Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the "CAPS Registry".

OBJECTIVE: To describe the clinical and laboratory features, as well as the precipitating factors, treatment and outcome of patients with catastrophic antiphospholipid syndrome (APS). METHODS: We analyzed the 280 patients included until September 2008 in the website based international registry of patients with catastrophic APS ("CAPS Registry") (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM). RESULTS: The entire series includes 201 (72%) female and 79 (28%) male patients with a mean age of 37 +/- 14 years (range, 11-60 years). A total of 129 (46%) patients suffered from primary APS, 112 (40%) from systemic lupus erythematosus, 14 (5%) from lupus-like disease, and 25 (9%) from other autoimmune diseases. The catastrophic episode was the first manifestation of the APS in 129 (46%) patients. A precipitating factor was reported in 53% of the patients. The first clinical manifestation at the time of the catastrophic episode was a pulmonary complication in 24% of the cases, a neurologic feature in 18% and a renal feature in 18%. During the catastrophic episode, intraabdominal involvement was identified in the majority of patients, mainly consisting of renal (71%), hepatic (33%), gastrointestinal (25%), splenic (19%), adrenal (13%), and pancreatic (8%) manifestations. 123 (44%) patients died at the time of the catastrophic APS event but the higher recovery rate was achieved by the combination of anticoagulants plus corticosteroids plus plasma exchange (PE) and/or intravenous immunoglobulins (IVIG) (69% versus 54%). CONCLUSIONS: The catastrophic APS is an uncommon but potentially life-threatening condition that needs high clinical awareness. The therapeutical connotation is that this may be corrected with the combination of anticoagulation plus steroids plus attempts at achieving a prompt reduction of antiphospholipid antibody titer (i.e. PE and/or IVIG).

Intestinal involvement secondary to the antiphospholipid syndrome (APS): clinical and immunologic characteristics of 97 patients: comparison of classic and catastrophic APS.

OBJECTIVE: To analyze the clinical and laboratory characteristics of 97 patients with intestinal involvement secondary to the antiphospholipid syndrome (APS) (37 patients with classic APS and 60 with catastrophic APS). METHODS: A computer-assisted (PubMed) search of the literature was performed to identify all cases of intestinal involvement associated with the APS from 1983 to December 2005. In addition, we analyzed the web-site-based international registry of patients with catastrophic APS ("CAPS Registry"). RESULTS: There were no differences in distribution by gender, mean age, and previous clinical manifestations of APS between the 2 groups. The prevalence of abdominal pain as the presenting manifestation of intestinal ischemia was higher in patients with classic APS (76% versus 37%; P < 0.005). The main difference in histopathologic findings between the 2 groups was the higher rate of microthrombosis in patients with catastrophic APS (75% versus 4%; P < 0.0005). The mortality rate was higher in patients with catastrophic APS (55% versus 17%; P < 0.0005). Follow-up was available in 22 patients with classical APS: 17 of them were discharged on oral anticoagulation and with a mean follow-up of 13 months (range, 1 to 48); all were in good health without the development of new thrombotic events. CONCLUSIONS: Intestinal involvement, although infrequent, is an important complication in patients with APS, especially in those with catastrophic APS. This would support the need for systematic screening for aPL in all cases of mesenteric thrombosis or ischemic colitis without clear underlying predisposing factors, and for systematic screening procedures in all classic APS patients complaining of abdominal pain.

Vasculitis in systemic lupus erythematosus: prevalence and clinical characteristics in 670 patients.

