Epigenetics as a Therapeutic Target in Osteoarthritis.

Osteoarthritis (OA) is a heterogenous, complex disease affecting the integrity of diarthrodial joints that, despite its high prevalence worldwide, lacks effective treatment. In recent years it has been discovered that epigenetics may play an important role in OA. Our objective is to review the current knowledge of the three classical epigenetic mechanisms-DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) modifications, including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs)-in relation to the pathogenesis of OA and focusing on articular cartilage. The search for updated literature was carried out in the PubMed database. Evidence shows that dysregulation of numerous essential cartilage molecules is caused by aberrant epigenetic regulatory mechanisms, and it contributes to the development and progression of OA. This offers the opportunity to consider new candidates as therapeutic targets with the potential to attenuate OA or to be used as novel biomarkers of the disease.

Histone Extraction from Human Articular Cartilage for the Study of Epigenetic Regulation in Osteoarthritis.

Osteoarthritis (OA) is a chronic disease that affects articular cartilage, causing its degeneration. Although OA is one of the most prevalent pathologies globally, there are no definitive treatments available. Recently, research has focused on elucidating the complex interplay that takes place between inflammatory processes and epigenetic regulation, showing that histone post-translational modifications (PTMs) can exert a pronounced effect on the expression of OA-related genes. OA chondrocytes enhance the production of interleukin 1ß (IL-1ß) and interleukin 8 (IL-8), which are epigenetically regulated. These cytokines upregulate the synthesis of matrix metalloproteinases (MMPs) and aggrecanases, which promote the extracellular matrix (ECM) destruction. This motivates the study of histone PTMs to investigate the epigenetic regulation of proinflammatory molecules, but the absence of specific protocols to extract histones from human articular cartilage has complicated this task. The lack of effective methods can be explained by the structural complexity and low cellularity of this tissue, which are responsible for the biomechanical properties that allow the movement of the joint but also complicate histone isolation. Here, we provide a histone extraction procedure specifically adapted for cryopreserved human articular cartilage that can be useful to understand epigenetic regulation in OA and accelerate the search for novel strategies.

Successful treatment of post-transplant CMV meningoencephalitis with third-party CMV virus-specific T cells: Lessons learned.

Cytomegalovirus encephalitis is a challenging life-threatening complication following hematopoietic stem cell transplantation for which medical treatment is usually ineffective or toxic. However, in recent years, adoptive T-cell therapy has been reported to provide a significant chance of cure for patients with viral infections. Herein, two cases of pediatric patients successfully treated with third-party donor-derived virus-specific T cells for CMV meningoencephalitis are reported.

Compliance with Good Manufacturing Practice in the Assessment of Immunomodulation Potential of Clinical Grade Multipotent Mesenchymal Stromal Cells Derived from Wharton's Jelly.

BACKGROUND: The selection of assays suitable for testing the potency of clinical grade multipotent mesenchymal stromal cell (MSC)-based products and its interpretation is a challenge for both developers and regulators. Here, we present a bioprocess design for the production of Wharton's jelly (WJ)-derived MSCs and a validated immunopotency assay approved by the competent regulatory authority for batch release together with the study of failure modes in the bioprocess with potential impact on critical quality attributes (CQA) of the final product. Methods: The lymphocyte proliferation assay was used for determining the immunopotency of WJ-MSCs and validated under good manufacturing practices (GMP). Moreover, failure mode effects analysis (FMEA) was used to identify and quantify the potential impact of different unexpected situations on the CQA. Results: A production process based on a two-tiered cell banking strategy resulted in batches with sufficient numbers of cells for clinical use in compliance with approved specifications including MSC identity (expressing CD73, CD90, CD105, but not CD31, CD45, or HLA-DR). Remarkably, all batches showed high capacity to inhibit the proliferation of activated lymphocytes. Moreover, implementation of risk management tools led to an in-depth understanding of the manufacturing process as well as the identification of weak points to be reinforced. Conclusions: The bioprocess design showed here together with detailed risk management and the use of a robust method for immunomodulation potency testing allowed for the robust production of clinical-grade WJ-MSCs under pharmaceutical standards.

