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.

[Epidemiological data on anaemia during malignant affections]. / Données épidémiologiques sur l'anémie dans les affections malignes.

FREQUENT IN THE CASE OF CANCER: According to a European multicentre study on 15 000 cancer patients, the percentage of anaemia exceeded 66% during the development of solid tumours and 72% during development of malignant tumours. The lowest levels of haemoglobin were correlated with the lowest performance status, however no treatment had been prescribed for anaemia in the majority of patients. MULTIPLE MYELOMAS AND LYMPHOMAS: The frequency of anaemia appeared just as high during these malignant affections and the correlation between haemoglobin levels and performance status was just as clear. Likewise, around one half of the anaemic patients had not been treated in an adapted or efficient manner. SIGNIFICANCE OF ANEMIA DURING LYMPHOMAS: It appeared that the anaemia of Hodgkin's disease, related to the inflammation, was correlated with shorter survival, whereas the anaemia of non-hodgkin lymphoma, related to medullar infiltration, generally affected the complete rate of response.

[The basis of treatment with recombinant human erythropoietin]. / Les bases du traitement par l'érythropoïétine humaine recombinante.

EXPERIMENTAL DATA: A line of transgenic mice overexpressing erythropoietin was created. These mice retained their capacity to reduce their gastro-intestinal absorption of iron and to regulate the changes in their iron metabolism and they could serve as a model for the in vivo study of iron homeostasis and erythropoiesis. NEW INDICATIONS FOR RECOMBINANT HUMAN ERYTHROPOIETIN: After chronic terminal kidney failure, the treatment of chronic dialysed kidney failure patients and patients treated with azathioprine or patients having undergone surgery and requiring transfusion, other indications have been proposed. Such as anaemia in children following inadequate production of endogenous erythropoietin and/or direct inhibition of the erythroid cell line in the bone marrow or anaemia during pregnancy and, since the Sixties, anaemia during cancer. TO ASSESS THE PHYSIOPATHOLOGY OF ANEMIA:In anaemic patients suffering from a malignant blood disease, it would be useful to calculate the relationship between the predicted and observed rates of erythropoietin as well as the transferin serum receptors.

[The benefits of treatment with recombinant human erythropoietin in cancer patients]. / Les bénéfices des traitements par l'érythropoïétine humaine recombinante chez les patients cancéreux.

IMPROVED QUALITY OF LIFE WITH EPOETIN BETA: In a study against a placebo, there was evidence that the quality of life scores were significantly improved in patients treated with epoetin beta, whether they exhibited a solid tumour or a malignant lymphoma. The same was noted in children with cancer exhibiting severe neoplasia and treated with chemotherapy. The efficacy and tolerance to treatment were equivalent, whatever the administration regimen. IN PATIENTS SUFFERING FROM MYELODYSPLASTIC SYNDROMES: A particular entity among malignant blood diseases, myelodysplastic syndromes are at the origin of anaemia against which repeated transfusions and growth factors are proposed with varying results and disadvantages, and against which erythropoietin may be moderately effective (a mean of 25% in non-selected cohorts of patients). DEPENDING ON THE PROTOCOLS OF ERYTHROPOIETIN ADMINISTRATION IN CASES OF MYELODYSPLASTIC SYNDROMES: Recombinant human erythropoietin, irrespective of its concentration in myelodysplastic cell culture, does not appear capable of restoring normal erythropoiesis. The influence of prolonged treatment is not admitted by all. The effects of the addition of growth factors (notably G-CSF) are obvious but some are controversial because of the costs and the prolonged duration of such treatments.

[The problem of acquired aplastic anaemia]. / Le problème des anémies aplastiques acquises.

PURE RED CELL APLASIA: Designated by the acronym PRCA or the term erythroblastopenia, pure red cell aplasia is characterised by severe anaemia with reticulocytopenia. It may occur in acute form induced by infectious agents, following drug toxicity or transplantation of allogeneic haematopoietic cells, associated with autoimmune haemolytic anaemia. The chronic form is rarely constitutional but can be acquired and is usually associated with blood or idiopathic diseases. IMMUNOLOGICAL INHIBITION OF ERYTHROPOIESIS: Among the mechanisms responsible for PRCA is immunological erythropoiesis inhibition. This may be of lymphocyte T cell origin or due to the presence of antibodies in the patient's serum. Although observations of PRCA with presence of neutralising antierythropoietin antibodies in patient's serum have multiplied over the past 5 years, they still remain extremely rare. From a therapeutic point of view, they require withdrawal of epoetin and often the administration of immunosuppressors and transfusion for symptomatic treatment. GROWTH FACTORS: The role of growth factors in restoring aplastic anaemia appears to be only partial, at random and temporary.

[rHU-EPO in cancer patients. Target or wider use?]. / rHu-EPO chez les patients cancéreux. Utilisation ciblée ou plus large?

THE DEBATE: Although some believe that rHu-EPO should not be widely used in malignant affections, others think that because of the varied impact of these anaemia, its wider use should be recommended. FOR A TARGET USE: Various observations (influence of the degree of extension of the myelomas to the skeleton and response to specific treatment in the case of myeloma, whatever the haemoglobin concentration, degree of prevention of rHu-EPO chemo-induced anaemia) are in favour of its use in selected patients. FOR A WIDER USE: The benefits of treatment with rHu-EPO are not limited to the symptomatology of anaemia but extend to its potential complications in the most fragile patients. Other than the risks of infection, the heavy costs of transfusions must also be taken into account.

[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.

[Life expectancy and aging, scientific and medical aspects]. / Longévité et vieillissement, aspects scientifiques et médicaux.

STUDIES ON THE BIOLOGY OF AGING: According to species demonstrate the role of certain synchronizers, such as calory restrictions, genetic modifications and environmental and living conditions. FUNCTIONAL OR PROTEIN GENOMICS: Are aimed at listing the human proteins and their localization. Study of the variations in proteome according to age has also been envisaged. Research on chronic (cardiovascular, and neurodegenerative or metabolic) diseases with multifactor causes (related both to environmental conditions and genetic sensitivity) must be accelerated. CELL SENESCENCE: Is expressed by the blocking of the mitosis signal, with modification in gene expression, and alteration in phenotype; it could be an anti-cancer mechanism, like apoptosis. THERE IS AN OBVIOUS RELATIONSHIP BETWEEN AGING AND CANCER: However the latter is not a consequence of aging, even if the absence of telomerase (enzyme maintaining DNA length) is observed in both cases. TO PERMIT HARMONIOUS AND GOOD QUALITY AGING: It is essential to intensify the screening and prevention of deficiencies and pathological phenomena in elderly subjects, notably cerebral aging and dementia, cardiovascular aging, osteo-articular diseases....