Objective. To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic... more Objective. To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF. Methods. Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients. Results. R92Q was found in 6% of the controls, with an especially high carrier rate among Moroccan Jews (8%). R92Q was found in 3 (3.2%) of the 92 FMF patients, 1 homozygous for the MEFV M694V mutation and 2 heterozygous for M694V. All 3 patients showed partial response to colchicine. R92Q was not found in patients unresponsive to colchicine, nor was it found in patients with amyloidosis or in patients with FMF-like disease without MEFV mutations. Conclusion. The frequency of the R92Q mutation in FMF patients is comparable with that of controls. Despite the fact that TRAPS and FMF share common biochemical pathways, we found no evidence for an interaction between these two genes.
Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mut... more Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. Methods: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. Results: The mean ± SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1 ± 13.2 vs. 70.7 ± 14.1 respectively, P value b 0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9% ± 6.6% and the MGs effect as 17.4% ± 15.5% in average. Conclusions: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively.
Objective: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders,... more Objective: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/ CARD15 gene mutations in the FMF disease phenotype was never studied before. Patients and methods: The cohort consisted of 103 consecutive children with FMF, followed in a single referral center. NOD2/CARD15 genotypes were analyzed in all patients and 299 ethnically matched unaffected controls. Demographic data, clinical characteristics, and disease course of FMF patients with and without NOD2/CARD15 mutation were compared. Results: A single NOD2/CARD15 mutation was detected in 10 (9.7%) FMF patients and 26 (8.7%) controls. No homozygous or compound heterozygous subjects were discovered in the 2 groups. FMF patients carrying a NOD2/CARD15 mutation had a higher rate of erysipelas-like erythema and acute scrotum attacks, a trend for a higher rate of colchicine resistance and a more severe disease as compared with patients without mutations. Conclusions: NOD2/CARD15 mutations are not associated with an increased susceptibility to develop FMF. Nevertheless, the presence of these mutations in FMF patients appears to be associated with a trend to a more severe disease.
The Israel Medical Association Journal Imaj, Nov 1, 2012
BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal ... more BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid.OBJECTIVES: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel.METHODS: We evaluated eight patients clinically and genetically during the years 2006 to 2011.RESULTS: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotoraxonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation.CONCLUSIONS: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.
We present here a first report on the biochemical analysis of intestinal amyloid deposits found i... more We present here a first report on the biochemical analysis of intestinal amyloid deposits found in two cases of hemodialysis-related amyloidosis. A new microtechnique was applied for extraction and immunochemical/chemical characterization of amyloid proteins in small amounts of fixed tissue, thus allowing precise identification of β2microglobulin amyloid (Aβ2M) in both cases studied. The molecular mass of the identified amyloid β2M
To develop widely accepted international severity score for children and adult patients with fami... more To develop widely accepted international severity score for children and adult patients with familial Mediterranean fever (FMF) that can be easily applied, in research and clinical practice. Candidate severity criteria were suggested by several FMF expert physicians. After three rounds of Delphi survey, the candidate criteria, defined by the survey, were discussed by experts in a consensus meeting. Each expert brought data of clinical manifestations, laboratory findings and physician's global assessments (PGAs) of minimum 20 patients from their centres. We used the PGAs for disease severity as a gold standard. Logistic regression analysis was used to evaluate the predicting value of each item, and receiver operating characteristic curve analysis was performed to demonstrate the success of the criteria set. A total of 281 patients consist of 162 children and 119 adults with FMF were enrolled and available for validity analysis: Nine domains were included in the final core set of ...
The American Journal of Human Genetics, Feb 1, 2003
In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These youn... more In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These young women responded to environmental temperatures of 18ЊC-7ЊC with profuse sweating on large segments on their back and chest. Both had additional abnormalities, including a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend their elbows, and kyphoscoliosis. We have observed this disorder in two Norwegian brothers. Genomewide screening in the two families, followed by saturation marker studies and linkage analysis, identified a 1.4-Mb homozygous candidate region on chromosome 19p12. The maximum multipoint LOD score was 4.22. In both families, DNA sequencing of 25 genes within the candidate region identified potentially deleterious CRLF1 sequence variants that were not found in unaffected control individuals. Our findings confirm that the cold-induced sweating syndrome is an autosomal recessive disorder that is probably caused by impaired function of the CRLF1 gene, and they suggest important developmental functions for human CRLF1.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but man... more Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.
