2.0 (2000-2011). For each disease group, incidence rate (IR), mortality rate (MR) and IR ratio (IRR) of SI with 95 % CI were estimated. Risks were then standardized by age and sex to the general population. Risk factors for SI were assessed by Poisson regression models. A total of 3,301 patients on anti-TNF (n = 3,166) or rituximab (n = 135), of which 176 (5 %) had ICTD other than RA, were analyzed. IR of SI was higher in non-RA ICTD than in RA, with an IRR of 3.15 (95 % CI 1.86, 5.31) before adjustment and 1.96 (95 % CI 1.06, 3.65) after adjustment for age, comorbidity and corticoid use. Mortality due to infections was higher in ICTD although it did not reach statistical significance. Age, disease duration, comorbidities, corticosteroids and ICTD different to RA were all independently associated with SI. Patients with ICTD other than RA are at a high risk of SI when prescribed anti-TNF or rituximab, partly due to the excess comorbidity and immunosuppressive co-treatment, but also to the inflammatory disease. When evaluating the risk/benefit ratio of off-label medications in ICTD patients, age, comorbidities and corticoid use should carefully be taken into account, applying adequate preventive measures. © 2014 Springer-Verlag.


Nishishinya M.B.,Instituto Traumatologico Quiron | Pereda C.A.,Clinica Mediterraneo | Munoz-Fernandez S.,Hospital Universitario Infanta Sofia | Pego-Reigosa J.M.,Complejo Hospitalario Universitario Of Vigo | And 6 more authors.
Rheumatology International | Year: 2015

To identify risk and predictors of lymphoma or lymphoproliferative disease in patients with primary Sjögren syndrome. Articles were identified through a comprehensive search strategy in Medline, Embase and Cochrane CENTRAL. Studies had to investigate primary Sjögren syndrome patients, 18 years of age or older, with the goal of examining potential clinical, immunological and hematological risk factors for lymphoma or lymphoproliferative disease. The quality of the studies was graded using the Oxford Levels of Evidence Scale. Whenever possible, the authors created evidence tables and performed meta-analysis. Of 900 studies identified, 18 were selected for inclusion. These studies provided data from over 15,000 patients (90 % female) for analysis. Lymphadenopathy, parotid enlargement, palpable purpura, low C4 serum levels and cryoglobulins were the most consistent non-Hodgkin´s lymphoma/lymphoproliferative disease predictors. Additionally, some of the studies identified splenomegaly, low C3 serum levels, lymphopenia and neutropenia as significant prognostic factors. The detection of germinal center-like lesions in primary Sjögren Syndrome diagnostic salivary biopsies was also proposed as highly predictive of non-Hodgkin´s lymphoma. In contrast, anemia, anti-Ro, anti-La, antinuclear antibodies, rheumatoid factor, male gender and hypergammaglobulinemia were not associated with lymphoma or lymphoproliferative disease. Patients with primary Sjögren syndrome have an increased risk of lymphoma or lymphoproliferative disease compared to the general population. Ascertaining relevant and reliable predictors in this patient population would greatly facilitate the identification of patients at elevated risk for closer monitoring in the context of limited resources. © Springer-Verlag Berlin Heidelberg 2014.


Pego-Reigosa J.M.,University of Vigo | Cobo-Ibanez T.,Sofia University | Calvo-Alen J.,Sierrallana Hospi Tal | Loza-Santamaria E.,Institute for Musculoskeletal Health | And 3 more authors.
Arthritis Care and Research | Year: 2013

Objective To analyze the efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus (SLE). Methods We conducted a sensitive literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials up to October 2011. The selection criteria were studies including adult patients with SLE, a treatment intervention with nonbiologic immunosuppressants, a placebo or active comparator group, and outcome measures assessing efficacy and/or safety. Meta-analyses, systematic reviews, clinical trials, and cohort studies were included. The quality of each study was evaluated using Jadad's scale and the Oxford Levels of Evidence. Results In total, 158 of the 2,827 initially found articles were selected for detailed review; 65 studies fulfilled the predetermined criteria. Overall, the studies were low quality, with only 11 randomized controlled trials (RCTs). Cyclophosphamide demonstrated efficacy for neuropsychiatric SLE, preventing relapses with an additional steroid-sparing effect, although its use was associated with cumulative damage, development of cervical intraepithelial neoplasia, and ovarian failure. Other immunosuppressants (azathioprine, methotrexate, leflunomide, mycophenolate mofetil, and cyclosporin A) demonstrated efficacy in reducing nonrenal activity and flares with a steroid-sparing effect, although only on occasion in non-placebo-controlled RCTs of small numbers of patients. Conclusion Several immunosuppressants demonstrated their safety and efficacy in nonrenal SLE. A specific drug for each particular manifestation cannot be recommended, although cyclophosphamide may be used in more severe cases, and methotrexate may be the first option in most cases of moderately active SLE. High-quality RCTs of larger numbers of patients are needed. Copyright © 2013 by the American College of Rheumatology.


Castrejon I.,Rush University Medical Center | Toledano E.,Hospital Clinico San Carlos | Rosario M.P.,Research Unit | Loza E.,Institute for Musculoskeletal Health | And 2 more authors.
Rheumatology International | Year: 2015

Allopurinol is the most widely used urate-lowering drug (ULD). Together with efficacy and cost, safety is an aspect that helps taking clinical decisions. This systematic review analyzes allopurinol safety. The literature search was performed in MEDLINE, EMBASE, and the Cochrane Library (January 2014). Selection criteria: (a) patients >18, (b) gout by the ACR criteria or evidence of urate crystal in synovial fluid, (c) comparator (placebo or other ULD), and (d) RCTs, cohorts, or meta-analysis. Primary outcomes: rate of adverse events and death. The quality was assessed with the Jadad’s scale. A meta-analysis with fixed effects was performed. From 544 studies, seven met the eligibility criteria and were included. All RCT presented a low power for safety. All RCTs included a mixed population of patients with gout and hyperuricemia. Allopurinol (300 mg) was compared to febuxostat (40–240 mg) in five RCTs, to benzbromarone and probenecid in two RCTs, and to placebo in one. In the RCTs comparing allopurinol with benzbromarone and probenecid, the highest discontinuation rate was with probenecid (26 %), followed by allopurinol (11 %) and benzbromarone (4 %). The incidence of adverse events was similar between allopurinol (range 38.6–85) and febuxostat (range 41.8–80). Six patients on febuxostat and three on allopurinol died during the studies; no deaths were judged related to drug. The combined risk of adverse events was RR = 1.04 (95 % CI 0.98, 1.11). Allopurinol is a safe option, slightly better than other ULDs. The grade of evidence is high, but further research is needed to evaluate higher doses and long-term safety. © 2014, Springer-Verlag Berlin Heidelberg.


PubMed | Institute for Musculoskeletal Health
Type: Journal Article | Journal: Clinical and experimental rheumatology | Year: 2013

To test the reliability of the Berlin MRI scoring method and the effect of a calibration exercise on the scores reliability among untrained readers in MRI examinations of patients with established ankylosing spondylitis (AS).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.The mean Berlin score increased from (mean standard deviation) 5.04 6.41 before to 6.407.08 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.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.

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