Anaemia may add information to standardised disease activity assessment to predict radiographic damage in rheumatoid arthritis: a prospective cohort study

OBJECTIVE: Anaemia in rheumatoid arthritis (RA) is prototypical of the chronic disease type and is often neglected in clinical practice. We studied anaemia in relation to disease activity, medications and radiographic progression. METHODS: Data were collected between 1996 and 2007 over a mean follow-up of 2.2 years. Anaemia was defined according to WHO (♀ haemoglobin<12 g/dl, ♂: haemoglobin<13 g/dl), or alternative criteria. Anaemia prevalence was studied in relation to disease parameters and pharmacological therapy. Radiographic progression was analysed in 9731 radiograph sets from 2681 patients in crude longitudinal regression models and after adjusting for potential confounding factors, including the clinical disease activity score with the 28-joint count for tender and swollen joints and erythrocyte sedimentation rate (DAS28ESR) or the clinical disease activity index (cDAI), synthetic antirheumatic drugs and antitumour necrosis factor (TNF) therapy. RESULTS: Anaemia prevalence decreased from more than 24% in years before 2001 to 15% in 2007. Erosions progressed significantly faster in patients with anaemia (p<0.001). Adjusted models showed these effects independently of clinical disease activity and other indicators of disease severity. Radiographic damage progression rates were increasing with severity of anaemia, suggesting a 'dose-response effect'. The effect of anaemia on damage progression was maintained in subgroups of patients treated with TNF blockade or corticosteroids, and without non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS: Anaemia in RA appears to capture disease processes that remain unmeasured by established disease activity measures in patients with or without TNF blockade, and may help to identify patients with more rapid erosive disease.

Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study

OBJECTIVE To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission. METHODS ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. RESULTS Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). CONCLUSIONS Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. TRIAL REGISTRATION NUMBER NCT00810199.

Management of Patients With Rheumatoid Arthritis in Latin America A Consensus Position Paper From Pan-American League of Associations of Rheumatology and Grupo Latino Americano De Estudio de Artritis Reumatoide

Objective: A consensus meeting of representatives of 18 Latin-American and Caribbean countries gathered in Renaca, Chile, for 2 days to identify problems and provide recommendations for the care of patients with rheumatoid arthritis (RA) in Latin America, a region where poverty and other health priorities make the efforts to provide effective and high quality care difficult. This report includes recommendations for health professionals, patients, and health authorities in Latin America, with an emphasis oil education and therapeutic issues. Methods: Fifty-one rheumatologists (list available only online on the JCR website) from 18 Latin-American and Caribbean countries with a special interest in RA participated in the consensus meeting. Participants were experts identified and appointed by the National Societies of Rheumatology affiliated with the Pan-American League of Associations for Rheumatology (PANLAR) and by the Grupo Latino Americano De Estudio de Artritis Reumatoide (GLADAR)-an independent group of Latin American rheumatologist researchers were also invited to the meeting. Eight topics were identified as priorities: patient, community and allied health professional education, health policy and decision making, programs for early detection and appropriate treatment of RA, role of classic disease modifying antirheumatic drugs (DMARDs), role of biologic therapy, and drug safety surveillance. To reach consensus, a survey with questions relevant to the topic of interest was sent to all participants before the meeting. During a 2 day meeting, the answers of the survey were reviewed and discussed by each group, with final recommendations on action items. Results: The specific topic of the survey was answered by 86% of the participants and 68% of them answered the entire survey. It was agreed that RA and rheumatic diseases which are currently not but should be public health priorities in Latin America, because of their prevalence and impact on quality of life. Conclusions: Strategic areas identified as priorities for our region included: early diagnosis and access to care by multidisciplinary teams, creation of databases to identify infections with the use of biologic agents in RA which are relevant to Latin America, and overall efforts to improve the care of RA patients in accordance with international standards. Implementation of educational programs aimed to improve self-management for patients with RA was also considered crucial.

