recurrent febrile syndromes what a rheumatologist needs to know

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1 recurrent febrile syndromes what a rheumatologist needs to know Hal M. Hoffman and Anna Simon abstract rheumatologists are likely to be asked to evaluate patients with recurrent febrile syndromes, so it is important that they are familiar with the clinical and diagnostic features, pathophysiology and therapeutic options for these rare autoinflammatory disorders. These syndromes are all characterized by recurrent episodes of fever and systemic inflammation; however, some syndromes have unique historical and physical features that can help with making a diagnosis. The primary associated morbidity is systemic amyloidosis, usually with renal involvement. Diagnostic testing is mostly limited to genetic testing. NsAiDs, colchicine and corticosteroids have roles in the treatment of some of these disorders, but biologic drugs that target interleukin 1β are emerging as consistently effective therapies. Hoffman, H. M. & simon, A. Nat. Rev. Rheumatol. 5, (2009); doi: /nrrheum Introduction Patients with recurrent fever can present a particular challenge to the practicing rheumatologist. Diagnosis and appropriate management require familiarity with the unique clinical characteristics and immune pathophysiology of this family of rare disorders, as well as knowledge of diagnostic techniques and the available therapeutic options. Patients might not be directly referred to a rheumatologist because joint symptoms are frequently absent. some are seen by infectious disease specialists or clinical immunologists for presumed recurrent infections, or are evaluated by dermatologists and allergists for unusual rashes. others are referred to gastroenterologists for recurrent abdominal pain, otolaryng o logists for recurrent oropharyngeal symptoms or hearing loss, and nephrologists for renal failure. the perception of autoimmune mechanisms and rheumato logic disease patterns, and the remarkable efficacy of therapeutic agents commonly used by rheumatolo gists for other conditions, has raised interest in these dis orders. early recognition can prevent severe morbidities such as systemic amyloidassociated (aa) amyloidosis. in addition, it is helpful for practicing physicians to be aware of the pathogenic disease mechanisms that are currently being elucidated for these genetic disorders, as they have implications for commoner inflammatory diseases, such as adult and childhood arthritis and gout. in this review, we discuss the most common clinical syndromes that are referred to as periodic fevers, although only some of these diseases are characterized by attacks with defined periodicity. the defining feature of this group of diseases is recurrent episodes of systemic inflammation Competing interests H. M. Hoffman has declared associations with the following companies/organizations: Novartis pharmaceuticals and regeneron pharmaceuticals. A. simon declared no competing interests. with fever, punctuated by spontaneous resolution to some degree. these conditions are now classified in the expanding group of autoinflammatory disorders, which can be distinguished from autoimmune dis orders by the absence of autoantibodies or antigen specific t cells. 1 instead of a pathophysiology based on an adaptive immune response involving antibodies and lymphocytes, the disease mechanisms in these conditions involve innate immune regulation of cytokines and neutro philic inflammation. the hereditary periodic fevers were the first diseases described as auto inflammatory, but this classifica tion has now expanded to include other nongenetic disorders with similar clinical patterns, other genetic diseases with similar under lying molecular mecha nisms, and more common diseases in which similar innate immune pathways have been implicated. we do not discuss infections characterized by relapsing fevers, malignancies with febrile episodes, or immune deficiencies with recurrent infections, such as cyclic neutropenia. we provide an overview of the clinical features, pathophysiologic mechanisms, diagnostic challenges, and therapeutic strategies for recurrent febrile syndromes. Clinical features the central common feature of these disorders is the intermittent occurrence of symptoms of systemic inflammation. Clinical manifestations of this feature usually include fever, frequently high (>39 C) and spiking in character, and fatigue caused by the intense inflammation. inflammation can also lead to involvement of several organ systems, including the skin, gastro intestinal tract, muscles and joints, with each syndrome having its own characteristic distribution of organ involvement, frequency and duration of inflammatory episodes (tables 1 and 2). Complete or partial spontaneous resolution of these symptoms is a characteristic feature, but as most University of California at san Diego, La Jolla, California, UsA (hm hoffman). radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (a Simon). Correspondence: HM Hoffman, UCsD, Mail code 0635, 9500 Gilman Drive, La Jolla, CA 92093, UsA hahoffman@ucsd.edu nature reviews rheumatology volume 5 may

