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Study |

Tumor Necrosis Factor Receptor–Associated Periodic Syndrome:  A Novel Syndrome With Cutaneous Manifestations FREE

Jorge R. Toro, MD; Ivona Aksentijevich, MD; Keith Hull, MD; Jane Dean, MSN; Daniel L. Kastner, MD, PhD
[+] Author Affiliations

From the National Cancer Institute (Dr Toro) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Drs Aksentijevich, Hull, and Kastner and Ms Dean), National Institutes of Health, Bethesda, Md.


Arch Dermatol. 2000;136(12):1487-1494. doi:10.1001/archderm.136.12.1487.
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Published online

Background  Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is an inflammatory disorder characterized by prolonged episodes of periodic fever and localized inflammation and dominantly inherited mutations in TNFRSF1A, the gene encoding the 55-kDa tumor necrosis factor receptor. To our knowledge, the cutaneous pathologic characteristics of TRAPS have not been described previously.

Objectives  To characterize the dermatologic manifestations of TRAPS by clinical, microscopic, and molecular methods, and to investigate its immunophenotype.

Design, Setting, and Patients  At the National Institutes of Health Clinical Center, Bethesda, Md, a tertiary care referral center, 25 patients with a clinical and molecular diagnosis of TRAPS were evaluated clinically and 10 biopsy specimens of lesional skin were examined by light microscopy and immunohistochemistry. Patients were screened for mutations in TNFRSF1A, the gene coding for the p55 tumor necrosis factor receptor.

Main Outcome Measures  Clinical, light microscopic, and immunohistochemical features.

Results  The skin eruption usually lasted 4 to 21 days (mean, 13 days). Of 25 patients, 21 (84%) presented with migratory erythematous macules and patches and 10 (40%) had edematous dermal plaques. Conjunctivitis, characterized by pain and redness and/or periorbital edema, was present in 11 patients (44%). Most patients had their first skin eruption during the first 2 years of life. All patients had fever associated with the skin eruption. Most patients had associated abdominal pain (22 [88%]) and myalgia (20 [80%]). Other symptoms included arthralgia (13 [52%]), pleuritic chest pain (10 [40%]), and headache (17 [68%]). Microscopic examination of 10 biopsy specimens of lesional skin showed a superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes. None of the biopsy specimens showed multinucleated macrophages or granulomatous or leukocytoclastic vasculitis. The results of immunohistochemistry showed a perivascular infiltrate of CD3+, CD4+, CD8+, CD68+, CD79a−, and CD20− cells. All the mutations were missense mutations in exons 2 through 4 of TNFRSF1A, directly affecting the extracellular domain of the protein.

Conclusions  TRAPS is characterized by a spectrum of dermatologic findings, including migratory patches, edematous plaques, periorbital edema, and/or conjunctivitis. TRAPS is characterized by a perivascular dermal infiltrate of lymphocytes and monocytes.

Figures in this Article

TUMOR NECROSIS factor receptor–associated periodic syndrome (TRAPS) is a disorder characterized by prolonged episodes of fever and local inflammation caused by dominantly inherited mutations in TNFRSF1A, the gene encoding the 55-kDa tumor necrosis factor (TNF) receptor.1 This nomenclature subsumes several older diagnoses, including familial Hibernian fever (FHF),2,3 benign autosomal dominant familial periodic fever,4 and autosomal dominant periodic fever with amyloidosis,5 all of which share a common molecular basis. In addition to TRAPS, there are 2 other well-characterized inherited periodic fever syndromes: familial Mediterranean fever (FMF)6,7 and the hyperimmunoglobulinemia D syndrome (HIDS) with periodic fever.8,9 Although these syndromes have recurring episodes of fever accompanied by cutaneous and other inflammatory manifestations, they are caused by mutations in different genes.

Familial Hibernian fever was first described in 1982 in a large Irish kindred,2 prompting the Hibernian appellation. In this family, 16 members over 3 generations exhibited periodic fevers, localized myalgia, and painful erythema inherited in a dominant pattern. In 1997, McDermott et al3 reexamined the original family described by Williamson et al.2 They found that in addition to febrile attacks, abdominal pain and localized myalgia were frequently present. Erythematous patches, conjunctivitis, and periorbital edema were also distinctive features present in these patients.3 Several families from different racial and ethnic backgrounds have been described who have similar clinical findings. In 1998, Mulley and coworkers4 characterized a large Australian kindred of Scottish ancestry with similar clinical features to FHF. Smaller families of Finnish,10 Dutch,11 Puerto Rican12,13 and mixed Irish, English, and German12 descent have also been described. Although all these families had prolonged attacks (>1 week) and poor response to colchicine use, there were clinical differences between the families, most notably the presence or absence of amyloidosis and skin eruption.

In 1999, several of these families were shown to have mutations in TNFRSF1A.1013 McDermott et al1 found 7 affected families with 6 different missense mutations in TNFRSF1A. Of these mutations, 5 are predicted to disrupt conserved extracellular disulfide bonds. Soluble plasma TNFRSF1A levels in patients were approximately half of the normal levels. Leukocytes bearing a C52F mutation showed little clearance of the p55 TNF receptor from the cell surface on activation and markedly reduced release of p55 into the supernatants relative to controls. The autoinflammatory phenotype may therefore result from impaired down-regulation of membrane TNFRSF1A and diminished shedding of soluble receptor. TNFR1 belongs to a family of receptors with repeating cysteine-rich extracellular motifs.14,15 Tumor necrosis factor homotrimers induce signaling by aggregation on membrane receptors.16 Cleavage of the extracellular domains of the TNFR1 by metalloproteases may contribute to the clearance of TNFRSF1A from the membrane, and it produces a pool of soluble receptors that compete with the membrane form.17 TNFRSF1A is widely expressed in a variety of cells. The biologic actions of TNFRSF1A include increased expression of adhesion molecules, induction of cytokine secretion, leukocyte activation, host resistance to intracellular pathogens, angiogenesis, pyrexia, anemia, and cachexia.18

Although cutaneous lesions are a common manifestation of TRAPS, the cutaneous manifestations of the disease have not been well characterized. We describe herein the clinical, histologic, and immunohistochemical features of the cutaneous lesions associated with TRAPS.