Levels of IL-17F and IL-33 correlate with HLA-DR activation in clinical-grade human bone marrow-derived multipotent mesenchymal stromal cell expansion cultures.

BACKGROUND AIMS: Multipotent mesenchymal stromal cell (MSC)-based medicines are extensively investigated for use in regenerative medicine and immunotherapy applications. The International Society for Cell and Gene Therapy (ISCT) proposed a panel of cell surface molecules for MSC identification that includes human leukocyte antigen (HLA)-DR as a negative marker. However, its expression is largely unpredictable despite production under tightly controlled conditions and compliance with current Good Manufacturing Practices. Herein, we report the frequency of HLA-DR expression in 81 batches of clinical grade bone marrow (BM)-derived MSCs and investigated its impact on cell attributes and culture environment. METHODS: The levels of 15 cytokines (interleukin [IL]-1ß, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon-γ, soluble CD40 ligand and tumor necrosis factor-α) were determined in sera supplements and supernatants of BM-MSC cultures. Identity, multipotentiality and immunopotency assays were performed on high (>20% of cells) and low (≤20% of cells) HLA-DR+ cultures. RESULTS: A correlation was found between HLA-DR expression and levels of IL-17F and IL-33. Expression of HLA-DR did neither affect MSC identity, in vitro tri-lineage differentiation potential (into osteogenic, chondrogenic and adipogenic lineages), nor their ability to inhibit the proliferation of stimulated lymphocytes. DISCUSSION: Out of 81 batches of BM-MSCs for autologous use analyzed, only three batches would have passed the ISCT criteria (<2%), whereas 60.5% of batches were compliant with low HLA-DR values (≤20%). Although a cause-effect relationship cannot be drawn, we have provided a better understanding of signaling events and cellular responses in expansion culture conditions relating with HLA-DR expression.

Treatment with methotrexate and risk of relapses in patients with giant cell arteritis in clinical practice.

OBJECTIVES: To assess the incidence and the risk of relapses in giant cell arteritis (GCA) patients treated with and without methotrexate (MTX) in clinical practice. Other associated factors were also investigated. METHODS: An inception cohort of GCA was assembled in the out-patient clinic at Hospital Clínico San Carlos, including patients from the date of diagnosis (Jan-1991 until Sept-2013), and followed-up until lost of follow up or Sept-2014. MAIN OUTCOME: relapse defined as recurrence of symptoms or signs of GCA with high ESR and the need to increase glucocorticoids at least 10mg over the previous dose. The independent variable was exposure to MTX over time. Covariables: Sociodemographic, clinical, and treatment. Incidence rates of relapses (IR) per 100 patient-year with their 95% confidence intervals [CI] were estimated using survival techniques. MTX influence on relapses was analysed by Cox models. RESULTS: 168 patients were included (675 patient-year). 31% of patients had relapses (IR of 12 [9.6-14.9]), and the median number of relapses was 1[1-2]. 65% of the patients were on MTX, (mean dose: 10mg). In the bivariate analysis, the risk of relapses in patients with and without MTX did not achieve statistical signification (p=0.1). After adjusting in the multivariate analysis, exposure to MTX had 72% less risk of relapse compared to those without MTX (p<0.05). Other variables included in the final model were: visual alterations and malaise at clinical presentation of GCA. CONCLUSIONS: The use of MTX seems to decrease the risk of recurrences. We also found other factors influencing on relapses.

Clinical translation of a mesenchymal stromal cell-based therapy developed in a large animal model and two case studies of the treatment of atrophic pseudoarthrosis.

