Antiphospholipid antibodies in neonates with stroke--a unique entity or variant of antiphospholipid syndrome?

OBJECTIVE: YB current affiliation: Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus, Israel YB and MJS contributed equally to the study and should be regarded as joint first authors on this manuscript. Antiphospholipid syndrome (APS) may present with thrombosis and persistently elevated titers of antiphospholipid antibodies (aPL) in the neonatal period. Our aim was to investigate the course and impact of elevated titers of aPL in a cohort of infants presenting with either perinatal arterial ischemic stroke (PAS) or cerebral sinus vein thrombosis (CSVT) during the perinatal period. STUDY DESIGN: Sixty-two infants with clinically and radiologically confirmed PAS or CSVT presenting in the neonatal period underwent thrombophilia workup that included Factor V Leiden (FVL), PII20210A mutation, MTHFR 677T polymorphism, protein C, protein S, aPL namely either circulating lupus anticoagulant (CLA), anticardiolipin antibodies (aCL) or anti-ß2-glycoprotein-1 (ß2GP1). Mothers also underwent thrombophilia workup. RESULTS: Twelve infants with persistently elevated aPL were prospectively followed. Infants with positive aPL showed no concordance with presence of maternal aPL. All children were followed for a median of 3.5 years (range: nine months to 19 years) with repeated aPL testing every three to six months. Anticoagulant therapy initiation and therapy duration varied at the physician's discretion. In 10/12 cases aPL decreased to normal range within 2.5 years; one female with complex thrombophilia risk factors required indefinite prolonged anticoagulation. None of the infants showed recurrent thrombosis or any other APS manifestations, despite lack of prolonged anticoagulation. CONCLUSIONS: The presence of aPL may be important in the pathogenesis of cerebral thrombosis in neonates. Nevertheless, the nature of thrombophilia interactions in this period and their therapeutic impact warrants further investigation.

Activation of phospholipase C in human B cells is dependent on tyrosine phosphorylation.

Cross-linking of the surface antigen receptor on B lymphocytes has been demonstrated to lead to activation of phospholipase C (PLC) with subsequent increases in production of inositol phosphates and diacylglycerol. In turn, these second messengers increase cytosolic free calcium [( Ca2+]i) and activate the serine threonine phosphotransferase protein kinase C (PKC). These processes are thought to play a major role in B cell activation and proliferation. However, the mechanism linking the B lymphocyte antigen receptor to phospholipase C remains to be identified. We demonstrate herein that activation of the antigen receptor on human lymphocytes, in addition to activation of PLC, increases tyrosine phosphorylation of specific substrates. Tyrphostins, a new class of tyrosine kinase inhibitors which compete for substrate binding site of specific tyrosine kinases have recently been synthesized. Preincubation of B lymphocytes with two different tyrphostins blocked anti-IgM-induced proliferation, oncogene expression, tyrosine phosphorylation, increases in [Ca2+]i, and production of inositol phosphates. The same inhibitors were without effect on B cell proliferation induced by phorbol esters and cation ionophores which directly activate PKC and increase [Ca2+]i thus bypassing PLC. These findings strongly indicate that tyrphostins do not exhibit significant nonspecific toxicity and suggest that they act proximal to PLC. The ability of the tyrphostins to block increases in [Ca2+]i and inositol phosphate production, after activation of the B cell antigen receptor, indicates that a tyrosine kinase acts as an essential link between the B cell antigen receptor and PLC.

Protracted febrile myalgia in children and young adults with familial Mediterranean fever: analysis of 15 patients and suggested criteria for working diagnosis.