Twenty-five patients who were admitted to the National Institutes of Health Clinical Center, Bethesda, Md, were enrolled in a study approved by the institutional review board. All patients had documented mutations in exons 2 through 4 of TNFRSF1A directly affecting the extracellular domain of the p55 TNF receptor.19 Skin lesions were classified as patches or plaques based on clinical appearance. Ten biopsy specimens of skin lesions, including erythematous macules, patches, papules, and plaques, were examined by light microscopy and immunohistochemistry. Routine morphological studies were done on 4-µm sections stained with hematoxylin-eosin. Sections from biopsy specimens were reviewed for the presence of vasculitis, interface reaction, neutrophils, mast cells, eosinophils, and plasma cells (J.R.T.).

IMMUNOPEROXIDASE STAINS

Antigen retrieval was performed as previously described.20 Staining was performed using an automated immunostainer (Ventana Medical Systems Inc, Tucson, Ariz). Immunoperoxidase stains were done using the following antibody panel: CD3, CD8, CD68 (Dako Corp, Carpinteria, Calif), CD20, CD79a (Becton Dickinson, Mountain View, Calif), CD4 (Novocastra Labs Ltd, Newcastle upon Tyne, England).

MOLECULAR STUDIES

DNA was extracted from the peripheral blood leukocytes of each patient using standard techniques. Approximately 100 ng of genomic DNA template was used in polymerase chain reactions to amplify exons21 and flanking intronic sequences, and mutation detection was done by fluorescent sequencing as previously described.1

CLINICAL FEATURES

The clinical findings in 25 patients with TRAPS are summarized in Table 1. We examined 25 individuals from 16 families. There were 15 males and 10 females aged from 4 to 56 years. There were 13 children. The age of onset varied from 3 weeks to 28 years. However, 22 patients (88%) developed their first skin eruption during the first 2 years of life. The skin eruptions were exacerbated by trauma and psychological or physical stress.

Table Graphic Jump LocationTable 1. Clinical Findings in 25 Patients With TRAPS*

Cutaneous manifestations were present in 21 patients (84%) during attacks (Figure 1). Patients presented with asymptomatic and nonscalying lesions distributed over the trunk and extremities. Most patients developed a skin eruption during a febrile attack. The skin eruption usually lasted 4 to 21 days, with a mean duration of 13 days. In addition, 10 patients (40%) exhibited edematous plaques. Lesions were from 1 to 28 cm in diameter. Large lesions tended to coalesce into annular and serpiginous patches. Most patients exhibited localized erythematous macules and patches, while others had generalized reticulated and serpiginous lesions. Migration of the lesion to the distal part of the extremity, which occurred within minutes to several days, was a distinctive feature. Nine patients (36%) stated that lesions resolved with an ecchymotic appearance. Conjunctivitis, characterized by conjunctival pain and redness and/or periorbital edema, was present in 11 patients (44%) (Figure 1).

Place holder to copy figure label and caption
Figure 1.

The clinical spectrum of cutaneous manifestations of TRAPS (tumor necrosis factor receptor–associated periodic syndrome). A, Periorbital edema in a child. B, A large annular patch. C, Erythematous dermal macules and patches. D, Generalized erythematous serpiginous patches and plaques.

Graphic Jump Location

All patients developed febrile episodes ranging in degree of severity and duration. Abdominal pain occurred in 22 patients (88%), and it was associated with nausea, vomiting, diarrhea, or constipation. Four patients were hospitalized for emergency laparotomies. Myalgia, characterized by muscle stiffness and tightness, was present in 20 patients (80%). The distal migration of the myalgia was a distinctive feature. True arthritis was rare, but arthralgia was present in 13 patients (52%). Other associated symptoms included pleuritic chest pain in 10 patients (40%) and headache in 17 patients (68%). In addition, 2 patients (8%) developed amyloidosis: one had undergone hepatic transplantation and the other had nephrotic proteinuria.1

HISTOLOGIC FEATURES

Microscopic evaluation of 10 biopsy specimens of erythematous macules, plaques, and annular lesions revealed a normal epidermis and both a superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes (Figure 2). None of the biopsy specimens showed granulomatous or leukocytoclastic vasculitis. One biopsy specimen showed scattered neutrophils and another had a few plasma cells. There were no multinucleated macrophages, mast cells, or eosinophils present. There was no difference between different types of lesions in the intensity or type of inflammatory infiltrate. There was slightly more dermal edema present in papules and plaques.

Place holder to copy figure label and caption
Figure 2.

Histologic and immunohistochemical findings. A, Microscopic examination shows a normal epidermis and superficial and deep perivascular infiltrate (hematoxylin-eosin, original magnification ×20). The high-magnification (original magnification ×200) inset shows small aggregates and individual lymphocytes and monocytes around vessels. B, Strongly positive CD3 cells around superficial venules. C, Perivascular infiltrate is strongly positive for CD8. D, Strongly positive CD68 cells around superficial venules. (B through D, immunoperoxidase, original magnification ×100.)

Graphic Jump Location
IMMUNOPHENOTYPE

The inflammatory infiltrate in all biopsy specimens was positive for CD3 (Figure 2). There were many CD4+, CD8+, and CD68+ cells present. The results were negative for all B-cell markers tested (CD20 and CD79a). There were no immunohistologic differences among different types of lesions.

