Long-term outcomes of childhood-onset systemic lupus erythematosus.

OBJECTIVE: Data on the long-term outcome of patients with childhood-onset Systemic Lupus Erythematosus (cSLE) are scarce. Aims of this study were to describe the long-term outcomes of cSLE and to identify factors associated with the development of damage and persistent disease activity. METHODS: We conducted a retrospective multicentre study using data from the PEDIALUP registry of the Juvenile Inflammatory Rheumatism (JIR) cohort database. Demographic characteristics, clinical manifestations, laboratory, radiological, histological and treatment data were collected from medical records during follow-up. RESULTS: A total of 138 patients with cSLE, diagnosed between 1971 and 2015, were included. With a median follow-up of 15.4 [9.6-22.4] years, 51% of patients had a SLICC-Damage Index score ≥ 1 at last follow-up with the musculoskeletal, cutaneous, renal, neurological, and cardiovascular damage being the most common manifestations. The proportion of patients with a SLICC-DI score ≥ 1 increased significantly with the duration of the follow-up (p< 0.001). On multivariate analysis, duration of follow-up was associated with increased risk of cumulative damage (OR 1.08, 95% CI 1.01, 1.15, p= 0.035). At the last visit, 34% of patients still had active disease with a SLEDAI score of ≥ 6. On multivariate analysis, Sub-Saharan African ethnicity was associated with 7-fold increased odds of having active disease at the last visit compared with Caucasians (OR 7.44, 95% CI 2.24, 24.74, p= 0.0002). CONCLUSION: The prevalence of damage remains high in patients with cSLE even when the diagnosis of c-SLE has been made in the recent decades.

Real-world data for marginal zone lymphoma patients in the French REALYSA cohort: The REALMA study.

Marginal Zone Lymphoma (MZL) comprises three subtypes: extranodal MZL (EMZL), splenic MZL (SMZL) and nodal MZL (NMZL). Since clinical trials have limited representativeness, there is a need for real-world data (RWD) evidence in MZL. Real-world data in Lymphoma and survival in Adults (REALYSA) is a prospective multicentric French cohort of newly diagnosed lymphoma patients. This study consists of the first abstraction of MZL patients prospectively included in REALYSA between 12/2018 and 01/2021 with at least 1 year of follow-up. It provides a landscape description of clinical characteristics, initial workup, quality of life and first-line therapy performed in routine practice. Among 207 included patients, 122 presented with EMZL, 51 with SMZL and 34 with NMZL. At baseline, median age was 67 years (range 28-96), and patients reported a favorable global health status (75/100 (IQR 58,83)) - which was higher in NMZL and lower in SMZL patients (p = 0.006). 18FDG-PET/CT was frequently performed at initial workup (EMZL 72%, SMZL 73%, NMZL 85%). Active surveillance was the initial management for 58 (28%) patients. The most prescribed therapies were rituximab-chlorambucil in the EMZL population (30%), rituximab monotherapy in the SMZL population (37%) and R-CHOP (24%)/bendamustine-rituximab (15%) in the NMZL population. At end of first line, overall response rate was 93% among treated patients with 75% of complete response. This French nationwide study provided for the first time prospective RWD on clinical characteristics, initial management and treatment response of MZL patients.

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.

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.

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.

Persistent inequalities in 90-day colon cancer mortality: an English cohort study.

BACKGROUND: Variation in colon cancer mortality occurring shortly after diagnosis is widely reported between socio-economic status (SES) groups: we investigated the role of different prognostic factors in explaining variation in 90-day mortality. METHODS: National cancer registry data were linked with national clinical audit data and Hospital Episode Statistics records for 69 769 adults diagnosed with colon cancer in England between January 2010 and March 2013. By gender, logistic regression was used to estimate the effects of SES, age and stage at diagnosis, comorbidity and surgical treatment on probability of death within 90 days from diagnosis. Multiple imputations accounted for missing stage. We predicted conditional probabilities by prognostic factor patterns and estimated the effect of SES (deprivation) from the difference between deprivation-specific average predicted probabilities. RESULTS: Ninety-day probability of death rose with increasing deprivation, even after accounting for the main prognostic factors. When setting the deprivation level to the least deprived group for all patients and keeping all other prognostic factors as observed, the differences between deprivation-specific averaged predicted probabilities of death were greatly reduced but persisted. Additional analysis suggested stage and treatment as potential contributors towards some of these inequalities. CONCLUSIONS: Further examination of delayed diagnosis, access to treatment and post-operative care by deprivation group may provide additional insights into understanding deprivation disparities in mortality.

Cancer incidence in France over the 1980-2012 period: Hematological malignancies.