Pseudoarthrosis is a relatively frequent complication of fractures, in which the lack of mechanical stability and biological stimuli results in the failure of bone union, most frequently in humerus and tibia. Treatment of recalcitrant pseudoarthrosis relies on the achievement of satisfactory mechanical stability combined with adequate local biology. Herein we present two cases of atrophic pseudoarthrosis that received a tissue-engineering product (TEP) composed of autologous bone marrow-derived mesenchymal stromal cells (BM-MSC) combined with deantigenized trabecular bone particles from a tissue bank. The feasibility of the treatment and osteogenic potential of the cell-based medicine was first demonstrated in an ovine model of critical size segmental tibial defect. Clinical-grade autologous BM-MSC were produced following a good manufacturing practice-compliant bioprocess. Results were successful in one case, with pseudoarthrosis resolution, and inconclusive in the other one. The first patient presented atrophic pseudoarthrosis of the humeral diaphysis and was treated with osteosynthesis and TEP resulting in satisfactory consolidation at month 6. The second case presented a recalcitrant pseudoarthrosis of the proximal tibia and the Masquelet technique was followed before filling the defect with the TEP. This patient presented a neuropathic pain syndrome unrelated to the treatment that forced the amputation of the extremity 3 months later. In this case, the histological analysis of the tissue formed at the defect site provided evidence of neovascularization but no overt bone remodelling activity. It is concluded that the use of expanded autologous BM-MSC to treat pseudoarthrosis was demonstrated to be feasible and safe, provided that no clinical complications were reported, and early signs of effectiveness were observed. Copyright © 2016 John Wiley & Sons, Ltd.

Design and validation of a consistent and reproducible manufacture process for the production of clinical-grade bone marrow-derived multipotent mesenchymal stromal cells.

BACKGROUND: Multipotent mesenchymal stromal cells (MSC) have achieved a notable prominence in the field of regenerative medicine, despite the lack of common standards in the production processes and suitable quality controls compatible with Good Manufacturing Practice (GMP). Herein we describe the design of a bioprocess for bone marrow (BM)-derived MSC isolation and expansion, its validation and production of 48 consecutive batches for clinical use. METHODS: BM samples were collected from the iliac crest of patients for autologous therapy. Manufacturing procedures included: (i) isolation of nucleated cells (NC) by automated density-gradient centrifugation and plating; (ii) trypsinization and expansion of secondary cultures; and (iii) harvest and formulation of a suspension containing 40 ± 10 × 10(6) viable cells. Quality controls were defined as: (i) cell count and viability assessment; (ii) immunophenotype; and (iii) sterility tests, Mycoplasma detection, endotoxin test and Gram staining. RESULTS: A 3-week manufacturing bioprocess was first designed and then validated in 3 consecutive mock productions, prior to producing 48 batches of BM-MSC for clinical use. Validation included the assessment of MSC identity and genetic stability. Regarding production, 139.0 ± 17.8 mL of BM containing 2.53 ± 0.92 × 10(9) viable NC were used as starting material, yielding 38.8 ± 5.3 × 10(6) viable cells in the final product. Surface antigen expression was consistent with the expected phenotype for MSC, displaying high levels of CD73, CD90 and CD105, lack of expression of CD31 and CD45 and low levels of HLA-DR. Tests for sterility, Mycoplasma, Gram staining and endotoxin had negative results in all cases. DISCUSSION: Herein we demonstrated the establishment of a feasible, consistent and reproducible bioprocess for the production of safe BM-derived MSC for clinical use.

Dose down-titration of biological DMARDs in patients with rheumatoid arthritis over time and in daily clinical practice.