OBJECTIVES: To present an analysis of patients with protracted febrile myalgia (PFM), a rarely reported manifestation of familial Mediterranean fever (FMF), and propose clinical criteria for working diagnosis. METHODS: A multicenter retrospective cohort study of children with PFM was performed. Clinical and laboratory data were obtained by medical record review. RESULTS: The study group included 15 patients with PFM. PFM occurred as the presenting sign of FMF in 33%. FMF was diagnosed clinically in all and by genetic analysis in 93%. M694V allelic involvement was noted in 93% of the patients. PFM occurred at a mean age of 9 +/- 3.4 years and was characterized by severe generalized muscle pain in all patients and fever in 71%. Mean duration up to diagnosis was 15.5 +/- 6 days. Mean erythrocyte sedimentation rate was 104 +/- 26 mm/h; mean C-reactive protein was 15.4 +/- 6.3 mg%. Creatine kinase was normal. Treatment included corticosteroids (4 patients) and nonsteroidal anti-inflammatory drugs (NSAIDs) (9 patients) with a symptomatic relief achieved at a mean of 7.7 +/- 4.3 days and 5 +/- 3.8 days, respectively (p = 0.14) (mean severity score 3 and 2.2, respectively, p = 0.075). Symptomatic relief in 2 untreated patients was achieved at a mean of 45.5 days. CONCLUSION: Based on our data, we propose criteria for working diagnosis including: severe disabling myalgia of at least 5 days in a young patient with FMF, associated with fever, elevated levels of inflammatory markers and presence of at least one M694V mutation.

A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD).

Although familial Mediterranean fever (FMF) is an autosomal recessive disorder, preliminary partial mutation analysis suggested that about 60% of FMF patients, who also suffer from Behçet's disease (FMF-BD), have only a single mutated FMF gene (MEFV). In this study, the possibility that patients with FMF-BD may indeed be carriers of a single mutated MEFV is further analysed. The presence of mutations in the coding region of MEFV of eight patients with FMF-BD, representing six families with 47 members, was determined by sequencing. A possible role for the non-carrier chromosome and for BD in the expression of FMF in patients with a single mutated MEFV allele was determined by analysing the association between these variables and the presence of FMF in heterozygous kin. Sequence analysis revealed that all eight patients had indeed only one mutation in the coding region of MEFV. The patients' non-carrier chromosomes converged into three different MEFV haplotypes and were shared by heterozygous unaffected kin in five of six families. BD was found in 10 of 11 carriers with FMF vs one of 16 carriers without FMF (P < 0.001). These results suggest that FMF may be expressed in individuals harbouring only one coding mutation in MEFV. The findings argue against a role for the non-carrier chromosome in the induction of FMF, and suggest that the FMF phenotype in this cohort was associated with the simultaneous presence of BD. These findings may mirror a more generalised rule, that FMF may be precipitated in carriers of a single mutated FMF gene by factors unrelated to the other MEFV allele.

Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state.

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. The recent cloning of the FMF gene (MEFV) and identification of disease-associated mutations in most patients made the direct determination of FMF carrier frequency feasible. The aim of the present study was to investigate the carrier rate of the most common MEFV mutations among different Jewish ethnic groups in Israel. Further, an attempt was made to elucidate the possible biological advantage that the heterozygote state may confer. Three hundred Ashkenazi, 101 Iraqi, and 120 Moroccan Jews were screened for the E148Q, V726A, and M694V mutations (at least two most common mutations per group), with a resulting overall carrier frequency in the respective ethnic group of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and non-carriers of MEFV mutations was discerned, although an excess of febrile episodes in carriers of the V726A and in carriers of either V726A or E148Q was evident (P < 0.02 and P < 0.05, respectively). The frequency of subjects with two MEFV mutations but not expressing FMF (phenotype III) was 1:300 in Ashkenazi Jews and 1:25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40-240 fold. These results affirm the high carrier rate among the studied Jewish ethnic groups in Israel and suggest that most subjects with FMF mutations are unaffected.

Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics.

