On the estimation of the effect of weight change on a health outcome using observational data, by utilising the target trial emulation framework.

BACKGROUND/OBJECTIVES: When studying the effect of weight change between two time points on a health outcome using observational data, two main problems arise initially (i) 'when is time zero?' and (ii) 'which confounders should we account for?' From the baseline date or the 1st follow-up (when the weight change can be measured)? Different methods have been previously used in the literature that carry different sources of bias and hence produce different results. METHODS: We utilised the target trial emulation framework and considered weight change as a hypothetical intervention. First, we used a simplified example from a hypothetical randomised trial where no modelling is required. Then we simulated data from an observational study where modelling is needed. We demonstrate the problems of each of these methods and suggest a strategy. INTERVENTIONS: weight loss/gain vs maintenance. RESULTS: The recommended method defines time-zero at enrolment, but adjustment for confounders (or exclusion of individuals based on levels of confounders) should be performed both at enrolment and the 1st follow-up. CONCLUSIONS: The implementation of our suggested method [adjusting for (or excluding based on) confounders measured both at baseline and the 1st follow-up] can help researchers attenuate bias by avoiding some common pitfalls. Other methods that have been widely used in the past to estimate the effect of weight change on a health outcome are more biased. However, two issues remain (i) the exposure is not well-defined as there are different ways of changing weight (however we tried to reduce this problem by excluding individuals who develop a chronic disease); and (ii) immortal time bias, which may be small if the time to first follow up is short.

Disease evolution in systemic juvenile idiopathic arthritis: an international, observational cohort study through JIRcohort.

BACKGROUND: Systemic juvenile idiopathic arthritis (systemic JIA) is a severe disease with both systemic and joint inflammation. This study aims to identify predictors of disease evolution within the systemic JIA population enrolled in the Juvenile Inflammatory Rheumatism cohort (JIRcohort). METHODS: Observational patient cohort study with 201 recruited children from 4 countries (3 European, 1 North Africa) from 2005 until 2019, using retrospectively (2005-2015) and prospectively (2015-2019) routine care collected data. RESULTS: Sixty-five patients with complete follow-up data for 24 months after first diagnosis were classified as monophasic (n = 23), polyphasic (n = 6) or persistent group (n = 36) corresponding to their evolution (unique flare, recurrent flares, or persistent disease activity respectively). The patients of the persistent group were more likely to have an earlier disease onset, before the age of 6 (OR 2.57, 95%-CI 0.70-9.46), persistence of arthritis at 12-months post-diagnosis (OR 4.45, 95%-CI 0.58-34.20) and higher use of synthetic DMARD (sDMARD, OR 5.28, 95%-CI 1.39-20.01). Other variables like global assessment by physician and by patient and C Reactive Protein levels at 12-months post-diagnosis were assessed but without any predictive value after adjusting for confounding factors. CONCLUSIONS: Our results suggest that the earlier disease onset, the persistence of arthritis throughout the first year of disease evolution and the need of sDMARD might predict a persistent disease course.

French National Diagnostic and Care Protocol for antiphospholipid syndrome in adults and children.

Antiphospholipid syndrome (APS) is a chronic autoimmune disease involving vascular thrombosis and/or obstetric morbidity and persistent antibodies to phospholipids or certain phospholipid-associated proteins. It is a rare condition in adults and even rarer in children. The diagnosis of APS can be facilitated by the use of classification criteria based on a combination of clinical and biological features. APS may be rapidly progressive with multiple, often synchronous thromboses, resulting in life-threatening multiple organ failure. This form is known as "catastrophic antiphospholipid syndrome" (CAPS). It may be primary or associated with systemic lupus erythematosus (associated APS) and in very rare cases with other systemic autoimmune diseases. General practitioners and paediatricians may encounter APS in patients with one or more vascular thromboses. Because APS is so rare and difficult to diagnosis (risk of overdiagnosis) any suspected case should be confirmed rapidly and sometimes urgently by an APS specialist. First-line treatment of thrombotic events in APS includes heparin followed by long-term anticoagulation with a VKA, usually warfarin. Except in the specific case of stroke, anticoagulants should be started as early as possible. Any temporary discontinuation of anticoagulants is associated with a high risk of thrombosis in APS. A reference/competence centre specialised in autoimmune diseases must be urgently consulted for the therapeutic management of CAPS.

