Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus.

The objective of this study was to assess the prevalence of the Mediterranean FeVer (MEFV) gene mutations in systemic lupus erythematosus (SLE) patients and their effect on organ involvement, as well as disease activity and severity. The frequencies of three familial Mediterranean fever-related MEFV gene mutations (M694V, V726A and E148Q) were investigated in 70 SLE patients. Organ involvement, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were correlated with mutation carriage. Eleven of 70 patients (15.7%) were found to carry an MEFV mutation. A single patient harbored two mutations, E148Q and V726A, without overt familial Mediterranean fever while the rest were heterozygous carriers. Four of the 11 carried an M694V mutation, four carried V726A and two carried E148Q. The majority of MEFV mutation carriers were Sephardic while non-carriers were mainly of Ashkenazi origin (72.7% vs. 45.7% and 47.4% vs. 9.1%, respectively, p = 0.02). SLE onset was significantly earlier in MEFV carriers (27.6 ± 9.7 vs. 38.2 ± 15.5 years, in carriers vs. non-carriers, p = 0.02). Hematologic and serologic parameters were comparable among mutation carriers and non-carriers. Febrile episodes were more common among MEFV mutation carriers (45.4% vs. 15.2%, p = 0.035) and there was a trend for excess episodes of pleuritis as well (54.5% vs. 23.7%, p = 0.06 in carriers vs. non-carriers, respectively). The frequency of secondary anti-phospholipid antibody syndrome was equivalent among the groups. Conversely, compound urinary abnormalities and renal failure was not observed among MEFV carriers yet was present in 33.4% and 18.6% of non-carriers (p = 0.027 and 0.19, respectively). SLICC damage index and SLEDAI activity index did not differ significantly between the groups. MEFV mutation carriage appears to modify the SLE disease phenotype in that it contributes to an excess of inflammatory manifestations such as fever and pleuritis on the one hand, while thwarting more severe renal involvement on the other.

False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy that can be associated with arterial or venous thrombosis and is caused by antibodies against platelet factor 4 (PF4)-heparin complex. Patients with antiphospholipid syndrome (APS) have been reported with positive tests for PF4-heparin complex antibodies by antigen assay. Whether such patients can be treated with heparin is a dilemma. OBJECTIVES: To determine the incidence and nature of the HIT immune reaction in patients with APS and/or systemic lupus erythematosus (SLE). METHODS: Antibodies against PF4-heparin complex were assayed by particle gel immunoassay (PaGIA), or enzyme immunoassay (EIA) with or without an excess of heparin. EIA for PF4 alone was also performed. Functional assays for HIT, that is, heparin-induced platelet activation (HIPA) and heparin-induced platelet aggregation, were also performed. RESULTS: In 32 of 42 patients (76.2%) with APS, APS and SLE, SLE, or SLE with antiphospholipid antibodies, EIA IgG or PaGIA for PF4-heparin complex antibodies were positive. Of these 32 samples, 26 (81.3%) tested positive for anti-PF4 antibodies. All 24 samples that were positive for PF4-heparin complex by EIA IgG were also positive for EIA IgG in the presence of heparin excess, and all were negative by the HIPA and heparin-induced platelet aggregation tests. CONCLUSION: A large proportion of patients with APS and/or SLE give false-positive HIT antigen test results that are presumably related to autoantibodies against PF4, which can be distinguished from true HIT antibodies by EIA for PF4-heparin complexes tested with heparin excess, and by functional assays.

Outcome of patients with scleroderma admitted to intensive care unit. A report of nine cases.

OBJECTIVE: Patients with systemic rheumatic disease constitute a small percentage of admissions to the medical intensive care units (ICUs). Systemic sclerosis (SSc) is one of the rheumatic diseases that together with secondary complications may lead to a critical illness requiring hospitalization in the ICU. We present the features, clinical course and outcome of critically ill patients with scleroderma that were admitted to the ICU. METHODS: The medical records of nine patients with diagnosis of scleroderma (8 female, 1 male), admitted to the intensive care unit of Sheba Medical Center during the 11-year interval between 1991 and 2002, were reviewed. RESULTS: The mean age of the patients at the time of admission to the ICU was 48 +/- 13 [SD] years. The mean duration of SSc from diagnosis to the ICU admission was 8 +/- 8 years. Six patients had diffuse SSc, two patients had limited SSc and one patient had juvenile diffuse morphea. The main reasons for admission to the ICU were: infection/ septic syndrome (n = 4), scleroderma renal crisis (SRC) with pulmonary congestion (n = 2), acute renal failure associated with diffuse alveolar hemorrhage namely scleroderma- pulmonary - renal syndrome (SPRS) (n = 1), iatrogenic pericardial tamponade (n = 1), mesenteric ischemia (n = 1). The patients had high severity illness score (mean APACHE II 25 +/- 3). Eight out of nine patients (89%) that were admitted to the ICU died during the hospitalization, six (66.6%) of them died in the ICU. Septic complications as the main cause of death were determined in five patients (62.5%), while four of them had pneumonia and acute respiratory failure along with underlying severe pulmonary fibrosis. Lungs and kidneys were the most common severely affected organs by SSc in our patients. CONCLUSION: The outcome of scleroderma patients admitted to the ICU was extremely poor. Infectious complication was the most common cause of death in our patients. Although infections are treatable, the high mortality rate for this group of patients was dependent on the severity of the underlying visceral organ involvement, particularly severe pulmonary fibrosis. The severity of this involvement is a poor outcome predictor. An early diagnosis and an appropriate treatment of such complications may help to reduce the mortality in scleroderma patients.

WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension.

BACKGROUND: WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride-transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4. DESIGN: Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF). RESULTS: Basal NPD was higher in FHH compared with controls (n = 20): 22.8 +/- 5.7 vs. 16.2 +/- 5.3 mV, respectively (P = 0.014). Maximal response to amiloride was also higher in FHH compared with controls: 14.8 +/- 3.5 vs. 10.0 +/- 4.8 mV, respectively (P = 0.03). In CF these values were 42.9 +/- 9.3 and 29.9 +/- 7.4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride-inhibitable residual PD in FHH was 50 +/- 30 vs. 81 +/- 9% in controls (P = 0.0003) and 56 +/- 7% in CF. The response to chloride-free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16.0 +/- 8.6 vs. 10.4 +/- 5.9 mV (P = 0.08)]. Sweat conductivity in FHH was 49.7 +/- 7.3 vs. 38.2 +/- 8.1 mmol (NaCl eq) L-1 in 16 controls (P = 0.007) and 94.0 +/- 19.3 in CF. CONCLUSIONS: Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild-type WNK4. This may be caused by a regulation of ENaC or a K+ channel.

Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus.

Autoimmune diseases are either tissue-specific like multiple sclerosis (MS) or multisystemic like systemic lupus erythematosus (SLE), although clinically both exhibit common features. To gain insight into the properties of the genes involved in each disease we have investigated the gene expression signature of peripheral blood mononuclear cells (PBMC) in MS and SLE in comparison to healthy subjects. Total RNA was purified, hybridized to Genechip array and analysed in 36 subjects (13 relapsing-remitting MS patients, five SLE patients and 18 age-matched healthy subjects that served as controls). Additional blood samples from 15 relapsing-remitting MS patients, 8 SLE patients and 10 healthy subjects were used for confirmation of microarray gene expression findings by ELISA and RT-PCR. MS and SLE patients demonstrated a common gene expression autoimmune signature of 541 genes which differentiated them from healthy subjects. The autoimmune signature included genes that encode proteins involved in apoptosis, cell cycle, inflammation and regulation of matrix metalloproteinase pathways. Specifically, decreased TIMP1 gene expression in the autoimmunity signature suggests increased MMP activity in target tissues as a result of the lack of feedback mechanism. An additional different disease specific signature identified the gene expression pattern for MS (1031 genes), mainly associated with over-expression of adhesion molecules and down-expression of heat shock proteins; the SLE specific signature (1146 genes) mainly involved DNA damage/repair pathways that result in production of nuclear autoantibodies. These results provide insights into the genetic pathways underlying autoimmune diseases, and identify specific disease-associated signatures that may enable targetted disease-related specific therapies to be developed.

Localized pericardial inflammation in systemic lupus erythematosus.

Regional or localized pericarditis has been infrequently reported. We report a patient with systemic lupus erythematosus (SLE), who presented with retrosternal pleuritic-type chest pain without audible friction rub, electrocardiographic changes or detectable pericardial effusion on echocardiography. Computed tomography, however, revealed a circumscribed area of pericardial inflammation, suggesting a diagnosis of localized lupus-associated pericarditis. This case demonstrates that localized pericarditis may occur in SLE and that chest CT may be required as part of the work-up in the diagnosis of lupus pericarditis.

Hepatic infarctions during pregnancy are associated with the antiphospholipid syndrome and in addition with complete or incomplete HELLP syndrome.

Antiphospholipid antibody syndrome (APS) is associated with adverse pregnancy outcomes and maternal complications including thrombotic events and early pre-eclampsia. HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) represents a unique form in the spectrum of pre-eclampsia. This report describes four patients with pregnancy-associated hepatic infarctions. All four had APS and HELLP syndrome, which was complete in one patient and incomplete in three patients, with elevated liver enzymes in all, and either thrombocytopenia or hemolysis in two. In the literature, we found descriptions of an additional 24 patients who had 26 pregnancies with concomitant hepatic infarction. Of the total 28 patients, anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LAC) were assessed in 16 patients, out of whom 15 were found to be positive. Hepatic infartction during pregnancy was associated almost always with APS, with HELLP (2/3 complete, 1/3 incomplete), and only in one-third of the pregnancies with pre-eclampsia (PE).