2 Key points The autoinflammatory disorders are diseases of innate immune dysregulation The recurrent febrile syndromes are characterized by episodes of systemic and tissue inflammation The recurrent febrile syndromes present a diagnostic challenge The primary long term morbidity of the inherited recurrent febrile syndromes is systemic amyloidosis Advances in the understanding of the genetics and pathogenesis of these disorders have led to improved diagnostic ability and therapy, including the development of biologic therapies that target interleukin 1β patients are given some kind of therapy (for example, antibiotics) during the first episodes, the resolution of symptoms will often be attributed to the therapy. Frequency and duration of the inflammatory episodes vary between patients and also within phases of a patient s life; often, there is no intrinsic periodicity. the inflammatory episodes are generally hypothe sized to be triggered by a minor or seemingly trivial and un noticed inflammatory stimulus, resulting in an exag gerated immune response. triggers recognized in specific syndromes include vacci nation, cold temperature, minor infections or local inflammatory processes (such as periodontal disease), as well as emotional stress. 2 in several of these dis orders, in particular familial mediterranean fever (FmF), patients describe a prodrome preceding the episodes. in all syndromes (with the exception of periodic fever, adenitis, pharyngitis and aphthous stomatitis [PFaPa]), patients frequently exhibit subclinical inflammation, demonstrated by an acute phase response in the absence of overt clinical symptoms, which contri butes to the risk of longterm complications. the clinical features of disorders commonly recognized as the recurrent febrile syndromes will now be briefly outlined. FmF the onset of FmF usually occurs during childhood, with 60% of patients showing first symptoms before the age of 10 years. 3 attacks usually last for 1 3 days, and a prominent feature, in addition to the fever, is serositis (either peritonitis, synovitis or pleuritis). 4 skin involvement is also common, generally as an erysipelas like rash that occurs most frequently on the shins and dorsum of the foot. FmF is caused by mutations in the mediterranean fever gene (MEFV), which codes for the protein pyrin. 5,6 in a consider able proportion of patients (up to 20%), no mutations can be detected; 7 these patients are distinguished as having clinical FmF, and they might represent patients with either difficult to detect abnormalities of the MEFV gene or an as yet unrecognized disorder that resembles FmF. traps a distinguishing characteristic of tumor necrosis factor (tnf) receptor associated periodic syndrome (traps) is the relatively long duration of most attacks, which can last 3 4 weeks. the age of onset is very variable, ranging between early childhood and several decades of age. Characteristic features, apart from the fever, are a migrating erythematous and centrifugal rash that spreads from the trunk to the extremities, often in combination with severe myalgia at the same location, eye involvement (such as conjunctivitis or periorbital edema) and abdominal pain. traps is caused by mutations in the gene encoding tnf receptor superfamily, member 1a (TNFRSF1A). 1 mevalonate kinase deficiency more than 90% of patients with hyper igd syndrome (HiDs) or mevalonate kinase deficiency show initial symptoms during their first year of life. Chills accompanying the rise in temperature, generalized lymphadeno pathy, splenomegaly, abdominal pain, and an erythematous rash are often features of this syndrome. aphthous ulcers might also be present. attacks generally last for 3 7 days. also characteristic are attacks triggered by (childhood) vaccinations. 8 HiDs is caused by mutations in the gene encoding mevalonate kinase, an enzyme in the isoprenoid pathway, 9,10 end products of which include cholesterol and isoprenylated proteins, such as rho and ras. 11 Certain mutations in this gene lead to a severe phenotype, which includes neurologic symptoms, mental retardation and decreased life expectancy. 