French national diagnostic and care protocol for Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis with a particular tropism for the coronary arteries. KD mainly affects male children between 6 months and 5 years of age. The diagnosis is clinical, based on the international American Heart Association criteria. It should be systematically considered in children with a fever, either of 5 days or more, or of 3 days if all other criteria are present. It is important to note that most children present with marked irritability and may have digestive signs. Although the biological inflammatory response is not specific, it is of great value for the diagnosis. Because of the difficulty of recognising incomplete or atypical forms of KD, and the need for urgent treatment, the child should be referred to a paediatric hospital as soon as the diagnosis is suspected. In the event of signs of heart failure (pallor, tachycardia, polypnea, sweating, hepatomegaly, unstable blood pressure), medical transfer to an intensive care unit (ICU) is essential. The standard treatment is an infusion of IVIG combined with aspirin (before 10 days of fever, and for a minimum of 6 weeks), which reduces the risk of coronary aneurysms. In case of coronary involvement, antiplatelet therapy can be maintained for life. In case of a giant aneurysm, anticoagulant treatment is added to the antiplatelet agent. The prognosis of KD is generally good and most children recover without sequelae. The prognosis in children with initial coronary involvement depends on the progression of the cardiac anomalies, which are monitored during careful specialised cardiological follow-up.

French practical guidelines for the diagnosis and management of relapsing polychondritis.

Relapsing polychondritis is a rare systemic disease. It usually begins in middle-aged individuals. This diagnosis is mainly suggested in the presence of chondritis, i.e. inflammatory flares on the cartilage, in particular of the ears, nose or respiratory tract, and more rarely in the presence of other manifestations. The formal diagnosis of relapsing polychondritis cannot be established with certainty before the onset of chondritis, which can sometimes occur several years after the first signs. No laboratory test is specific of relapsing polychondritis, the diagnosis is usually based on clinical evidence and the elimination of differential diagnoses. Relapsing polychondritis is a long-lasting and often unpredictable disease, evolving in the form of relapses interspersed with periods of remission that can be very prolonged. Its management is not codified and depends on the nature of the patient's symptoms and association or not with myelodysplasia/vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS). Some minor forms can be treated with non-steroidal anti-inflammatory drugs, or a short course of corticosteroids with possibly a background treatment of colchicine. However, the treatment strategy is often based on the lowest possible dosage of corticosteroids combined with background treatment with conventional immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil, rarely cyclophosphamide) or targeted therapies. Specific strategies are required if relapsing polychondritis is associated with myelodysplasia/VEXAS. Forms limited to the cartilage of the nose or ears have a good prognosis. Involvement of the cartilage of the respiratory tract, cardiovascular involvement, and association with myelodysplasia/VEXAS (more frequent in men over 50years of age) are detrimental to the prognosis of the disease.

French recommendations for the management of non-infectious chronic uveitis.

This French National Diagnostic and Care Protocol (NDPC) includes both pediatric and adult patients with non-infectious chronic uveitis (NICU) or non-infectious recurrent uveitis (NIRU). NICU is defined as uveitis that persists for at least 3 months or with frequent relapses occurring less than 3 months after cessation of treatment. NIRU is repeated episodes of uveitis separated by periods of inactivity of at least 3 months in the absence of treatment. Some of these NICU and NIRU are isolated. Others are associated with diseases that may affect various organs, such as uveitis associated with certain types of juvenile idiopathic arthritis, adult spondyloarthropathies or systemic diseases in children and adults such as Behçet's disease, granulomatoses or multiple sclerosis. The differential diagnoses of pseudo-uveitis, sometimes related to neoplasia, and uveitis of infectious origin are discussed, as well as the different forms of uveitis according to their main anatomical location (anterior, intermediate, posterior or panuveitis). We also describe the symptoms, known physiopathological mechanisms, useful complementary ophthalmological and extra-ophthalmological examinations, therapeutic management, monitoring and useful information on the risks associated with the disease or treatment. Finally, this protocol presents more general information on the care pathway, the professionals involved, patient associations, adaptations in the school or professional environment and other measures that may be implemented to manage the repercussions of these chronic diseases. Because local or systemic corticosteroids are usually necessary, these treatments and the risks associated with their prolonged use are the subject of particular attention and specific recommendations. The same information is provided for systemic immunomodulatory treatments, immunosuppressive drugs, sometimes including anti-TNFα antibodies or other biotherapies. Certain particularly important recommendations for patient management are highlighted in summary tables.