We conducted the current study to determine the prevalence and clinical characteristics of vasculitis in a large series of patients with systemic lupus erythematosus (SLE), focusing on the classification and clinical significance of the different types of vasculitis. We studied 670 consecutive patients who fulfilled 4 or more of the 1997 revised criteria for SLE. Definite vasculitis was diagnosed histologically and/or by arteriography, and probable vasculitis was diagnosed clinically when there were characteristic cutaneous lesions. Vasculitides were categorized according to the definitions adopted by the Chapel Hill Consensus Conference. Seventy-six (11%) patients with SLE had vasculitis (68 female patients and 8 male; mean age, 37.8 yr); only 32 (42%) fulfilled the Chapel Hill definitions. Cutaneous lesions were the main clinical presentation of vasculitis, present in 68 (89%) patients, while the remaining 8 (11%) had isolated visceral vasculitis. Compared with SLE patients without vasculitis, patients with vasculitis had a higher prevalence of livedo reticularis (22% vs. 3%; p = 0.028); a higher mean European Consensus Lupus Activity Measurement (ECLAM) score (5.86 vs. 3.87; p < 0.001); and a higher frequency of anemia (62% vs. 17%; p < 0.001), erythrocyte sedimentation rate (ESR) >50 mm/h (60% vs. 15%; p < 0.001), and anti-La/SS-B antibodies (19% vs. 5%; p = 0.014) in the multivariate analysis. With respect to the size of the vessels involved, 65 (86%) patients had small vessel vasculitis (SVV) and 11 (14%) had medium-sized vessel vasculitis (MVV). SLE patients with MVV had a higher prevalence of mononeuritis multiplex (54% vs. 2%; p < 0.001), visceral vasculitis (100% vs. 5%; p < 0.001), and ulcerated/ischemic cutaneous lesions (36% vs. 11%; p = 0.047) and a higher percentage of surgical interventions (45% vs. 0%; p < 0.001) compared with patients with SVV. In conclusion, we observed a heterogeneous presentation of vasculitides arising in the setting of SLE, with nearly 60% of cases not fulfilling the names and definitions adopted by the Chapel Hill Consensus Conference. SVV was the most frequent vasculitis, overwhelmingly cutaneous and clearly differentiated from MVV, which was less frequent but had predominantly visceral involvement (especially of the peripheral nerves). The presence of vasculitis in our patients with SLE was associated with a higher ECLAM score, livedo reticularis, hematologic parameters (anemia, high ESR), and anti-La/SS-B antibodies.

Antiphospholipid antibodies associated with malignancies: clinical and pathological characteristics of 120 patients.

OBJECTIVE: To describe the different types of malignancies associated with antiphospholipid antibodies (aPL). METHODS: We performed a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature from 1966 to 2003 to identify all cases of malignancies having aPL. RESULTS: One hundred twenty patients were found. The mean age was 56+/-17 years (range 5 to 88). Sixty-two (52%) patients were men and 58 (48%) were women. A heterogeneous group of malignancies were found. Regarding hematological malignancies, 10 (8%) patients suffered from B-cell lymphoma, 8 (7%) from spleen lymphoma, 7 (6%) from chronic myeloid leukemia, and 6 (5%) from non-Hodgkin's lymphoma (NHL). Regarding solid tumors, renal cell carcinoma was diagnosed in 7 (6%) patients, primary tumor with unknown origin in 7 (6%), lung adenocarcinoma in 6 (5%), breast carcinoma in 6 (5%), and melanoma in 6 (5%). The main aPL-related manifestations were thrombocytopenia (25%), cerebrovascular accidents (24%), deep vein thrombosis (19%), pulmonary embolism (15%), and heart valve lesions (9%). In 17 cases, catastrophic antiphospholipid syndrome was considered to be triggered by the malignancy. Seventy-one (63%) of 113 patients recovered or are still alive after cancer treatment. Twenty-three (35%) of 65 patients achieved aPL remission after proper treatment of the malignancy. CONCLUSIONS: It is important to bear in mind, especially in elderly patients, that thrombotic events associated with aPL can be the first manifestation of malignancy. At the same time, the presence of aPL in patients with malignancies has important implications in their treatment and prognosis.

Circulating auto-antibodies against nuclear and non-nuclear antigens in primary Sjögren's syndrome: prevalence and clinical significance in 335 patients.

