Playing jeopardy by not treating the whole person with arthritis

Availability of potent medications, earlier diagnosis and use of drug combinations should have made rheumatoid arthritis yesterday’s disease. Unfortunately the majority of patients never reach remission. The focus of treatment has been based on the biomedical model aiming to reduce inflammation, regulate the immune system, and prevent joint damage – all worthy outcomes. A whole person care approach would add to patient care by including attention to the psychosocial aspects of illness that contribute to clinical outcomes. Two studies using data from a longitudinal cohort followed out to four years with early arthritis patients will be highlighted. The first identified predictors of pain one year after baseline in 211 patients. While overall pain decreased over time, emotion-oriented coping contributed to pain intensity and affective pain. The second study examined the link between depression and clinical outcomes four years later using data from 275 patients. It was found that when depression persisted into the first year it was the most potent predictor of disease activity at each follow-up visit. Moreover, the proportion of patients who ever reached remission decreased from 84.3% to 31.3% for patients with depressive symptoms at 12 months. vailability of potent medications, earlier diagnosis and use of drug combinations should have made rheumatoid arthritis yesterday’s disease.   Unfortunately the majority of patients never reach remission. The focus of treatment has been based on the biomedical model aiming to reduce inflammation, regulate the immune system, and prevent joint damage – all worthy outcomes. A whole person care approach would add to patient care by including attention to the psychosocial aspects of illness that contribute to clinical outcomes.   Two studies using data from a longitudinal cohort followed out to four years with early arthritis patients will be highlighted. The first identified predictors of pain one year after baseline in 211 patients. While overall pain decreased over time, emotion-oriented coping contributed to pain intensity and affective pain. The second study examined the link between depression and clinical outcomes four years later using data from 275 patients. It was found that when depression persisted into the first year it was the most potent predictor of disease activity at each follow-up visit. Moreover, the proportion of patients who ever reached remission decreased from 84.3% to 31.3% for patients with depressive symptoms at 12 months.  It is recommended that both curing and healing be considered when treating arthritis patients given the importance of psychosocial factors to the trajectory of the disease. This could be done by screening for and treating depression in arthritis patients. Antidepressant medications and/or psychological interventions such as Mindfulness-Based Stress Reduction or Cognitive Behavioural Therapy are options to be considered

Caractérisation et immunogénicité de l'autoantigène Ro et signification clinique des autoanticorps anti-Ro