12 CaPS Cryopyrin associated periodic syndromes (CaPs) encompass a continuum of three phenotypes of increasing severity: familial cold autoinflammatory syndrome (FCas), muckle wells syndrome (mws), and neonatal onset multisystem inflammatory disease (nomid). these disorders are caused by mutations in the NLRP3 gene, which encodes cryopyrin, 13,14 and are charac terized by disease onset in the neonatal period that persists through early childhood, with a generalized urticaria like painful rash as the predominant symptom. other symptoms common to all three phenotypes include arthralgia, headache, fatigue and conjunctivitis. FCas is distinguished by inflammatory episodes induced by exposure to modestly cold environ ments and a common diurnal pattern of symptoms that worsen throughout the day. mws is characterized by progressive sensorineural hearing loss and a substantial risk of systemic aa amyloido sis. nomid is distinguished by marked central nervous system involvement, including seizures, developmental delay and eye complications, and a deforming arthropathy involving the distal femur and patella Pathologic analysis of involved skin in patients with CaPs revealed severe tissue neutrophilia in the dermis. 18 PFaPa the clinical syndrome that is commonly known as PFaPa presents in early childhood, with recurrent febrile episodes lasting 2 5 days that occur regularly every 3 6 weeks. Patients might experience one or more of the pathognomonic symptoms during an episode, but the joint and skin symptoms commonly observed in the hereditary 250 MAY 2009 volume 5

3 Table 1 Clinical features and management of FMF, TrAPs and MKD Syndrome feature FmF traps mkd hids mevalonic aciduria Mode of inheritance Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive Age at onset (years) <20 <20 <1 <1 Duration of <2 > attack (days) a Musculoskeletal features Monoarthritis, myalgia severe myalgia, monoarthritis Arthralgia, occasional oligoarthritis Arthralgia Abdominal features sterile peritonitis severe pain splenomegaly, severe pain splenomegaly, pain might occur Cutaneous features erysipelas like erythema, often on the shins and dorsum of foot Centrifugal rash starting on trunk and migrating to extremities Ocular features Conjunctivitis, periorbital edema Distinguishing clinical symptoms erysipelas like erythema Migratory myalgia and rash Maculopapular rash Cervical lymphadenopathy Gene MEFV TNFRSF1A MVK MVK Morbilliform rash Dysmorphic features, neurological symptoms Protein Pyrin TNFrsF1A Mevalonate kinase Mevalonate kinase estimated incidence of amyloidosis ~50% (precolchicine era) 10 20% <10% Unknown standard therapy Colchicine Corticosteroids NA NA Therapies or treatment approaches requiring additional study il 1 blocking drugs, TNF inhibitors etanercept, anakinra Anakinra, TNF inhibitors NA a Duration is variable; values given here are typical. Abbreviations: FMF, familial Mediterranean fever; HiDs, hyper igd syndrome; il, interleukin; MKD, mevalonate kinase deficiency; NA, not applicable; TNF, tumor necrosis factor; TrAPs, TNF receptor associated periodic syndrome. fever disorders are not seen in PFaPa. a family history of recurrent fevers is unusual, and this disorder is unique in that complete resolution often occurs within 5 8 years of onset. although symptoms of fever, malaise and anorexia can be debilitating during the episode, children are completely asympto matic and healthy between episodes, with no evidence of long term morbidity. Clinical presentation can resemble that of HiDs. 19 other recurrent fever disorders more than half of patients with recurrent fevers who present to large referral centers do not have an identifiable syndrome. while some of these patients present with clinical pictures that are inconsistent with known dis orders, others with classic presentations might not possess readily identifiable mutations in the known disease genes, making the diagnosis difficult. new genetic syndromes in this group are still elucidated at a rate of about one every 2 years. other systemic autoinflammatory diseases owing to space limitations, we have not included in this review the following disorders that are commonly considered to be systemic autoinflammatory syndromes: pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PaPa) syndrome, characterized by severe arthritis and skin lesions; 20 Blau syndrome, which involves arthritis, uveitis, rash and granulomas; 21 schnitzler syndrome, charac terized by urticarial rash, fever and pain in bone and joints; 22 and chronic recurrent multifocal osteomyelitis /majeed syndrome, which presents with pain and swelling in the extremities. 