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OBJECTIVE: To characterize familial Mediterranean fever (FMF) in Ashkenazi patients, a Jewish subgroup in which FMF has rarely been described before. METHODS: A retrospective analysis, comparing demographic, clinical, and genetic measures of the cohort of Ashkenazi Jewish patients with FMF (n = 57), followed at the National Center for FMF in Israel, to age and sex matched patients of Iraqi Jewish (n = 62) and North African Jewish (NAJ; n = 61) origin. RESULTS: Age at disease onset and diagnosis was earlier in NAJ than among Ashkenazi and Iraqi patients. Family history of FMF was described by only 30% of Ashkenazi patients as opposed to the majority of Iraqi and NAJ patients (p = 0.001). The frequency of abdominal and febrile attacks was similar among the 3 groups, while chest and joint attacks were far less common in Ashkenazi and Iraqi compared to NAJ patients. A good response to colchicine was noted in a similar proportion of Ashkenazi and Iraqi patients (82–84%) as opposed to only 56% of NAJ patients (p = 0.0001). Proteinuria, renal failure, and amyloidosis were most frequent among the NAJ patients (18, 6.6, and 9.8% compared to 5.3, 0, and 3.5% and 1.6, 0, and 0% in Ashkenazi and Iraqi patients, respectively). CONCLUSION: Ashkenazi patients with FMF stand at the mildest end of the clinical spectrum of FMF. This is notwithstanding the tendency for amyloidosis, the frequency of which is not trivial and which deserves particular awareness.

OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS:. Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.

OBJECTIVE: To identify and characterize pre-attack symptoms (prodrome) in patients with familial Mediterranean fever (FMF). METHODS: Forty-eight patients with FMF whose attacks are preceded by a prodromal period composed the study population. Clinical, demographic, and genetic characteristics of the study group were compared to those of a control group of 48 patients with FMF whose attacks begin without a premonitory phase. Patients of both groups were recruited consecutively, during their routine followup visit to the FMF clinic. RESULTS: A prodrome was found to be a common manifestation of FMF, experienced by about 50% of the patients. Overall, demographic, clinical, and genetic variables were comparable between study and control groups. In affected patients prodrome recurs in most attacks, lasts a mean of 20 hours, and manifests with either a mildly unpleasant sensation at the site of the forthcoming spell (discomfort prodrome), or with a spectrum of physical, emotional, and neuropsychological complaints (variant prodrome). The 2 types of prodromata are frequently accompanied by a host of constitutional symptoms. CONCLUSIONS: A prodromal period heralding attacks is a newly defined and reliable FMF manifestation that reproducibly predicts attacks and may help prevent attacks and elucidate the pathogenesis of the disease.

OBJECTIVE: To clinically and genetically characterize patients with familial Mediterranean fever (FMF) in whom arthritis constitutes the only manifestation, and to establish the most important features distinguishing FMF arthritis in such a setting from other forms of mono/oligo arthritides. METHODS: The study population comprised 14 patients with episodes of arthritis as the only manifestation of FMF who nevertheless fulfilled the diagnostic criteria for FMF. The control group consisted of 28 patients with episodic mono/oligo arthritis of different disease entities (palindromic, reactive, inflammatory bowel disease, Reiter's, seronegative spondyloarthropathy, chronic juvenile, Behçet's, and gouty arthritis) who presented to the rheumatology clinic during the study period. Patients in both groups underwent clinical evaluation and donated blood for FMF gene analysis. RESULTS: The study and control groups shared similar age and sex distribution and experienced the monoarthritic attacks at similar sites, usually the knee and ankle joint. The 2 groups differed significantly in features of arthritis (which were febrile and of short duration in FMF), family history of FMF, mutation analysis, and response to colchicine. These differences allowed the defining of a rule, which readily distinguishes FMF arthritis from other forms of episodic mono/oligo arthritis. CONCLUSION: The clinical, ethnic, and genetic features of recurrent monoarthritis of FMF are specific and may separate FMF from other entities with mono/oligo arthritis.