Two pediatric cases of multisystem inflammatory-like syndrome following COVID-19 vaccination.

Multisystem inflammatory syndrome in children (MIS-C) is a novel post-infectious disease occurring in the context of SARS-CoV2 infection. COVID-19 vaccines have been authorized since December 2020, and adverse events including myocarditis have been reported following vaccination. We describe the cases of two pediatric patients presenting with clinical and laboratory features suggestive of MIS-C a few days after receiving their first dose of the Pfizer BNT162b2 vaccine. The outcome was favorable for both patients (after corticosteroid and immunoglobulin administration for one patient). These cases suggest an association between the COVID-19 vaccine and the occurrence of MIS-C.

[Autoinflammatory diseases associated with RIPK1 mutations: A review of the literature]. / Revue de la littérature sur les maladies auto-inflammatoires associées aux mutations du gène RIPK1.

Autoinflammatory diseases related to RIPK1 mutations have been recently described. Two distinct clinical phenotypes have been reported and depend on the type and location of the mutation. When the mutation is recessive with loss of function, patients develop a combined phenotype of immune deficiency with recurrent bacterial and fungal infections and signs of early inflammatory bowel disease, non-erosive polyarthritis and growth retardation. On the other hand, when the mutation is dominant, gain of function, the manifestations are only auto-inflammatory with extensive lymphoproliferation, oral lesions such as aphthosis or ulcers, abdominal pain and hepatosplenomegaly. The mutations described for the dominant form affect only the cleavage site of caspase 8 and the clinical phenotype is called CRIA for Cleavage-Resistant RIPK1-Induced Autoinflammatory syndrome. The recessive form is severe and life-threatening requiring hematopoietic stem cell transplantation while the dominant form responds well to interleukin-6 receptor antagonists. Thus, RIPK1 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because of their recent description, these diseases can be suspected by an internist, in front of recurrent digestive features and will be increasingly diagnosed in the future through the integration of this gene in the diagnostic chips dedicated to autoinflammatory diseases and early inflammatory bowel diseases, using next generation sequencing.

[Transition from pediatric to adult care: Recommendations of the French network for autoimmune and autoinflammatory diseases (FAI2R)]. / La transition de la pédiatrie à l'âge adulte : recommandations de prise en charge de la filière des maladies auto-immunes et auto-inflammatoires rares FAI2R.

Autoimmune and autoinflammatory diseases (AIDs) are a heterogeneous group of diseases. They can occur in childhood and account for significant morbidity and mortality. Transitioning from pediatric to adult healthcare can be difficult for patients and their families. It can interfere with patient follow-up and management, and eventually lead to complications. Although recommendations exist for the successful transition of patients with chronic diseases, few are specifically adapted to children and adults with AIDs (Suris et al., 2015-Solau-Gervais, 2012). The French working group on transition of the rare autoimmune and autoinflammatory diseases presents its reflections and recommendations for a successful transition. Preparation for transition should start early. Its goals are to empower adolescents by providing them with the knowledge to manage their own care, respond appropriately to changes in their condition, and evolve within the adult healthcare system. This requires the active participation of the patient, his or her family, as well as the pediatric and adult medical teams. The transition process involves multidisciplinary care and dedicated therapeutic education programs. Finally, the identification of medical specialists by region, trained in rare AIDs and accompanied by expert patients, may improve the management of patients with rare AIDs from adolescence to adulthood.

[Human papillomavirus and systemic lupus erythematosus]. / Papillomavirus humain et lupus érythémateux systémique.