We found that 21 patients (87%) in this study had cutaneous manifestations. Migratory macules and patches were the most common findings. In addition, 10 patients (40%) exhibited erythematous edematous plaques. The high frequency of occurrence suggests that the cutaneous lesions are true manifestations of the syndrome. The skin lesions occurred during febrile episodes, indicating that they are part of the disease. Cutaneous manifestations usually lasted 4 to 21 days, with a mean duration of 13 days. The most common site was an extremity, where lesions began proximally and moved distally during the attack. To our knowledge, there are only a few reports in the literature about the cutaneous manifestations of FHF. In the original article of Williamson et al,2 "painful erythemas" were described in 11 patients, and the arms were the most common site associated with underlying myalgia. In 1997, McDermott et al3 reported skin eruptions in 11 (69%) of 16 individuals with FHF. While 9 individuals exhibited red patches, 8 had indurated lesions. We also found that cutaneous lesions were commonly associated with underlying myalgia. The myalgia moved down the extremity in conjunction with the skin lesions, affecting different muscle groups and limiting joint movement during the progression of the attack. We had the opportunity to observe the evolution of several cutaneous lesions. Early lesions consisted of solitary or groups of erythematous macules and papules. As these lesions progressed, they expanded at the periphery, coalescing into large patches or plaques. This finding of migrating large patches and plaques associated with underlying myalgia differs from HIDS, which is characterized by fixed small lesion. We also found ecchymosis in 6 patients. A previous report3 described purpuric lesions in 3 individuals affected with FHF. In 1 individual the lesions were described as "anaphilatoid purpura" and "purpuric rash," and the diagnosis of Henoch-Schönlein purpura was made based on these dermatologic findings. Other characteristic findings in patients with TRAPS include conjunctivitis and/or periorbital edema.

We found that the cutaneous histologic findings of TRAPS were nonspecific. Histologically, we could not differentiate TRAPS from a viral exanthem or serum sickness–like reaction. Biopsy specimens of individuals with TRAPS showed a superficial and deep perivascular infiltrate of lymphocytes and monocytes. We also found no histologic difference among clinically different types of lesions. To our knowledge, there are only few reports of the histologic characteristics of skin lesions associated with this syndrome. In the original report of Williamson et al,2 the histologic findings of "painful erythema" in 2 individuals with TRAPS were a perivascular infiltrate of mononuclear cells in the dermis and swelling of vessels. In 1997, McDermott et al3 confirmed the earlier cutaneous histologic findings of a nonspecific perivascular infiltrate in most cases. However, they also reported a case that showed upper dermal edema with telangiectasia, a low-grade lymphocytic vasculitis, increased number of mast cells, and extensive neutrophilic migration. The dermatologic characteristics in this case were not discussed. Immunofluorescence studies of a skin lesion of an individual with FHF with a history of "erythematous swelling of both legs for 15 years" showed a diffuse deposition of IgA, IgG, and C3; fibrinogen throughout the upper dermis2; and a fine granular deposition of IgM and C3 throughout the length of the dermal-epidermal junction.3

Immunohistochemical studies confirmed the T-cell phenotype in the patients in the present study. All biopsy specimens of lesional skin stained strongly positive for CD3, a pan–T-cell marker, and CD4 and CD8. In addition, we also found CD68 positive cells in the infiltrate. Therefore, TRAPS is characterized by an infiltrate of monocytes and T cells in sites of cutaneous inflammation. In contrast, cutaneous lesions of FMF are characterized by a neutrophilic infiltrate.8 Our findings suggest that T lymphocytes and monocytes rather than neutrophils play a role in the pathogenesis of cutaneous lesions associated with TRAPS.

The differential diagnosis of TRAPS includes other syndromes characterized by periodic fever, such as FMF and HIDS. The clinical features of these 3 syndromes are compared in Table 2. Although these syndromes share some features, they have some distinctive characteristics. Most individuals affected with these syndromes present with initial symptoms at infancy or early childhood. The diagnosis is based on a spectrum of clinical features rather than a single characteristic. While FMF and HIDS are inherited in an autosomal recessive fashion, TRAPS is inherited in an autosomal dominant pattern. Each disorder is caused by a mutation in a different gene. The susceptibility gene for TRAPS was initially mapped to chromosome 12p134,22 and was subsequently found to be TNFRSF1A, the gene coding the 55-kDa receptor for TNF.1TNFRSF1A has a 2-kilobase (kb) coding sequence and is composed of 10 exons.21 Five of the first 6 mutations identified were single nucleotide substitutions leading to missense changes in highly conserved extracellular cysteines, thus disrupting the stability of the extracellular domain by preventing the formation of disulfide bonds.1 The sixth of these mutations, a threonine to methionine substitution adjacent to an extracellular cysteine, prevents the formation of a highly conserved hydrogen bond. Eight additional mutations in TNFRSF1A have been identified in patients with TRAPS.19 All 14 mutations are clustered in exons 2 through 4, directly affecting the extracellular domain of the resultant protein. Seven of the 14 result in cysteine substitutions. Only 3 mutations have been identified in more than 1 family, and mutations continue to be found in a broad range of ethnic groups.

Table Graphic Jump LocationTable 2. Differential Diagnosis of TRAPS, FMF, and HIDS*

The FMF gene, MEFV, has been mapped to 16p13.3. It encodes a protein named pyrin (referring to pyrus, the Greek word for fever23) or marenostrin (referring to mare nostrum, the Latin name of the Mediterranean Sea24). The gene is 15 kb long and has 10 exons. It predicts a basic protein of 781 amino acid residues23 thought to be a leukocyte-specific regulator of inflammation25 and is homologous to proteins of the B30.2 family.26 A total of 26 mutations have been described in FMF.23,24,2732 Eleven of the mutations are in exon 10, which encodes most of the B30.2 domain, and 8 of these mutations are localized within a region of 44 nucleotides (16 amino acids). Only 1 of the mutations outside exon 10 (E148Q) is seen in several different populations, and haplotype analysis suggests a third major ancient founder effect.27

Hyperimmunoglobulinemia D syndrome is a disease that presents in early childhood with a median age of onset of 6 months.9,33 The gene for HIDS is encoded on the long arm of chromosome 12 (12q24).34 The syndrome is caused by mutations in the mevalonate kinase (MVK) gene. Initially, I268T, V377I, P165L, and H20P missense substitutions, and a 92-base pair deletion at the 5′ end of the gene were described.34,35 A number of new mutations were recently presented (see http://hids.net).33 V377I appears to be the most common mutation associated with HIDS. The relatively high frequency of this mutation, combined with the geographic concentration of cases in northern Europe, suggest a founder effect. MVK codes for mevalonate kinase, an enzyme that phosphorylates mevalonic acid to 5-phosphomevalonic acid in the sterol biosynthesis pathway.36,37 Biochemical analysis of skin fibroblasts from patients harboring MVK mutations have demonstrated 1% to 3% of the mevalonate kinase enzymatic activity found in control fibroblasts. Patients with HIDS have elevated concentrations of mevalonic acid in their urine during, but not between, episodes of fever.34,35