23 of these four disorders, only schnitzler syndrome is commonly characterized by fever. Prevalence recurrent febrile syndromes are rare, but exact figures on prevalence are unavailable. the most common syndromes are PFaPa and FmF, with numbers worldwide probably reaching the thousands. Carrier frequency for MEFV mutations in certain populations can be high (for example, in non ashkenazi Jews and armenians). the other disorders are rarer, with numbers probably in the hundreds worldwide. some of the syndromes have a clear ethnic distribution: FmF occurs most commonly in people from around the mediterranean sea, 24 while HiDs and traps are predominantly seen in people with a western european background; 25 however, these ethnic associations are not absolute. FmF and HiDs have an autosomal recessive inheritance pattern, although autosomal dominant transmission has been reported for FmF in rare cases. traps and CaPs have an autosomal dominant inheritance pattern, and PFaPa does not seem to be genetically inherited. nature reviews rheumatology volume 5 may

4 Table 2 Clinical features and management of CAPs and PFAPA Syndrome feature CaPS PFaPa FCaS mws NomID Mode of inheritance Autosomal dominant Autosomal dominant Autosomal dominant None Age at onset (years) <1 <20 <1 <5 Duration of attack (days) a <2 1 2 Unknown 3 5 Musculoskeletal features Arthralgia, occasional myalgia Limb pain, arthralgia, arthritis epiphyseal bone formation Abdominal features None Might occur Hepatomegaly splenomegaly Cutaneous features Cold induced generalized urticaria like rash Generalized urticaria like rash Generalized urticaria like rash Ocular features Conjunctivitis Conjunctivitis Papilledema, uveitis Distinguishing clinical symptoms Cold induced episodes sensorineural hearing loss Chronic aseptic meningitis, sensorineural hearing loss, arthropathy Gene NLRP3 NLRP3 NLRP3 None Protein Cryopyrin Cryopyrin Cryopyrin None estimated incidence of amyloidosis <10% ~25% Unknown None Aphthous ulcers, lymphadenopathy, pharyngitis standard therapy Anakinra, rilonacept Anakinra, rilonacept Anakinra single dose corticosteroid (limited use) Therapies or treatment approaches requiring additional study Canakinumab Canakinumab Canakinumab, thalidomide Colchicine, cimetidine, montelukast, tonsillectomy a Duration is variable; values given here are typical. Abbreviations: CAPs, cryopyrin associated periodic syndrome; FCAs, familial cold autoinflammatory syndrome; Mws, Muckle wells syndrome; NOMiD, neonatal onset multisystem inflammatory disease; PFAPA, periodic fever adenitis pharyngitis and aphthous stomatitis. Pathophysiology the identification of the genetic basis of the hereditary recurrent fever disorders has helped the elucidation of the underlying disease pathophysiology. a common theme of dysregulation of proinflammatory cytokine responses and innate immune cells, including monocytes, macrophages and neutrophils, has emerged. the innate immune system has evolved as a highly regulated, rapid response mechanism for the recognition of danger signals of nonself (pathogen associated molecular patterns) and self (danger associated molecular patterns) origins. sensing of these potentially harmful signals is mediated by toll like receptors and nod like receptors, including cryopyrin (also known as nlrp3), the protein altered in CaPs. 26 upon activation, cryopyrin forms an intracellular protein complex that controls the activation and release of interleukin (il) 1β, through activation of the cleaving enzyme caspase 1 (Figure 1). 27 mutations in NLRP3 are likely to be gain of function, resulting in increased secretion of il 1β. 28 Pyrin, the protein altered in FmF, also intersects with this pathway, either through direct activation of caspase 1 or via negative regulation of the cryopyrin inflammasome. 29 the exact function of pyrin, and the direct consequences of disease associated mutations, are not known. Cytokine mediated responses are also regulated at the receptor level in several ways. many receptors have natural, endogenous, soluble antagonists, which competitively inhibit receptor activation. in some cases, receptor activation can also be inhibited via cleavage of the receptor from the cell membrane, preventing signaling and the competitive binding of receptor agonists. Decreased cleavage of the mutated tnf receptor tnfrsf1a from the cell surface was one proposed mechanism for the unregulated inflammation observed in traps. 