OBJECTIVES: To describe and compare dosing optimisation in biological DMARDs (bDMARDs) and relapses after that, in a cohort of rheumatoid arthritis (RA) during clinical practice. METHODS: Observational retrospective longitudinal study of RA patients taking bDMARDs from December 1999 to November 2013. Optimisation was defined as a 15% decrease in dose either reducing single dose or separating dose interval administration, for at least 4 times the recommended period between dosages. Relapse was defined as suspension or starting again with the recommended dose after optimisation. Incidence rates (IR) per 100 patient-years were estimated using survival techniques. Cox multivariate models were conducted to compare bDMARDs expressed in hazard ratios (HR) and confidence intervals [95%CI]. RESULTS: 443 patients and 752 different courses of bDMARDs treatments were included. We observed 146 optimisations with an IR of 8.1. The HR of optimisation in: a) adalimumab, etanercept and rituximab compared to infliximab was 1.56 [1.01-2.4], 1.5 [0.9-2.4] and 0.6 [0.3-1.4], respectively; b) adalimumab, etanercept compared to rituximab were 2.3 [1.2-4.5] and 2.2 [1.2-4.3]. There were no statistically significant differences between adalimumab and etanercept. Following optimisation, 36% relapsed (78% due to disease activity). The IR related to disease activity was 6.3, and was lower for adalimumab and etanercept compared to infliximab (HR: 0.42; [0.19-0.94]; HR: 0.34; [0.13-0.89], respectively). There were no statistically significant differences between etanercept and adalimumab. No patients on rituximab relapsed. CONCLUSIONS: Optimisation was similar between adalimumab and etanercept, and was lower for infliximab and rituximab. After optimisation, rituximab did not relapse, but infliximab did with the highest hazard.

Trasplante autólogo "potenciado" de células madre cd34+ de médula ósea, en pacientes con angina refractaria. estudio piloto: pilot study / Transplant autologous "enhanced" stem cells cd34+ bone marrow in patients with refractory angina: estudo piloto / Transplante autólogo "melhorado" stem cells medula óssea cd34+ em pacientes com angina refratária

Objetivo: Evaluar la eficacia a 6 meses del trasplante autólogo de células madre CD34+ de médula ósea "potenciado", mediante pre-condicionamiento isquémico en pacientes con angina refractaria. Métodos: Estudio piloto con 14 pacientes con angina refractaria, clase funcional clínica mayor o igual a III (NYHA y CCS), del Servicio de Cardiología del Hospital Militar Central. Fueron seleccionados por conveniencia 14 pacientes los cuales se asignaron aleatoriamente a 2 grupos, el primero (intervención) con trasplante autólogo de células madre CD34+ de médula ósea potenciado mediante pre-condicionamiento isquémico por vía intravenosa más tratamiento médico convencional, y el segundo (control) con tratamiento médico convencional. Se realizaron mediciones basales a 6 meses del umbral de angina/isquemia medido en mets y clase funcional. Resultados: Al comparar las medianas, el cambio en el valor umbral de angina/isquemia 6 meses después, para el grupo intervenido fue de 3.5 mets vs 0.9 mets, para el grupo control P= 0.013. No se registraron complicaciones inherentes al tratamiento. Conclusiones: En esta investigación, los pacientes con angina refractaria intervenidos con trasplante autólogo de células madre de médula ósea CD34+ potenciado mediante pre-condicionamiento isquémico mostraron mejoría del umbral de angina y clase funcional a 6 meses.

Objective: To evaluate the efficacy of 6 months of autologous CD34+ stem cells in bone marrow "enhanced" by ischemic preconditioning in patients with refractory angina. Methods: A pilot study with 14 patients with refractory angina, with a functional class greater than or equal to III clinical (NYHA and CCS), of the Department of Cardiology of the Central Military Hospital. They were selected by convenience 14 patients who were randomly assigned to two groups, the first (intervention) with autologous stem cells CD34+ bone marrow powered by ischemic preconditioning, intravenously more conventional medical treatment, and the second (control) with conventional medical treatment. Baseline measurements were performed and six months' threshold angina/ischemia measured in mets and functional class. Results: Comparing the medians, the change in threshold value angina/ischemia six months later for the intervention group was 3.5 mets vs 0.9 mets for the control group P = 0.013. No inherent complications to treatment were recorded. Conclusions: In this study patients with refractory angina who underwent autologous stem cell transplant of bone marrow CD34+ powered by ischemic preconditioning, showed an improvement in threshold angina and functional class of 6 months.