Anti-DNA antibodies are autoantibodies unique to systemic lupus erythematosus. Studies of their s... more Anti-DNA antibodies are autoantibodies unique to systemic lupus erythematosus. Studies of their structure have demonstrated cross reactive idiotypes present in genetically unrelated individuals. Despite much research, it is still not clear what triggers their production and what governs the presence of particular idiotypic determinants in their structure. To study the role of genetic and environmental factors in the expression of idiotype, we analyzed sera of SLE patients, their family members and nonautoimmune individuals vaccinated with pneumococcal polysaccharide, for the presence of the 8.12 idiotype, which is present on lambda light chains of anti-DNA antibodies. Elevated titers of the 8.12 idiotype was found in the serum of 57% of SLE patients. Elevated titers were present in only 9% of family members, and always associated with the presence of high levels of IgG anti-DNA antibodies. Following vaccination with pneumococcal polysaccharide, 8.12 reactive anti-pneumococcal antibodies were produced by 7 of 10 non-autoimmune individuals and 8.12 reactive anti-DNA antibodies by one. These results suggest that 8.12 reactive antibodies are antigen driven and bind structurally related antigens, but there is no evidence that expression of this idiotype is genetically controlled.
... content in AA amyloidosis by inhibition ELISA Shoshana Yakar, Batia Kaplan, Galina German, Av... more ... content in AA amyloidosis by inhibition ELISA Shoshana Yakar, Batia Kaplan, Galina German, Avi Livneh, Katsutoshi Miura', Shmuel Shtrasburg and Mordechai Pras ... J Chrornatogr 15 Pras M, Schubert M, Zucker-Franklin D, Rimon A and Franklin EC (1 968). ...
OBJECTIVE: Previous reports on interferon-alpha (IFN-alpha) were conflicting with respect to its ... more OBJECTIVE: Previous reports on interferon-alpha (IFN-alpha) were conflicting with respect to its efficacy in familial Mediterranean fever (FMF) refractory to colchicine treatment. We investigated the effect of IFN-alpha in patients with colchicine-resistant FMF.METHODS: In a prospective, patient self-controlled, open-label study evaluating the safety and efficacy of IFN-alpha in patients with FMF with a severe phenotype, refractory to intensified (oral plus intravenous) colchicine therapy, we advised patients to subcutaneously inject IFN-alpha, 3 million international units, at the onset of the FMF attack. Attacks not treated with IFN-alpha of the same patients and in the same sites served as control attacks. Features of each attack were recorded in a questionnaire, eventually used to compare between IFN-alpha-treated and non-treated attacks.RESULTS: Ten patients with a total of 80 attacks were recruited. Compared to 22 untreated attacks, a > 20% and > 50% reduction in the duration of the attacks was noted in 100% and 90% of the 58 IFN-alpha-treated attacks, respectively (p < 0.001 for both). The severity (degree of pain) of the IFN-alpha-treated attacks was attenuated by > 20% and > 50% in 88% and 49% of these attacks, respectively (p < 0.001 for both). The most common drug-related adverse events were chills and fatigue.CONCLUSION: Early intervention with IFN-alpha injections was associated with reduced attack length and/or severity in a substantial number of bouts, with an acceptable cost of adverse events.
Familial Mediterranean fever (FMF) is a major cause of AA amyloidosis. Recently, the gene (MEFV) ... more 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 E148Q and V726A were found on one allele, while V726A was found on the second allele. Amyloidosis was far more common among patients homozygous for M694V compared to patients with other mutations (P &lt; 0.0001). In 3 patients homozygous for M694V, amyloidosis was the sole manifestation of the disease.
To determine the surface expression of neutrophil beta2 integrin (CD11b/CD18) and L-selectin (LS)... more To determine the surface expression of neutrophil beta2 integrin (CD11b/CD18) and L-selectin (LS) adhesion molecules in patients with familial Mediterranean fever (FMF) and to investigate the in vitro regulation of their expression in response to chemoattractant stimuli. Neutrophil surface expression of CD11b and LS molecules was analyzed by flow cytometry in anticoagulated whole blood drawn from FMF patients and normal controls, and the in vitro regulation of these molecules induced by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP) was assayed. Patients during acute FMF attacks showed a statistically significant increased neutrophil surface CD11b compared with normal controls (mean fluorescence intensity: 22.8 +/- 13.7 vs 12.8 +/- 10.41, respectively; p = .03). There was no difference in LS expression between the groups. Neutrophils of FMF patients regulate CD11b and LS expression induced by chemoattractant (FMLP) stimulation to a degree similar to that in controls. beta2 Integrin is up-regulated during an acute attack of FMF in dissociation with LS expression, suggesting a unique nonchemoattractant-mediated neutrophil activation.