The patient's ethnic background is also helpful in raising the suspicion of one of these syndromes. Individuals with Jewish, Armenian, Arab, Italian, or Turkish background suggest FMF.7 To date, about half of reported cases of HIDS are in patients of Dutch ancestry; most of the remainder are from Europe (predominantly from the northern part of France), although cases have been reported in patients from Japan, Turkey, and the United States.9,38,39 However, these syndromes can occur in patients without a typical ethnic background. Individuals with TRAPS have diverse ethnic backgrounds; however, patients of Irish and Scottish heritage are overrepresented.

Duration of attacks is another feature that differentiates FMF, TRAPS, and HIDS. Episodes of FMF are typically shorter (1-3 days) than episodes of TRAPS and HIDS. Patients with TRAPS tend to have the longest attacks, with many episodes lasting more than 1 week. It is not uncommon for patients to have episodes lasting more than 1 month and to exhibit nearly continuous inflammation. Patients with HIDS develop recurrent high fever, often preceded by headache that gradually decreases after 3 to 7 days. More than half of the patients with HIDS have a history of at least 1 attack precipitated by child immunizations. Arthralgia is common in TRAPS, FMF, and HIDS. As in FMF, arthritis in HIDS is seen with greater frequency in younger patients, tends to affect the large joints, and is characterized by a large influx of polymorphonuclear leukocytes into the synovial space.9,4042 Unlike FMF, HIDS arthritis frequently occurs with abdominal pain and is nondestructive; protracted arthritis in HIDS has not been observed. While oligoarticular and symmetric arthritis is seen in HIDS, monoarticular arthritis is most frequently seen in FMF. Abdominal pain is a frequent symptom in patients with all these disorders. Migratory myalgia is typically present in TRAPS but usually absent in FMF and HIDS. Patients with TRAPS complain of tightness or tension of muscle groups. Pleuritic chest pain is a frequent finding in TRAPS and FMF. Lymphadenopathy is also common is HIDS but usually absent in FMF. Hyperimmunoglobulinemia D syndrome is characterized by diffuse tender lymphadenopathy, most prominent on the neck during attacks. Splenomegaly is also observed during febrile episodes in about 50% of children. Systemic amyloidosis has been described in 4 of the first 7 families with TRAPS.1 Amyloidosis in TRAPS is due to the deposition of serum amyloid A and can lead to renal and/or hepatic failure. In the additional families we identified, the number of families with amyloidosis has now decreased to approximately 25%. To date, there are not sufficient data to know whether the risk of amyloidosis is increased for certain TNFRSF1A mutations, as it is for the M694V MEFV mutation in FMF.28,43,44 Amyloidosis has not been reported in HIDS.

Elevated serum IgD in individuals affected with HIDS may contribute to the pathogenesis of HIDS by potentiating the release of proinflammatory cytokines.45 Before the identification of MVK as the gene that causes HIDS, the diagnostic criteria of HIDS required IgD levels exceeding 140 mg/L (14 mg/dL) on 2 occasions at least a month apart.46 However, elevated IgD levels are not specific for HIDS. Approximately 10% to 13% of patients with TRAPS and FMF have elevated serum IgD levels. In addition, a number of other conditions have been associated with elevated serum IgD levels, including IgD multiple myeloma, Hodgkin disease, cigarette smoking, pregnancy, immunodeficiency syndromes, and recurrent infections.9,47,48 Furthermore, some individuals with typical findings of HIDS and mutations in MVK do not have elevated serum IgD levels.34 New laboratory methods, such as genetic testing for MVK or biochemical analysis of urine for elevated mevalonic acid, may be better to establish or confirm the diagnosis of HIDS.

We found that migratory patches and plaques are common cutaneous manifestations of TRAPS. Similarly, cutaneous lesions are common in HIDS.4750 In a study,47 79% of patients with HIDS had skin lesions during febrile attacks. Erythematous macules were the most common cutaneous manifestation (n = 15), followed by erythematous papules (n = 12), urticarial lesions (n = 9), and erythematous nodules (n = 7). The histologic findings of cutaneous lesions associated with HIDS are varied. Most biopsy specimens showed "mild vasculitis." Other histologic findings include Sweet-like, cellulitis-like, or deep vasculitis. Henoch-Schönlein purpura and erythema elevatum diutinum have been also reported in children with HIDS.40,51 Erysipelaslike lesions are the most distinctive cutaneous lesion associated with FMF.52 In published studies,53,54 the observed frequency of these lesions varies from 3% to 46%, and they have been reported to occur in 15% to 20% of children.5557 Patients typically exhibit erysipelaslike lesions limited to the lower extremities. Erysipelaslike lesions consist of well-demarcated, erythematous, edematous, warm plaques up to 15 cm in diameter. These lesions occur either unilaterally or symmetrically below the knee on the anterior aspect of the leg or the dorsum of the foot. Erysipelas-like lesions are histologically characterized by a dermal infiltrate of predominantly neutrophils and nuclear dust.58 In addition, vascular inflammations, such as Henoch-Schönlein purpura and polyarteritis nodosa, have been reported to be associated with FMF. Henoch-Schönlein purpura has been reported to occur in 5% of children with FMF.54,55,57 Purpuric lesions on the face, trunk, and extremities are also frequently found in children.56 There have been several reports of polyarteritis nodosa with FMF.5963 Polyarteritis nodosa tends to occur at a younger age in FMF and is more likely to be complicated by perirenal hematoma.

