French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

French practical guidelines for the diagnosis and management of AA amyloidosis.

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.

[Periodic fever syndrome associated with mutations in the TNF type 1 receptor gene: A differential diagnosis of familial Mediterranean fever that should not be overlooked in patients of Mediterranean origin]. / Le syndrome de fièvre prolongée associée aux mutations du gène du récepteur au TNF de type 1 : un diagnostic différentiel de la fièvre méditerranéenne familiale à ne pas méconnaître chez les patients d'origine méditerranéenne.

INTRODUCTION: Tumor Necrosis Factor Type 1 Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autosomal autoinflammatory disease associated with mutations in the TNF type 1 receptor gene (TNFRSF1A). It is characterized by relatively long recurrent febrile seizures with an average duration of 7 days accompanied by arthralgia, myalgia, and usually a rash. In a patient of Mediterranean origin with recurrent fever, familial Mediterranean fever is the first diagnosis to be suspected by argument of frequency. METHODS: A retrospective observational study was conducted on patients from Mediterranean origin followed for TRAPS and included in the "Juvenile Inflammatory Rheumatism" (JIR) observational cohort in the national French autoinflammatory center. The age of onset of symptoms, age of diagnosis, number of years of wandering and treatments received were collected for each index case. RESULTS: Nine patients from 6 families of Mediterranean origin were included. A molecular diagnosis confirmed TRAPS in all patients. The median age at diagnosis was 26 years, the mean number of years of wandering was 17 years. The diagnosis of FMF was made first in all patients. AA amyloidosis revealed TRAPS in 2 patients. Colchicine was started without any efficacy in all cases. Five patients were treated with interleukin-1 inhibitory biotherapy with 100% efficacy. CONCLUSION: In a patient of Mediterranean origin presenting with recurrent febrile abdominal pain of AA amyloidosis, the first diagnosis to be suspected is FMF. Long relapses, dominant transmission, a non-Mediterranean relative, and the ineffectiveness of colchicine should evoke TRAPS.

[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.

[Familial Mediterranean fever]. / La fièvre méditerranéenne familiale.

Familial Mediterranean Fever (FMF) is the most frequent monogenic auto-inflammatory disease. FMF is an autosomal recessive disease, which affects populations from Mediterranean origin and is associated with MEFV gene mutations encoding for the protein pyrin. Pyrin activation enhances the secretion of interleukin 1 by myelo-monocytic cells. Main features of the disease are acute attacks of serositis mainly located on the abdomen, less frequently on chest and joints, accompanied by fever and biological inflammatory markers elevation. Usually attacks last 1 to 3 days and spontaneously stop. A daily oral colchicine intake of 1 to 2mg/day is able to prevent attack's occurrence, frequency, intensity and duration among most patients. Colchicine is also able to prevent the development of inflammatory amyloidosis, the most severe complication of FMF. This state of the art article will focus on the diagnosis of FMF, the treatment and an update on the pathophysiology including the recent described dominant form of MEFV-associated new auto-inflammatory diseases.

Anakinra in the Treatment of Patients with Refractory Scleritis: A Pilot Study.

PURPOSE: This study aimed to evaluate the safety and efficacy of anakinra for severe and refractory scleritis. METHODS: Ten patients with severe (i.e. at least 2 ocular relapses per year despite treatment) and refractory [i.e. at least to one disease modifying antirheumatic drugs (DMARDS)] scleritis were treated with anakinra (100 mg/day subcutaneously). Scleritis was associated with inflammatory systemic diseases in 60% of cases. The remission rate defined the primary outcome. RESULTS: Ninety percent of patients were complete responders with a mean follow-up of 19.4 months after starting anakinra. The corticosteroids daily dose decreased from 18.3 ± 4.1 mg to 4.2 ± 4.9 mg, (p < 0.05), at initiation of anakinra and at end of follow-up, respectively. Associated immunosuppressants were stopped in all cases except one. Side effects were observed in 4 patients who did not need anakinra withdrawal. CONCLUSIONS: This pilot study suggests the efficacy of anakinra in patients with refractory scleritis.