To determine the prevalence and characterize demographic, clinical, and genetic features of familial Mediterranean fever (FMF) of late onset, all patients experiencing their first FMF attack at age 40 years or more were identified using the computerized registry of our FMF clinic, and then thoroughly interviewed and examined. The control group consisted of 40 consecutive FMF patients, who arrived at the FMF clinic for their regular follow-up visit and were 40 years of age or older at the time of the examination. The severity of the disease in patients and controls was determined using a modified score, developed previously. Mutational analysis in the FMF gene was performed using a commercial kit. Only 20 of 4000 (0.5%) patients had late-onset FMF. These patients were mostly men, of non-North African origin, P < 0.05 compared to controls. All had abdominal attacks and in most these were the only manifestation of their disease, P < 0.001. None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P < 0.001. The response to treatment was good despite using low colchicine dose, P < 0.05. The overall severity score indicated a mild disease, P < 0.001. Mutational analysis revealed absence of M694V homozygosity, P < 0.01, compared to our regular FMF population. We conclude that the onset of FMF in a late age defines a milder form of disease with typical clinical, demographic, and molecular genetic characteristics.

The changing face of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a genetic disease characterized by painful febrile "attacks" of serositis and the development of amyloidosis. Although FMF has been extensively studied and described, new data have accumulated during the last decade. This report gives an update, focusing specifically on (1) newly characterized manifestations, such as acute scrotal "attacks," protracted febrile myalgia, and spondyloarthropathy; (2) progress made in the diagnosis and treatment of FMF-amyloidosis; (3) experience acquired with colchicine, establishing its safety in common practice, childhood, conception, and pregnancy; (4) colchicine's role in the prevention and treatment of FMF-amyloidosis; (5) new laboratory findings; and (6) new considerations in the differential diagnosis. The most important achievement in recent years, however, is the mapping of the FMF susceptibility gene to chromosome 16p, a finding that raises hopes for prompt cloning of the gene and elucidation of the mechanisms involved in FMF expression.

Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF).

Familial Mediterranean fever (FMF) is characterized by recurrent attacks of febrile serositis. While arthritis, pleuritis and peritonitis are common in FMF, no association of pericarditis with FMF has been described in detail. We retrospectively studied about 4000 FMF patients, using a computer chart review. Pericarditis was diagnosed when patients sustained attacks of pleuritic retrosternal chest pain and had typical findings in the electrocardiogram, echocardiogram or chest radiogram. The incidence and features of pericarditis in FMF were compared to published data. Over a period of 20 years, one or more episodes of pericarditis were recorded in 27 patients, a significantly higher incidence than in the general population (68 vs. 6 per 10(5) per year, p < 0.001). Each patient experienced 1-3 pericarditis attacks, lasting a mean of 4.2 days, accompanied by high temperature and symptoms of FMF attack at another site. The pericarditis attack resolved spontaneously and left no sequelae. FMF patients with pericarditis were comparable to other FMF patients in most demographic and clinical parameters. Pericarditis may be considered another rare manifestation of FMF.

Erythromelalgia following influenza vaccine in a child.

Erythromelalgia is a rare disease characterised by palmar and plantar erythema, burning pain and local increases in temperature. Erythromelalgia in adults most commonly appears secondary to myeloproliferative disorders, essential thrombocytosis and polycythemia vera; however, in children primary forms predominate. Erythromelalgia in children is characterised by a chronic relapsing course, usually refractory to treatment. We describe a case of erythromelalgia which developed in a 4.5 year old girl following influenza vaccination. Low dose aspirin, carbamazepine and propranolol induced a rapid resolution of the syndrome.

Juvenile Behçet's disease in Israel. The Pediatric Rheumatology Study Group of Israel.