La production d'anticorps dirigés contre l'autoantigène Ro, un ensemble de ribonucléoprotéines formées par l'association d'un polypeptide antigénique de 60 kiloDalton (kD) et de 4 ARNs de petit poids moléculaire (hY1, hY3, hY4, et hY5), représente l'une des manifestations sérologiques les plus fréquentes chez les patients atteints de collagénoses telles que le Lupus Erythémateux Disséminé (LED) et le syndrome de Sjögren (SS). Nous avons tenté au cours de ce travail d'aider à définir les conditions menant à la formation de ces anticorps et à raffiner leurs corrélations cliniques. Dans un premier temps, nous avons mis en évidence une hétérogénéité immunologique des anticorps anti-Ro qui correspond à une hétérogénéité biochimique des ribonucléoprotéines Ro. En particulier, nous avons démontré qu'une proportion significative des autoanticorps anti-Ro sont dirigés contre des déterminants antigéniques présents uniquement sur la ribonucléoprotéine contenant l'ARN hY5 (RohY5) intacte. Ce déterminant antigénique n'est présent ni sur les composantes protéiniques (Ro ou La) et ARN (hY5) isolées, ni sur les autres ribonucléoprotéines Ro, qu'elles soient d'origine humaine ou animale. Cette population d'anti-Ro représente donc de véritables AUTOanticorps qui, de plus, reconnaissent spécifiquement des déterminants conformationnels. Dans un travail antérieur complété par Sylvie Lapointe, nous avions démontré que la majorité des sera anti-Ro contiennent des anticorps dirigés contre des déterminants conformationnels sur l'antigène Ro de 60 kD. Afin de tenir compte de ces nouvelles données, nous proposons que les stimuli conduisant à la production de certains autoanticorps impliquent une immunisation directe par un autoantigène intact. Afin de préciser les éléments structurels ou fonctionnels qui favorisent l'immunogénicité des ribonucléoprotéines RohY5, nous avons développé une technique de purification biochimique qui nous a permis d'obtenir et de caractériser ces ribonucléoprotéines intactes. Nous avons ainsi démontré que les ribonucléoprotéines Ro présentent un poids moléculaire apparent beaucoup plus élevé que la somme de leurs constituantes individuelles, suggérant une dimérisation de ces constituantes ou une association avec des protéines non encore caractérisées. De plus, nous avons démontré que la ribonucléoprotéine Rohy5 est associée de façon stable avec la protéine La. Cette dernière observation pourrait expliquer la fréquente production concomitante des anticorps anti-Ro, anti-RohY5, et anti-La, et constitue un nouvel argument en faveur de l'immunogénicité de la ribonucléoprotéine Rohy5 intacte. Dans un deuxième temps, nous avons voulu définir plus précisément la signification clinique de la production d'autoanticorps anti-Ro. Dans une étude pilote, nous avons observé qu'en comparaison avec un groupe de patients rhumatoïdes non producteurs d'anti-Ro appariés pour l'âge, les rhumatoïdes producteurs d'anti-Ro présentaient des caractéristiques démographiques et articulaires semblables mais présentaient une fréquence plus élevée de manifestations extra-articulaires. Pour donner suite à ces données préliminaires, nous avons établi une étude de cohorte portant sur toute la population de patients atteints de PR soignés à l'Unité des Maladies Rhumatismales (UMR) du Centre Hospitalier Universitaire de Sherbrooke (CHUS). À l'aide des résultats de notre étude pilote, nous avons défini 5 manifestations cibles pré-établies: 1) développement de LED/PR, 2) manifestations vasculitiques, 3) abaissement simultané des composantes C3 et C4 du complément, 4) leucopénie persistante (moins de 4.0 x 109\L) non reliée à la prise d'une médication myélotoxique, et 5) mise au monde d'un enfant atteint de lupus néonatal avec ou sans bloc atrioventriculaire cardiaque congénital (bloc AV). Nous avons ainsi établi qu'un échantillon de 292 patients (intervalle de 180 à 600 selon les hypothèses) permettrait de détecter, avec une puissance de 80%, une différence significative à 5% entre les patients rhumatoïdes producteurs et non-producteurs d'anti-Ro. Entre Novembre 1985 et Mai 1987, trois cent trois patients rhumatoïdes consécutifs ont été évalués, desquels 278 (91.7%) ont été inclus. Les patients inclus représentent un reflet non biaisé de la population rhumatoïde suivie par l'UMR, et présentent des caractéristiques cliniques comparables à celles d'autres populations Nord-Américaines de rhumatoïdes. Neuf patients (3.2%) produisaient des anticorps anti-Ro détectables par double immunodiffusion en gel d'agarose (ID). Ces 9 patients rhumatoïdes producteurs d'anti-Ro avaient des caractéristiques démographiques et articulaires semblables au groupe contrôle; ils présentaient toutefois plus fréquemment des manifestations de SS. Globalement, les patients producteurs d'anti-Ro avaient un risque relatif (RR) de 7.87 (p?0.001) de présenter l'une ou l'autre des manifestations cibles, notamment un abaissement simultané de C3 et de C4 (RR 2.30), une leucopénie en cours d'évolution (RR 6.64) et du purpura non thrombocytopénique de type vasculite leucocytoclasique (RR 44.83). Seuls des patients producteurs d'anti-Ro ont donné naissance à un enfant atteint de bloc AV (1 patiente) et développé un syndrome de chevauchement LED\PR caractérisé par le développement d'un lupus érythémateux cutané subaigu (LECS) (1 patient). De façon intéressante, les patients producteurs d'anti-Ro avaient aussi un risque plus élevé de présenter une photosensibilité marquée (RR 19.93) et d'être traités avec des doses élevées de corticostéroïdes et/ou avec des immunosuppresseurs (RR 2.37). Compte tenu de l'hétérogénéité biochimique et immunologique que nous avons démontrée dans le système Ro/anti-Ro, nos résultats obtenus par la technique relativement peu sensible de l'ID pourraient être raffinés par l'utilisation de techniques de détection plus sophistiquées. Notre travail ouvre de larges possibilités de recherche fondamentale pour définir les caractéristiques structurelles et fonctionnelles qui déterminent l'immunogénicité de l'autoantigène Ro. De même, il devient possible de définir la sensibilité et la spécificité de nouvelles techniques pour la détection des anti-Ro ainsi que d'établir leur utilité clinique éventuelle. C'est dans cette voie que nous sommes maintenant engagés