Infection with human papillomavirus (HPV) is one of the most widespread sexually transmitted diseases and the main risk factor for cervical cancer. Underlying conditions, like immunosuppression, favour the persistence and the progression of cervical lesions to an aggressive form. Patients with autoimmune diseases, and particularly systemic lupus erythematosus (SLE), may be prone to HPV infection and cervical dysplasia. However, the risk factors for developing persistent HPV-related infection, dysplasia and cancer are not identified for patients with SLE. The existence of an increased risk of cervical cancer compared to the general population remains debated. Thus, HPV vaccine is recommended for SLE patients as well as for the general population. Vaccine coverage of SLE patients is not known in France. Adolescents with chronic health condition seem to be insufficiently vaccinated regarding their vulnerability to infectious diseases. Strategies are required to decrease HPV vaccination barriers.

Protracted viral shedding and viral load are associated with ICU mortality in Covid-19 patients with acute respiratory failure.

BACKGROUND: Protracted viral shedding is common in hospitalized patients with COVID-19 pneumonia, and up to 40% display signs of pulmonary fibrosis on computed tomography (CT) after hospital discharge. We hypothesized that COVID-19 patients with acute respiratory failure (ARF) who die in intensive care units (ICU) have a lower viral clearance in the respiratory tract than ICU patients discharged alive, and that protracted viral shedding in respiratory samples is associated with patterns of fibroproliferation on lung CT. We, therefore, conducted a retrospective observational study, in 2 ICU of Lyon university hospital. RESULTS: 129 patients were included in the study, of whom 44 (34%) died in ICU. 432 RT-PCR for SARS-CoV-2 were performed and 137 CT scans were analyzed. Viral load was significantly higher in patients deceased as compared to patients alive at ICU discharge (p < 0.001), after adjustment for the site of viral sampling and RT-PCR technique. The median time to SARS-CoV-2 negativation on RT-PCR was 19 days [CI95 %:15-21] in patients alive at ICU discharge and 26 days [CI95 %:17-infinity] in non-survivors at ICU discharge. Competitive risk regression identified patients who died in ICU and age as independent risk factors for longer time to SARS-CoV-2 negativation on RT-PCR, while antiviral treatment was independently associated with shorter time. None of the CT scores exploring fibroproliferation (i.e., bronchiectasis and reticulation scores) were significantly associated with time to SARS-CoV-2 negativation. CONCLUSIONS: Viral load in respiratory samples is significantly lower and viral shedding significantly shorter in ICU survivors of COVID-19 associated acute respiratory failure. Protracted viral shedding is unrelated to occurrence of fibrosis on lung CT.

Patients' association programs for adolescents and young adults: The JAP study.

INTRODUCTION: A dozen innovative care clinics have recently opened in France to support the transition of adolescents with chronic conditions between pediatric and adult healthcare units through various interventions. Some patients' associations have set up specific programs for adolescents and young adults (AYAs) in order to facilitate the transition process, but they are not well-known among healthcare professionals. Our aim was to describe these programs and to evaluate the quality of their implementation and transferability into transition clinics. MATERIEL AND METHODS: We conducted semistructured interviews with representatives of associations that proposed interventions dedicated to AYAs with chronic conditions. We collected quantitative and qualitative data to describe these interventions. Descriptive statistics were run on quantitative data and a thematic analysis of the qualitative data was made. RESULTS: A questionnaire was sent to 55 associations, 19 (36%) of them had established programs and were contacted; interviews were conducted with 16 of them. Thirteen were national associations, 11 focused on a specific chronic disease, three supported multiple chronic conditions, and two were available to any AYA with chronic disease. Programs were mainly camps (n=5; from 2days to 3weeks) and workshops (n=5). Educational considerations and hobbies were more frequently discussed when peers were directly involved in the program. Stakeholders were mainly other patients and peers (9/16). Fourteen out of 16 were perceived as successful (perceived improvement in AYA quality of life and/or positive feedback). Twelve out of 16 associations thought that their program could be transferable to transition clinics and all were interested in collaboration. DISCUSSION: This work highlights five key points to be considered in the clinical care setting before building programs: unique tailoring and customization, complementarity with existing programs in patients' associations, viability based on peer involvement and evaluation, a common main goal, and using transition clinics' assets to direct AYAs towards the most suitable program.