Objetivo: Avaliar a eficácia de 6 meses de células-tronco autólogas CD34+ na medula óssea "aumentada" pelo pré-condicionamento isquêmico em pacientes com angina refratária. Métodos: Um estudo piloto com 14 pacientes com angina refratária, com classe funcional maior ou igual a III clínica (NYHA e CCS), Do Departamento de Cardiologia do Hospital Militar Central. Eles foram selecionados por conveniência 14 pacientes que foram aleatoriamente designados para dois grupos, a primeira (intervenção) com células- tronco autólogas CD34+ medula óssea alimentado por pré-condicionamento isquêmico, tratamento intravenoso mais convencional, e o segundo (controle) com tratamento médico convencional. Medidas de linha de base foram realizadas e seis meses de angina limiar /isquemia medido em mets e classe funcional. Resultados: Comparando as mediana, a alteração do valor limiar angina / isquemia seis meses depois para o grupo de intervenção foi de 3,5 mets vs 0,9 mets para o grupo de controlo P = 0,013. Não foram registadas complicações inerentes ao tratamento. Conclusões: Neste estudo, pacientes com angina refratária submetidos a transplante de células-tronco autólogas de medula óssea CD34+ alimentado por pré-condicionamento isquêmico, apresentaram melhora da angina limiar e classe funcional de 6 meses.

Bone mineral density and mammographic density in Mexican women.

BACKGROUND: Bone mineral density (BMD) is a putative marker for lifetime exposure to estrogen. Studies that have explored whether BMD is a determinant of mammographic density (MD) have observed inconsistent results. Therefore,we examined this potential association in a sample of women (n = 1,516) from the clinical sub-cohort in the Mexican teachers' cohort (n = 115,315). METHODS: We used multivariable linear regression to assess the association between quartiles of BMD and percent MD, as well as total dense and non-dense area of the breast, stratified by menopausal status. We also examined the associations by body mass index (BMI) (< 30 kg/m(2), ≥ 30 kg/m(2)). RESULTS: Overall, there was no association between BMD and MD among premenopausal women. However, when we stratified by BMI, there was a modest inverse association between BMD and percent MD (difference between extreme quartiles = -2.8, 95 % CI -5.9, 0.27, p trend = 0.04) among women with BMI < 30 kg/m(2), but a positive association among obese women (comparable difference = 5.1, 95 % CI 0.02, 10.1, p trend = 0.03;p interaction < 0.01). Among postmenopausal women, BMD and percent MD were positively associated after adjustment for BMI (p trend < 0.01). Postmenopausal women in the highest two quartiles of BMD had 4­5 % point higher percent MD compared to women in the lowest quartile. The association did not differ by BMI in postmenopausal women (p interaction = 0.76). CONCLUSION: Among obese premenopausal women as well as postmenopausal women, BMD was positively associated with percent MD. Among leaner premenopausal women, BMD and percent MD were modestly inversely associated. These findings support the hypothesis that cumulative exposure to estrogen (as measured by BMD) may influence MD.

Evaluation of a cell-banking strategy for the production of clinical grade mesenchymal stromal cells from Wharton's jelly.