Phase II Trial of Infusional Fluorouracil, Irinotecan, and Bevacizumab for Metastatic Colorectal Cancer: Efficacy and Circulating Angiogenic Biomarkers Associated With Therapeutic Resistance

Purpose We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance. Patients and Methods We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD). Results Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001). Conclusion Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

Association of clinical, radiological and synovial immunopathological responses to anti-rheumatic treatment in rheumatoid arthritis

Objectives. To compare immunohistochemical scoring with clinical scoring and radiology for the assessment of rheumatoid arthritis (RA) disease activity, synovial tissue (ST) biopsied arthroscopically was assessed from 18 patients before and after commencement of disease-modifying anti-rheumatic drug (DMARD) therapy. Methods. Lymphocytes, macrophages, differentiated dendritic cells (DC), vascularity, tumour necrosis factor (TNF)alpha and interleukin-1 beta levels were scored. Clinical status was scored using the American College of Rheumatology (ACR) core set and serial radiographs were scored using the Larsen and Sharp methods. Histopathological evidence of activity included infiltration by lymphocytes, DC, macrophages. tissue vascularity, and expression of lining and sublining TNF alpha. These indices co-varied across the set of ST biopsies and were combined as a synovial activity score for each biopsy. Results. The change in synovial activity with treatment correlated with the ACR clinical response and with decreased radiological progression by the Larsen score, The ACR response to DMARD therapy. the change in synovial activity score and the slowing of radiological progression were each greatest in patients with high initial synovial vascularity. Conclusions. The data demonstrate an association between clinical, radiological and synovial immunopathological responses to anti-rheumatic treatment in RA. High ST vascularity may predict favourable clinical and radiological responses to treatment.

Diagnostic and prognostic value of antibodies against chimeric fibrin/filaggrin citrullinated synthetic peptides in rheumatoid arthritis

Introduction: Evidence suggests that citrullinated fibrin(ogen) may be a potential in vivo target of anticitrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis (RA). We compared the diagnostic yield of three enzyme-linked immunosorbent assay (ELISA) tests by using chimeric fibrin/filaggrin citrullinated synthetic peptides (CFFCP1, CFFCP2, CFFCP3) with a commercial CCP2-based test in RA and analyzed their prognostic values in early RA. Methods: Samples from 307 blood donors and patients with RA (322), psoriatic arthritis (133), systemic lupus erythematosus (119), and hepatitis C infection (84) were assayed by using CFFCP- and CCP2-based tests. Autoantibodies also were analyzed at baseline and during a 2-year follow-up in 98 early RA patients to determine their prognostic value. Results: With cutoffs giving 98% specificity for RA versus blood donors, the sensitivity was 72.1% for CFFCP1, 78.0% for CFFCP2, 71.4% for CFFCP3, and 73.9% for CCP2, with positive predictive values greater than 97% in all cases. CFFCP sensitivity in RA increased to 80.4% without losing specificity when positivity was considered as any positive anti-CFFCP status. Specificity of the three CFFCP tests versus other rheumatic populations was high (> 90%) and similar to those for the CCP2. In early RA, CFFCP1 best identified patients with a poor radiographic outcome. Radiographic progression was faster in the small subgroup of CCP2-negative and CFFCP1-positive patients than in those negative for both autoantibodies. CFFCP antibodies decreased after 1 year, but without any correlation with changes in disease activity. Conclusions: CFFCP-based assays are highly sensitive and specific for RA. Early RA patients with anti-CFFCP1 antibodies, including CCP2-negative patients, show greater radiographic progression.

Diagnostic and prognostic value of antibodies against chimeric fibrin/filaggrin citrullinated synthetic peptides in rheumatoid arthritis

Introduction: Evidence suggests that citrullinated fibrin(ogen) may be a potential in vivo target of anticitrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis (RA). We compared the diagnostic yield of three enzyme-linked immunosorbent assay (ELISA) tests by using chimeric fibrin/filaggrin citrullinated synthetic peptides (CFFCP1, CFFCP2, CFFCP3) with a commercial CCP2-based test in RA and analyzed their prognostic values in early RA. Methods: Samples from 307 blood donors and patients with RA (322), psoriatic arthritis (133), systemic lupus erythematosus (119), and hepatitis C infection (84) were assayed by using CFFCP- and CCP2-based tests. Autoantibodies also were analyzed at baseline and during a 2-year follow-up in 98 early RA patients to determine their prognostic value. Results: With cutoffs giving 98% specificity for RA versus blood donors, the sensitivity was 72.1% for CFFCP1, 78.0% for CFFCP2, 71.4% for CFFCP3, and 73.9% for CCP2, with positive predictive values greater than 97% in all cases. CFFCP sensitivity in RA increased to 80.4% without losing specificity when positivity was considered as any positive anti-CFFCP status. Specificity of the three CFFCP tests versus other rheumatic populations was high (> 90%) and similar to those for the CCP2. In early RA, CFFCP1 best identified patients with a poor radiographic outcome. Radiographic progression was faster in the small subgroup of CCP2-negative and CFFCP1-positive patients than in those negative for both autoantibodies. CFFCP antibodies decreased after 1 year, but without any correlation with changes in disease activity. Conclusions: CFFCP-based assays are highly sensitive and specific for RA. Early RA patients with anti-CFFCP1 antibodies, including CCP2-negative patients, show greater radiographic progression.