OBJECTIVE: To evaluate the efficacy and safety of weekly intravenous (IV) colchicine, in addition to oral colchicine therapy, in a subset of patients with familial Mediterranean fever (FMF) unresponsive to oral colchicine prophylaxis. METHODS: Thirteen patients with frequent FMF attacks, despite oral doses of 2–3 mg/day colchicine, were treated with weekly IV injections of 1 mg colchicine for 12 weeks in an open-label pilot study. Patients were evaluated periodically for the number and severity of their attacks, use of analgesics, and erythrocyte sedimentation rate (ESR). RESULTS: A 50% reduction in attack frequency and attack severity in at least one site was achieved by 10 and 6 of the 13 study patients, respectively (p < 0.001 and p < 0.01). Mean number of abdominal attacks declined significantly from 4.2 ± 3.0 per patient at baseline to 1.9 ± 2.6 attacks at the end of the third month of the study (p = 0.0002). The mean severity of abdominal attacks declined from a baseline of 6.1 ± 0.95 to 3.9 ± 2.8 after 3 months (p = 0.02). Comparable significant change was observed in chest attacks, ESR, and number of analgesic tablets used. Joint attacks were unrelieved during the study period. The treatment was safe and well tolerated, without side effects. CONCLUSION: Treatment with weekly IV colchicine injections in addition to oral colchicine therapy is effective and safe in patients with FMF refractory to oral colchicine.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease with diverse clinical presentation. The FMF gene (MEFV) has recently been cloned and 30 point mutations causing the disease have been identified. We appraised the value of mutation analysis as a diagnostic test for FMF in symptomatic pediatric patients, and explored the possible correlations between MEFV genotypes and the diverse phenotypic expression of the disease. METHODS: Two hundred sixteen children who met the clinical criteria for FMF underwent molecular genetic studies to detect the 3 most common mutations in the Israeli FMF patient population (M694V, V726A, E148Q). The mutations found were related to clinical presentation and disease severity, using the Tel-Hashomer severity score. RESULTS: Of the 216 children who fulfilled the diagnostic criteria for FMF, 82 (38.0%) had 2 of the tested mutations, 73 (33.8%) had only one mutation, and 61 (28.2%) had none of the mutations studied. The M694V was the most frequent mutation, detected in 174 of 432 MEFV alleles (40.0%). The V726A mutation was found in 39 alleles (9.0%) and the E148Q mutation in 25 (5.8%). The severity score correlated with the number of mutations. Children with no mutations presented at an older age compared to children with one or 2 mutations. Children homozygous for the M694V mutation presented at a younger age, had a higher severity score, and more commonly had arthritis. CONCLUSION: Limited genetic molecular testing for MEFV mutations may explain some of the FMF clinical variability, but is diagnostically ineffective. The use of clinical criteria remains essential in establishing the diagnosis of FMF.

Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 ± 10.0 yr versus 26.2 ± 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.

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 &lt; 0.02 and P &lt; 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. © 2001 Wiley-Liss, Inc.

To evaluate the abdominal CT features of reactive amyloidosis, abdominal CT scans of 20patients with amyloidosis of familial Mediterranean fever (FMF) were reviewed and compared with abdominal CT scans of2 control groups: 22 patients with chronic renal failure (CRF) due to non-amyloidotic kidney diseases and 40 patients with normal kidney function. The kidney size of patients with amyloidosis of FMF were found to vary during the course of the disease from normal or slightly larger than normal at the proteinuric phase, to smaller than normal and comparable to kidney size in CRF, at the uremic stage. Compared to kidney disease of other causes, more patients with FMF-amyloidosis had dense kidneys with coarse parenchymal calcification and calcification in other abdominal organs. Patients with FMF-amyloidosis had fewer aortic calcifications than patients with non-amyloidotic kidney disease. These findings suggest that kidney disease of reactive amyloidosis may have abdominal CT findings distinguishing it from other types of kidney diseases.