On the use of flexible excess hazard regression models for describing long-term breast cancer survival: a case-study using population-based cancer registry data.

BACKGROUND: Breast cancer prognosis has dramatically improved over 40 years. There is, however, no proof of population 'cure'. This research aimed to examine the pattern of long-term excess mortality due to breast cancer and evaluate its determinants in the context of cancer registry data. METHODS: We used data from the Geneva Cancer Registry to identify women younger than 75 years diagnosed with invasive, localised and operated breast cancer between 1995 and 2002. Flexible modelling of excess mortality hazard, including time-dependent (TD) regression parameters, was used to estimate mortality related to breast cancer. We derived a single "final" model using a backward selection procedure and evaluated its stability through sensitivity analyses using a bootstrap technique. RESULTS: We analysed data from 1574 breast cancer women including 351 deaths (22.3%). The model building strategy retained age at diagnosis (TD), tumour size and grade (TD), chemotherapy and hormonal treatment (TD) as prognostic factors, while the sensitivity analysis on bootstrap samples identified nodes involvement and hormone receptors (TD) as additional long-term prognostic factors but did not identify chemotherapy and hormonal treatment as important prognostic factors. CONCLUSIONS: Two main issues were observed when describing the determinants of long-term survival. First, the modelling strategy presented a lack of robustness, probably due to the limited number of events observed in our study. The second was the misspecification of the model, probably due to confounding by indication. Our results highlight the need for more detailed data and the use of causal inference methods.

Invasive cervical cancer in HIV-infected women: risk and survival relative to those of the general population in France. Results from the French Hospital Database on HIV (FHDH)-Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) CO4 cohort study.

OBJECTIVES: We examined trends in the incidence rates of invasive cervical cancer (ICC) and in the rate of survival after ICC among women living with HIV (WLHIV) in France and compared them to those of the general population. METHODS: Histologically validated incident cases of ICC in the period 1992-2009 from the French Hospital Database on HIV (FHDH-ANRS CO4) were included in the study. Age-standardized incidence rates were estimated for FHDH and the general population in France for 1992-1996 [pre-combination antiretroviral therapy (cART) period], 1997-2000 (early cART period), 2001-2004 (intermediate cART period), and 2005-2009 (late cART period). Age-standardized incidence ratios (SIRs) were calculated. Five-year survival was compared with that of the general population for ICC diagnosed in 2005-2009 after standardization for age. RESULTS: Among 28 977 WLHIV, 60 incident ICCs were histologically validated. There was a nonsignificant decreasing trend for the incidence across the cART periods (P = 0.07), from 60 to 36/100 000 person-years. The risk of ICC was consistently significantly higher in WLHIV than in the general population; the SIR was 5.4 [95% confidence interval (CI) 3.0-8.9] during the pre-cART period and 3.3 (95% CI 2.2-4.7) in 2005-2009. Survival after ICC did not improve across periods (log-rank P = 0.14), with overall estimated 5-year survival of 78% (95% CI 0.67-0.89%). Five-year survival was similar for WLHIV and the general population for women diagnosed with ICC in 2005-2009, after standardization (P = 0.45). CONCLUSIONS: ICC risk is still more than three times higher in WLHIV than in the general population. Survival after ICC did not improve over time and was similar to that of the general population during the most recent period. Such results call for promotion of the uptake of screening in WLHIV.

French expert opinion for the management of juvenile dermatomyositis.

A guideline group consisting of a pediatric rheumatologist, internists, rheumatologists, immunologists, a physiotherapist and a patient expert elaborated guidelines related to the management of juvenile dermatomyositis on behalf of the rare autoimmune and autoinflammatory diseases network FAI2R. A systematic search of the literature published between 2000 and 2015 and indexed in PubMed was undertaken. Here, we present the expert opinion for diagnosis and treatment in juvenile dermatomyositis.