A novel approach to measure the contribution of matrix metalloproteinase in the overall net proteolytic activity present in synovial fluids of patients with arthritis

Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity, and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis

Mindfulness-Based Reduction Stress Reduction for Patients with Rheumatoid Arthritis and Depressive Symptoms: a Pilot Trial

Background : Despite their efficacy at controlling joint inflammation, current treatments of rheumatoid arthritis (RA) leave up to 40% of patients into non-remission. Non-remission, frequently due to persistently negative self-reported impact of RA, was found to be associated with significant persistent depressive symptoms 6-7 months after initiation of arthritis treatment. Mindfulness-Based Stress Reduction (MBSR) is proposed to improve depressive symptoms and RA-related clinical outcomes. To pave the way for an eventual randomized controlled trial, a feasibility and acceptability study of MBSR has been realized. Methods: A standardized 8-week MBSR program was offered to groups of patients with controlled inflammatory disease but high levels of depressive symptoms.Qualitative interviews based on a theoretical framework of acceptability were conducted. Change in depressive symptoms (CES-D tool), fatigue and pain (SF-36), anxiety (GAD-7), pain, disease activity (PtVAS and SDAI scores) was measured over a 6-month period. Results: 27 patients have been recruited (3 distinct MBSR groups). Factors leading to a higher rate of success in recruitment were identified. Despite the small sample, the intervention was found to have a clear impact on depressive symptoms (p=0.004), anxiety (p=0.005), and social functioning (from the SF-36; p=0.04). Patients reported that MBSR gave them the opportunity to control their reactions in face of stressful situations.Perceptions were almost uniformly positive towards MBSR, and most appear to have integrated some part of the intervention in their daily life. Conclusions: Although recruitment was challenging, a MBSR trial on depressed patients with controlled inflammatory disease was found acceptable and feasible within this population. Preliminary clinical results showed positive impacts of such intervention. 

Retropseudogenes derived from the human Ro/SS-A autoantigen-associated hY RNAs

We report the characterization in the human genome of 966 pseudogenes derived from the four human Y (hY) RNAs, components of the Ro/SS-A autoantigen. About 95% of the Y RNA pseudogenes are found in corresponding locations on the chimpanzee and human chromosomes. On the contrary, Y pseudogenes in mice are both infrequent and found in different genomic regions. In addition to this rodent/primate discrepancy, the conservation of hY pseudogenes relative to hY genes suggests that they occurred after rodent/primate divergence. Flanking regions of hY pseudogenes contain convincing evidence for involvement of the L1 retrotransposition machinery. Although Alu elements are found in close proximity to most hY pseudogenes, these are not chimeric retrogenes. Point mutations in hY RNA transcripts specifically affecting binding of Ro60 protein likely contributed to their selection for direct trans retrotransposition. This represents a novel requirement for the selection of specific RNAs for their genomic integration by the L1 retrotransposition machinery. Over 40% of the hY pseudogenes are found in intronic regions of protein-coding genes. Considering the functions of proteins known to bind subsets of hY RNAs, hY pseudogenes constitute a new class of L1-dependent non-autonomous retroelements, potentially involved in post-transcriptional regulation of gene expression

Anti-Sa antibodies and antibodies against cyclic citrullinated peptide are not equivalent as predictors of severe outcomes in patients with recent-onset polyarthritis

The prognostic value of two antibodies targeting citrullinated antigens, anti-Sa and anti-cyclic citrullinated peptide (CCP), present at inclusion, was evaluated prospectively in a cohort of 165 consecutive patients with recent-onset or early polyarthritis (EPA) followed for up to 30 months. Patients were treated according to current Good Clinical Practice standards. Predefined outcomes were severe arthritis and persistent arthritis. At inclusion, a median of 3 months after disease onset, 133 (81%) patients fulfilled at least four American College of Rheumatology criteria for rheumatoid arthritis and 30 (18%) had erosive changes on radiographs of hands and feet. Disease-modifying anti-rheumatic drugs were used in close to 80% of the patients at 30 months. Joint damage increased linearly over time, whereas disease activity declined markedly and remained low at each follow-up. Autoantibodies were identified in 76 (46%) patients: rheumatoid factor (RF) in 68 (41%), anti-CCP in 53 (33%), and anti-Sa in 46 (28%). All three antibodies were correlated, but anti-Sa antibodies best predicted severity at 18 and 30 months. RF and anti-CCP performed less well. For both outcomes, anti-Sa alone performed better than any combination of antibodies. The presence of any autoantibody identified about 50 to 60% of the patients with poor outcomes. In multivariate analysis, anti-Sa (odds ratio (OR) 8.83), the presence of erosions at inclusion (OR 3.47) and increasing age (OR 1.06/year) were significantly associated with severity, whereas RF and anti-CCP were not significant predictors. Persistent arthritis was present in up to 84% of patients; autoantibodies were specific but poorly sensitive predictors of this outcome. We conclude that assays for antibodies against citrullinated antigens differ in their ability to predict poorer outcomes in patients with EPA. In our EPA cohort treated in accordance with current standards, detection of anti-Sa but not of RF or anti-CCP antibodies, in combination with clinical and radiological variables present at the first encounter, allowed the identification of a subgroup of EPA patients suffering more rapid and more severe joint damage over 30 months

