Lydia Abasolo

Cancer in Patients with Rheumatic Diseases Exposed to TNF Antagonists

OBJECTIVE To describe the risk of cancer in patients exposed to tumor necrosis factor (TNF) antagonists. METHODS The following 2 clinical cohorts were studied: (1) BIOBADASER 2.0: a registry of patients suffering from rheumatic diseases exposed to TNF antagonists (2531 rheumatoid arthritis (RA), 1488 spondyloarthropathies, and 675 other rheumatic conditions); and (2) EMECAR: a cohort of 789 RA patients not exposed to TNF antagonists. Cancer incidence rates (IR) per 1000 patient-years and incidence rate ratios (IRR) were calculated for BIOBADASER 2.0 and EMECAR patients. The IR over time in BIOBADASER 2.0 patients was analyzed by joinpoint regression. The IRR was estimated to compare cancer rates in exposed versus nonexposed RA patients. Standardized incidence and mortality ratios (SIR, SMR) were also estimated. Risk factors for cancer in patients exposed to TNF antagonists were investigated by generalized linear models. RESULTS The SMR for cancer in BIODASER 2.0 was 0.67 (95% CI: 0.51-0.86), and the SIR was 0.1 (95% CI 0.03-0.23). The IR in RA patients exposed to TNF antagonists was 5.8 (95% CI: 4.4-7.6), and the adjusted IRR was 0.48 (95% CI: 0.09-2.45). The IR in patients with previous cancer was 26.4 (95% CI: 4.1-171.5). Age, chronic obstructive pulmonary disease, and steroids were associated with a higher risk of developing cancer. The IR decreased after the first 4 months of exposure, without statistical significance. CONCLUSION Overall cancer and mortality rates in patients with rheumatic diseases exposed to TNF antagonists are no higher than in the background Spanish population. However special attention should be paid to elderly patients, those with previous cancers, and patients treated with steroids.

A Health System Program To Reduce Work Disability Related to Musculoskeletal Disorders