BACKGROUND: The classification of hematological malignancies (HMs) has changed in recent decades. For the first time, the French network of cancer registries (Francim) provides estimates for incidence and trends of HM in France between 1980 and 2012 for major HM subtypes. METHODS: Incidence was directly estimated by modeling the incidence rates measured in the cancer registry area. For each HM subtype, a "usable incidence period" was defined a priori, corresponding to the years for which all the registries collected them in a homogeneous way. For both sexes and each HM subtype, age-period-cohort models were used to estimate national incidence trends. RESULTS: Overall in France, there were an estimated 35,000 new HMs in 2012 (19,400 in men and 15,600 in women). Lymphoid malignancies accounted for more than two-thirds of HM incident cases (n=25,136). The incidence sex ratio (M/F) varied from 1.1 for classical Hodgkin lymphoma to 4.0 for mantle-cell lymphoma. The median age at diagnosis ranged from 62 to 81 years according to the major HM subtypes. Overall in both sexes, the top five most frequent HMs in 2012 were plasma cell neoplasm (about 4900 estimated cases), chronic lymphocytic leukemia/small lymphocytic lymphoma (4500 cases), diffuse large B-cell lymphoma and myelodysplastic syndromes (4100 cases), and acute myeloid leukemia (2800 cases). The incidence rates increased for follicular lymphoma and plasma cell neoplasm during the study period in both sexes. Classical Hodgkin lymphoma was relatively stable in men between 1980 and 2012 and increased in both sexes during the most recent period. Chronic myeloproliferative neoplasms, other than chronic myelogenous leukemia, are the only subtype that showed a slightly downward trend in incidence between 2003 and 2012 in both sexes. CONCLUSION: The striking differences in the incidence patterns by histologic subtype strongly suggest a certain level of etiologic heterogeneity among hematological malignancies and support the pursuit of epidemiologic analysis by subtype for HMs in international studies. Age-standardized incidence rates are essential to analyze trends in risk, whereas the number of incident cases is necessary to make provisions for healthcare resources and to evaluate the overall burden of HM.

[Prostate cancer incidence and mortality trends in France from 1980 to 2011]. / Le cancer de la prostate, évolution de l'incidence et de la mortalité en France entre 1980 et 2011.

UNLABELLED: The prostate cancer became for two decades the most frequent cancer in men. We describe the evolution of its incidence and mortality from 1980 to 2011 for France. METHODS: Incidence data were collected from registries and national incidence estimates were based on the use of mortality as a correlate of incidence. RESULTS: After a very strong increase of incidence between 1980 (24.8/100,000) and 2005 (124.5/100,000), we observe a net decline since (97.7/100,000, in 2011). The reduction began earlier for the old patients. The evolution of mortality is very different. We observe a regular reduction since the end of 1990s (from 18.0/100,000 in 1990 to 10.5/100,000 in 2011). The reduction began earlier for the young patients. CONCLUSION: This pattern of evolution is observed in all the countries where the use of the PSA had caused an important increase of the diagnosis of prostate cancer. LEVEL OF EVIDENCE: 3.

Cancer incidence and mortality in France over the 1980-2012 period: solid tumors.

BACKGROUND: Cancer incidence and mortality estimates for 19 cancers (among solid tumors) are presented for France between 1980 and 2012. METHODS: Incidence data were collected from 21 local registries and correspond to invasive cancers diagnosed between 1975 and 2009. Mortality data for the same period were provided by the Institut national de la santé et de la recherche médicale. The national incidence estimates were based on the use of mortality as a correlate of incidence. The observed incidence and mortality data were modeled using an age-period-cohort model. The numbers of incident cases and deaths for 2010-2012 are the result of short-term projections. RESULTS: In 2012, the study estimated that 355,000 new cases of cancer (excluding non-melanoma skin cancer) and 148,000 deaths from cancer occurred in France. The incidence trend was not linear over the study period. After a constant increase from 1980 onwards, the incidence of cancer in men declined between 2005 and 2012. This recent decrease is largely related to the reduction in the incidence of prostate cancer. In women, the rates stabilized, mainly due to a change in breast cancer incidence. Mortality from most cancer types declined over the study period. A combined analysis of incidence and mortality by cancer site distinguished cancers with declining incidence and mortality (e.g., stomach) and cancers with increasing incidence and mortality (e.g., lung cancer in women). Some other cancers had rising incidence but declining mortality (e.g., thyroid). CONCLUSION: This study reveals recent changes in cancer incidence trends, particularly regarding breast and prostate cancers.

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.

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 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 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.

[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.

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.

[Epidemiology of oral cavity cancers in France]. / Épidémiologie des cancers de la cavité buccale en France.

INTRODUCTION: We had for objective to describe the updated epidemiology of oral cancers in France. MATERIAL AND METHODS: Estimates made from data collected from various French cancer institutions. The distribution by topography, histology, regions, mean age, and specific incidence rates were calculated from the collected data. The survival data was taken from the Francim network studies. RESULTS: Approximately 7000 oral cavity cancers were diagnosed in France in 2005. In 2007, 1746 people died of that cancer. Standardized (world population) incidence rates are respectively, in men and women, 12.3 and 3.0 cases per 100,000 person-years. These cancers have significantly decreased in men: the standardized incidence rate decreased by 43.2% between 1980 and 2005. Among women, the trend is reversed with an increased incidence of 51.7% over the same period. CONCLUSION: In France, the incidence of oral cavity cancers has been strongly decreasing in men and strongly increasing in women. This trend should be compared to the frequency of the main risk factors: alcohol and tobacco.

[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.