Brigitte Ranque

Geoepidemiology of systemic sclerosis.

Systemic sclerosis (SSc) is a rare and potentially severe connective-tissue disease, characterized by skin fibrosis and involvement of internal organs. Because of its rarity and heterogeneous clinical presentation, reliable epidemiological studies on SSc have been particularly difficult to carry out. SSc prevalence is estimated between 3 and 24 per 100,000 population and appears to be higher in North America and Australia as compared to Europe and Japan. Incidence estimates have significantly increased between the fifties and the eighties, but this could result from greater physician awareness of the disease and more reliable ascertainment methods. Risk factors for SSc include female sex and African origin. Reports of sporadic clusters of higher prevalence also suggest environmental risk factors. In particular, silica and solvents exposure has been associated with SSc by several rigorous case-control studies. The ten-year cumulative survival of SSc has improved significantly from 50% in the seventies to over 70% at the present time. Pulmonary fibrosis and pulmonary arterial hypertension are now the two main causes of death. Diffuse cutaneous forms, as well as cardiac, pulmonary, and renal involvement are independent risk factors for SSc-related mortality.

An autosomal dominant major gene confers predisposition to pulmonary tuberculosis in adults

The molecular basis of genetic predisposition to pulmonary tuberculosis in adults remains largely elusive. Few candidate genes have consistently been implicated in tuberculosis susceptibility, and no conclusive linkage was found in two previous genome-wide screens. We report here a genome-wide linkage study in a total sample of 96 Moroccan multiplex families, including 227 siblings with microbiologically and radiologically proven pulmonary tuberculosis. A genome-wide scan conducted in half the sample (48 families) identified five regions providing suggestive evidence (logarithm of the odds [LOD] score >1.17; P < 0.01) for linkage. These regions were then fine-mapped in the total sample of 96 families. A single region of chromosome 8q12-q13 was significantly linked to tuberculosis (LOD score = 3.49; P = 3 × 10−5), indicating the presence of a major tuberculosis susceptibility gene. Linkage was stronger (LOD score = 3.94; P = 10−5) in the subsample of 39 families in which one parent was also affected by tuberculosis, whereas it was much lower (LOD score = 0.79) in the 57 remaining families without affected parents, supporting a dominant mode of inheritance of the major susceptibility locus. These results provide direct molecular evidence that human pulmonary tuberculosis has a strong genetic basis, and indicate that the genetic component involves at least one major locus with a dominant susceptibility allele.

Age Is an Important Risk Factor for Onset and Sequelae of Reversal Reactions in Vietnamese Patients with Leprosy

BACKGROUND Reversal, or type 1, leprosy reactions (T1Rs) are acute immune episodes that occur in skin and/or nerves and are the leading cause of neurological impairment in patients with leprosy. T1Rs occur mainly in patients with borderline or multibacillary leprosy, but little is known about additional risk factors. METHODS We enrolled 337 Vietnamese patients with leprosy in our study, including 169 subjects who presented with T1Rs and 168 subjects with no history of T1Rs. A multivariate analysis was used to determine risk factors for T1R occurrence, time to T1R onset after leprosy diagnosis, and T1R sequelae after treatment. RESULTS Prevalence of T1Rs was estimated to be 29.1%. Multivariate analysis identified 3 clinical features of leprosy associated with T1R occurrence. Borderline leprosy subtype (odds ratio, 6.3 [95% confidence interval, 2.9-13.7] vs. polar subtypes) was the major risk factor; 2 other risk factors were positive bacillary index and presence of > 5 skin lesions. In addition, age at leprosy diagnosis was a strong independent risk factor for T1Rs (odds ratio, 2.4 [95% confidence interval, 1.3-4.4] for patients aged > or = 15 years old vs. < 15 years old). We observed that T1Rs with neuritis occurred significantly earlier than pure skin-related T1Rs. Sequelae were present in 45.1% of patients who experienced T1Rs after treatment. The presence of a motor or sensory deficit at T1R onset was an independent risk factor for sequelae, as was the age at diagnosis of leprosy (odds ratio, 4.4 [95% confidence interval, 1.7-11.6] for patients > or = 20 years old vs. < 20 years old). CONCLUSION In addition to specific clinical features of leprosy, age is an important risk factor for both T1R occurrence and sequelae after treatment for T1Rs.