Context Nonoccupational musculoskeletal disorders account for a large proportion of work disability and represent a major financial burden on society. Contribution A voluntary, randomized, controlled intervention study consisted of avoidance of bed rest, early mobilization, avoidance of splints, stretching exercises, ergonomic training, provision of educational booklets, and suggestions for optimal levels of physical activity. Although return to work was never forced, temporary work disability, long-term disability, and costs were significantly decreased in the intervention group. Implications The personal and financial impact of work disability due to musculoskeletal disorders (not related to work injury) may be mitigated by a voluntary program of education and rehabilitation. The Editors Musculoskeletal disorders (MSDs) are prevalent and potentially disabling conditions (1) that consume a large proportion of health care resources (2-4) and together are the leading cause of functional loss in adults (3-8). The social costs of MSDs are enormous, often overshadowing those of other chronic conditions (9, 10). In industrialized societies, MSDs are one of the most common causes of temporary work disability and the chief cause of permanent work disability (11), accounting for productivity losses equivalent to 1.3% of the U.S. gross national product (12). Work disability related to MSDs is a challenge to employability, business productivity, and the capacity of health and social security systems. Various strategies for addressing MSD-related work disability have been promoted in the field of occupational health, including strategies involving legislation, risk management, ergonomics, prevention, education, and social work (13). However, the role of health systems remains ill-defined in this field. The purpose of this study was to evaluate whether an intervention program, integrated into the health system and offered to the working population, could reduce the impact of recent-onset MSD-related temporary work disability. Methods Setting Of the 5.5 million persons in Madrid, Spain, 98% receive health coverage from the Instituto Madrileo de Salud. Care is organized into 11 health districts. Patients have direct access to primary care physicians, who refer patients to specialized care if needed. Disability compensation payments are made by the Instituto Nacional de la Seguridad Social (INSS), a division of the Ministry of Work. Any worker who requires sick leave is given a temporary work disability initiation form that states the diagnosis made by the primary care physician and entitles the worker to receive INSS compensation payments. The form is renewed weekly by the primary care physician until the worker 1) recovers and receives an ending form, 2) reaches a maximum of 18 months of temporary work disability, or 3) receives a proposal for evaluation for permanent work disability. Proposals for permanent work disability are evaluated by the INSS, which determines the need for and type of long-term compensation. Inspection services in each health district oversee all administrative aspects of these processes. Design We did a randomized, controlled study, unblinded for both patients and physicians, to test whether a clinical intervention could improve the outcome of patients with recent-onset MSD-related temporary work disability. The study began in March 1998 in health district 7 and in March 1999 in health districts 4 and 9. Selection and randomization of patients was done during the first year of the study in each district. Follow-up lasted for another year. Patients and Selection Criteria Health districts 4, 7, and 9 were chosen. Health district 4 had a total population of 508249 persons and an active working population of 192939 persons; health district 7 had a total population of 522742 persons and an active working population of 179155 persons; and health district 9 had a total population of 371294 persons and an active working population of 135475 persons (14). The inclusion criterion was the issue of a common diseases temporary work disability initiation form, with an MSD-related cause reported by the primary care physician, within the inclusion period. The MSD-related causes included all arthropathies, connective tissue disorders, back disorders, soft-tissue rheumatisms, bone and cartilage disorders, musculoskeletal pain not caused by cancer, and nerve entrapment syndromes. Patients were excluded if they had a common diseases temporary work disability form with an MSD-related cause resulting from trauma or surgery. They were also excluded if they had work accidents or professional diseases noted on the temporary work disability initiation form. Work accidents are primarily sudden, external, violent causes of disease occurring at work or during travel to work, and they represent less than 27% of cases of temporary work disability. Professional diseases include silicosis, asbestos-related mesothelioma, and noise-induced hearing loss, and they represent less than 1% of cases of temporary work disability. Randomization All temporary work disability initiation forms meeting the selection criteria were collected daily by a study rheumatologist and coded. The patients associated with the forms were randomly assigned to either the intervention group, which received a specific care program, or the control group, which received standard care (Figure 1). Computer-generated lists of pseudorandom numbers were produced for each district. Group assignments were randomly done in blocks of 50 patients with intervention:control ratios of 1:1 in district 7 and 2:3 in districts 4 and 9. This was done so that similar numbers of patients would be seen by the rheumatologists in all areas. The ratios were based on the number of episodes of MSD-related temporary work disability registered in previous years. Patients maintained their group assignments in successive episodes of MSD-related temporary work disability during follow-up. Figure 1. Flow diagram of the study. Care in the Intervention Group A secretary contacted all patients assigned to the intervention group by telephone or mail as soon as possible after the initiation form was issued, offering them an appointment in the program. Patients who voluntarily decided to enter the program were attended by 2 rheumatologists in each district who worked full-time for the study. Patients were seen as often as necessary until the episode of temporary work disability was resolved or recovery was deemed unrealistic. Patients who were assigned to the intervention group but were unable or unwilling to participate, were already working, or could not be located were considered to be assigned to the intervention group throughout the study for statistical purposes. Within the intervention program, care was delivered in regular visits and included education, clinical management, and administrative duties. Education At the first 45-minute visit, patients received a specific diagnosis, reassurance that no serious disease was present, instructions on self-management, instructions on taking medications on a fixed schedule, and information on indications for return to work before complete symptom remission. Return to work was negotiated with patients and was never forced on them. Instructions on self-management included instructions to avoid bed rest, instructions to promote early mobilization of the painful regions, restrictions on the use of splint and neck collars, training in stretching and strengthening exercises (15-18), teaching of ergonomic care (19), delivery of booklets in instances of back or neck pain (19), and information on optimal levels of physical activity (20). Patients with higher degrees of disability or abnormal pain behavior received immediate extra reassurance, information on pain-relieving positions, and a telephone call or second visit within 72 hours. Specific protocols were created for low-back (21), neck, shoulder, arm and hand, knee, and foot pain (19, 22-25) and included the 3-level clinical-management system described later. Moving a patient from the lower to the upper levels of the system implied the need for further diagnostic or therapeutic procedures and was indicated 1) after a patient spent a predefined period at the lower level without return to work or substantial clinical improvement or 2) by the clinical judgment of the rheumatologist. At the first level of the system, patients received the clinical management started at the first visit, including a diagnosis based on clinical criteria, pharmacologic treatment of pain and inflammation, pharmacologic treatment of anxiety and depression, peripheral intra- and periarticular injections (26), and education. Time spent at the first level averaged 2 to 6 weeks. At the second level, patients received maintenance of therapy plus referral for formal rehabilitation and laboratory tests, radiography, computerized tomography, magnetic resonance imaging, and electromyography. After 4 to 8 weeks with no improvement at the second level, patients were moved to the third level and received further diagnostic procedures or referral for surgical or other specialized care. Red flags were defined, including age older than 50 years for patients with axial pain, previous trauma, cancer, serious medical illness, inflammatory pain, night pain, drug abuse, corticosteroid use, fever, weight loss, progressively deteriorating function, and progressive neurologic deficit. The presence of a red flag precluded the use of the level system, and the patient in question was managed according to clinical criteria, with a focus on excluding serious illness. Treatment Failures Patients who did not respond to interventions at the second level of the system were examined for the presence of yellow flags, which included psychiatric illness, family problems, sociolabor conflicts, unemployment, and occupational causes of disability. The presence of a yell

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.

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.