La influencia del tabaquismo en la actividad de la artritis reumatoide y progresión de erosiones articulares: Una revision sistemática y meta-análisis.

Objetivos: Sintetizar a través de una revisión sistemática y un meta-análisis los datos disponibles en la literatura sobre el tabaquismo y la artritis reumatoide (AR), teniendo en cuenta su efecto sobre la actividad de la enfermedad y la progresión radiográfica de erosiones. Métodos: Se realizo una revisión sistemática usando las guías PRISMA en las bases de datos de MEDLINE hasta Julio 2013. Los términos de búsqueda incluían tabaquismo, tabaco, humo, cigarrillo y artritis reumatoide. Se consideró incluir cualquier tipo de de estudio realizado con casos de AR, definida por criterios aceptados de clasificación y que incluyeran información que indicara la relación entre tabaquismo y DAS28 o por lo menos un puntaje de erosión. Un tamaño común del efecto se calculó usando un modelo de efectos aleatorios. Resultados: De un total de 2215 artículos obtenidos, 45 cumplían los criterios de inclusión. De estos 27 fueron incluidos en el meta-análisis. Doce contenían información sobre la relación con DAS28 y 17 acerca del efecto en progresión radiográfica. Se encontró una asociación negativa entre tabaquismo y respuesta EULAR (OR: 0.72; 95% CI:0.57-0.91; p=0.005) y Remisión definida por DAS28 (OR:0.78; 95%CI:0.63-0.96; p=0.023). EL puntaje de DAS28 era significativamente mas alto en fumadores actuales (MD:0.29; 95% CI:0.12-0.44;p<0.001) de igual forma el puntaje de erosión era mas alto en fumadores actuales (SMD:0.38;95% CI:0.04-0.72; p=0.028). Los datos para progresión de erosiones eran ambiguos (OR: 0.93; 95% CI: 0.72-1,2; p=0.59). Un análisis de sensibilidad confirmo que los resultados no eran sensibles a la restricción de los datos incluidos. El sesgo de publicación fue mínimo. Conclusiones: El tabaquismo se encuentra asociado a una respuesta disminuida a tratamiento (definido por criterios EULAR) y un puntaje de erosión, pero no se logro demostrar una mayor progresión radiográfica en los pacientes fumadores.

Tripartite patella: late appearance of a third ossification center in childhood

Bilateral radiographic progression of the supero-lateral fragment of a bipartite- into a tripartite patella with unilateral symptoms. An 8 year old girl presented a bilateral bipartite patella Stage III as an incidental finding after fall on the flexed right knee. Serial radiographs two years later revealed a bilateral progression of the bipartite- into a tripartite patella with complaints only on the post-traumatic right side. Observation was opted as therapy. There was no correlation of symptoms and radiological findings of the fragmentation of the bipartite- into a tripartite patella. Therefore we conclude the etiology of a bilateral late appearance of a third ossification center.

