JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study.

OBJECTIVES: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment. METHODS: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology. RESULTS: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment. CONCLUSION: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.

[Enhancing awareness of the modalities in the management of chronic inflammatory diseases]. / Sensibilisation aux modalités de prise en charge des pathologies inflammatoires chroniques.

From an epidemiologic point of view, the incidence of rheumatoid arthritis in the French regions we studied appears relatively stable and about the same as the prevalence of rheumatoid spondylosis. The incidence of Crohn's disease, among the chronic inflammatory bowel diseases, is currently increasing. Treatment for rheumatoid arthritis, other than symptomatic and maintenance treatments, now includes various specific forms of "biotherapy". Their development was made possible through the decoding of the pathophysiological mechanisms of inflammation and joint destruction, basically involving pro-inflammatory cytokines. Currently, it appears that these treatments should be limited to severe or active progressive rheumatoid arthritis that is resistant to maintenance therapy. For rheumatoid spondylosis, the prescription of anti-TNF alpha agents requires early diagnosis and prognostic assessment of the disease, together with the implementation of an individualized therapeutic strategy for the global multidisciplinary management of each patient. The introduction of immunosuppressors and anti-TNF alpha agents for chronic inflammatory bowel diseases constitutes a major advance in the management of their severe forms, but nevertheless raises the issues of whether their use should be systematic or depend on the severity of the disease. They also require the training of practitioners in their use and monitoring. Patients' groups have requested more collegial decision-making, decompartmentalization of practices, widespread development of health care networks, the development of clinical trials and improved communication. The regional disparities in patient management stem from epidemiologic variations in the demand for care and from social and demographic differences in the populations. They also depend on the overall health-care supply. Health networks can be defined as structures of coordination and non-mandatory, non-hierarchical services to patients that help to improve care and/or prevention by the appropriate involvement of various healthcare professionals. Regional particularities are observed, as is shown by the studies conducted in Brittany, the Loire Valley and Nord Pas-de Calais. The questions regarding the networks do not concern their effectiveness in the management of chronic inflammatory diseases, but their structure, day-to-day operations, and financing.

[Proof of the pharmacodynamic activity of Flector Plaster in healthy volunteers and patients suffering from osteo-arthritis of the knee]. / Mise en évidence de l'activité pharmacodynamique de Flector Tissugel 1% chez des volontaires sains et des patientes souffrant de gonarthrose.

STUDY OF HEALTHY VOLUNTEERS: This double blind study (bioadhesive plaster of diclofenac epolamine versus placebo), showed that the application of diclofenac epolamine for 24 hours induced a selective hypoanalgesic effect on the muscle, proportional to the degree of hypersensitivity to the pain observed in baseline conditions. The enhanced effect on the hyperalgic muscle can be explained by the direct impact of the active ingredient on the nociceptors and/or its inhibiting effect on the local production of prostaglandins. STUDY OF PATIENTS SUFFERING FROM BILATERAL OSTEO-ARTHRITIS OF THE KNEE: In a 24 hour trial of the treatment (bioadhesive plaster impregnated with diclofenac epolamine (Flector Plaster) versus placebo), the active treatment had a significant impact on the spontaneous pain during rest that was enhanced during mouvement. In a longer term trial (72 hours), the regression of the spontaneous pain on the visual analog scale appeared even more significant, still lasting 96 hours after withdrawal of the plaster, not only at rest but also on mouvement.

[Assessment of a topical NSAIDs in the treatment of pain and inflammation. The example of Flector Plaster, a local bioadhesive plaster containing diclofenac epolamine]. / Evaluation d'un anti-inflammatoire non stéroïdien topique dans le traitement de la douleur et de l'inflammation. Exemple de Flector Tissugel 1% dispositif local bioadhésif de diclofénac épolamine.

ADVANTAGES AND INCONVENIENCIES OF TRANSDERMAL SYSTEMS: Regarding the advantages, one notes the reduction or even suppression of the gastro-intenstinal disorders related to the oral administration of non-steroidal anti-inflammatories (NSAIDs), the absence of first pass hepatic effect and the better control of the quantities administered of a strong acting drug. Regarding the inconveniencies, one should bear in mind the impossibility of administering or the diffusion of high doses of irritant or sensitizing molecules on the skin. A preparation for application on the skin must be both hydrophilic and lipophilic, with great solubility in water and affinity for the lipids, as is the case with diclofenac epolamine. FROM AN EXPERIMENTAL POINT OF VIEW: Diclofenac epolamine has demonstrated a strong anti-inflammatory effect in the rat or the rabbit, with transfer following repeated local applications, measurable concentrations in the plasma and adjacent tissues, excellent general tolerance and the safety of the plaster. VARIOUS CLINICAL TRIALS: Have shown that the Flector Plaster is well tolerated and effective in the treatment of epicondylitis, sprained ankles, minor sport-induced trauma and osteo-arthrosis of the knee.

[COART France 2003 report on new socioeconomic data on osteoarthritis in France]. / COART France rapport 2003 sur les nouvelles données socio-économiques de l'arthrose en France.

RISING COSTS: According to the first evaluation of the socioeconomic impact of osteoarthritis in France conducted in 1993, the estimated annual cost was slightly less than one billion euros. In 2003, the annual cost was approximately 1.8 billion euros. Overall costs for osteoarthritis have thus increased by more than 80%, i.e. 8% per year. COST OF OFFICE VISITS: In 2002, 13.4 million office visits for osteoarthritis yielded an overall cost of 270 million euros and led to 17 million drug prescriptions (1.5 per consultation) yielding an overall cost of 574 million euros. HOSPITAL COSTS: With 127,000 acute-care admissions, 175,000 hospital days for day care and/or rehabilitation, and implantation of 118,000 hip or knee prostheses, the overall hospital cost came to 820 million euros in 2002. INDIRECT COSTS: Five million days of sick leave in 2002, in 88% of the cases for peripheral osteoarthritis, led to 180 million euros in indemnities.