The symptoms in most patients with HIDS and TRAPS respond poorly to colchicine use. The clinical response to colchicine use is an important clinical feature of FMF. About 90% to 95% of patients with FMF note marked improvement after treatment with the drug and about 75% of patients with FMF experience almost complete remission. Neutrophils in patients with FMF receiving colchicine have reduced migratory ability.64,65 In addition, it has been shown that colchicine alters the expression of the E-selectin on vascular endothelium and L-selectin in neutrophils.66 Both these adhesion molecules are essential for extravasation and migration to the site of inflammation. How colchicine prevents or ameliorates the attacks of FMF is still unknown. Colchicine is effective in preventing the development of amyloidosis in patients with FMF.67 Variable results with cyclosporine, intravenous immunoglobulin, and corticosteroids have been observed in patients with HIDS. Articular manifestations in HIDS respond to either nonsteroidal anti-inflammatory drugs or corticosteroids. Preliminary results31 using lovastatin have been encouraging for the treatment of HIDS and randomized trials are now under way. In addition, TNF inhibitors are also under investigation for HIDS. The symptoms in individuals with TRAPS respond rapidly to corticosteroid use. Nonsteroidal anti-inflammatory drugs are effective in mild attacks. Etanercept, which is a promising novel treatment for TRAPS,68 is a bioengineered fusion protein of the p75 soluble TNF receptor (TNFR:Fc or Enbrel; Immunex Corp, Seattle, Wash) that neutralizes TNF-α. The US Food and Drug Administration approved the use of etanercept for the treatment of rheumatoid arthritis and juvenile rhematoid arthritis.69,70

The differential diagnosis of TRAPS also includes 2 other periodic fever syndromes in children: infantile-onset multisystem inflammatory disease (IOMID) and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). IOMID is a rare disorder involving a triad of arthropathy, rash, and central nervous system involvement. IOMID is differentiated from TRAPS by a neutrophilic eccrine hidradenitis, a histologic finding not present in TRAPS.71,72 TRAPS lacks the distinctive deforming arthropathy with unique epiphyseal radiologic findings preferentially affecting large joints present in IOMID.73 Eye involvement and neurological symptoms, including chronic meningitis, macrocephaly, and developmental delay, are common findings in IOMID and rare in TRAPS.72,73 PFAPA is characterized by cervical adenitis, pharyngitis, aphthous stomatitis, features that rarely occur in TRAPS. Although both syndromes are characterized by periodic fever, attacks in PFAPA are shorter (4.7 days) than those in TRAPS (7-21 days).74

In conclusion, our data suggest that TRAPS is characterized by a spectrum of dermatologic findings, including migratory patches and plaques associated with fever and myalgia, conjunctivitis and/or periorbital edema, and ecchymotic lesions. TRAPS is characterized by a superficial and deep dermal perivascular infiltrate of monocytes and lymphocytes.

Accepted for publication September 5, 2000.

Presented at the Society of Investigative Dermatology Annual Meeting, Chicago, Ill, May 13, 2000.

Corresponding author and reprints: Jorge R. Toro, MD, National Cancer Institute, National Institutes of Health, Bldg 10, Room 12N-238, 10 Center Dr, MSC 1908, Bethesda, MD 20892-1908 (e-mail: torojo@exchange.nih.gov).