The American Journal of the Medical Sciences, 2003
Left ventricular pseudoaneurysm is an uncommon complication of infective endocarditis, usually pr... more Left ventricular pseudoaneurysm is an uncommon complication of infective endocarditis, usually presenting within several weeks of the infective episode. We describe a 37-year-old man who presented with exertional dyspnea nearly a year after a prolonged hospitalization for lung abscess. Imaging studies showed new aortic valve regurgitation and a giant pseudoaneurysm extending inferoposteriorly from the left ventricle. At thoracotomy, a perforated aortic valve was found, suggesting a healed endocarditis. The patient underwent successful aneurysmectomy and patch closure with aortic valve repair. This case underscores the potential for very late nonvalvular cardiac complications of infective endocarditis and is also distinctive because of the large size of the pseudoaneurysm.
Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. T... more Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. The acute phase response during attacks of FMF results from the release of cytokines, which in turn induce increased expression and changed glycosylation of acute phase proteins. A recent study indicated that attacks in FMF are accompanied by a rise of plasma concentrations of serum amyloid A (SAA) and C reactive protein (CRP), which remain significantly raised during remission relative to healthy controls. Another study suggested that obligatory heterozygotes also display an inflammatory acute phase response.
The Israel Medical Association Journal Imaj, Mar 1, 2004
... Attacks of fever, rash, arthralgias and lymphadenopathy occur in 90% of patients, and splenom... more ... Attacks of fever, rash, arthralgias and lymphadenopathy occur in 90% of patients, and splenomegaly in 70%. The liver is enlarged in 40% of patients. ... PFAPA syndrome. Clin Exp Rheum 2002;20:s-73 17. El-Shanti HI, Tayeh MK, Majeed HA, et al. ...
Objective. To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic... more Objective. To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF. Methods. Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients. Results. R92Q was found in 6% of the controls, with an especially high carrier rate among Moroccan Jews (8%). R92Q was found in 3 (3.2%) of the 92 FMF patients, 1 homozygous for the MEFV M694V mutation and 2 heterozygous for M694V. All 3 patients showed partial response to colchicine. R92Q was not found in patients unresponsive to colchicine, nor was it found in patients with amyloidosis or in patients with FMF-like disease without MEFV mutations. Conclusion. The frequency of the R92Q mutation in FMF patients is comparable with that of controls. Despite the fact that TRAPS and FMF share common biochemical pathways, we found no evidence for an interaction between these two genes.
Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mut... more Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. Methods: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. Results: The mean ± SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1 ± 13.2 vs. 70.7 ± 14.1 respectively, P value b 0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9% ± 6.6% and the MGs effect as 17.4% ± 15.5% in average. Conclusions: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively.
Objective: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders,... more Objective: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/ CARD15 gene mutations in the FMF disease phenotype was never studied before. Patients and methods: The cohort consisted of 103 consecutive children with FMF, followed in a single referral center. NOD2/CARD15 genotypes were analyzed in all patients and 299 ethnically matched unaffected controls. Demographic data, clinical characteristics, and disease course of FMF patients with and without NOD2/CARD15 mutation were compared. Results: A single NOD2/CARD15 mutation was detected in 10 (9.7%) FMF patients and 26 (8.7%) controls. No homozygous or compound heterozygous subjects were discovered in the 2 groups. FMF patients carrying a NOD2/CARD15 mutation had a higher rate of erysipelas-like erythema and acute scrotum attacks, a trend for a higher rate of colchicine resistance and a more severe disease as compared with patients without mutations. Conclusions: NOD2/CARD15 mutations are not associated with an increased susceptibility to develop FMF. Nevertheless, the presence of these mutations in FMF patients appears to be associated with a trend to a more severe disease.
The Israel Medical Association Journal Imaj, Nov 1, 2012
BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal ... more BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid.OBJECTIVES: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel.METHODS: We evaluated eight patients clinically and genetically during the years 2006 to 2011.RESULTS: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotoraxonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation.CONCLUSIONS: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.
We present here a first report on the biochemical analysis of intestinal amyloid deposits found i... more We present here a first report on the biochemical analysis of intestinal amyloid deposits found in two cases of hemodialysis-related amyloidosis. A new microtechnique was applied for extraction and immunochemical/chemical characterization of amyloid proteins in small amounts of fixed tissue, thus allowing precise identification of β2microglobulin amyloid (Aβ2M) in both cases studied. The molecular mass of the identified amyloid β2M
To develop widely accepted international severity score for children and adult patients with fami... more To develop widely accepted international severity score for children and adult patients with familial Mediterranean fever (FMF) that can be easily applied, in research and clinical practice. Candidate severity criteria were suggested by several FMF expert physicians. After three rounds of Delphi survey, the candidate criteria, defined by the survey, were discussed by experts in a consensus meeting. Each expert brought data of clinical manifestations, laboratory findings and physician's global assessments (PGAs) of minimum 20 patients from their centres. We used the PGAs for disease severity as a gold standard. Logistic regression analysis was used to evaluate the predicting value of each item, and receiver operating characteristic curve analysis was performed to demonstrate the success of the criteria set. A total of 281 patients consist of 162 children and 119 adults with FMF were enrolled and available for validity analysis: Nine domains were included in the final core set of ...