1 Current thinking, strengthened by the observation that il 1β blockade can be more effective than tnf blockade in treating traps patients, supports a proinflammatory effect of the mutated tnfrsf1a on intracellular signaling that is only partially dependent on tnf. 30 the pathophysiology of HiDs involves a defect in isoprenoid metabolism, a pathway that seems to have no direct relationship with innate immunity; 31 however, data suggest a link between a shortage of isoprenoid end products and dysregulation of the signaling protein rac1, which induces caspase 1 mediated il 1β release. 32 the pathophysiologic mechanisms of PFaPa are still enigmatic. Diagnosis the first step in reaching a diagnosis of one of these rare syndromes is to recognize the common phenotype (tables 1 and 2). as patients can be completely symptom free between the febrile episodes, examination 252 MAY 2009 volume 5

5 of a patient during an inflammatory episode is helpful; if this is not possible, the patient should at least provide a blood sample during a febrile episode. systemic inflammation will always result in high serum concentrations of the acute phase protein C reactive protein (CrP) during the febrile episodes. a normal serum CrP level at the height of symptom severity excludes the presence of one of these disorders. the many common causes of recurring fever and inflammation should be considered before a diagnosis is made; however, when episodes have been occurring for more than 1 2 years in the absence of another diagnosis, a systemic autoinflammatory syndrome becomes a likely explanation. although there is some variability in presenting symptoms, as well as an overlap in disease phenotypes, clinical presentation is the most important guide in the diagnostic process (tables 1 and 2 and Figure 2). a complete medical history is important, and should include information on age at the onset of symptoms, family history and ethnic origin of the patient. a detailed description of a typical inflammatory episode, including accompanying symptoms, duration and possible triggers, might also be informative. when a patient has had symptoms for years, sometimes the presence of longterm complications, such as systemic aa amyloidosis or hearing loss, will help in the differential diagnosis. the clinical information might single out one or two of the syndromes as likely diagnoses; however, physicians who rarely encounter these patients can have difficulty distinguishing the disorders. Figure 3 shows a straightforward scoring system for practical clini cal use, based on expert experience, which will aid practicing physicians; it lists the distinguishing charac teristics that should be noted in the patient, and helps in directing further diagnostic testing by suggesting the most likely candidate syndromes for each particular patient. the one or two most likely syndromes can then be further investigated. For FmF, evaluation of the response to colchicine is an important diagnostic tool. to test the effectiveness of colchicine, patients should use at least 0.5 mg three times a day for an adequate period, during which two or three attacks would be expected to occur; a subjective improvement of symptoms should be seen, although symptoms might not disappear completely. to reach a diagnosis of HiDs, high serum concentrations of igd and iga are helpful, though not absolutely required. an increased serum igd concentration can be found in all the recurrent febrile syndromes, and in many inflam matory conditions, but in HiDs it is usually more markedly increased (greater than three times the normal value). 33 serum igd levels are elevated similarly during fever and during remission. measurement of any detectable level of mevalonate in the urine by gas chromatography mass spectrometry during a fever episode is diagnostic for HiDs. apart from these labora tory tests, genetic testing is the most definitive method of diagnosis for most of the syndromes. the exceptions are FmF in patients that are not of mediterranean origin 34 and nomid, where mutations are Macrophage Nucleus TNF TNF TNFRSF1A Pro-IL-1β Monocyte Cryopyrin IL-1R Caspase 1 IL-1β Pyrin only identified in 50% of cases. 35 PFaPa requires a purely clinical diagnosis. if this first round of testing for one or two syndromes does not yield a diagnosis, the chances of reaching a positive genetic diagnosis with further testing for other, less likely syndromes are small. 