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Henry  JMather  IHMcDermott  MFPontarotti  P B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins. Mol Biol Evol. 1998;151696- 1705
Link to Article
Aksentijevich  ITorosyan  YSamuels  J  et al.  Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999;64949- 962
Link to Article
Cazeneuve  CSarkisian  TPecheux  C  et al.  MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet. 1999;6588- 97
Link to Article
Booth  DRGillmore  JDBooth  SEPepys  MBHawkins  PN Pyrin/marenostrin mutations in familial Mediterranean fever. QJM. 1998;91603- 606
Link to Article
Bernot  Ada Silva  CPetit  JL  et al.  Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998;71317- 1325
Link to Article
Domingo  CTouitou  IBayou  A  et al.  Familial Mediterranean fever in the "Chuetas" of Mallorca: a question of Jewish origin or genetic heterogeneity. Eur J Hum Genet. 2000;8242- 246
Link to Article
Dode  CPecheux  CCazeneuve  C  et al.  Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet. 2000;92241- 246
Link to Article
Simon  ADrenth  JPH Genes associated with periodic fevers highlighted at Dutch workshop. Lancet. 1999;3542141
Link to Article
Drenth  JPCuisset  LGrateau  G  et al. for the International Hyper-IgD Study Group, Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet. 1999;22178- 181
Link to Article
Houten  SMKuis  WDuran  M  et al.  Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22175- 177
Link to Article
Goldstein  JLBrown  MS Regulation of the mevalonate pathway. Nature. 1990;343425- 430
Link to Article
Brown  MSGoldstein  JL The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89331- 340
Link to Article
Topaloglu  RSaatci  U Hyperimmunoglobulinaemia D and periodic fever mimicking familial Mediterranean fever in the Mediterranean. Postgrad Med J. 1991;67490- 491
Link to Article
Grose  CSchnetzer  JRFerrante  AVladutiu  AO Children with hyperimmunoglobulinemia D and periodic fever syndrome. Pediatr Infect Dis J. 1996;1572- 77
Link to Article
Haraldsson  AWeemaes  CMDe Boer  AWBakkeren  JAStoelinga  GB Immunological studies in the hyper-immunoglobulin D syndrome. J Clin Immunol. 1992;12424- 428
Link to Article
Loeliger  AEKruize  AABijilsma  JWLoeliger  AEDerksen  RH Arthritis in hyperimmunoglobulinaemia D. Ann Rheum Dis. 1993;5281
Link to Article
Drenth  JPPrieur  AM Occurrence of arthritis in hyperimmunoglobulinaemia D. Ann Rheum Dis. 1993;52765- 766
Link to Article
Shohat  MMagal  NShohat  T  et al.  Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet. 1999;7287- 292
Link to Article
Livneh  ALangevitz  PShinar  Y  et al.  MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid. 1999;61- 6
Link to Article
Drenth  JPGoertz  JDaha  MRvan der Meer  JW Immunoglobulin D enhances the release of tumor necrosis factor-alpha and interleukin-1 beta as well as interleukin-1 receptor antagonist from human mononuclear cells. Immunology. 1996;88355- 362
Link to Article
Valle  D You give me fever. Nat Genet. 1999;22121- 122
Link to Article
Drenth  JPBoom  BWToonstra  Jvan der Meer  JWfor the International Hyper IgD Study Group, Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. Arch Dermatol. 1994;13059- 65
Link to Article
Boom  BWDaha  MRVermeer  BJvan der Meer  JW IgD immune complex vasculitis in a patient with hyperimmunoglobulinemia D and periodic fever. Arch Dermatol. 1990;1261621- 1624
Link to Article
Guillet  GLe Ru  YCartier  H Syndrome hyper-IgD: manifestations cutanees. Presse Med. 1997;261503- 1508
Cartier  HGuillet  MHLemoigne  E  et al.  Syndrome hyper-IgD ou pseudo-maladie periodique: manifestations cutanees dans 3 observations. Ann Dermatol Venereol. 1996;123314- 321
Miyagawa  SKitamura  WMorita  KSaishin  MShirai  T Association of hyperimmunoglobulinemia D syndrome with erythema elevatum diutinum. Br J Dermatol. 1993;128572- 574
Link to Article
Azizi  EFisher  BK Cutaneous manifestations of familial Mediterranean fever. Arch Dermatol. 1976;112364- 366
Link to Article
Barakat  MHKarnik  AMMajeed  HWel-Sobki  NIFenech  FF Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med. 1986;60837- 847
Sohar  EGafni  JPras  MHeller  H Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med. 1967;43227- 253
Link to Article
Gedalia  AAdar  AGorodischer  R Familial Mediterranean fever in children. J Rheumatol Suppl. 1992;351- 9
Majeed  HAQuabazard  ZHijazi  ZFarwana  SHarshani  F The cutaneous manifestations in children with familial Mediterranean fever (recurrent hereditary polyserositis): a six-year study. Q J Med. 1990;75607- 616
Rawashdeh  MOMajeed  HA Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr. 1996;155540- 544
Link to Article
Barzilai  ALangevitz  PGoldberg  I  et al.  Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic correlation. J Am Acad Dermatol. 2000;42791- 795
Link to Article
Sachs  DLangevitz  PMorag  BPras  M Polyarteritis nodosa and familial Mediterranean fever. Br J Rheumatol. 1987;26139- 141
Link to Article
Glikson  MGalun  ESchlesinger  M  et al.  Polyarteritis nodosa and familial Mediterranean fever: a report of 2 cases and review of the literature. J Rheumatol. 1989;16536- 539
Schlesinger  MOren  SFano  MViskoper  JR Perirenal and renal subcapsular haematoma as presenting symptoms of polyarteritis nodosa. Postgrad Med J. 1989;65681- 683
Link to Article
Tinaztepe  KGucer  SBakkaloglu  ATinaztepe  B Familial Mediterranean fever and polyarteritis nodosa: experience of five paediatric cases: a causal relationship or coincidence? Eur J Pediatr. 1997;156505- 506
Ozdogan  HArisoy  NKasapcapur  O  et al.  Vasculitis in familial Mediterranean fever. J Rheumatol. 1997;24323- 327
Dinarello  CAChusid  MJFauci  ASGallin  JIDale  DCWolff  SM Effect of prophylactic colchicine therapy on leukocyte function in patients with familial Mediterranean fever. Arthritis Rheum. 1976;19618- 622
Link to Article
Bar-Eli  MEhrenfeld  MLevy  MGallily  REliakim  M Leukocyte chemotaxis in recurrent polyserositis (familial Mediterranean fever). Am J Med Sci. 1981;28115- 18
Link to Article
Cronstein  BNMolad  YReibman  JBalakhane  ELevin  RIWeissmann  G Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest. 1995;96994- 1002
Link to Article
Zemer  DPras  MSohar  EModan  MCabili  SGafni  J Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;3141001- 1005
Link to Article
Kastner  DLAksentijevich  IGalon  J  et al.  TNF receptor–associated periodic syndromes (TRAPS): novel TNFR1 mutations and early experience with etanercept therapy [abstract]. Arthritis Rheum. 1999;42S117
Pisetsky  DS Tumor necrosis factor blockers in rheumatoid arthritis. N Engl J Med. 2000;342810- 811
Link to Article
Luong  BTChong  BSLowder  D Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab. Ann Pharmacother. 2000;34743- 760
Link to Article
Huttenlocher  AFrieden  IJEmery  H Neonatal onset multisystem inflammatory disease. J Rheumatol. 1995;221171- 1173
Mallouh  AAbu-Osba  YKTalab  Y Infantile-onset arthritis and multisystem inflammatory disease: "a new syndrome." J Pediatr Orthop. 1987;7227- 230
Link to Article
Kaufman  RALovell  DJ Infantile-onset multisystem inflammatory disease: radiologic findings. Radiology. 1986;160741- 746
Padeh  SBrezniak  NZemer  D  et al.  Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr. 1999;13598- 101
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The clinical spectrum of cutaneous manifestations of TRAPS (tumor necrosis factor receptor–associated periodic syndrome). A, Periorbital edema in a child. B, A large annular patch. C, Erythematous dermal macules and patches. D, Generalized erythematous serpiginous patches and plaques.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Histologic and immunohistochemical findings. A, Microscopic examination shows a normal epidermis and superficial and deep perivascular infiltrate (hematoxylin-eosin, original magnification ×20). The high-magnification (original magnification ×200) inset shows small aggregates and individual lymphocytes and monocytes around vessels. B, Strongly positive CD3 cells around superficial venules. C, Perivascular infiltrate is strongly positive for CD8. D, Strongly positive CD68 cells around superficial venules. (B through D, immunoperoxidase, original magnification ×100.)