The aim of this study was to analyze the prevalence and clinical significance of circulating auto-antibodies against nuclear and non-nuclear antigens in a large cohort of Spanish patients with primary Sjögren's syndrome (SS). We studied 335 patients diagnosed with primary SS seen consecutively in our department since 1994 and tested for anti-nuclear antibodies (ANA), anti-Ro/SS-A, anti-La/SS-B, anti-Sm, anti-ribonucleoprotein (anti-RNP), anti-smooth muscle antibodies (anti-SMA), anti-parietal cell antibodies (anti-PCA), anti-liver-kidney microsome type-1 (anti-LKM-1) antibodies and anti-mitochondrial antibodies (AMA). ANA were detected in 278 (83%) patients. The association of positive ANA with the presence of anti-Ro/SS-A and anti-La/SS-B antibodies reached statistical significance at a titre of ANA >1/80 (p<0.001), while the presence of anti-Sm and anti-RNP was associated with positive ANA at a titre > or =1/320 (p=0.037 for Sm and p=0.016 for RNP). ANA titres correlated with the number of positive antibodies against specific nuclear antigens (p<0.001) but not with the number of positive antibodies against non-nuclear antigens. We found positive anti-Ro/SS-A antibodies in 111 (33%) patients, anti-La/SS-B in 78 (23%), anti-RNP in 8 (2%) and anti-Sm in 4 (1%). Anti-SMA antibodies were detected in 208 (62%) patients, with no significant associations with clinical or analytical SS features, while anti-PCA antibodies were found in 90 (27%) patients and were associated with a higher prevalence of thyroiditis and liver involvement. AMA were detected in 28 (8%) patients, although only 14 presented clinical and/or analytical evidence of liver involvement. No patient presented anti-LKM antibodies. ANA play a central role in the immunological expression of primary SS, due to their frequency and close association with the underlying presence of one or more anti-ENA antibodies. Positivity for antibodies against non-nuclear antigens such as anti-PCA and AMA suggests an association with some organ-specific autoimmune diseases (thyroiditis and primary biliary cirrhosis), while the presence of anti-SMA, in spite of their high prevalence, has no clinical significance in primary SS.

Severe valvular regurgitation and antiphospholipid antibodies in systemic lupus erythematosus: a prospective, long-term, followup study.

OBJECTIVE: To assess whether the presence of antiphospholipid antibodies is related to the incidence and progression of severe valvular dysfunction and the need for valve replacement in patients with systemic lupus erythematosus (SLE). METHODS: In this prospective, long-term followup study, the initial echocardiographic findings in a cohort of 61 consecutive SLE patients were compared with those of 40 matched controls. All patients were serially evaluated for 14 +/- 3 years and had a followup echocardiogram 8 +/- 3 years after the initial evaluation. Serial determinations of anticardiolipin antibodies and lupus anticoagulant were performed in all cases. RESULTS: The number of SLE patients with valvular abnormalities increased from 39% to 73% between the initial and the followup echocardiography, but only 7 patients (12%) developed severe valvular regurgitation. Severe valvular regurgitation was significantly associated with the presence of high levels of IgG anticardiolipin antibodies (P = 0.001). The combined incidence of stroke, peripheral embolism, need for valve surgery, and death was 86% in patients with severe valvular regurgitation, compared with 25% in those without (P = 0.003). CONCLUSION: In SLE patients, the presence of high levels of IgG anticardiolipin antibodies is associated with the development of severe valvular regurgitation and with a high incidence of thromboembolic events and the need for valvular surgery.

Circulating monoclonal immunoglobulins in Sjögren syndrome: prevalence and clinical significance in 237 patients.

We conducted the current study to analyze the prevalence and clinical significance of circulating monoclonal immunoglobulins in patients with Sjögren syndrome (SS), focusing on the association with extraglandular features, immunologic markers, hematologic neoplasia, and hepatitis C virus (HCV) infection. We performed serum immunoelectrophoresis in 200 patients with primary SS and 37 patients with HCV-related SS. All patients fulfilled 4 or more of the 1993 European classification criteria for SS.Of the 200 patients with primary SS, 35 (18%) presented circulating monoclonal immunoglobulins. The monoclonal bands identified were 20 IgG (13 kappa, 7 lambda), 10 IgM (5 kappa, 5 lambda), 2 IgAkappa, and 3 free circulating light chains. Of the 37 SS-HCV patients, 16 (43%) had circulating monoclonal immunoglobulins. The monoclonal bands identified were 10 IgMkappa, 5 IgGlambda, and 1 free light lambda chain. Compared with primary SS patients, SS-HCV patients presented a higher frequency of monoclonal immunoglobulins (43% vs 18%, p = 0.001), with monoclonal IgMkappa being the most frequent monoclonal band. Six (12%) of the 51 SS patients with circulating monoclonal immunoglobulins presented hematologic neoplasia, compared with 3 (1.6%) of those without monoclonal immunoglobulins (p = 0.004; odds ratio = 8.13; 95% confidence intervals, 1.64-51.54). In 2 of the 6 patients with monoclonal immunoglobulins and lymphoproliferative disorders, a change of the monoclonal component was detected in previous immunoelectrophoresis determinations before the development of hematologic neoplasia. Circulating monoclonal immunoglobulins were detected in nearly 20% of patients with primary SS, with monoclonal IgG being the most frequent type of immunoglobulin detected. In SS-HCV patients, the prevalence of monoclonal immunoglobulins was higher (43%), with monoclonal IgM being the most frequent type found. SS-HCV patients presented a more restrictive monoclonal expression (limited to either monoclonal IgMkappa or monoclonal IgGlambda) than primary SS patients, who showed all types of heavy and light chains.