BACKGROUND AIMS: Umbilical cord (UC) has been proposed as a source of mesenchymal stromal cells (MSCs) for use in experimental cell-based therapies provided that its collection does not raise any risk to the donor, and, similar to bone marrow and lipoaspirates, UC-MSCs are multipotent cells with immuno-modulative properties. However, some of the challenges that make a broader use of UC-MSCs difficult include the limited availability of fresh starting tissue, time-consuming processing for successful derivation of cell lines, and the lack of information on identity, potency and genetic stability in extensively expanded UC-MSCs, which are necessary for banking relevant cell numbers for preclinical and clinical studies. METHODS: Factors affecting the success of the derivation process (namely, time elapsed from birth to processing and weight of fragments), and methods for establishing a two-tiered system of Master Cell Bank and Working Cell Bank of UC-MSCs were analyzed. RESULTS: Efficient derivation of UC-MSCs was achieved by using UC fragments larger than 7 g that were processed within 80 h from birth. Cells maintained their immunophenotype (being highly positive for CD105, CD90 and CD73 markers), multi-potentiality and immuno-modulative properties beyond 40 cumulative population doublings. No genetic abnormalities were found, as determined by G-banding karyotype, human telomerase reverse transcriptase activity was undetectable and no toxicity was observed in vivo after intravenous administration of UC-MSCs in athymic rats. DISCUSSION: This works demonstrates the feasibility of the derivation and large-scale expansion of UC-MSCs from small and relatively old fragments of UC typically discarded from public cord blood banking programs.

Prognostic factors for long-term work disability due to musculoskeletal disorders.

The objective of this study is to identify risk factors for permanent work disability (PWD) related to musculoskeletal disorders (MSDs). This is a secondary data analysis of a randomized controlled intervention study in Temporary Work Disability (TWD) due to MSDs. The association of PWD (claim submission and status recognition) with baseline clinical, sociodemographic, work-related administrative and occupational factors was analyzed by Cox proportional hazards models. Of 3,311 patients with TWD, 47 submitted a PWD claim, of whom 32 achieved PWD status. The main alleged causes of the PWD were back pain, sciatica, and inflammatory diseases. The following factors were independently associated with an increased probability of PWD claim submission: age (odds ratio (OR) 5.1), being woman (OR 2.1), self-employment (OR 3.4), unemployment (OR 13.8), previous musculoskeletal surgery (OR 16), repeated TWD (OR 3.4), sitting (OR 2.8), and raising arms frequently (OR 3.1). Patients with inflammatory disease were more likely to file PWD claims (OR 10.4) while tendonitis was associated with lower probability (OR 0.3). The sociodemographic factors that better predicted PWD status recognition were age (OR 5.7), low educational level (OR 4.2), previous musculoskeletal surgery (OR 14.9), unemployment (OR 17.6), sitting (OR 2.6), and raising arms frequently (OR 2.7). Inflammatory diseases were the diagnoses associated with a higher rate of PWD status recognition (OR 6.1). Inflammatory diseases have a high chronic disability potential in active workers. Sociodemographic, work-related, occupational factors, and other clinical factors, some of which are modifiable, may explain the development of long-term work disability related to MSDs.

Diagnostic concordance between primary care physicians and rheumatologists in patients with work disability related to musculoskeletal disorders.

To assess the diagnostic correlation between primary care physicians and rheumatologists in patients with temporary work disability (TWD) related to musculoskeletal diseases (MSD). All patients with TWD related to MSDs in three health districts of Madrid, Spain, were randomized into standard care by primary care physicians (PCP) or the intervention group by rheumatologists. According to the cause, every TWD episode was classified into 11 syndrome categories. To examine the concordance between the rheumatologist and the referring PCP for each diagnosis, we used Kappa statistic (k) and 95% confidence interval (CI). A total of 3,311 (62.8%) were analyzed, 49.8% women, with a mean age of 41 years ± 12 years, 93.3% were general workers. The agreement between PCP and rheumatologists in all the diagnoses was moderated (k = 0.62). The highest agreement was found in tendonitis (k = 0.81, 95% CI 0.78-0.84), and microcrystalline and undifferentiated arthritis (k = 0.72, 95% CI 0.68-0.77). Lowest agreements were found for peripheral osteoarthritis (k = 0. 48 95% CI 0.38-0.57), knee pain (k = 0.40, 95% CI 0.29-0.52), and muscular pain (k = 0.15, 95% CI 0.10-0.20) Although the global agreement on the musculoskeletal diagnosis between PCPs and rheumatologist in patients with TWD related to MSDs was reasonable, the correlation for peripheral osteoarthritis, knee pain, and muscular pain was low.