Durand et al 2012 Supplemental figures

Objective. Our objective was to compare the osteoclastogenic capacity of peripheral blood mononuclear cells (PBMCs) from patients with osteoarthritis (OA) to that of PBMCs from self-reported normal individuals. Methods. PBMCs from 140 patients with OA and 45 healthy donors were assayed for CD14+ expression and induced to differentiate into osteoclasts (OCs) over 3 weeks in vitro. We assessed the number of the OCs, their resorptive activity, OC apoptosis, and expression of the following cytokine receptors: receptor activator of nuclear factor κB (RANK), interleukin-1 receptor type I (IL-1R1) and IL-1R2. A ridge logistic regression classifier was developed to discriminate OA patients from controls. Results. PBMCs from OA patients gave rise to more OCs that resorbed more bone surface than did PBMCs from controls. The number of CD14+ precursors was comparable in both groups, but there was less apoptosis in OCs obtained from OA patients. Although no correlation was found between osteoclastogenic capacity and clinical or radiologic scores, levels of IL-1R1 were significantly lower in cultures from patients with OA compared to controls. OC apoptosis and expression levels of IL-1R1 and IL-1R2 were used to build a multivariate predictive model for OA. Conclusion. During 3 weeks of culture under identical conditions, monocytes from patients with OA display enhanced capacity to generate OCs compared to cells from controls. Enhanced osteoclastogenesis is accompanied by increased resorptive activity, reduced OC apoptosis and diminished IL-1R1 expression. These findings support the possibility that generalized changes in bone metabolism affecting OCs participate in the pathophysiology of OA

Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity

Abstract Introduction Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives. Methods Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry. Results We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait. Conclusions The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity

Feasibility and safety of a 6-month exercise program to increase bone and muscle strength in children with juvenile idiopathic arthritis

Background: Arthritis in childhood can be associated with muscle weakness around affected joints, low bone mass and low bone strength. Exercise is recognized as an important part of management of children with juvenile idiopathic arthritis (JIA) but the exercise prescription to best promote bone and muscle health is unknown. We therefore aimed to: 1. assess feasibility and safety of a 6-month home- and group-based exercise program for children with JIA; 2. estimate the effect of program participation on bone mass and strength, muscle function and clinical outcomes and 3. determine if any positive changes in bone and muscle outcomes are maintained 6 months later. Methods: We recruited 24 children with JIA who were part of the Linking Exercise, Physical Activity and Pathophysiology in Childhood Arthritis (LEAP) study to participate in a 6-month home-based exercise program involving jumping and handgrip exercises, resistance training and one group exercise session per month. We assessed lumbar spine bone mass (dual energy X-ray absorptiometry), distal tibia and radius bone microarchitecture and strength (high-resolution peripheral quantitative computed tomography), muscle function (jumping mechanography, dynamometry) and clinical outcomes (joint assessment, function, health-related quality of life) at baseline, 6- and 12-months. Adherence was assessed using weekly activity logs. Results: Thirteen children completed the 6-month intervention. Participants reported 9 adverse events and post-exercise pain was rare (0.4%). Fatigue improved, but there were no other sustained improvements in muscle, bone or clinical outcomes. Adherence to the exercise program was low (47%) and decreased over time. Conclusion: Children with JIA safely participated in a home-based exercise program designed to enhance muscle and bone strength. Fatigue improved, which may in turn facilitate physical activity participation. Prescribed exercise posed adherence challenges and efforts are needed to address facilitators and barriers to participation in and adherence to exercise programs among children with JIA. Trial registration: Data of the children with JIA are from the LEAP study (Canadian Institutes of Health Research (CIHR; GRANT# 107535). http://www.leapjia.com/