Biotherapies in large vessel vasculitis.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) and aortic involvement is not uncommon in Behcet's disease (BD) and relapsing polychondritis (RP). Glucocorticosteroids are the mainstay of therapy in LVV. However, a significant proportion of patients have glucocorticoid dependance, serious side effects or refractory disease to steroids and other immunosuppressive treatments such as cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate. Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with LVV. Anti-tumor necrosis factor-α drugs seem effective in patients with refractory Takayasu arteritis and vascular BD but have failed to do so in giant cell arteritis. Preliminary reports on the use of the anti-IL6-receptor antibody (tocilizumab), in LVV have been encouraging. The development of new biologic targeted therapies will probably open a promising future for patients with LVV.

Th1 and Th17 cytokines drive inflammation in Takayasu arteritis.

OBJECTIVE: Takayasu arteritis (TAK) is a large-vessel vasculitis that induces damage to the aorta and its branches. Glucocorticoids remain the gold standard of therapy for TAK. The nature of the T cells driving vascular inflammation and the effects of glucocorticoids on the systemic components of TAK are not understood. The aim of this study was to analyze T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta in patients with TAK. METHODS: T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta were analyzed using Luminex analysis, flow cytometry, and immunohistochemical analysis. The study included 41 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK (17 patients with active TAK and 24 patients with disease in remission), 30 patients with giant cell arteritis and 39 patients with Behçet's disease (disease controls), and 20 age- and sex-matched healthy control subjects. RESULTS: We observed a marked increase in the expression of Th1 and Th17 cells, which correlated with TAK disease activity. The addition of serum from patients with active TAK to sorted CD4+ T cells from healthy donors in culture medium induced significant production of interferon-γ (IFNγ) and interleukin-17A (IL-17A). We demonstrated the presence of IFNγ-, IL-6-, and IL-17A-producing T cells in vascular inflammatory infiltrates in patients with TAK. Corticosteroid therapy was associated with decreased levels of circulating Th1 cytokines in corticosteroid-treated patients with TAK compared with steroid-free patients with TAK (for IL-2, mean ± SD 5,079 ± 5,300 versus 7,359 ± 3,197 pg/ml; for IFNγ, 2,592 ± 3,072 versus 8,393 ± 3,392 pg/ml; for tumor necrosis factor α, 847 ± 724 versus 1,491 ± 392 pg/ml). However, glucocorticoids had essentially no effect on the frequency of Th17 cytokines (IL-1 receptor, IL-17, and IL-23). CONCLUSION: The Th17 and Th1 pathways contribute to the systemic and vascular manifestations of TAK. Glucocorticoid treatment suppresses Th1 cytokines but spares Th17 cytokines in patients with TAK.

[Acute pelvic pain in women]. / Douleurs pelviennes aiguës chez la femme.

Acute pelvic pains in women can reflect highly diverse disorders of varying severity, sometimes requiring surgery. It thus is clearly a part of abdominal emergencies in the adult. Good knowledge of underlying gynaecological disorders usually avoids unnecessary surgery. The use of echography has greatly contributed to reducing coelioscopy for diagnosis.

[An MRI study of the normal pelvis in the immediate postpartum period]. / Etude IRM du pelvis normal en post-partum immédiat.

PURPOSE: To describe the MR findings of the pelvis in the early post-partum period, after vaginal delivery or cesarean section. MATERIALS AND METHODS: Fifteen asymptomatic patients were imaged using a 1.5 Tesla MR unit between 1 and 7 days following delivery. Eight patients had a vaginal delivery, and seven patients had a cesarean section. RESULTS: The following items were evaluated: uterus size, architecture, and contents; uterine and abdominal wall scars; parametrium; peritoneal cavity; ovarian veins. CONCLUSION: MRI provided a good evaluation of the pelvic changes related to pregnancy and delivery. Knowledge of the normal findings should improve diagnosis of early post-partum complications.

Maternal serum human chorionic gonadotropin level at fifteen weeks is a predictor for preeclampsia.