Effectiveness of an early cognitive-behavioral treatment in patients with work disability due to musculoskeletal disorders.

OBJECTIVE: To evaluate whether an early cognitive-behavioral treatment complementary to a rheumatologic care program, for patients with recent-onset temporary work disability caused by musculoskeletal disorders (MSDs) is effective. METHODS: Patients with an MSD-related temporary work disability episode from 3-8 weeks' duration who were in a rheumatologic care program were randomized into a control group (rheumatologic care program) or an intervention group (rheumatologic care program plus cognitive-behavioral treatment). Enrollment lasted 24 months and followup lasted 6-24 months. Efficacy variables included duration of temporary work disability episodes, total number of work days saved, relative efficacy, and relative rate to return to work. An economic evaluation was also performed. RESULTS: One hundred eighty-one patients were included (66 control and 115 intervention patients), generating 222 episodes of MSD-related temporary work disability. Episodes tended to be shorter in the intervention group than in the control group (mean 98 versus 127 days; P = 0.053), with a relative efficacy of 22.9%. There were no differences in duration of the first episode between groups (mean 105 versus 110 days; P = 0.79), but relapse episodes were significantly shorter in the intervention group (mean 63 days versus 197 days; P = 0.0002). Costs were also lower in the intervention group. To save 1 day of temporary work disability, $13.50 had to be invested in the program. Each dollar invested generated a benefit of $4.08. The program had a net benefit of $172,607. CONCLUSION: Early cognitive-behavioral treatment complementary to a rheumatologic care program is cost-effective, adds >20% efficacy to the rheumatologic care program, and reduces the duration of relapses.

Tuberculous peritonitis after treatment with adalimumab.

We present a case of tuberculous peritonitis in a woman with rheumatoid arthritis (RA), treated with adalimumab, and we review the association between anti-tumour necrosis factor (anti-TNF) therapy and tuberculosis. There have been only 2 case reports of peritoneal tuberculosis associated with anti-TNF and only 1 with adalimumab.

Prognostic factors in short-term disability due to musculoskeletal disorders.

OBJECTIVE: To identify factors associated with poor outcome in temporary work disability (TWD) due to musculoskeletal disorders (MSDs). METHODS: We conducted a secondary data analysis of a 2-year randomized controlled trial in which all patients with TWD due to MSDs in 3 health districts of Madrid (Spain) were included. Analyses refer to the patients in the intervention group. Primary outcome variables were duration of TWD and recurrence. Diagnoses, sociodemographic, work-related administrative, and occupational factors were analyzed by Cox proportional hazards models. RESULTS: We studied 3,311 patients with 4,424 TWD episodes. The following were independently associated with slower return to work: age (hazard ratio [HR] 0.99, 95% confidence interval [95% CI] 0.98-0.99), female sex (HR 0.84, 95% CI 0.78-0.90), married (HR 0.90, 95% CI 0.83-0.97), peripheral osteoarthritis (HR 0.77, 95% CI 0.6-0.9), sciatica (HR 0.59, 95% CI 0.54-0.65), self-employment (HR 0.56, 95% CI 0.48-0.65), unemployment (HR 0.41, 95% CI 0.28-0.58), manual worker (HR 0.86, 95% CI 0.79-0.94), and work position covered during sick leave (HR 0.84, 95% CI 0.77-0.92). The factors that better predicted recurrence were peripheral osteoarthritis (HR 1.75, 95% CI 1.14-2.6), inflammatory diseases (HR 1.66, 95% CI 1.009-2.72), sciatica (HR 1.30, 95% CI 1.08-1.56), indefinite work contract (HR 1.43, 95% CI 1.14-1.75), frequent kneeling (HR 1.39, 95% CI 1.15-1.69), manual worker (HR 1.19, 95% CI 1.003-1.42), and duration of previous episodes (HR 1.003, 95% CI 1.001-1.005). CONCLUSION: Sociodemographic, work-related administrative factors, diagnosis, and, to a lesser extent, occupational factors may explain the duration and recurrence of TWD related to MSD.