Clinical features related to antiphospholipid syndrome in patients with chronic viral infections (hepatitis C virus/HIV infection): description of 82 cases.

We analyzed the spectrum of clinical features related to antiphospholipid syndrome (APS) in patients with chronic viral infections, such as hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection. We selected patients from the HISPAMEC registry who repeatedly tested positive for antiphospholipid antibodies (aPL) and who had features of APS, and we searched the MEDLINE database for additional cases. A total of 82 patients were included (45 had chronic HCV infection, 32 had HIV infection, and 5 had HCV-HIV coinfection). The main features of APS were avascular bone necrosis (20 patients), peripheral thrombosis (17), thrombocytopenia (15), neurologic features (13), cardiac manifestations (12), pulmonary embolism (9), gastrointestinal manifestations (8), and cutaneous manifestations (8). The main APS-related features in HCV-infected patients were intraabdominal thrombosis and myocardial infarction, whereas, in HIV-infected patients, the main features were avascular bone and cutaneous necrosis. These viruses might act in some patients as chronic triggering agents that induce a heterogeneous, atypical presentation of APS.

Triple association between hepatitis C virus infection, systemic autoimmune diseases, and B cell lymphoma.

OBJECTIVE: To analyze the clinical characteristics of patients from a Department of Autoimmune Diseases presenting chronic hepatitis C virus (HCV) infection, systemic autoimmune disease, and B cell lymphoma. METHODS: We analyzed the records of 100 consecutive patients with systemic autoimmune diseases and associated HCV infection seen in our department between 1994 and 2000. We retrospectively investigated the development of B cell malignancies after the diagnosis of HCV related autoimmune disease. RESULTS: Six patients with HCV related systemic autoimmune disease presented B cell non-Hodgkin's lymphoma (NHL). These patients fulfilled the diagnostic criteria for Sjögren's syndrome (n = 4) and polyarteritis nodosa (PAN; n = 2). Four patients were female and 2 male, with a mean age at lymphoma diagnosis of 62 years (range 45-78). The main immunologic markers were hypocomplementemia in all patients and cryoglobulinemia in 5 (83%). Primary extranodal localization of lymphoma was observed in 3 (50%) patients: prostate (n = 1), liver and ovary (n = 1), and ocular annexa (n = 1). Clinically, NHL was classified as indolent lymphoma in 3 patients and aggressive lymphoma in 3. NHL histologic types were diffuse large cell lymphoma (n = 4), extranodal marginal zone B cell lymphoma (n = 1), MALT lymphoma (n = 1), and lymphoplasmacytic lymphoma (n = 1). CONCLUSION: We describe 6 patients with a triple association of HCV infection, systemic autoimmune disease, and NHL. Characteristics of these patients included a high prevalence of cryoglobulinemia (that clearly contributes to fulfillment of diagnostic criteria for PAN) and an elevated frequency of primary extranodal involvement. We recommend careful evaluation of patients with B cell NHL to detect silent autoimmune or chronic viral diseases. This triple association reinforces the suspected links between autoimmunity, infection, and cancer.

Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center.