[Clinical overview of auto-inflammatory diseases]. / Panorama des maladies auto-inflammatoires.

Monogenic auto-inflammatory diseases are characterized by genetic abnormalities coding for proteins involved in innate immunity. They were initially described in mirror with auto-immune diseases because of the absence of circulating autoantibodies. Their main feature is the presence of peripheral blood inflammation in crisis without infection. The best-known auto-inflammatory diseases are mediated by interleukines that consisted in the 4 following diseases familial Mediterranean fever, cryopyrinopathies, TNFRSF1A-related intermittent fever, and mevalonate kinase deficiency. Since 10 years, many other diseases have been discovered, especially thanks to the progress in genetics. In this review, we propose the actual panorama of the main known auto-inflammatory diseases. Some of them are recurrent fevers with crisis and remission; some others evaluate more chronically; some are associated with immunodeficiency. From a physiopathological point of view, we can separate diseases mediated by interleukine-1 and diseases mediated by interferon. Then some polygenic inflammatory diseases will be shortly described: Still disease, Schnitzler syndrome, aseptic abscesses syndrome. The diagnosis of auto-inflammatory disease is largely based on anamnesis, the presence of peripheral inflammation during attacks and genetic analysis, which are more and more performant.

[NLRC4 associated autoinflammatory diseases: A systematic review of the current literature]. / Les maladies auto-inflammatoires associées aux mutations de NLRC4 : revue systématique de la littérature.

The auto-inflammatory diseases linked to NLRC4 mutations are recently described entities. Transmission is autosomal dominant in 80 % of cases; cases of somatic mutation have already been reported. The disease may display two very different clinical phenotypes: the phenotype 1 (30 %), severe, is dominated by a multisystemic inflammation starting in the first year of life with symptoms of chronic inflammatory bowel disease (IBD), macrophagic actication syndrome (MAS), or even a presentation suggesting a cryopyrinopathy in its CINCA form; the mortality of this phenotype is high (25 %). The phenotype 2 (70 %), mild, usually starts after the age of 3 and is characterized by cold urticaria, arthralgia, ocular features and fever in 50 % of cases without visceral failure. Anti-interleukin-1 inhibitors are effective in most cases (83 %). Interleukin-18 (IL-18) levels are very high in both clinical forms. Interleukin-18 inhibitors and anti-interferon-gamma inhibitors were remarkably effective in two very severe phenotype 1 patients. Thus, NLRC4 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because very recently described, this group of diseases could be evoked by an internist in front of cold familial urticarial; probably more and more cases will be diagnosed thanks to the major progresses of genetic diagnostic tools such as next generation sequencing.

[Multiple facets of ADA2 deficiency: Vasculitis, auto-inflammatory disease and immunodeficiency: A literature review of 135 cases from literature]. / Les multiples facettes du déficit en ADA2, vascularite, maladie auto-inflammatoire et immunodéficit : mise au point à partir des 135 cas de la littérature.

Deficiency of adenosine deaminase 2 (DADA2) is a recently described auto-inflammatory disorder. It is an autosomal recessive inherited disease, caused by mutations in the ADA2 gene (formerly known as CECR1) encoding ADA2 enzyme. Besides its role in the purine metabolism, it has been postulated that ADA2 may act as a growth factor for endothelial cells and in the differenciation of monocytes. Thus, deficiency of ADA2 would lead to endothelial damage and a skewing of monocytes into M1 pro-inflammatory macrophage, causing DADA2 manifestations. Three core clinical features have been described: inflammatory-vascular signs, hematologic abnormalities and immunodeficiency. Clinically, patients display intermittent fever, cutaneous vascular manifestations, such as livedo, ischemic strokes, arthralgia and abdominal pain crisis. Corticosteroids and immunosuppressive agents (i.e. cyclophosphamide, azathioprine, ciclosporin, methotrexate) appear to be poorly effective. Although the mechanism has not been elucidated, anti-TNF agents have been proven efficient in DADA2 and should therefore be used as first line therapy for vasculitis. Role of anti-platelet and anticoagulant therapies in stroke-prophylaxis remains to be discussed, as those patients display a high risk of intracranial bleeding.