A descriptive and prognostic study of systemic sclerosis-associated myopathies

Objectives: To describe the clinical characteristics and muscle pathological features of patients with systemic sclerosis (SSc) and myopathy and analyse their impact on muscle outcome. Methods: Thirty-five patients with myopathy and available muscle biopsy were restrospectively investigated from the charts of four hospital centres. Results: Twenty-six (74%) cases had diffuse SSc. The median time from SSc diagnosis was 5 years (range 0–23) at myopathy onset. The main myopathological features were mononuclear inflammation (63%), muscle atrophy (60%), necrosis (59%), regeneration (44%), fibrosis (24%) or microangiopathy (27%). After a median follow-up of 4.4 years, 24 patients (69%) showed complete or partial muscle remission. Only histological muscle inflammation was associated with good muscle prognosis in multivariate analysis (odds ratio 44.7, 95% CI 2.8 to 704.7). Patients without muscle inflammation had a poor response to corticosteroids (38% favourable response vs 90% in patients with inflammation). Conclusion: Muscle histopathology is critical in the therapeutic management of SSc-associated myopathy.

Systemic Sclerosis‐Associated Myopathy

Abstract:  Skeletal muscle involvement is a common feature in systemic sclerosis (SSc) because muscle weakness is found in up to 90% SSc patients when systematically assessed. Muscle clinical, biological, and electromyographic features are similar to those of polymyositis or dermatomyositis, except for a higher proportion of mild symptoms. SSc‐associated myopathy is more prevalent in diffuse SSc and is also associated with cardiomyopathy. The pathophysiological process leading to SSc‐associated myopathy is likely to be complex, given the heterogeneity of pathological muscle findings, including stigma of microangiopathy, and also inflammatory infiltrate in about half of the cases and interstitial fibrosis. Conflicting results have been reported regarding the correlation between clinicobiological presentation and pathological muscle features, nevertheless there is a general agreement that histologically proven inflammatory myopathies usually regress under high‐dose corticosteroid therapy, or even low dose in case of positive anti‐PM/Scl antibody. In contrast, noninflammatory myopathies often result in milder clinical expression but do not respond to immunosuppressive treatment.

Mood and anxiety disorders in systemic sclerosis patients

OBJECTIVE To assess the prevalence of mood and anxiety disorders in systemic sclerosis (SSc) patients and the association of these disorders with clinical features. METHODS Between May 2002 and May 2004, 100 SSc patients fulfilling the American Rheumatism Association and/or Leroy & Medsger criteria were recruited: 51 were from a SSc patient association meeting, and 49 were hospitalized in an internal medicine department and recruited consecutively. Mood and anxiety disorders were assessed by use of a structured clinical interview [the Mini International Neuropsychiatric Interview (MINI)] performed by a psychiatrist and a self-reporting questionnaire [the Hospital Anxiety and Depression Scale (HADS)]. On the same day, psychiatric treatment and clinical features were recorded by a physician. RESULTS As assessed by the MINI, 19% [95% confidence interval 12-28%] of all SSc patients were currently experiencing a major depressive episode (MDE), 56% [46-65%] had a lifetime history of MDE and 14% [8-22%] had current dysthymia. Current MDE was more prevalent among hospitalized patients than among other patients (28% versus 10%, p=0.02). Specific anxiety disorders were diagnosed in 37 [28-47] patients. Less than 50% of the patients with mood disorders received psychiatric treatment. Patients with or without current depression did not differ in clinical symptoms of SSc, except for digestive symptoms. CONCLUSION The current and lifetime prevalence of major depression and anxiety disorders is high in SSc patients, especially during hospitalization. However, only half of such patients receive adequate psychiatric treatment. Therefore, a better assessment of psychiatric disorders in SSc patients is needed.

The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.

Vascular Ehlers–Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n=71), (2) splice-site and in-frame insertions–deletions (n=36), (3) variants leading to haplo-insufficiency (n=7), (4) non-glycine missense variants within the triple helix (n=4 variants), and (5) non-glycine missense variants or in-frame insertions–deletions, in the N- or C-terminal part of the protein (n=8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22–39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3–5, with extreme median ages at first major complication of 23–47 years. Patients of groups 3–5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C- and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care.