OBJECTIVE: Behçet's disease (BD) is a vasculitis mainly observed in young adult males. Juvenile BD is rare and only small series of pediatric cases have been reported. The objective of this study was to define the epidemiology and clinical features of BD among Israeli children. METHODS: A questionnaire was sent to 8 pediatric rheumatology units in Israel and 30 cases of BD diagnosed before the age of 16 years were identified. RESULTS: Fifteen patients fulfilled the International Study Group Criteria for BD, while 15 had an incomplete form of BD. Among the patients with complete BD, stomatitis and skin involvement were the most common manifestations. Other symptoms included genital ulcers, uveitis, CNS involvement, arthritis, and gastrointestinal involvement. A positive family history was elicited in 3 patients. HLA B5 was found in 7 of 12 patients (58%). The 15 patients with incomplete BD all had recurrent stomatitis; other manifestations included uveitis, arthritis, and genital ulcers. HLA B5 was found in 94% of this group. CONCLUSION: Juvenile BD in Israel is not uncommon, and is frequently associated with HLA B5 positivity. This could indicate a genetic susceptibility in our region. Half of the patients in our series had an incomplete form of BD, which may represent a less severe variant of the disease. In any case, careful follow-up is required, since their condition could eventually evolve into complete BD.

[Systemic lupus erythematosus in children in Israel].

Systemic lupus erythematosus (SLE) is a rare disease in children that might possibly be modulated by genetic and environmental factors. In order to delineate the characteristic features of SLE among Israeli children, we reviewed the medical records of 38 cases from 8 pediatric rheumatology clinics. All fulfilled the 1982 American Rheumatism Association revised criteria for SLE. The illness became apparent at the age of 16 years or younger and the mean age of onset was 11.9 +/- 2.4 y (range 7-16) and the mean duration of follow-up 4.0 +/- 4.8 y (range 0.5-15). The female to male ratio was 2.8:1; 28 were Jewish and 10 Arabs. Systemic complaints, such as fever, malaise and weight loss, were noted in 90%, malar rash in 65%, and other skin manifestations in 40%. Arthritis was noted in 57% and additional musculoskeletal complaints in 70%; 90% had hematological abnormalities. Major organ system involvement included: renal disease in 50% pulmonary involvement 28% and CNS involvement 28%. 2 patients are currently on renal dialysis and 1 died from hypertensive crisis. We conclude that the features of SLE in children in Israel are not influenced by ethnic or geographic factors, and are similar to those reported worldwide.

Outcome of a national Israeli cohort of pediatric systemic lupus erythematosus.

The aim of this study was to describe the clinical manifestations and outcomes of a national cohort of childhood systemic lupus erythematosus (cSLE). All cases of cSLE registered in the Israeli national registry of children with rheumatic diseases between 1987-2003 were examined for disease activity and damage by the SLE disease activity index (SLEDAI) and SLE collaborating clinics/American College of Rheumatology (SLICC/ACR) damage index. Demographic, clinical, laboratory and treatment factors were analysed for their effect on the outcome. One-hundred and two patients were identified, 81% females, with a mean age at diagnosis of 13.3 +/- 2.6 years. The mean SLEDAI score was 17.2 +/- 9.0 (range 2-60). Fifty four patients were followed for at least five years. The mean SLEDAI decreased to 7.6 +/- 6.3 (0-29) and the mean SLICC/ACR damage index was 0.7 +/- 1.6 (0-8). Five patients developed chronic renal failure. No patients died. No factors were found to be significantly associated with the outcome except the initial SLEDAI score. The five-year outcome of our national cSLE cohort was good; with relatively low activity and minimal damage in most patients. The initial SLEDAI predicted the development of late damage.

Antiphospholipid syndrome and recurrent thrombosis in children.