Ascending aortic pseudoaneurysm following coronary bypass in a hemodialysis patient with fever of unknown origin.

A unique patient who developed pseudoaneurysm of the ascending aorta after coronary artery bypass grafting is presented. This case is peculiar due to the presenting symptom being fever of unknown origin. It is the first description of a patient on hemodialysis, who developed ascending aortic pseudoaneurysm.

Anti-insulin antibodies and the natural autoimmune response in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the finding of ample serum autoantibodies. The role and the origin of many of these antibodies are still obscure. The aim of this work was to study the occurrence of anti-insulin antibodies (AIA) in SLE, and to postulate, based on AIA determination, on the mechanisms involved in the production of some autoantibodies in SLE. IgG and lgM AIA, anti-DNA antibodies (ADA) and anti-tetanus toxoid antibodies (ATA) were determined using ELISA in sera and B-lymphocytes culture media of 24 SLE patients, 10 healthy controls and 19 insulin-dependent diabetes mellitus (IDDM) patients. B- and T-lymphocytes were isolated using Ficoll gradient, depleted of T-cells using cyclosporin A, EBV infected and grown in medium. The frequencies of IgM-AIA and IgG-ADA were higher in SLE patients than in healthy controls (P < 0.02 and P < 0.05, respectively). The rate of IgM-AIA in SLE and IDDM was comparable, while IgG-AIA was significantly less common in SLE than in IDDM (P < 0.05). The prevalence of ATA in SLE patients and healthy controls was similar. These findings increase the spectrum of the humoral autoimmune response in SLE and suggest that part of it (natural autoantibodies) is independent of antigen driven response.

Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy.

Fifty-seven pregnancies in women with antiphospholipid syndrome (APS) are presented. These were treated with s.c. enoxaparin and low dose aspirin. In fourteen pregnancies warfarin was prescribed between weeks 15-34 (warfarin group). The decision to switch to warfarin depended on a morbidity score, and the patient's consent. Neither teratogenicity nor significant maternal, fetal or neonatal hemorrhage was observed. Despite the higher pretreatment morbidity score of the warfarin group, the live birth rate was high in both groups: 86% in the warfarin group and 87% in the non-warfarin group. There was no significant difference in week of delivery, birth weight, or incidence of thrombosis between the groups. The study demonstrates the efficacy and safety of anticoagulants during pregnancy. The use of LMWH in pregnant women with APS not being moot, warfarin might be justified in selected patients.

Evaluation of predictive factors for neurocognitive dysfunction in patients with inactive systemic lupus erythematosus.

OBJECTIVE: To determine predictive factors associated with the cognitive dysfunction in patients with inactive systemic lupus erythematosus (SLE). METHODS: Consecutive patients followed at the Lupus Clinic with inactive SLE (SLE Disease Activity Index, SLEDAI, = 0) underwent a battery of neuropsychological tests; Beck Depression Inventory and psychiatric assessment were also performed. Neurocognitive dysfunction was defined as 3 abnormal scores. Data were analyzed using chi-square tests, ANOVA tests, and logistic regression. RESULTS: Twenty-five of the 58 patients with SLE (43%) versus 9 of 47 healthy controls (19%) demonstrated neurocognitive dysfunction (p < 0.01). Neurocognitive dysfunction was not associated with depression or a psychiatric diagnosis, use of steroids, or previous or current evidence for fibromyalgia. SLEDAI > 10 at first presentation to the Lupus Clinic and previous vasculitis were associated with neurocognitive dysfunction, but previous central nervous system disease, renal disease, renal damage, or atherosclerotic complications were not. Neurophysiologic studies at the time of the assessment were not predictive of neurocognitive dysfunction. CONCLUSION: Patients with inactive SLE demonstrate neurocognitive dysfunction. This is associated with more disease activity at presentation, but is not associated with specific organ involvement or organ damage.

[High alkaline phosphatase in subacute thyroiditis].

Subacute thyroiditis may be hard to diagnose, therefore patients are sometimes misdiagnosed and subjected to unnecessary work-up. We report a 37-year-old man with subacute thyroiditis and a high concentration of serum alkaline phosphatase. After aspirin treatment there was clinical improvement and decrease in rapid ESR, and in high serum thyroxin and alkaline phosphatase. The increased alkaline phosphatase, seen in as many as 50% of patients, is of hepatic origin, and is not caused by high serum thyroxin. Awareness of this relationship may help in diagnosis and may prevent unnecessary diagnostic procedures, which may be invasive.