The American Journal of Human Genetics, Feb 1, 2003
In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These youn... more In 1978, Sohar et al. described a strikingly peculiar syndrome in two Israeli sisters. These young women responded to environmental temperatures of 18ЊC-7ЊC with profuse sweating on large segments on their back and chest. Both had additional abnormalities, including a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend their elbows, and kyphoscoliosis. We have observed this disorder in two Norwegian brothers. Genomewide screening in the two families, followed by saturation marker studies and linkage analysis, identified a 1.4-Mb homozygous candidate region on chromosome 19p12. The maximum multipoint LOD score was 4.22. In both families, DNA sequencing of 25 genes within the candidate region identified potentially deleterious CRLF1 sequence variants that were not found in unaffected control individuals. Our findings confirm that the cold-induced sweating syndrome is an autosomal recessive disorder that is probably caused by impaired function of the CRLF1 gene, and they suggest important developmental functions for human CRLF1.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but man... more Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, but many rheumatologists are not well acquainted with its management. The objective of this report is to produce evidence-based recommendations to guide rheumatologists and other health professionals in the treatment and follow-up of patients with FMF. A multidisciplinary panel, including rheumatologists, internists, paediatricians, a nurse, a methodologist and a patient representative, was assembled. Panellists came from the Eastern Mediterranean area, Europe and North America. A preliminary systematic literature search on the pharmacological treatment of FMF was performed following which the expert group convened to define aims, scope and users of the guidelines and established the need for additional reviews on controversial topics. In a second meeting, recommendations were discussed and refined in light of available evidence. Finally, agreement with the recommendations was obtained from a larger group of experts through a Delphi survey. The level of evidence (LoE) and grade of recommendation (GR) were then incorporated. The final document comprises 18 recommendations, each presented with its degree of agreement (0-10), LoE, GR and rationale. The degree of agreement was greater than 7/10 in all instances. The more controversial statements were those related to follow-up and dose change, for which supporting evidence is limited. A set of widely accepted recommendations for the treatment and monitoring of FMF is presented, supported by the best available evidence and expert opinion. It is believed that these recommendations will be useful in guiding physicians in the care of patients with FMF.
Anti-DNA antibodies are autoantibodies unique to systemic lupus erythematosus. Studies of their s... more Anti-DNA antibodies are autoantibodies unique to systemic lupus erythematosus. Studies of their structure have demonstrated cross reactive idiotypes present in genetically unrelated individuals. Despite much research, it is still not clear what triggers their production and what governs the presence of particular idiotypic determinants in their structure. To study the role of genetic and environmental factors in the expression of idiotype, we analyzed sera of SLE patients, their family members and nonautoimmune individuals vaccinated with pneumococcal polysaccharide, for the presence of the 8.12 idiotype, which is present on lambda light chains of anti-DNA antibodies. Elevated titers of the 8.12 idiotype was found in the serum of 57% of SLE patients. Elevated titers were present in only 9% of family members, and always associated with the presence of high levels of IgG anti-DNA antibodies. Following vaccination with pneumococcal polysaccharide, 8.12 reactive anti-pneumococcal antibodies were produced by 7 of 10 non-autoimmune individuals and 8.12 reactive anti-DNA antibodies by one. These results suggest that 8.12 reactive antibodies are antigen driven and bind structurally related antigens, but there is no evidence that expression of this idiotype is genetically controlled.
... content in AA amyloidosis by inhibition ELISA Shoshana Yakar, Batia Kaplan, Galina German, Av... more ... content in AA amyloidosis by inhibition ELISA Shoshana Yakar, Batia Kaplan, Galina German, Avi Livneh, Katsutoshi Miura', Shmuel Shtrasburg and Mordechai Pras ... J Chrornatogr 15 Pras M, Schubert M, Zucker-Franklin D, Rimon A and Franklin EC (1 968). ...