Shell brace for stage II posterior tibial tendon insufficiency

BACKGROUND: The nonoperative treatment of posterior tibial tendon insufficiency (PTTI) can lead to unsatisfactory functional results. Short-term results are available but the impact on the evolution of the deformity is not known. To address these problems, a new brace for the flexible Stage II deformity was developed, and midterm followup was obtained. MATERIALS AND METHOD: In a prospective case series, eighteen patients (mean age 64.2 years; range, 31 to 82; four male, 14 female) with flexible Stage II PTTI were fitted with the new custom-molded foot orthosis. At latest followup of a mean of 61.4 (range, 20 to 87) months, functional results were assessed with the AOFAS ankle hindfoot score and clinical or radiographic progression was recorded. RESULTS: The score improved significantly from a mean of 56 points (range, 20 to 64) to a mean of 82 points (range, 64 to 100, p < 0.001). Three patients (3/18, 16%) had a clinical progression to a fixed deformity (Stage III) and a radiographic increase of their deformity. All the other patients were satisfied with the brace's comfort and noted an improvement in their mobility. Complications were seen in three patients (3/18, 16%), and consisted of the development of calluses. CONCLUSION: The "shell brace" is a valuable option for nonoperative treatment of the flexible Stage II PTTI. Hindfoot flexibility was conserved throughout the observation period in all but three patients. Functional outcome and patient acceptance was above average. Problems were few, and closely associated with a progression to a fixed, Stage III deformity.

Impacto de la resiliencia en pacientes con Artritis Reumatoide

Introducción: La artritis reumatoide (AR) es una enfermedad autoinmune-inflamatoria, que compromete las articulaciones diartrodiales. Tiene una importante repercusión sistémica que incluye la depresión; por lo tanto, tiene un severo impacto sobre la calidad de vida. Es posible que mecanismos de defensa, tales como la resiliencia, puedan amortiguar dicho impacto. Metodología: estudio de corte transversal, multicéntrico (análisis inicial dentro del grupo AR, con muestra no probabilística de 66 pacientes, posterior selección aleatoria simple de 16 pacientes de la muestra inicial y selección de 16 individuos sanos pareados). Posteriormente, se comparó la resiliencia entre sujetos con AR y sujetos sanos, mediante las escalas RS y CD-RISC25. Adicionalmente, se aplicaron las escalas EEAE, EADZ, SF-36 y PANAS. Los datos fueron evaluados mediante el coeficiente de correlación de Spearman, las pruebas U Mann-Whitney, Kruskall-Wallis, T de Student y análisis de varianza. Resultados: se encontraron diferencias significativas en las estrategias de afrontamiento no espirituales en grupos de resiliencia baja, media y alta; diferencias en las medianas de resiliencia en los grupos de depresión por EAZD en los pacientes. No se encontraron resultados significativos en las variables clínicas de la AR ni en la comparación con sujetos sanos. Conclusiones: el uso de estrategias de afrontamiento no espirituales y la ausencia de depresión, se asoció a mayores niveles de resiliencia en los pacientes con AR, por lo cual, los componentes emocionales y cognitivos se asocian a la resiliencia.

Progression of experimental chronic peri-implantitis in dogs: Clinical and radiographic evaluation

Background: the aim of this study was to evaluate the progression of experimental peri-implantitis in dogs using implants with different surface coatings.Methods: Thirty-six dental implants with four different surface coatings, commercially pure titanium (cpTi), titanium plasma-sprayed (TPS), hydroxyapatite (HA), and acid-etched (AE), were placed in six mongrel dogs. Five months after implantation, peri-implantitis was induced by cotton ligatures to facilitate plaque accumulation for 60 days. After 60 days, the ligatures were removed and supragingival plaque control was initiated for 12 months. Probing depth (PD), clinical attachment level (CAL), vertical bone level (VBL), horizontal bone level (HBL), and mobility were obtained at baseline, and 20, 40, 60 (acute phase), and 425 days (chronic phase) after ligature removal.Results: PD and CAL changed around all implant surfaces after ligature placement (P < 0.0001). However, the means of PD and CAL were not statistically significant among the different surfaces (P > 0.05). The range of CAL variation, calculated between baseline and 60 days (acute phase) and between 60 and 425 days (chronic phase), decreased (P < 0.05). Bone loss increased during the entire experiment (P < 0.0001). The HA surface showed the greatest bone loss measurement (5.06 +/- 0.38 mm) and the TPS showed the smallest bone loss (4.27 +/- 0.62 mm). However, statistical significance was not assessed for different coatings (P > 0.05).Conclusions: the clinical data at the initial phase showed rapid and severe peri-implant tissue breakdown. However, removal of ligatures did not convert the acute destructive peri-implant phase to a non-aggressive lesion and the progression of peri-implantitis was observed at chronic phase. The,experimental peri-implantitis in dogs may be a useful model to evaluate the progression of peri-implantitis.