OBJECTIVE: To analyze the prevalence and characteristics of the main clinical, hematologic, and immunologic manifestations of systemic lupus erythematosus (SLE) in a cohort of 600 consecutive patients from a single center, and to determine the specific characteristics of organ involvement in a homogeneous SLE population. METHODS: Patients were consecutively seen in our department either as inpatients or outpatients between 1980 and 2001. All had documented medical histories and underwent a medical interview as well as a routine general physical examination. Clinical and serologic characteristics of all patients were consecutively collected in a protocol form. RESULTS: The final cohort (survival cohort) consisted of 533 (89%) women and 67 (11%) men (female to male ratio, 8:1), with an average of 29 new patients per year. Mean age at onset of symptoms attributable to the disease was 31 years (range, 5 to 84 years) and mean age at the time of diagnosis of SLE was 33 years (range, 6 to 85 years). The most frequent SLE involvement was articular involvement, found in 498 patients (83%), followed by hematologic involvement in 451 patients (75%), specific SLE cutaneous involvement in 354 patients (59%), constitutional features in 252 patients (42%), and nephropathy in 203 patients (34%). Patients enrolled in the protocol before 1991 had a higher frequency of central nervous system (CNS) involvement (27% vs 10%, P <.001), thrombotic events (17% vs 9%, P =.003), and abnormal hematologic parameters (85% vs 66%, P <.01), but a lower frequency of articular involvement (79% vs 86%, P =.038) than those enrolled after 1991. The following were observed associations: specific SLE cutaneous involvement was associated with anti-Sm antibodies; renal involvement with hemolytic anemia and anti-double-stranded DNA antibodies; CNS involvement with thrombocytopenia and immunoglobulin G-anticardiolipin; thrombotic events with low total hemolytic complement, immunoglobulin G-anticardiolipin, and lupus anticoagulant; and myositis with anemia and anti-ribonucleoprotein antibodies. CONCLUSION: This large study, performed in a single center, has shown cluster associations between certain clinical, hematologic, and immunologic features of SLE, reflecting specific patterns of disease expression. The accurate evaluation of clinical features and laboratory markers at disease diagnosis and during evolution may improve the clinical treatment of SLE patients.

Relationship of p53 with other oncogenes, cytokines and systemic lupus erythematosus activity.

INTRODUCTION: Defects in the regulation of apoptosis of autoreactive lymphocytes are involved in the pathogenesis of systemic lupus erythematosus (SLE). The apoptotic process relies on adequate functioning of numerous molecules, including oncogenes and diverse cytokines. p53 has been implicated in the control of the cell cycle through the stimulation of apoptosis of these autoreactive cells. OBJECTIVE: To study the role of the p53 pathway on the regulation of apoptosis in SLE patients and analyze the relationship of the p53 oncoprotein with disease activity and other oncogenes (bcl-2, Fas) and cytokines (interleukin-10, IL-10, and tumor necrosis factor-alpha, TNF-alpha), implicated in the apoptotic process and the pathogenesis of SLE. PATIENTS AND METHODS: p53 and bcl-2 antigen expression were determined in lyzed lymphocytes from 74 patients with SLE and 30 healthy controls. Serum levels of soluble-Fas (sFas) and cytokines IL-10 and TNF-alpha were studied by enzyme-linked immunonosorbent assay. RESULTS: SLE patients had higher levels of p53 protein (0.16 +/- 0.33 ng/dl) than controls (0.014 +/- 0.02 ng/dl; p = 0.006). Patients with active SLE had higher levels of p53 (0.31 +/- 0.48 ng/dl) than those with inactive disease (0.08 +/- 0.17 ng/dl; p = 0.003) who in turn had higher levels than controls (0.01 +/- 0.02 ng/dl; p = 0.035). A significant correlation was found between p53 levels and the SLE disease activity index (R = +0.24/ p = 0.04), anti-DNA antibodies (R = +0.23/p = 0.048) and IL-10 levels (R = +0.4/p = 0.004). No correlation was found between p53 levels and bcl-2, sFas or TNF-alpha levels. CONCLUSIONS: The p53 oncoprotein may play a role in the pathogenesis and activity of SLE. IL-10 may influence SLE activity by inhibiting the p53 and bcl-2/Fas apoptosis pathway of autoreactive cells.

Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients.