OBJECTIVE: Our purpose was to study the correlation between maternal serum human chorionic gonadotropin levels measured at 15 to 18 weeks of amenorrhea and pregnancy-induced hypertension, preeclampsia, and small-for-gestational-age neonates. STUDY DESIGN: Prospective trisomy 21 human chorionic gonadotropin screening data from 5776 patients were examined in a retrospective investigation of the relationship between human chorionic gonadotropin and pregnancy-induced hypertension (234 cases), preeclampsia (34 cases), and small-for-gestational-age neonates (238 cases). RESULTS: Maternal serum human chorionic gonadotropin (multiples of the median) was higher in the three populations with pathologic disorders. This difference was statistically significant in patients with small-for-gestational-age neonates (p < 0.0163) and preeclampsia (p < 0.0001) but not in those with pregnancy-induced hypertension. In the preeclampsia subgroup, with a cutoff value of 2 multiples of the median, specificity was 32% and sensitivity was 10%; with a cutoff value of 1 multiples of the median, specificity was 100% and sensitivity was 50%. CONCLUSION: High maternal serum human chorionic gonadotropin levels at 15 weeks are related to a risk for preeclampsia. Depending on the human chorionic gonadotropin cutoff value, 32% or 100% of preeclampsia patients would be selected. The usefulness of preventive aspirin treatment from the fifteenth week needs more investigation in a larger multicenter study of preeclampsia.

[Krukenberg tumors. Analysis of a series of 28 cases]. / Tumeurs de Krukenberg. Analyse d'une série de 28 observations.

We report a retrospective series of 28 patients with Krukenberg tumors treated at the Gustave Roussy Institute from 1973 to 1990. Mean age of these women was 42 years. The patients were classed into two groups: depending on whether the ovarian metastasis (group 1) or the primary cancer (group 2) was discovered first. The primary tumor was identified in 20 cases (18 cases of linitis, 1 tumor of the cecum, 1 tumor of the appendix). The primary tumor remained unknown in 8 cases. Twenty-seven patients underwent radical total hysterectomy or bilateral adnexectomy. Gastrectomy was possible for 11 of the 18 cases of linitis; hemicolectomy and appendectomy were performed for the cecal and appendicular tumors respectively. Diagnosis of a primary tumor of the appendix was made after systematic appendectomy and of two Krukenberg tumors after systematic bilateral adnexectomy. In the first group of patients, both localizations were treated in 6 cases, one in 12 including 4 because gastrectomy was not initially possible and in 8 because the primary tumor was unknown. In the second group, the two localizations were treated in 7 cases, and one in 2 cases because gastrectomy was not possible. Surgery was not performed in one patient due to diffuse carcinosis. Bilateral ovarian metastases were seen in 26 out of the 28 cases and 26/28 had chemotherapy without any appreciable effect. Bone metastasis predominated (9 cases), followed by pleuropulmonary (5 cases) and liver (3 cases) metastasis. Overall median survival was 20 months; 14 months in the first group and 29 months in the second. Appendectomy and exploration of the colon and the stomach were performed in all cases in which the Krukenberg tumor was discovered intraoperatively. An endosonographic exploration of the stomach is recommended if the primary tumor is not localized. Bilateral adnexectomy should always be performed in patients with linitis whatever the age. Surgical treatment of the two localizations is not always sufficient for cure.

[Drug treatment of threatened premature labor]. / Le traitement médicamenteux de la menace d'accouchement prématuré.

The problem of the treatment of premature labor has not yet been resolved. The positive effect of using sympathomimetics is not as significant as was initially thought and they are not free of side-effects. A review of the literature forms the basis of a comparison of sympathomimetics with nifedipine and indomethacin. The latter sometimes offer a better alternative but must be used with care. The potential benefits of oxytocin antagonists are still being evaluated.

[Parvovirus B19 infection and pregnancy]. / Infection à parvovirus B19 et grossesse.

Parvovirus B19 was identified in 1975. It causes infections megalerythemia in adults associated with skin eruptions and joint pain (about 50% of the adult population is immunized). The risk of contamination in case of an epidemia is high in school teachers and school personnel. In 1984, the parvovirus B19 was implicated as the cause of fetal anasarca. The risk of transplacental contamination is estimated at 33% in case of maternal infection. Pregnant women with parvovirus B19 infection and confirmed serology should have an echography every 15 days. Fetal anasarca can be complicated by in utero fetal death related to erythroid stem-cell anaemia. The diagnosis of fetal infection is based on PCR techniques on fetal blood. Symptomatic antenatal treatment with in utero transfusion was proposed as early as 1988. This method does not however appear to be necessary in all cases as the outcome in several reports of untreated fetuses was delivery of a normal child. There is the possibility of myocardial damage caused by parvovirus B19 which would make in utero transfusion difficult and limit its beneficial effect. Finally associated thrombopenia is often severe and increased fetal risk.