Familial Mediterranean fever (FMF) is an autosomal, recessively inherited disease, affecting people of Jewish, Arabic, Turkish and Armenian ancestry. The disease is the prototype of the periodic febrile syndromes. Its hallmark is short attacks of fever and painful manifestations in the abdomen, joints, chest, scrotum and skin. Chronic and protracted manifestations, particularly nephropathic amyloidosis, chronic arthritis, and protracted myalgia, may also occur in the disease. The diagnosis of FMF should be considered in individuals of an appropriate ethnic background who present with febrile disease of episodic nature. The differential diagnosis in this case is broad and includes a large number of infectious, inflammatory and genetic diseases. However, in most cases, the very specific general and site-restricted features of the FMF attacks on the one hand, and the absence of manifestations typical of other conditions on the other hand, determine the diagnosis of FMF. This chapter presents clues and tips that help in the diagnosis and treatment of FMF.

Background:Familial Mediterranean fever (FMF) is an autosomal recessive disease that tends to affect certain ethnic groups. It is characterized by recurrent, self-limited attacks of peritonitis, pleuritis, and synovitis. Erysipelas-like erythema (ELE) is the pathognomonic skin manifestation. Lesions are characterized by tender erythematous plaques, usually located on the lower legs. They may be triggered by physical effort and subside spontaneously within 48 to 72 hours of bed rest. Fever and leukocytosis may accompany this condition. Objective:The purpose of this study was to describe the histology and the immunofluorescence findings in ELE and to discuss these observations in relation to the clinical findings in FMF. Methods:We studied 7 patients with FMF in whom ELE developed. In all patients a biopsy was performed within 18 hours from onset of the lesion. In addition to routine hematoxylin and eosin stains, immunohistochemistry to evaluate the infiltrate and direct immunofluorescence were performed. Patients were followed up for their ELE lesions. Results:Histologic examination revealed edema of the superficial dermis and sparse perivascular infiltrate composed of a few lymphocytes, neutrophils, and nuclear dust. Vasculitis was not observed. Direct immunofluorescence showed, in all cases, deposits of C3 in the wall of the small vessels of the superficial vascular plexus. In some cases fibrinogen and IgM were also observed. Conclusion:These findings are in accordance both with those found previously in the erysipelas-like phenomenon and those in the peritoneum of patients with FMF. The sparse infiltrate and the deposition of C3 also are compatible with the clinical picture of self-resolving lesions of short duration. It also suggests that erysipelas-like erythema belongs to the spectrum of neutrophilic dermatoses and supports a pathogenesis that involves abnormal inhibition of the inflammatory cascade. (J Am Acad Dermatol 2000;42:791-5.)

To create monoclonal anti–endothelial cell antibodies (mAECA) from a patient with Takayasu arteritis to evaluate their ability to activate human umbilical vein endothelial cells (HUVEC), and to characterize the mechanism of EC activation. A panel of mAECA was generated from peripheral blood lymphocytes of a patient with Takayasu arteritis, using Epstein-Barr virus transformation. Activity against macrovascular EC (HUVEC) and microvascular EC (human bone marrow EC immortalized by SV40) antigens was detected by enzyme-linked immunosorbent assay. Inhibition studies were used to select the monoclonal antibodies (mAECA) which share the same EC epitope binding specificity as the total IgG-AECA from the Takayasu arteritis patient. The binding of the mAECA to human aortic EC was studied by immunohistochemistry. The secretion levels of interleukin-6 (IL-6) and von Willebrand factor (vWF) were determined, to serve as markers for EC activation. The activated EC were examined for the adherence of a monocytic cell line (U937), as well as for expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin. In addition, nuclear extracts of the mAECA-treated EC were analyzed for the induction of translocation of nuclear factor κB (NF-κB), using a specific NF-κB oligoprobe in an electrophoretic mobility shift assay. Six mAECA were selected, the mixture of which produced 100% inhibition of binding of the original IgG (from the patient with Takayasu arteritis) to HUVEC. All mAECA possessed high activity against macrovascular EC, but none had significant anti–microvascular EC activity. The mAECA, but not normal human IgG, had anti–human aortic EC activity. Four of the 6 mAECA activated EC, manifested by increased IL-6 and vWF secretion. The 4 mAECA induced EC expression of adhesion molecules and increased adhesion of U937 monocytic cells to EC. In addition, these mAECA stimulated the nuclear translocation of the NF-κB transcription factor. Our findings suggest that AECA may directly stimulate EC in Takayasu arteritis through elevation of adhesion molecule expression associated with NF-κB activation and adhesion of monocytes, and may therefore play a pathogenic role in the development of the vasculopathy in Takayasu arteritis.