In the present study, we assessed the frequency and characteristics of the main causes of morbidity and mortality in systemic lupus erythematosus (SLE) during a 10-year period and compared the frequency of early manifestations with those that appeared later in the evolution of the disease. In 1990, we started a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 10 years (1990-2000).A total of 481 (48.1%) patients presented 1 or more episodes of arthritis at any time during the 10 years, 311 (31.1%) patients had malar rash, 279 (27.9%) active nephropathy, 194 (19.4%) neurologic involvement, 166 (16.6%) fever, 163 (16.3%) Raynaud phenomenon, 160 (16.0%) serositis (pleuritis and/or pericarditis), 134 (13.4%) thrombocytopenia, and 92 (9.2%) thrombosis. When the prevalences of the clinical manifestations during the initial 5 years of follow-up (1990-1995) were compared with those during the ensuing 5 years (1995-2000), most manifestations were found to be more frequent during the initial 5 years. Of the 1,000 patients, 360 (36%) presented infections, 169 (16.9%) hypertension, 121 (12.1%) osteoporosis, and 81 (8.1%) cytopenia due to immunosuppressive agents. Twenty-three (2.3%) patients developed malignancies; the most frequent primary localizations were the uterus and the breast.Sixty-eight (6.8%) patients died, and the most frequent causes of death were similarly divided between active SLE (26.5%), thromboses (26.5%), and infections (25%). A survival probability of 92% at 10 years was found. A lower survival probability was detected in those patients who presented at the beginning of the study with nephropathy (88% versus 94% in patients without nephropathy, p = 0.045). When the causes of death during the initial 5 years of follow-up (1990-1995) were compared with those during the ensuing 5 years (1995-2000), active SLE and infections (28.9% each) appeared to be the most common causes during the initial 5 years, while thromboses (26.1%) became the most common cause of death during the last 5 years.In conclusion, most of the SLE inflammatory manifestations appear to be less common after a long-term evolution of the disease, probably reflecting the effect of therapy as well as the progressive remission of the disease in many patients. Meanwhile, a more prominent role of thrombotic events is becoming evident, affecting both morbidity and mortality in SLE.

Hematologic malignancies in patients with cryoglobulinemia: association with autoimmune and chronic viral diseases.

OBJECTIVE: To determine the prevalence and clinical characteristics of hematologic malignancies occurring in a large series of patients diagnosed with cryoglobulinemia, and to study their association and overlap with autoimmune and/or chronic viral diseases. METHODS: We retrospectively analyzed the occurrence of hematologic malignancies in 607 patients diagnosed with cryoglobulinemia in a single institution. Clinical, histologic, and serologic characteristics of patients were recorded on a protocol form. Hematologic malignancies were diagnosed according to the Revised European-American Lymphoma/World Health Organization classification criteria. RESULTS: Of the total cohort of 607 patients with cryoglobulinemia, we retrospectively identified 27 patients (5%) in whom a hematologic malignancy was diagnosed, including 24 (89%) lymphoproliferative and 3 (11%) myeloid malignancies. Fifteen (56%) were men and 12 (44%) women, with a median age at diagnosis of hematologic malignancy of 67 years (range, 44 to 88 years). The identified hematologic malignancies were non-Hodgkin lymphoma (n = 18), Hodgkin lymphoma (n = 2), chronic lymphocytic leukemia (n = 2), and 1 case each of multiple myeloma, Waldenström macroglobulinemia, Castleman disease, chronic myeloid leukemia and myelodysplastic syndrome. Of the 18 patients with non-Hodgkin lymphoma, there was a predilection for specific histologic types (diffuse large B-cell lymphoma in 8 cases and small lymphocytic lymphoma in 4) and a higher frequency of a primary extranodal origin in 6 (33%) cases. Conditions associated with hematologic malignancies were hepatitis C virus (HCV) infection in 14 patients (52%) and systemic autoimmune diseases in 13 (48%), with both HCV and systemic autoimmune disease in 6 cases (22%). CONCLUSIONS: Hematologic neoplasia associated with cryoglobulinemia is defined by a clear predominance of lymphoproliferative disorders (mainly non-Hodgkin lymphoma), with substantial extranodal involvement and an elevated presence of immunologic markers. HCV infection is the main etiologic factor associated with hematologic malignancies in patients with cryoglobulinemia, followed by specific systemic autoimmune diseases such as Sjögren syndrome and systemic lupus erythematosus, highlighting the close relationship between lymphoproliferation, autoimmunity, and viruses.

Pure sensory neuropathy in primary Sjögren's syndrome. Longterm prospective followup and review of the literature.