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical Findings in 25 Patients With TRAPS*
Table Graphic Jump LocationTable 2. Differential Diagnosis of TRAPS, FMF, and HIDS*

References

McDermott  MFAksentijevich  IGalon  J  et al.  Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97133- 144
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Williamson  LMHull  DMehta  RReeves  WGRobinson  BHToghill  PJ Familial Hibernian fever. Q J Med. 1982;51469- 480
McDermott  EMSmillie  DMPowell  RJ Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin Proc. 1997;72806- 817
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Mulley  JSaar  KHewitt  G  et al.  Gene localization for an autosomal dominant familial periodic fever to 12q13. Am J Hum Genet. 1998;62884- 889
Link to Article
Gertz  MAPetitt  RMPerrault  JKyle  RA Autosomal dominant familial Mediterranean fever-like syndrome with amyloidosis. Mayo Clin Proc. 1987;621095- 1100
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Heller  HSohar  ESherf  L Familial Mediterranean fever. Arch Intern Med. 1958;10250- 71
Link to Article
Samuels  JAksentijevich  ITorosyan  Y  et al.  Familial Mediterranean fever at the millennium: clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine. 1998;77268- 297
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van der Meer  JWMVossen  JMRadl  J  et al.  Hyperimmunoglobulinemia D and periodic fever: a new syndrome. Lancet. 1984;11087- 1090
Link to Article
Drenth  JPHaagsma  CJvan der Meer  JWfor the International Hyper-IgD Study Group, Hyperimmunoglobulinemia D and periodic fever syndrome: the clinical spectrum in a series of 50 patients. Medicine (Baltimore). 1994;73133- 144
Link to Article
Karenko  LPettersson  TRoberts  P Autosomal dominant "Mediterranean fever" in a Finnish family. J Intern Med. 1992;232365- 369
Link to Article
Zweers  EJErkelens  DW A Dutch family with familial Mediterranean fever [in Dutch]. Ned Tijdschr Geneeskd. 1993;1371570- 1573
Zaks  NKastner  DLSohar  EedGafni  JedPras  Med Clinical syndromes resembling familial Mediterranean fever. Familial Mediterranean Fever. London, England Freund1997;211- 215
Gadallah  MFVasquez  FAbreo  FAbreo  K A 38-year-old man with nephrotic syndrome, episodic fever and abdominal pain. J La State Med Soc. 1995;147493- 499
Smith  CADavis  TAnderson  D  et al.  A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 1990;2481019- 1023
Link to Article
Bazzoni  FBeutler  B The tumor necrosis factor ligand and receptor families. N Engl J Med. 1996;3341717- 1725
Link to Article
Engelmann  HHoltmann  HBrakebusch  C  et al.  Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem. 1990;26514497- 14504
Engelmann  HAderka  DRubinstein  MRotman  DWallach  D A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity. J Biol Chem. 1989;26411974- 11980
Vassalli  P The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10411- 452
Link to Article
Aksentijevich  IGalon  JMcDermott  MF  et al.  TNF receptor-associated periodic fever syndrome (TRAPS): novel TNFR1 mutations and early experience with etanercept therapy [abstract]. Am J Hum Genet. 2000;65A281
Macon  WRSalhany  KE T-cell subset analysis of peripheral T-cell lymphomas by paraffin section immunohistology and correlation of CD4/CD8 results with flow cytometry. Am J Clin Pathol. 1998;109610- 617
Fuchs  PStrehl  SDworzak  MHimmler  AAmbros  PF Structure of the human TNF receptor 1 (p60) gene (TNFR1) and localization to chromosome 12p13. Genomics. 1992;13219- 224
Link to Article
McDermott  MFOgunkolade  BWMcDermott  EM  et al.  Linkage of familial Hibernian fever to chromosome 12p13. Am J Hum Genet. 1998;621446- 1451
Link to Article
International FMF Consortium, Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90797- 807
Link to Article
French FMF Consortium, A candidate gene for familial Mediterranean fever. Nat Genet. 1997;1725- 31
Link to Article
Centola  MAksentijevich  IKastner  DL The hereditary periodic fever syndromes: molecular analysis of a new family of inflammatory diseases. Hum Mol Genet. 1998;71581- 1588
Link to Article
Henry  JMather  IHMcDermott  MFPontarotti  P B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins. Mol Biol Evol. 1998;151696- 1705
Link to Article
Aksentijevich  ITorosyan  YSamuels  J  et al.  Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999;64949- 962
Link to Article
Cazeneuve  CSarkisian  TPecheux  C  et al.  MEFV-gene analysis in Armenian patients with familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet. 1999;6588- 97
Link to Article
Booth  DRGillmore  JDBooth  SEPepys  MBHawkins  PN Pyrin/marenostrin mutations in familial Mediterranean fever. QJM. 1998;91603- 606
Link to Article
Bernot  Ada Silva  CPetit  JL  et al.  Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998;71317- 1325
Link to Article
Domingo  CTouitou  IBayou  A  et al.  Familial Mediterranean fever in the "Chuetas" of Mallorca: a question of Jewish origin or genetic heterogeneity. Eur J Hum Genet. 2000;8242- 246
Link to Article
Dode  CPecheux  CCazeneuve  C  et al.  Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet. 2000;92241- 246
Link to Article
Simon  ADrenth  JPH Genes associated with periodic fevers highlighted at Dutch workshop. Lancet. 1999;3542141
Link to Article
Drenth  JPCuisset  LGrateau  G  et al. for the International Hyper-IgD Study Group, Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet. 1999;22178- 181
Link to Article
Houten  SMKuis  WDuran  M  et al.  Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22175- 177
Link to Article
Goldstein  JLBrown  MS Regulation of the mevalonate pathway. Nature. 1990;343425- 430
Link to Article
Brown  MSGoldstein  JL The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89331- 340