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 &lt; 0.05 compared to controls. All had abdominal attacks and in most these were the only manifestation of their disease, P &lt; 0.001. None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P &lt; 0.001. The response to treatment was good despite using low colchicine dose, P &lt; 0.05. The overall severity score indicated a mild disease, P &lt; 0.001. Mutational analysis revealed absence of M694V homozygosity, P &lt; 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. Am. J. Med. Genet. 87:30–35, 1999. © 1999 Wiley-Liss, Inc.

Familial Mediterranean fever (FMF) is a major cause of AA amyloidosis. Recently, the gene (MEFV) causing this disease was cloned and 16 disease associated mutations have been described. We have analyzed 178 FMF patients, 30 of whom also suffered from amyloidosis, for 4 mutations in MEFV. Mutations were identified in 29 of the FMF amyloidosis patients. 27 FMF amyloidosis patients were homozygous for M694V. One patient was found to be homozygous for both V726A and E148Q. In another patient EI48Q and V726A were found on one allele, while V726A was found on the second allele. Amyloidosis was far more common among patients homozygous for M694 V compared to patients with other mutations (P<0,0001). In 3 patients homozygous for M694V, amyloidosis was the sole manifestation of the disease.

We report 28 patients (20 male) with a syndrome characterized by abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis, and cervical adenopathy (PFAPA syndrome). Episodes of fever occurred at intervals of 5.1 ± 1.3 weeks beginning at the age of 4.2 ± 2.7 years. Fever, malaise, tonsillitis with negative throat cultures, and cervical adenopathy were reported in all 28 patients, aphthae in 19, headache in 5, abdominal pain in 5, and arthralgia in 3. Mild hepatosplenomegaly was observed in 6 patients. Mild leukocytosis, elevation of the erythrocyte sedimentation rate, and fibrinogen were found during attacks. These episodes of illness resolved spontaneously in 4.3 ± 1.7 days. Serum IgD was found elevated (>100 U/mL) in 12 of the 18 patients tested (140.2 ± 62.4 U/mL). Affected children grow normally, have no associated diseases, and have no long-term sequelae. Attacks were aborted by a single dose of oral prednisone (2 mg/kg) at the beginning of the attack in all 15 patients in whom this medication was prescribed. In 9 patients the syndrome has completely resolved (beginning at the age of 2.9 ± 1.3 and lasting 8 ± 2.5 years). In 3 other patients complete resolution of the attacks occurred after tonsillectomy was performed. PFAPA is sporadic, and no ethnic predilection was found. Increased awareness of the clinical syndrome has resulted in more frequent diagnosis and adequate treatment. (J Pediatr 1999;135:98-101)

