Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families. We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.

From January 1996 to January 1997, 321 patients with an average age of 46 +/- 16 years and chronically infected with hepatitis C virus (HCV) were prospectively enrolled in a study designed to determine the prevalence of extrahepatic manifestations associated with HCV infection in a large cohort of HCV patients, to identify associations between clinical and biologic manifestations, and to compare the results obtained in human immunodeficiency virus (HIV)-positive versus HIV-negative subsets. In a cross-sectional study, clinical extrahepatic manifestations, viral coinfections with HIV and/or hepatitis B virus, connective tissue diseases, and a wide panel of autoantibodies were assessed. Thirty-eight percent (122/321) of patients presented at least 1 clinical extrahepatic manifestation including arthralgia (60/321, 19%), skin manifestations (55/321, 17%), xerostomia (40/321, 12%), xerophthalmia (32/321, 10%), and sensory neuropathy (28/321, 9%). Main biologic abnormalities were mixed cryoglobulins (110/196, 56%), thrombocytopenia (50/291, 17%), and the presence of the following autoantibodies: antinuclear (123/302, 41%), rheumatoid factor (107/280, 38%), anticardiolipin (79/298, 27%), antithyroglobulin (36/287, 13%) and antismooth muscle cell (27/288, 9%). At least 1 autoantibody was present in 210/302 (70%) of sera. By multivariate logistic regression analysis, 4 parameters were significantly associated with cryoglobulin positivity: systemic vasculitis (p = 0.01, odds ratio OR[ = 17.3), HIV positivity (p = 0.0006, OR = 10.2), rheumatoid factor positivity (p = 0.01, OR = 2.8), and sicca syndrome (p = 0.03, OR = 0.27). A definite connective tissue disease was noted in 44 patients (14%), mainly symptomatic mixed cryoglobulinemia and systemic vasculitis, HIV coinfection (23%) was associated with 3 parameters: anticardiolipin (p = 0.003, OR = 4.18), thrombocytopenia (p = 0.01, OR = 3.56), and arthralgia or myalgia (p = 0.017, OR = 0.23). HIV-positive patients presented more severe histologic lesions (p = 0.0004). Extrahepatic clinical manifestations in HCV patients involve primarily the skin and joints. The most frequent immunologic abnormalities include mixed cryoglobulins, rheumatoid factor, antinuclear, anticardiolipin, and antithyroglobulin antibodies. Cryoglobulin positivity is associated with systemic vasculitis and rheumatoid factor and HIV positivity. HIV coinfection is associated with arthralgia or myalgia, anticardiolipin antibodies, and thrombocytopenia.

Objectives:To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with prognostic significance.Methods:The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed.Results:200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected.Conclusion:Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).

Dermatologic manifestations of relapsing polychondritis (RP) have been relatively poorly studied compared to other manifestations. In this study we describe dermatologic manifestations in a large series of patients with RP and the corresponding pathologic findings. In this retrospective, single-center review of 200 patients diagnosed with RP according to Michet's criteria, we analyzed separately those suffering from associated diseases with potential dermatologic involvement or chronic dermatitis. Skin or mucosal biopsies taken from 59 patients were examined without knowledge of the clinical data. Among the 200 patients with RP, 73 had chronic dermatitis or associated diseases with potential dermatologic involvement, especially hematologic disorders (n = 24) and connective tissue diseases (n = 22). Among the other 127 patients, 45 (35.4%) had dermatologic manifestations: aphthosis (n = 21; oral in 14 and complex in 7), nodules on the limbs (n = 19), purpura (n = 13), papules (n = 10), sterile pustules (n = 9), superficial phlebitis (n = 8), livedo reticularis (n = 7), ulcerations on the limbs (n = 6), and distal necrosis (n = 4). Dermatologic manifestations were the presenting feature of RP in 15 cases (12%), and appeared concomitantly (n = 23) or not (n = 22) with attacks of chondritis. Histologic findings included vasculitis (n = 19, leukocytoclastic in 17 and lymphocytic in 2), neutrophil infiltrates (n = 6), thrombosis of skin vessels (n = 4), septal panniculitis (n = 3), and minor changes (n = 2). Patients with and without dermatologic manifestations did not differ with regard to male/female ratio; age at RP onset; frequency of auricular, nasal, or tracheobronchial chondritis; or frequency of rheumatologic, ocular, audiovestibular, renal, arterial, or venous involvement. The frequency of dermatologic manifestations (91% versus 35.4%; p < 0.0001), sex ratio (18 male/4 female versus 44 male/83 female, p < 0.0001), and age at first chondritis (63.3 +/- 14 yr versus 41.4 +/- 17 yr; p < 0.0002) were significantly higher in the 22 patients with myelodysplastic syndrome than in the 127 patients without any associated disease. In conclusion, although dermatologic manifestations occur frequently in patients with RP, especially in association with myelodysplasia, they are nonspecific and sometimes resemble those observed in Behçet disease or inflammatory bowel diseases. Their presence in the elderly warrants repeated blood cell counts to detect a smouldering myelodysplasia.

Amicrobial pustulosis of the folds is a new entity which was initially described in association with systemic lupus erythematosus (SLE). We report four cases of this rare pustulosis occurring in the course of various auto-immune disorders. Dermatological features were similar in all patients. The primary lesions were small pustules which coalesced and formed erosive areas underlined with pustular lesions. They were localized in the folds. Three of the four patients had also isolated pustules on the scalp. Spongiform pustules were histologically present. A primary bacterial or fungal infection was ruled out by cultures on appropriate media. Serum calcium level was normal. Associated auto-immune diseases were: systemic lupus erythematosus, incomplete systemic lupus erythematosus, 'idiopathic' thrombocytopenic purpura and myasthenia gravis without thymoma (one of each). The relationship between this peculiar form of pustulosis and autoimmunity remains to be elucidated. The pustulosis did not respond to antibiotics but disappeared with systemic or topical corticosteroids.

Thirty one patients with antiphospholipid antibodies who developed multi-organ failure ("Catastrophic Antiphospholipid Syndrome") are reviewed. Thirteen suffered from a 'Primary' antiphospholipid syndrome, 13 from defined SLE, 4 from 'lupus-like' disease and one from rheumatoid arthritis. In more than one third precipitating factors were evident (e.g. infections, major/minor surgical procedures, oral contraceptives). Death occurred in 60% of patients from a variety of causes (myocardial failure, ARDS, CNS causes or, often a combination). Disseminated Intravascular Coagulation was present in 8 of 31 patients. Plasmapheresis appeared to be useful in several who had not responded to conventional therapy (e.g. IV heparin, steroids, immunosuppression).

Through monitoring, antimyeloperoxidase antibodies are a useful marker of disease activity and a good predictor of relapse in antimyeloperoxidase-associated vasculitides.

Due to recent acquisitions, diagnostic criteria for the antiphospholipid/cofactors syndrome need to be improved. In the absence of a “common biological denominator”, the best approach should be based on a scoring system mixing clinical and immunological items. APS might be composed of different biological subsets characterized by antibodies directed to various cofactors. Among clinical subsets, the categorization between “primary” and SLE-related APS may be difficult to achieve. Contrasting with the innumerable conditions associated with the presence of aPL, the diversity of “true” secondary APS should probably be restrained. Attempts at establishing correlations between clinical and biological APS subsets will require further studies.