OBJECTIVE: To study the clinical course, response to therapy, and longterm outcome of pure sensory neuropathy (PSN) in a series of patients with primary Sjögren's syndrome (SS) followed prospectively in our referral centers. METHODS: We studied 15 patients (13 women, 2 men) with primary SS and PSN. All patients fulfilled 4 or more of the European diagnostic criteria. RESULTS: At diagnosis of PSN, clinical manifestations included numbness and paresthesias (11 patients), trigeminal neuropathy (6 patients), and Adie's pupil syndrome (4 patients). In 7 patients, PSN was diagnosed prior to SS, in 5 the diagnoses were made simultaneously, and in the remaining 3 patients PSN was diagnosed after the appearance of SS symptomatology. The mean duration of the prospective PSN followup was 10 years (range 1-20). The progression of PSN was acute in 1 patient (producing severe dysfunction in less than 1 month), subacute in 3 patients, and in the remaining 11, the symptoms progressed slowly over the ensuing years to other extremities. Patients were treated with corticosteroids (n = 13), cyclophosphamide (n = 4), and intravenous immunoglobulins (n = 1), and 2 patients received no treatment. In spite of treatment, most patients showed an indolent and insidious longterm PSN course. CONCLUSION: We found 3 differentiated clinical courses of the PSN in patients with primary SS: subacute progression in less than 1 month (7%), late acceleration of PSN 2-4 years after an initial indolent onset (20%), and a very longterm insidious, chronic evolution (73%). Prospective analysis of the longterm course of PSN shows a chronic and insidious evolution in most patients with PSN and SS, with a poor response to treatment, although stabilization of symptomatology for long periods is often observed.

The epidemiology of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is the most diverse of the autoimmune diseases because it may affect any organ of the body and display a broad spectrum of clinical and immunological manifestations. Although previously considered a rare disease, SLE now appears to be relatively common in certain groups of the population. This is probably due to the development of several immunological tests that have allowed the description of many atypical or benign cases that otherwise might not be diagnosed. Furthermore, with the introduction since 1982 of a set of more sensitive criteria for SLE classification, more cases can nowadays be detected. In the present article, we review the most important data regarding the incidence and prevalence of this disease in the general population, the epidemiologic information on the patterns of disease expression in specific subsets and the studies on mortality in SLE. An important amount of information comes from the data obtained from the "Euro-Lupus Cohort," a series of 1000 patients with SLE from several European countries that have been followed prospectively since 1991.

Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 35 cases.

To determine the clinical characteristics and outcome of patients with chronic hepatitis C virus (HCV) infection presenting severe autoimmune cytopenia unrelated to interferon alpha therapy, we analyzed characteristics and outcomes of 35 patients with HCV (16 from our departments and 19 from the literature). We considered active autoimmune hemolytic anemia (AHA) as a decrease of at least 2 g/dL in hemoglobin levels, an increase of at least 0.6 mg/dL in the serum unconjugated bilirubin level, a reticulocyte count >5%, and a positive direct Coombs test. Severe neutropenia was defined as a neutrophil count <0.5 x 10(9)/L, and severe thrombocytopenia as a platelet count <30 x 10(9)/L. We identified the following cytopenias: AHA (17 cases), severe thrombocytopenia (16 cases), aplastic anemia (2 cases), severe neutropenia (1 case), refractory sideroblastic anemia (1 case), and pure red cell aplasia (1 case). Three patients simultaneously presented 2 types of severe cytopenias. Twenty-seven patients (77%) were female and 8 (23%) male, with a mean age at diagnosis of cytopenia of 51.7 years (range, 18-84 yr). Immunologic markers were detected in 19 (68%) of 28 patients, the most frequent being hypocomplementemia in 16 (57%), cryoglobulins in 15 (54%), antinuclear antibodies in 12 (43%), and rheumatoid factor in 5 (18%). Other associated processes were autoimmune diseases in 14 (50%) of 28 and human immunodeficiency virus (HIV) coinfection in 3 (9%) of 32. We found clinical and immunologic differences between HCV patients with AHA and those with severe thrombocytopenia. Patients with HCV-related AHA showed a higher prevalence of associated autoimmune diseases (71%), cryoglobulins (67%), and cirrhosis (59%). All had a good response to corticosteroids, but a poor prognosis (47% mortality). In contrast, patients with HCV-related severe thrombocytopenia had a lower prevalence of associated autoimmune diseases (11%), a poorer response to corticosteroids (55%), and lower mortality (6%), with HIV/HBV coinfections in some patients. The 35 cases presented demonstrate that different types of immune-mediated cytopenias may be severe and clinically significant in patients with HCV infection. Hemolytic anemia and severe thrombocytopenia were the most frequent cytopenias observed. Most patients responded well to corticosteroids, although a higher rate of mortality was observed in those with liver cirrhosis.

Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients.

To describe the clinical and immunologic characteristics of patients with adrenal involvement and antiphospholipid syndrome (APS), we conducted a computer-assisted (PubMed) search of the literature to identify all cases of primary adrenal insufficiency associated with antiphospholipid antibodies published in English, French, and Spanish from 1983 (when APS was first defined) through March 2002. We reviewed 86 patients (80 from the literature plus 6 from our cohort); 55% were male, and the mean age at presentation was 43 +/- 16 years. Sixty-one (71%) patients had primary APS, and 14 (16%) had systemic lupus erythematosus. In 31 (36%) patients, adrenal insufficiency was the first clinical manifestation of APS. Abdominal pain was present in 55% of patients, followed by hypotension (54%), fever (40%), nausea or vomiting (31%), weakness or fatigue (31%), and lethargy or altered mental status (19%). The main finding in imaging techniques was compatible with adrenal hemorrhage (59%) and in histopathologic study was a hemorrhagic infarction with vessel thrombosis (55%). Lupus anticoagulant was detected in 97% of patients and the anticardiolipin antibodies titer was positive in 93% of patients. Most patients (95%) were positive for the IgG isotype of anticardiolipin antibodies, whereas 40% were positive for the IgM isotype. Baseline cortisol levels were decreased in 98% of patients, ACTH hormone levels were increased in 96% of patients, and the cosyntropin stimulation test was positive in 100% of patients tested. Steroid replacement therapy was the most frequent treatment (84%), followed by anticoagulation (52%) and aspirin (6%). Thirty-two of 35 (91%) patients with prolonged anticoagulant therapy were in good health with a mean follow-up of 25 months, whereas 25 of the 69 (36%) patients with outcome data available had died. The results of the present review stress the clinical importance of systematic screening for lupus anticoagulant and anticardiolipin antibodies in all cases of adrenal hemorrhage or infarction. An initial screening for hypoadrenalism is mandatory in any antiphospholipid antibody-positive patient who complains of abdominal pain and undue weakness or asthenia.

Effects of beta2-glycoprotein I and monoclonal anticardiolipin antibodies in platelet interaction with subendothelium under flow conditions.

OBJECTIVE: To evaluate whether the effect of human monoclonal anticardiolipin antibodies (aCL) on platelet interaction with the subendothelium under flow conditions is dependent on beta(2)-glycoprotein I (beta(2)GPI). METHODS: Three monoclonal IgM aCL with anti-beta(2)GPI activity (TM1B3, GR1D5, and EY2C9) obtained from patients with antiphospholipid syndrome, a monoclonal aCL with lupus anticoagulant activity but without anti-beta(2)GPI activity (FRO) obtained from a patient with a splenic lymphoma, and a control monoclonal IgM without aCL activity were used. TM1B3, GR1D5, EY2C9, FRO, and control IgM (30 microg/ml) were added to reconstituted blood containing gel-filtered platelets (200 x 10(9)/liter), factor VIII (100 units/dl), and fibrinogen (1.5 gm/liter). Samples were perfused (wall-shear rate 800 seconds(-1)), with and without the addition of purified beta(2)GPI (20 microg/ml), through annular chambers containing collagen-rich denuded vascular segments, and the percentages of surface covered by platelets and by thrombi were evaluated. RESULTS: No differences in the percentages of surface covered by platelets and by thrombi were observed among samples with TM1B3, GR1D5, EY2C9, FRO, and control IgM added when reconstituted blood samples without beta(2)GPI were used. However, a significant increase in the percentage of surface covered by platelets was observed in the presence of TM1B3, GR1D5, and EY2C9 but not in the presence of FRO when samples containing beta(2)GPI were used. Increased thrombi formation was induced by TM1B3 and GR1D5 but not by EY2C9 or FRO in samples with added beta(2)GPI. CONCLUSION: Monoclonal aCL require anti-beta(2)GPI activity to promote platelet interaction with the subendothelium under flow conditions.

Lupus eritematoso sistémico y enfermedad cardiovascular / Systemic lupus erythematosus and cardiovascular disease

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