36 Prognosis and long-term complications the primary morbidity associated with the recurrent febrile syndromes is related to chronic inflammation, which can result in the development of systemic aa amyloido sis with destructive deposition of amyloid in tissues, such as the kidney. this feature is the main concern regarding the management of these patients. an early sign is proteinuria, which should be closely monitored. the frequency of amyloidosis varies considerably among Inflammasome Isoprenoids Neutrophil Mevalonate kinase Figure 1 Pathophysiology of hereditary recurrent febrile syndromes. each of the disorders involves dysregulation of innate immunity, affecting cytokine responses and sensing of pathogens and danger signals by myeloid cells (macrophages, monocytes and neutrophils). Mutations in the gene encoding TNFrsF1A that affect its function are responsible for TrAPs, whereas mutations in the genes encoding cryopyrin (NLRP3) and pyrin (MEFV), which regulate il 1β release, are responsible for CAPs and FMF, respectively. HiDs is caused by mutations in the gene encoding mevalonate kinase (MVK), which regulates isoprenoid metabolism. The mechanisms of all these disorders intersect with the il 1 pathway. Mutations are denoted by orange stars; red crosses indicate current therapeutic targets. Abbreviations: CAPs, cryopyrin associated periodic syndromes; FMF, familial mediterranean fever; HiDs, hyper igd syndrome; il, interleukin; il 1r, interleukin 1 receptor; TNF, tumor necrosis factor; TNFrsF1A, tumor necrosis factor receptor superfamily, member 1A; TrAPs, TNF receptor associated periodic syndrome. nature reviews rheumatology volume 5 may

6 a Body temperature ( C) Body temperature ( C) Body temperature ( C) b FMF FMF HIDS FCAS Time (hours after cold exposure) HIDS FCAS 8 10 TRAPS PFAPA MWS TRAPS PFAPA MWS Figure 2 Patterns of fever seen in recurrent febrile syndromes. Typical patterns of a fever during an inflammatory attack in the recurrent febrile syndromes, and b recurrence. even when there are no overt symptoms, patients might experience subclinical inflammation, as indicated by an acute phase response except in PFAPA. Abbreviations: FCAs, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; HiDs, hyper igd syndrome; Mws, Muckle wells syndrome; PFAPA, periodic fever, adenitis, pharyngitis and aphthous stomatitis; TrAPs, TNF receptor associated periodic syndrome. Adapted with permission from elsevier simon, A. et al. Familial autoinflammatory syndromes. in Kelley s Textbook of Rheumatology, 8th edn, Ch. 113 (eds Firestein, G. s. et al.) (saunders, Philadelphia, 2008). 56 the syndromes, with high rates observed in patients with FmF and mws, lower frequencies observed in patients with HiDs, traps, FCas, and absence in patients with PFaPa (tables 1 and 2). 37 in addition, there are genetic factors, such as family history and specific polymorphisms in the serum amyloid a (SAA) gene, 38 and environmental factors, including geography that must be taken into account. one of the chief goals in the manage ment of patients with these disorders, therefore, is to reduce chronic inflammation in order to prevent the development of amyloidosis. saa level is an excellent predictive marker for the development of tissue amyloidosis, with levels below 10 mg/l being associated with a greatly reduced risk; however, the saa test is not available in many countries, so some physicians use CrP as a surrogate marker, although the sensitivity can be less than that of saa. serum amyloid P scintigraphy is being used in some centers to detect early amyloid deposition and to evaluate amyloid tissue distribution, but this is not widely available. Joint destruction, as seen in chronic inflammatory diseases, is rare in these syndromes, with the exception of nomid. Chronic recurring inflammation is associated with an increase in risk factors for cardiovascular disease, 39 although an epidemiological study in FmF patients found no increased incidence of ischemic heart disease. 40 stojanov et al. 41 describe a family with traps, caused by a special mutation in TNFRSF1A, in which two patients developed cardiovascular complications (lethal heart attack and peripheral arterial thrombosis). Therapy Febrile attacks in patients with these diseases can have a notable effect on quality of life, affecting school, work and interpersonal relationships. thus, in many patients there is a need for therapy to prevent, lessen the severity or shorten the duration of these episodes. in some fever syndromes, nonpharmacologic approaches have been used successfully, such as avoidance of cold in FCas (supported by the southern geographical distribution of FCas patients in the us) and tonsillectomy in PFaPa (supported by multiple case reports and a small controlled trial). 