OBJECTIVE: Few studies have addressed antiphospholipid syndrome (APS) among children. Our aims were to analyze the clinical and laboratory manifestations in a pediatric APS cohort and to assess the influence of inherited thrombophilia factors on the outcome of children with APS. METHODS: This was a multicenter study of children with APS who had no previous systemic autoimmune disease. We retrospectively reviewed their clinical and laboratory data, including hereditary thrombophilic deficits and outcomes. RESULTS: The cohort comprised 28 patients (17 females, mean +/- SD age at onset 10.6 +/- 6.1 years). The most common initial manifestations of APS were venous thrombosis, stroke, and thrombocytopenia. Lupus anticoagulant was detected in 96% of those tested. After a mean +/- SD followup of 5.7 +/- 4.8 years, 16 children (57.1%) had central nervous system disease, 9 exhibited hematologic involvement, and 5 (all females) had systemic lupus erythematosus (SLE). None had renal, heart, or new skin disease. Seven of 24 patients exhibiting vascular thrombotic events had recurrences. Infants with perinatal stroke had monophasic disease, and other manifestations of APS did not develop later. Hereditary thrombophilia was more common in children who experienced a single episode of APS (8 [53.3%] of 15 patients) than in those who experienced recurrences (2 [28.6%] of 7 patients). However, only 2 patients in the latter group (28.6%) received anticoagulants after the first manifestation, compared with 12 (70.6%) of the 17 patients without recurrences. CONCLUSION: APS in children has unique features. SLE may develop in a significant percentage of girls presenting with APS. Hereditary thrombophilia did not predict recurrent thrombosis, whereas the preventive impact of anticoagulant treatment following the first thrombotic event was noteworthy.

Intraarticular corticosteroid injection in the management of children with chronic arthritis.

OBJECTIVE: Intraarticular (IA) corticosteroid injection is a common therapeutic approach in the management of adult rheumatoid arthritis. This study examined the safety and efficacy of IA corticosteroid injection in 71 patients with juvenile arthritis who were being seen at the Sheba Medical Center during the years 1991-1996. METHODS: Sixty-one patients fulfilled the American College of Rheumatology revised criteria for the diagnosis of juvenile rheumatoid arthritis (JRA), 6 patients had reactive arthritis, and 4 patients had various other arthritic conditions. The mean +/- SD age was 9.4 +/- 5.6 years (range 0.5-18 years); 47 were female (mean age 8.1 +/- 5.5 years) and 24 were male (mean age 10.8 +/- 5.4 years). A total of 300 joints were injected with triamcinolone hexacetonide. The most common sites of injection were the knees (124 injections), ankles (71 injections), wrists (46 injections), shoulders (10 injections), and elbows (7 injections). Children under the age of 6 (n = 17), or older children who received more than 4 joint injections at one time (n = 10) were sedated with either ketamine HCI or propofol. All other children received their joint injections under local anesthesia. RESULTS: Full remission of the joint inflammation lasting >6 months following injection was achieved in 246 of the 300 injections (82.0%). In 54 (18.0%) of the injected joints, the inflammation recurred within 6 months of injection. In patients with pauciarticular arthritis, 115 of 141 injections (81.6%) resulted in full remission. Discontinuation of all oral medications was accomplished in 43 patients (60.6%) of the total group of 71 patients and in 32 of the 43 patients with pauciarticular disease (74.4%). Correction of joint contraction was achieved in 42 children (55 joints). In all 11 patients with Baker's cyst and in 12 patients with tenosynovitis, complete remission was achieved following injection. No infection or other serious complications occurred in any of the patients following the procedure. CONCLUSION: IA corticosteroid joint injection in children with juvenile arthritis is a safe and effective mode of therapy. It may be the only therapy needed in patients with pauciarticular JRA, obviating the need for prolonged oral medications, and is effective in correcting joint contractions and deformities.

Systemic lupus erythematosus presenting as idiopathic intracranial hypertension.

We describe a 13-year-old girl who presented with an acute febrile disease accompanied by headache, dizziness, nausea, decreased visual acuity, and diplopia. Examination showed papilledema, enlarged blind spots, and visual field defects with an otherwise normal neurological examination. The diagnosis of idiopathic intracranial hypertension was confirmed by increased intracranial pressure (cerebrospinal pressure > 200 mm water) in the absence of any abnormal radiological findings of the brain. Initially, only positive serology tests showing elevated titers of anti-DNA antibodies and positive tests for anti-Sm and anti-RNP antibodies were found; however, 6 mo later clinical and laboratory findings were compatible with systemic lupus erythematosus (SLE). Our patient illustrates that the possibility of SLE needs to be considered in the differential diagnosis of idiopathic intracranial hypertension.