Gastrointestinal manifestations in mastocytosis: A study of 83 patients

BACKGROUND Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in 1 or more organs. Gastrointestinal manifestations of systemic mastocytosis have been previously studied in small cohorts of patients, and no specific histologic description is available. OBJECTIVE We sought to assess the clinical and pathologic features of gastrointestinal manifestations in patients with mastocytosis. METHODS Medical history and gastrointestinal symptoms of patients with mastocytosis (n = 83) were compared with those of matched healthy subjects (n = 83) by means of patient questionnaire. Data were analyzed for epidemiologic, clinical, biological, and genetic factors associated with gastrointestinal symptoms for patients with mastocytosis. A comparative analysis of gastrointestinal histology from patients with mastocytosis (n = 23), control subjects with inflammatory bowel disease (n = 17), and healthy subjects (n = 19) was performed. RESULTS The following gastrointestinal symptoms occurred more frequently and were more severe in patients with mastocytosis than in healthy subjects: bloating (33% vs 7.2%, P < .0001), abdominal pain (27.3% vs 4.8%, P < .0001), nausea (23% vs 8.4%, P = .02), and diarrhea (33.85% vs 1.2%, P < .0001). Patients with mastocytosis had a significantly higher incidence of personal history of duodenal ulcer (P = .02). Wild-type (WT) c-Kit was associated with diarrhea (P = .03). Specific histologic lesions were present in patients with mastocytosis but were not correlated with clinical symptoms. CONCLUSION Gastrointestinal manifestations in patients with mastocytosis are highly prevalent and often severe. Clinical symptoms do not correspond to histologic findings, are nonspecific, and can simulate irritable bowel syndrome.

Clinical, functional and health-related quality of life correlates of clinically significant symptoms of anxiety and depression in patients with systemic sclerosis: a cross-sectional survey.

Objectives To identify clinical, functional and health-related quality of life (HRQoL) correlates of clinically significant symptoms of anxiety and depression in patients with systemic sclerosis (SSc). Methods Three-hundred-and-eighty-one patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria for SSc were assessed for visceral involvement, disability and HRQoL (assessed by SF-36). Clinically significant symptoms of anxiety and depression were evaluated with the Hospital Anxiety Depression Scale (HAD) (defined cut-off≥8). Results 9.2% the patients had limited SSc, 50.5% limited cutaneous SSc (lcSSc), and 40.3% diffuse cutaneous SSc (dcSSc). Overall, 40.4% and 58.8% of the patients had clinically significant symptoms of depression and anxiety, respectively. Compared to patients without clinically significant symptoms of depression, patients with clinically significant symptoms of depression had poorer health status, HRQoL mental and physical component, and greater global disability, hand disability and aesthetic impairment. Compared to patients without clinically significant symptoms of anxiety, patients with clinically significant symptoms of anxiety had poorer SF-36 mental and physical component scores. On multivariable analysis, excluding mental component score of SF-36, variables independently associated with clinically significant symptoms of depression and anxiety were global disability and physical component of SF-36, plus female gender for clinically significant symptoms of anxiety only. Remarkably, patients with and without clinically significant psychiatric symptoms were comparable for all disease-related clinical features assessed. Conclusion High levels of clinically significant symptoms of anxiety and depression are observed among SSc patients. Clinically significant psychiatric symptoms are rather associated with increased disability and altered HRQoL, than with disease-specific organ manifestations.

Strong Correlations of Anti–Viral Capsid Antigen Antibody Levels in First-Degree Relatives from Families with Epstein-Barr Virus–Related Lymphomas

BACKGROUND Markers of Epstein-Barr virus (EBV) infection include anti-viral capsid antigen (VCA) immunoglobulin (Ig) G. High anti-VCA titers are associated with EBV-related lymphoproliferation, such as Burkitt lymphoma (BL) and Hodgkin lymphoma (HL). METHODS Intrafamilial correlations of anti-VCA IgG levels were studied in 3 settings: 127 families recruited through patients with HL in France (population A), 31 families recruited through patients with BL in Uganda (population B), and 74 large families from a general population in Cameroon (population C). Titers were determined by enzyme-linked immunosorbent assay (populations A and C) or by immunofluorescence analysis (population B). RESULTS In populations A and B, the anti-VCA IgG titers of the relatives of patients with HL or BL increased significantly (P = .01 and P < .001, respectively) with those of the index case patient. In all 3 populations, anti-VCA IgG titers were significantly correlated (P < .001 for A, P = .002 for B, and P < .001 for C) between genetically related individuals (father-offspring, mother-offspring, and sibling-sibling) but not between spouses. Similar results were obtained for population A after adjustment for total IgG levels. In all cases, the pattern of correlations was consistent with a polygenic model, with heritability ranging from 0.32 to 0.48. CONCLUSION These results provide evidence for the genetic control of anti-VCA IgG titers and pave the way for identification of the loci involved.