Orthopedic Surgery in Rheumatoid Arthritis in the Era of Biologic Therapy

Objective. To analyze sociodemographic and clinic-related factors associated with the use of orthopedic surgical procedures in rheumatoid arthritis (RA), focusing on the potential role of new biologic therapies. Methods. A retrospective medical record review was performed in a probability sample of 1272 patients with RA from 47 units distributed in 19 Spanish regions. Sociodemographic and clinical features, use of drugs, and arthritis-related joint surgeries were recorded following a standardized protocol. Results. A total of 94 patients (7.4%) underwent any orthopedic surgery during their disease course, with a total of 114 surgeries; 47 (41.2%) of these surgeries were total joint replacement (TJR). The median time to first orthopedic procedure was 7.9 years from the onset of RA symptoms, and the rate of orthopedic surgery (excluding TJR) was 4.5 procedures per 100 person-years from the beginning of RA, while the rate of TJR was 2.25 interventions per 100 person-years. A higher risk of undergoing an orthopedic surgical procedure was associated with taking nonsteroidal antiinflammatory drugs (NSAID) in the previous 2 years, female sex, longterm disease, and the presence of extraarticular complications. The risk factors for undergoing a TJR were being old, having a longterm disease, and taking biologic therapies. Conclusion. In the era of biologics, our national audit found a low percentage of patients who underwent orthopedic surgery, probably reflecting a thorough management of the RA. Sociodemographic factors, longterm RA, extraarticular complications, and NSAID were associated with orthopedic surgery.

Influence of IL6R rs8192284 Polymorphism Status in Disease Activity in Rheumatoid Arthritis

Objective. To analyze the influence of IL6R rs8192284 polymorphism on the disease activity of rheumatoid arthritis (RA). Methods. Patients with RA (n = 281) were followed for a median of 4.2 years. A total of 1143 disease activity measurements using the 28-joint count Disease Activity Score (DAS28) were performed. A mixed-effect model was used to analyze the measurements. Results. A statistically significant interaction was observed between IL6R rs8192284 polymorphism and the presence of anticyclic citrullinated peptide (anti-CCP) antibodies (p = 0.008). An inverse relationship between the polymorphism and DAS28 was observed depending on anti-CCP status. Conclusion. The anti-CCP status in patients with RA determines the association between the IL6R rs8192284 polymorphism and disease activity.

Altered Expression of Wnt Signaling Pathway Components in Osteogenesis of Mesenchymal Stem Cells in Osteoarthritis Patients

Introduction Osteoarthritis (OA) is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs). WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis. Methods MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases. Results Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2) signaling node was present in OA-MSCs. Conclusion Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential.

Alternative splicing and proteolytic rupture contribute to the generation of soluble IL-6 receptors (sIL-6R) in rheumatoid arthritis

OBJECTIVE To describe the relationship between the two mechanisms involved in sIL6R generation in rheumatoid arthritis (RA). METHOD RA patients were selected from a group of subjects genotyped for the rs8192284 SNP, located at the proteolytic cleavage site of IL-6R. sIL6R and protease levels (ADAM17) were measured and the contribution of alternative splicing in the generation of sIL-6R was evaluated through qRT-PCR. RESULT Increased sIL-6R plasma levels and expression of spliced isoform generating sIL-6R are genotype dependent. ADAM17 concentrations were independent of the genotype studied. CONCLUSION Alternative splicing and proteolytic cleavage participate in sIL-6R generation in RA. The rs8192284 polymorphism determines the sIL-6R plasma level through differential proteolytic rupture controlled by ADAM17.

Disminución del tiempo hasta el primer tratamiento con fármacos modificadores de la enfermedad en pacientes con artritis reumatoide

OBJECTIVE To analyze changes in the lag time to first disease modifying antirheumatic drug (DMARD) prescription since onset of symptoms of rheumatoid arthritis (RA) over the last 2 decades in Spain. PATIENTS AND METHOD Review of medical records of 865 patients diagnosed with RA living in Spain and attended in specialty care settings of the National Health System. The principal variable was the lag time between the onset of symptoms of RA and the date of first DMARD therapy prescription. Analyses were performed by year and five-year periods and differences between groups were assessed by χ(2) test, Student t test and analysis of variance. RESULTS Sociodemographic and clinical characteristics corresponded to a typical cross-sectional population of patients diagnosed with RA. The median lag time between symptom onset and first DMARD therapy was 14 months (6-36) for the whole group. However, a significant shortening of time to first DMARD was observed over the last two decades (-4.59±0.2 months by year; P<001). Shortening of time to first DMARD was mainly due to a shortening of time to first visit with specialists since onset of symptoms with a smaller decrease in time from first visit to first prescription of a DMARD agent. CONCLUSIONS A significant shortening in the lag time to first DMARD therapy was observed over the last 2 decades in Spain, being a significant reduction in the time to first visit with a specialists its major cause.

Weather conditions may worsen symptoms in rheumatoid arthritis patients: The possible effect of temperature

OBJECTIVE Patients with rheumatoid arthritis (RA) complain that weather conditions aggravate their symptoms. We investigated the short-term effects of weather conditions on worsening of RA and determined possible seasonal fluctuations. METHODS We conducted a case-crossover study in Madrid, Spain. Daily cases of RA flares were collected from the emergency room of a tertiary level hospital between 2004 and 2007. RESULTS 245 RA patients who visited the emergency room 306 times due to RA related complaints as the main diagnostic reason were included in the study. Patients from 50 to 65 years old were 16% more likely to present a flare with lower mean temperatures. CONCLUSIONS Our results support the belief that weather influences rheumatic pain in middle aged patients.