OBJECTIVE: Previous reports on interferon-alpha (IFN-alpha) were conflicting with respect to its ... more OBJECTIVE: Previous reports on interferon-alpha (IFN-alpha) were conflicting with respect to its efficacy in familial Mediterranean fever (FMF) refractory to colchicine treatment. We investigated the effect of IFN-alpha in patients with colchicine-resistant FMF.METHODS: In a prospective, patient self-controlled, open-label study evaluating the safety and efficacy of IFN-alpha in patients with FMF with a severe phenotype, refractory to intensified (oral plus intravenous) colchicine therapy, we advised patients to subcutaneously inject IFN-alpha, 3 million international units, at the onset of the FMF attack. Attacks not treated with IFN-alpha of the same patients and in the same sites served as control attacks. Features of each attack were recorded in a questionnaire, eventually used to compare between IFN-alpha-treated and non-treated attacks.RESULTS: Ten patients with a total of 80 attacks were recruited. Compared to 22 untreated attacks, a > 20% and > 50% reduction in the duration of the attacks was noted in 100% and 90% of the 58 IFN-alpha-treated attacks, respectively (p < 0.001 for both). The severity (degree of pain) of the IFN-alpha-treated attacks was attenuated by > 20% and > 50% in 88% and 49% of these attacks, respectively (p < 0.001 for both). The most common drug-related adverse events were chills and fatigue.CONCLUSION: Early intervention with IFN-alpha injections was associated with reduced attack length and/or severity in a substantial number of bouts, with an acceptable cost of adverse events.
Familial Mediterranean fever (FMF) is a major cause of AA amyloidosis. Recently, the gene (MEFV) ... more 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 E148Q and V726A were found on one allele, while V726A was found on the second allele. Amyloidosis was far more common among patients homozygous for M694V compared to patients with other mutations (P &lt; 0.0001). In 3 patients homozygous for M694V, amyloidosis was the sole manifestation of the disease.
To determine the surface expression of neutrophil beta2 integrin (CD11b/CD18) and L-selectin (LS)... more To determine the surface expression of neutrophil beta2 integrin (CD11b/CD18) and L-selectin (LS) adhesion molecules in patients with familial Mediterranean fever (FMF) and to investigate the in vitro regulation of their expression in response to chemoattractant stimuli. Neutrophil surface expression of CD11b and LS molecules was analyzed by flow cytometry in anticoagulated whole blood drawn from FMF patients and normal controls, and the in vitro regulation of these molecules induced by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP) was assayed. Patients during acute FMF attacks showed a statistically significant increased neutrophil surface CD11b compared with normal controls (mean fluorescence intensity: 22.8 +/- 13.7 vs 12.8 +/- 10.41, respectively; p = .03). There was no difference in LS expression between the groups. Neutrophils of FMF patients regulate CD11b and LS expression induced by chemoattractant (FMLP) stimulation to a degree similar to that in controls. beta2 Integrin is up-regulated during an acute attack of FMF in dissociation with LS expression, suggesting a unique nonchemoattractant-mediated neutrophil activation.
The American Journal of the Medical Sciences, 2003
Left ventricular pseudoaneurysm is an uncommon complication of infective endocarditis, usually pr... more Left ventricular pseudoaneurysm is an uncommon complication of infective endocarditis, usually presenting within several weeks of the infective episode. We describe a 37-year-old man who presented with exertional dyspnea nearly a year after a prolonged hospitalization for lung abscess. Imaging studies showed new aortic valve regurgitation and a giant pseudoaneurysm extending inferoposteriorly from the left ventricle. At thoracotomy, a perforated aortic valve was found, suggesting a healed endocarditis. The patient underwent successful aneurysmectomy and patch closure with aortic valve repair. This case underscores the potential for very late nonvalvular cardiac complications of infective endocarditis and is also distinctive because of the large size of the pseudoaneurysm.
Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. T... more Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. The acute phase response during attacks of FMF results from the release of cytokines, which in turn induce increased expression and changed glycosylation of acute phase proteins. A recent study indicated that attacks in FMF are accompanied by a rise of plasma concentrations of serum amyloid A (SAA) and C reactive protein (CRP), which remain significantly raised during remission relative to healthy controls. Another study suggested that obligatory heterozygotes also display an inflammatory acute phase response.
The Israel Medical Association Journal Imaj, Mar 1, 2004
... Attacks of fever, rash, arthralgias and lymphadenopathy occur in 90% of patients, and splenom... more ... Attacks of fever, rash, arthralgias and lymphadenopathy occur in 90% of patients, and splenomegaly in 70%. The liver is enlarged in 40% of patients. ... PFAPA syndrome. Clin Exp Rheum 2002;20:s-73 17. El-Shanti HI, Tayeh MK, Majeed HA, et al. ...
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