Link to Article
Topaloglu  RSaatci  U Hyperimmunoglobulinaemia D and periodic fever mimicking familial Mediterranean fever in the Mediterranean. Postgrad Med J. 1991;67490- 491
Link to Article
Grose  CSchnetzer  JRFerrante  AVladutiu  AO Children with hyperimmunoglobulinemia D and periodic fever syndrome. Pediatr Infect Dis J. 1996;1572- 77
Link to Article
Haraldsson  AWeemaes  CMDe Boer  AWBakkeren  JAStoelinga  GB Immunological studies in the hyper-immunoglobulin D syndrome. J Clin Immunol. 1992;12424- 428
Link to Article
Loeliger  AEKruize  AABijilsma  JWLoeliger  AEDerksen  RH Arthritis in hyperimmunoglobulinaemia D. Ann Rheum Dis. 1993;5281
Link to Article
Drenth  JPPrieur  AM Occurrence of arthritis in hyperimmunoglobulinaemia D. Ann Rheum Dis. 1993;52765- 766
Link to Article
Shohat  MMagal  NShohat  T  et al.  Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet. 1999;7287- 292
Link to Article
Livneh  ALangevitz  PShinar  Y  et al.  MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid. 1999;61- 6
Link to Article
Drenth  JPGoertz  JDaha  MRvan der Meer  JW Immunoglobulin D enhances the release of tumor necrosis factor-alpha and interleukin-1 beta as well as interleukin-1 receptor antagonist from human mononuclear cells. Immunology. 1996;88355- 362
Link to Article
Valle  D You give me fever. Nat Genet. 1999;22121- 122
Link to Article
Drenth  JPBoom  BWToonstra  Jvan der Meer  JWfor the International Hyper IgD Study Group, Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome. Arch Dermatol. 1994;13059- 65
Link to Article
Boom  BWDaha  MRVermeer  BJvan der Meer  JW IgD immune complex vasculitis in a patient with hyperimmunoglobulinemia D and periodic fever. Arch Dermatol. 1990;1261621- 1624
Link to Article
Guillet  GLe Ru  YCartier  H Syndrome hyper-IgD: manifestations cutanees. Presse Med. 1997;261503- 1508
Cartier  HGuillet  MHLemoigne  E  et al.  Syndrome hyper-IgD ou pseudo-maladie periodique: manifestations cutanees dans 3 observations. Ann Dermatol Venereol. 1996;123314- 321
Miyagawa  SKitamura  WMorita  KSaishin  MShirai  T Association of hyperimmunoglobulinemia D syndrome with erythema elevatum diutinum. Br J Dermatol. 1993;128572- 574
Link to Article
Azizi  EFisher  BK Cutaneous manifestations of familial Mediterranean fever. Arch Dermatol. 1976;112364- 366
Link to Article
Barakat  MHKarnik  AMMajeed  HWel-Sobki  NIFenech  FF Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med. 1986;60837- 847
Sohar  EGafni  JPras  MHeller  H Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med. 1967;43227- 253
Link to Article
Gedalia  AAdar  AGorodischer  R Familial Mediterranean fever in children. J Rheumatol Suppl. 1992;351- 9
Majeed  HAQuabazard  ZHijazi  ZFarwana  SHarshani  F The cutaneous manifestations in children with familial Mediterranean fever (recurrent hereditary polyserositis): a six-year study. Q J Med. 1990;75607- 616
Rawashdeh  MOMajeed  HA Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr. 1996;155540- 544
Link to Article
Barzilai  ALangevitz  PGoldberg  I  et al.  Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic correlation. J Am Acad Dermatol. 2000;42791- 795
Link to Article
Sachs  DLangevitz  PMorag  BPras  M Polyarteritis nodosa and familial Mediterranean fever. Br J Rheumatol. 1987;26139- 141
Link to Article
Glikson  MGalun  ESchlesinger  M  et al.  Polyarteritis nodosa and familial Mediterranean fever: a report of 2 cases and review of the literature. J Rheumatol. 1989;16536- 539
Schlesinger  MOren  SFano  MViskoper  JR Perirenal and renal subcapsular haematoma as presenting symptoms of polyarteritis nodosa. Postgrad Med J. 1989;65681- 683
Link to Article
Tinaztepe  KGucer  SBakkaloglu  ATinaztepe  B Familial Mediterranean fever and polyarteritis nodosa: experience of five paediatric cases: a causal relationship or coincidence? Eur J Pediatr. 1997;156505- 506
Ozdogan  HArisoy  NKasapcapur  O  et al.  Vasculitis in familial Mediterranean fever. J Rheumatol. 1997;24323- 327
Dinarello  CAChusid  MJFauci  ASGallin  JIDale  DCWolff  SM Effect of prophylactic colchicine therapy on leukocyte function in patients with familial Mediterranean fever. Arthritis Rheum. 1976;19618- 622
Link to Article
Bar-Eli  MEhrenfeld  MLevy  MGallily  REliakim  M Leukocyte chemotaxis in recurrent polyserositis (familial Mediterranean fever). Am J Med Sci. 1981;28115- 18
Link to Article
Cronstein  BNMolad  YReibman  JBalakhane  ELevin  RIWeissmann  G Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest. 1995;96994- 1002
Link to Article
Zemer  DPras  MSohar  EModan  MCabili  SGafni  J Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;3141001- 1005
Link to Article
Kastner  DLAksentijevich  IGalon  J  et al.  TNF receptor–associated periodic syndromes (TRAPS): novel TNFR1 mutations and early experience with etanercept therapy [abstract]. Arthritis Rheum. 1999;42S117
Pisetsky  DS Tumor necrosis factor blockers in rheumatoid arthritis. N Engl J Med. 2000;342810- 811
Link to Article
Luong  BTChong  BSLowder  D Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab. Ann Pharmacother. 2000;34743- 760
Link to Article
Huttenlocher  AFrieden  IJEmery  H Neonatal onset multisystem inflammatory disease. J Rheumatol. 1995;221171- 1173
Mallouh  AAbu-Osba  YKTalab  Y Infantile-onset arthritis and multisystem inflammatory disease: "a new syndrome." J Pediatr Orthop. 1987;7227- 230
Link to Article
Kaufman  RALovell  DJ Infantile-onset multisystem inflammatory disease: radiologic findings. Radiology. 1986;160741- 746
Padeh  SBrezniak  NZemer  D  et al.  Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome: clinical characteristics and outcome. J Pediatr. 1999;13598- 101
Link to Article

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