We have identified and characterized the tissue distribution of the antigen recognized by a novel monoclonal antibody (mAb) 1B10, raised against an activated γδ T cell clone. Immunohistochemistry of tissue sections, analysis of single cell suspensions by flow cytometry revealed that mAb 11110 weakly reacted with 6% of normal human peripheral blood mononuclear cells (PBMC). After 5-6 days of in vitroculture of PBMC activated with phytohemagglutinin (PHA), 55% of the CD4+and 25% of the CD8+T cells became 11310+. 1B10 expression was maintained on long term cultured interleukin 2 (IL-2)-dependent T cell receptor (TCR) αβ+and γδ+clones, importantly, in contrast to resting T cells, the majority of in vivoactivated synovial T lymphocytes from a patient with rheumatoid arthritis were 1 B10+. In addition, myelo-monocytic U927 cells, tissue macrophages and some epithelia and fibroblasts were found to react with mAb 1B10. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of molecules immuno-precipitated by mAb 1B10 from radio-iodinated cell surface membrane lysates of T lymphocyte and U937 cells revealed 26 and 29 kiloDalton (kDa) glycoproteins respectively. In conclusion, mAb 1B10 recognizes a novel -late- appearing 26 kDa T cell activation antigen that may be useful for further studies of activated T cells in health and disease.

Familial Mediterranean fever (FMF) is an autosomal recessive disease prevalent among non-Ashkenazi Jews, Armenians, Arabs, and Turks. The Bedouin are nomad Arab tribes residing in desert margins of the Middle East and Arabia. FMF is quite rare in Bedouins, and here we report on two Bedouin families from southern Israel suffering from this disorder. The MEFV mutations found in the Bedouin patients M694I, V726A, and E148Q are consistent with their Arab origin. The disease severity score showed a mild to moderate severity disease in six patients. The Bedouins, leading a unique nomadic life, may prove instrumental in unraveling the role of environmental factors in the course and severity of FMF. Am. J. Med. Genet. 92:247–249, 2000. © 2000 Wiley-Liss, Inc.

ABSTRACT: The effect of cyclophosphamide pulse therapy given in relatively small doses (10 mg/kg per pulse) in 17 females with lupus nephritis has been studied. Four females developed menopause; in one transient amenorrhea occurred. No changes in menstrual cycle were noted in the other 11 females, four of whom subsequently delivered five normal babies. These data suggest the relative safety of small doses of cyclophosphamide pulse therapy on gonadal function in females under age 40 years.

The tunica vaginalis is 1 of the sites involved in the recurrent febrile attacks of serositis, which are the hallmark of familial Mediterranean fever. The attacks present clinically as “orchitis.” We report on a patient with familial Mediterranean fever in whom recurrent episodes of scrotal attacks were complicated by testicular necrosis requiring orchiectomy. The case emphasizes the challenge of recognizing and differentiating these attacks from other causes of acute scrotum.

Two hundred and thirty-seven patients with systemic sclerosis were followed prospectively in a scleroderma clinic. The overall 3, 6, and 9-year survival rates were 86, 76 and 61 per cent respectively. Renal, cardiac and pulmonary disease, and older age at enrolment were adverse prognostic factors associated with reduced survival. There were no significant differences in survival between males and females or in patients with restricted compared to those with diffuse skin thickening. Death from systemic sclerosis was most frequently due to pulmonary hypertension, with fewer than expected deaths from renal or cardiac causes. Twenty-eight per cent of deaths were due to causes unrelated to systemic sclerosis, most commonly cancer and ischaemic heart disease, and in older patients

Minocycline therapy is associated with black discoloration of various tissues, including the thyroid gland,1 bones,2 and skin.3 A patient with black discoloration of the tongue that appeared 1 week after minocycline (300 mg/d) was administered for acne vulgaris is presented. This is the first report of tongue involvement as a sole untoward effect of minocycline therapy. REPORT OF A CASE. A 19-year-old woman was referred to the Department of Oral Medicine, Sheba Medical Center, Tel Hashomer, Israel, for black pigmentation in patchy forms appearing on the lateral and central aspects of the tongue, which was otherwise normal (Figure). The patient was in good health except for acne vulgaris for which she received minocycline (300 mg/d). She stated that the black discoloration of the tongue developed gradually 1 week after the drug was administered. The possibility of the adverse reaction of minocycline was raised and the patient decided