[Total hip arthroplasty indication, evaluation criteria for structure modifying trials. Lessons from the ECHODIAH and PHARE studies]. / L'indication de la prothèse totale de hanche, critère principal d'évaluation des traitements structuro-modulateurs. Enseignements des études ECHODIAH et PHARE arthrose.

RADIOLOGICAL EVALUATION CRITERIA: To date, outcome of therapeutic trials examining structure modifying treatments has been basically assessed with repeated measurement of joint spaces on plain x-rays. In the ECHODIAH study, these measurements demonstrated an advantage in favor of treatment with diacerein. Magnetic resonance imaging has not been validated for therapeutic trials. TOTAL ARTHROPLASTY: Total hip replacement has been proposed as an objective evaluation criterion for the efficacy of structure modifying therapy, which raised several criticisms. The PHARE study on the epidemiology of osteoarthritis includes three types of patients referred to orthopedic surgeons for degenerative hip disease and undergoing total hip replacement within three Months. Analysis of data collected should provide a better understanding of the factors leading to implantation of total hip prosthesis in daily practice and help determine the validity of total hip replacement or its indication as the main outcome assessment criterion for therapeutic trials.

[Biological markers of osteoarthritis: data from the ECHODIAH cohort]. / Marqueurs biologiques de l'arthrose: les données de la cohorte ECHODIAH.

CORRELATIONS OF BIOLOGICAL MARKERS: Ten biological markers collected from blood or urine were analysed in the ECHODIAH cohort (patients with hip OA with a 3 Years follow up). In multivariate analysis, after adjustment for age, gender, and body mass index, some markers were found to be significantly correlated with clinical and radiological parameters. C-telopeptide of type II collagen (CTX-II) was correlated with pain, functional impairment, joint space narrowing, and subchondral sclerosis. C-reactive protein was correlated with pain. N-propeptide of type I collagen (PINP) was correlated with functional impairment, and cartilage oligomeric matrix protein (COMP) was correlated with inflammation. PREDICTIVE VALUE OF BIOLOGICAL MARKERS: High levels of urinary C-telopeptide of type II collagen (uCTX-II), a marker of cartilage degradation, and serum hyaluronic acid (sAH), a marker of synovial inflammation, were associated with higher risk of structure degeneration in osteoarthritis patients. Combined assay of these two markers could help identify patients with a higher risk of radiological progression, but many questions remain to be resolved.

[Mechanisms of action of diacerein, the first inhibitor of interleukin-1 in osteoarthritis]. / Les mécanismes d'action de la diacerhéine, premier inhibiteur de l'interleukine 1 dans l'arthrose.

DEGRADATION AND REPAIR: Osteoarthritis generally occurs in a context of an overloaded normal cartilage matrix or normal loading of a vulnerable cartilage matrix. Interleukin-1 appears to be principally indicated in degradation phenomena while transforming growth factor (TGFbeta) is mainly implicated in phenomena of excessive synovial and chondrocyte repair observed at the same time as degradation. MECHANISMS OF ACTION OF DIACEREIN: Diacerein is a slow acting symptomatic treatment of osteoarthritis which has demonstrated efficacy on functional manifestations of osteoarthritis and on the structural component. Two mechanisms of action have been validated: in vitro inhibition of interleukin-1 (IL-1) synthesis, the main cytokine involved in cartilage destruction, and activity on the synthesis of proteoglycans, and hyaluronic acid, the principal component of cartilage. Other studies presented here have provided further details concerning other mechanisms of action of diacerein.

[Management of patients with osteoarthritis: contribution and limitations of clinical and radiological follow-up]. / Prise en charge du patient arthrosique. Intérêt et limites du suivi clinique et radiologique.

THE RHEUMATOLOGIST'S CONTRIBUTION: Several data favor regular referral of patients with osteoarthritis to rheumatology specialists and/or continued follow-up by general practitioners. Important elements include difficulties in establishing the initial diagnosis, technical procedures, and individual adaptation of drugs and/or non-drug treatments. FOLLOW-UP: The different elements of follow-up include the patient's overall opinion concerning disease progression, pain assessment, control of body weight and body mass index, evaluation of joint movement, analysis of treatment efficacy and tolerance, and radiological surveillance to evaluate the rate of progression of joint space narrowing. A NOVEL FOLLOW UP TOOL: An annual follow up visit appears to be advisable in addition to those motivated by acute events. NEGMA-LERADS Laboratories proposes to rhumatologists a novel follow up tool, ART'ROSE, designed to facilitate patient adherence to disease management by focusing attention on priority elements.

[Osteoarthritis, disability, travel and recreational activities: comments from physicians and travel specialists]. / Arthrose, handicap, voyages et loisirs. Le regard des médecins et des professionnels du tourisme.

IMPACT OF DISABILITY: A survey of general practitioners, rheumatology specialists, and tourism specialists conducted by NEGMA-LERADS Laboratories demonstrated that subjects with osteoarthritis avoid vacation trips more readily than recreational activities. VACATION TRIPS ARE STILL POSSIBLE: Certain tourism organisms have nevertheless developed specialized services for disabled persons. Special emphasis is placed on adequate preparation before the vacation trip. PROBLEMS WITH WALKING: Many persons disabled by osteoarthritis do not require a wheel chair, yet have difficulty walking long distances. It is important to recognize the specific disabilities related to osteoarthritis and their effects on grip force and/or ambulation.