Experimental peri-implant tissue breakdown around different dental implant surfaces: Clinical and radiographic evaluation in dogs

Purpose: Tissue reactions to 4 different implant surfaces were evaluated in regard to the development and progression of ligature-induced peri-implantitis. Materials and Methods: In 6 male mongrel dogs, a total of 36 dental implants with different surfaces (9 titanium plasma-sprayed, 9 hydroxyapatite-coated, 9 acid-etched, and 9 commercially pure titanium) were placed 3 months after mandibular premolar extraction. After 3 months with optimal plaque control, abutment connection was performed. Forty-five days later, cotton ligatures were placed around the implants to induce peri-implantitis. At baseline and 20, 40, and 60 days after placement, the presence of plaque, peri-implant mucosal redness, bleeding on probing, probing depth, clinical attachment loss, mobility, vertical bone loss, and horizontal bone loss were assessed. Results: The results did not show significant differences among the surfaces for any parameter during the study (P > .05). All surfaces were equally susceptible to ligature-induced peri-implantitis over time (P < .001). Correlation analysis revealed a statistically significant relationship between width of keratinized tissue and vertical bone loss (r 2 = 0.81; P = .014) and between mobility and vertical bone loss (r 2 = 0.66; P = .04), both for the titanium plasma-sprayed surface. Discussion and Conclusions: The present data suggest that all surfaces were equally susceptible to experimental peri-implantitis after a 60-day period.

Reparative phase events on periodontal disease progression: interpretation and considerations

Periodontal disease progress by destructive acute phases intercalated by reparative chronic phases. The aim of this study was to investigate the clinical and histological evidence of the periodontal disease reparative phase by analyzing bone wall conditions inside periodontal pockets and histologic images of periodontal pockets, identified in relevant publications. 81 patients with periodontitis, were randomly assigned into this study. Clinical and radiographic parameters were established to diagnose periodontal disease providing a sample of 133 diseased areas, which were treated by modified Widman flap. Documentation by digital photography were recorded in the surgery. Relevant publications showing histological images of periodontal pockets, were identified in Medline, PubMed and Google data base, were scanned and digitalized. All images obtained were evaluated and the presences of the reparative evidence in the zone around the underlying destroyed alveolar bone were critically analyzed. All periodontal bone defects, showed cortical bone reparations at different levels inside periodontal bone defects. All histologic images of periodontal pockets identified in relevant publications showed repaired gingival-attached connective tissue localized above underlying destroyed alveolar bone. All the evidences analyzed in this study suggested that periodontal disease is predominantly chronic, quiescent, showing reparative phases in different levels.

Comparison of six radiographic projections to assess femoral head/neck asphericity

Early radiographic detection of femoroacetabular impingement might prevent initiation and progression of osteoarthritis. The structural abnormality in femoral-induced femoroacetabular impingement (cam type) is frequently asphericity at the anterosuperior head/neck contour. To determine which of six radiographic projections (anteroposterior, Dunn, Dunn/45 degrees flexion, cross-table/15 degrees internal rotation, cross-table/neutral rotation, and cross-table/15 degrees external rotation) best identifies femoral head/neck asphericity, we studied 21 desiccated femurs; 11 with an aspherical femoral head/neck contour and 10 with a spherical femoral head/neck contour. To radiographically quantify femoral head asphericity, we measured the angle where the femoral head/neck leaves sphericity (angle alpha). The aspherical femoral head/neck contours had a greater maximum angle alpha (70 degrees ) compared with the spherical head/neck contours (50 degrees ). The angle alpha varied depending on the radiographic projection: it was greatest in the Dunn view with 45 degrees hip flexion (71 degrees +/- 10 degrees ) and least in the cross-table view in 15 degrees external rotation (51 degrees +/- 7 degrees ). Diagnosis of a pathologic femoral head/neck contour depends on the radiologic projection. The Dunn view in 45 degrees or 90 degrees flexion or a cross-table projection in internal rotation best show femoral head/neck asphericity, whereas anteroposterior or externally rotated cross-table views are likely to miss asphericity. Level of Evidence: Prognostic study, level II-1 (retrospective study).