Musculoskeletal work disability for clinicians: time course and effectiveness of a specialized intervention program by diagnosis.

OBJECTIVE: To evaluate how an intervention program modifies the clinical course of work disability in musculoskeletal diagnoses. METHODS: All patients with temporary work disability related to musculoskeletal disorders (MSDs) in 3 health districts of Madrid, Spain were randomized into standard care (control group) or the intervention group. Intervention consisted of a specific program, run by rheumatologists, following detailed proceedings. Inclusion and followup lasted 12 months each. According to the cause, every temporary work disability episode was classified into 11 syndrome categories. For each we calculated efficacy, as the difference between groups in the number of days on sick leave per temporary work disability episode; relative efficacy, or the percentage of days saved in the intervention group; and time of maximum program effect. Analyses were performed on an intent-to-treat basis. Survival techniques were run and results were expressed as the hazard ratio (HR) in the intervention versus control group. RESULTS: A total of 13,077 patients were included, generating 16,297 temporary work disability episodes. The most frequent cause was back pain. Temporary work disability episodes were significantly shorter in the intervention group than in the controls in all syndrome categories except knee pain (excluding osteoarthritis). Program relative efficacy varied from 28-72%. The program was highly efficacious in carpal tunnel syndrome (HR 2.09, 95% confidence interval [95% CI] 1.17-3.75), peripheral osteoarthritis (HR 1.58, 95% CI 1.14-2.19), and inflammatory diseases (HR 1.52, 95% CI 1.09-2.12). The maximum effect of the program always took place within the first 2 months. CONCLUSION: The implementation of this type of specialist-run, protocol-based early intervention program would be very beneficial in the treatment of patients with work disability related to MSDs, except for those with knee pain (excluding osteoarthritis).

A health system program to reduce work disability related to musculoskeletal disorders.

BACKGROUND: Musculoskeletal disorders (MSDs) are a frequent cause of work disability, accounting for productivity losses in industrialized societies equivalent to 1.3% of the U.S. gross national product. OBJECTIVE: To evaluate whether a population-based clinical program offered to patients with recent-onset work disability caused by MSDs is cost-effective. DESIGN: Randomized, controlled intervention study. The inclusion and follow-up periods each lasted 12 months. SETTING: Three health districts in Madrid, Spain. PATIENTS: All patients with MSD-related temporary work disability in 1998 and 1999. INTERVENTION: The control group received standard primary care management, with referral to specialized care if needed. The intervention group received a specific program, administered by rheumatologists, in which care was delivered during regular visits and included 3 main elements: education, protocol-based clinical management, and administrative duties. MEASUREMENTS: Efficacy variables were 1) days of temporary work disability and 2) number of patients with permanent work disability. All analyses were done on an intention-to-treat basis. RESULTS: 1,077 patients were included in the study, 7805 in the control group and 5272 in the intervention group, generating 16,297 episodes of MSD-related temporary work disability. These episodes were shorter in the intervention group than in the control group (mean, 26 days compared with 41 days; P < 0.001), and the groups had similar numbers of episodes per patient. Fewer patients received long-term disability compensation in the intervention group (n = 38 [0.7%]) than in the control group (n = 99 [1.3%]) (P < 0.005). Direct and indirect costs were lower in the intervention group than in the control group. To save 1 day of temporary work disability, 6.00 dollars had to be invested in the program. Each dollar invested generated a benefit of 11.00 dollars. The program's net benefit was in excess of 5 million dollars. LIMITATIONS: The study was unblinded. CONCLUSIONS: Implementation of the program, offered to the general population, improves short- and long-term work disability outcomes and is cost-effective.