Outcome of pregnancy in three patients with primary antiphospholipid syndrome after stroke.

OBJECTIVE: Ischemic stroke is the most common neurological manifestation in patients with antiphospholipid syndrome (APS). Pregnancy in APS patients markedly increases the risk of thrombosis. There is no data on pregnancy outcome in patients with APS with a history of an ischemic stroke. We report our experience with three APS patients with a history of stroke who had successful pregnancies and deliveries. PATIENTS: Three patients with APS and previous stroke were treated with small doses of aspirin and anticoagulants during pregnancy. RESULTS: The patients remained free of attacks of cerebral ischemia during their pregnancies and at follow-up periods of 1 to 4 years. CONCLUSIONS: Successful pregnancy and delivery is possible in APS patients with a history of stroke, treated with low-dose aspirin and anticoagulants. A previous episode of cerebral ischemia should not be considered an absolute contraindication for an APS patient to become pregnant.

Aspergillosis in systemic lupus erythematosus.

Infection is the major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Although various fungi account for a substantial number of these lethal infections, aspergillosis, an important opportunistic infection in immunosuppressed patients, is described rarely. Only 23 cases have been reported in the English-language medical literature. Risk factors for acquiring aspergillosis in these patients were high grade disease activity, granulocytopenia, use of steroids and other immunosuppressive treatment and presence of bacterial infection. The diagnosis in most patients was delayed and they died. Here, we describe three SLE patients with invasive aspergillosis. Features of our patients' diseases were similar to those reported previously. Aspergillosis appeared while they had active SLE treated with high dose corticosteroids. In 2 patients the fungal infection was systemic and diagnosed post mortem. Both were leukopenic and had concurrent bacterial infection and one received amphotericin B prior to death. In the third, the infection was localized to a transplanted kidney and was cured by nephrectomy. Aspergillosis should be suspected in patients with active SLE, who are immunocompromised and sustain concomitant bacterial infections. The currently poor prognosis may be improved with more aggressive diagnostic investigation and treatment.

Bilateral patellar metastases as the clinical presentation of bronchogenic adenocarcinoma.

Common symptoms of the musculoskeletal system may occur as a rare presentation of an underlying malignancy. We describe a case of bronchogenic adenocarcinoma presenting as bilateral knee pain with arthritis due to bilateral metastases to the patellae. We also review the literature of patellar metastases.

Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies.

OBJECTIVE: To describe experience with 41 pregnancies treated with the low-molecular-weight heparin enoxaparin. METHODS: The medical charts of 34 women (a total of 41 pregnancies) treated between January 1992 and March 1995 with the low-molecular-weight heparin enoxaparin were reviewed. Most patients (87.5%) received one daily 40-mg injection. In all cases, treatment was continued throughout labor, delivery, and the immediate postpartum period. RESULTS: Therapy was administered for 5-280 days (median 91). One case of a thromboembolic event was recorded during treatment. No systemic or local side effects were reported. During pregnancy, only one patient had mild vaginal bleeding, which resolved spontaneously while therapy was continued. There was no excessive intrapartum bleeding in any of these patients, whether delivered vaginally or abdominally. During treatment, 19 of the 34 patients underwent 24 surgical procedures, including 13 cesarean deliveries, without excessive bleeding. Epidural anesthesia was used during labor in nine of the patients, with no specific complications. The corrected perinatal mortality rate, (ie, the rate of fetal death after 24 weeks' gestation plus neonatal death, excluding a neonate with multiple anomalies) for those neonates delivered after 24 weeks' gestation was 2.7%. There were no cases of intraventricular hemorrhage in any of the neonates. CONCLUSION: This preliminary series, the largest reported to date, demonstrates the relative safety and efficacy of low-molecular-weight heparin therapy in pregnancy and delivery.

Prolactin in systemic lupus erythematosus.

OBJECTIVE: To estimate the prevalence and evaluate the clinical significance of hyperprolactinemia in a cohort of 82 consecutively reviewed patients with systemic lupus erythematosus (SLE). METHODS: Basal prolactin levels and clinical data were analyzed in 82 consecutive patients with SLE, and longitudinal studies were carried out in 30/82 patients. RESULTS: Hyperprolactinemia was not associated with active disease in the group as a whole (p = 0.145) or in longitudinal studies in 30 patients (p = 0.294). However, SLE was more often active in patients with hyperprolactinemia without any obvious causes (8/9 samples) compared with patients with known secondary causes for hyperprolactinemia (p = 0.088). CONCLUSION: Hyperprolactinemia is likely not associated with disease activity in SLE.