42 until recently, oral anti inflammatory drugs were the main therapy used. in many cases, antipyretics, such as nsaids and acetaminophen, have some effect at reducing fever and associated symptoms, but they do not prevent or change the course of an attack. regular, repeated dosing is often required for the duration of the episode, which raises concern for the occurrence of adverse effects, including gastrointestinal irritation or liver toxic ity. For the past 30 years, maintenance dose colchicine has been the mainstay of therapy for preventing attacks and substantially reducing the risk of amy loidosis in patients with FmF. 43,44 occasionally, compliance can be affected by the gastrointestinal adverse effects that are sometimes associated with increasing the dose. there are rare patients with FmF who are considered to be colchicine resistant (incomplete response to adequate colchicine dosing); however, determining whether this is true drug resistance or is merely caused by compliance issues, inadequate absorption or indivi dual pharmaco kinetic features, is difficult. interestingly, colchicine is less effective in the treatment of the other recurrent febrile syndromes, 254 MAY 2009 volume 5

7 although a report of clinical benefit in PFaPa has been published. 45 Corticosteroids have limited clinical efficacy in most of the recurrent febrile syndromes, with reports of very high doses being required to achieve any benefit. the exceptions are patients with traps, who respond to sustained therapy during attacks, 46 and patients with PFaPa, who can be extremely sensitive to a single, low dose (1 mg/kg) administered early in the attack. 19 the major advance in the treatment of recurrent fever disorders in the past decade has been the use of targeted biologic therapies. the first translational success story was the use of soluble tnf receptor (etanercept) in patients with traps, soon after the identification of the molecular basis of this syndrome. 47 Drugs targeting il 1β have, however, had the greatest impact on these diseases, following the identification of cryopyrin and the subsequent elucidation of its role in il 1 biology. the ready availability of recombinant, injectable il 1 receptor antagonist (anakinra) enabled the performance of initial proof of concept studies, which showed that this approach had remarkable, rapid clinical efficacy in CaPs. 18,48 larger, open label studies have confirmed the impressive response to anakinra in all three of the CaPs phenotypes this success prompted controlled trials of additional il 1 targeted therapies, such as rilonacept, the first FDa approved drug for CaPs, 52 and monoclonal antibodies against il 1β, such as canakinumab (acz885). il 1 blocking drugs have not only been useful in CaPs, but, in case reports, have also been shown to be effective in colchicine resistant patients with FmF, 53 HiDs, 8,54 and traps, 55 suggesting that il 1 is the central mediator of the recurrent febrile syndromes. the efficacy data in support of il 1 directed therapies in the recurrent febrile syndromes is still limited, and cost issues are a barrier to widespread use of these biologics. additional studies are required to establish the safety of these drugs, as concerns about infection and cardiovascular risk surround any new anti inflammatory agents. Conclusions the recurrent fever syndromes described here are a welldefined subgroup of the autoinflammatory dis orders, a new classification of inflammatory conditions that share some clinical features with autoimmune disorders. Both autoinflammatory and autoimmune disorders are associ ated with increased inflammation, with the former involving primarily innate immune mechanisms and Therapeutic response Colchicine Low dose prednisone Length of attack 1 day 1 3 days 4 6 days >7 days Continuous Trigger Cold Vaccination Inheritance Dominant Recessive FMF TRAPS CAPS HIDS PFAPA the latter involving both innate and adaptive immune pathways. these inflammatory diseases, therefore, can be seen as a continuous spectrum of immune dysregulation. elucidation of the mechanisms involved in the recurrent fever syndromes has led to rapid advances in diagnosis and treatment; further study will result in new therapeutic options for all inflammatory disorders. Skin rash Erysipelas-like Migrating erythema Urticaria Clinical features Serositis Orbital edema Meningitis Hearing loss Patellar overgrowth Lymphadenopathy Aphthous ulcers Pharyngitis Uveitis Figure 3 Diagnostic features and differential diagnosis of recurrent febrile syndromes. First, exclude other, more common causes of fever and inflammation in the patient. when a recurrent febrile syndrome seems likely, check the clinical characteristics found in your patient on the right and left of the diagram and assign one point to each syndrome that is linked to these characteristics by an arrow (one characteristic could point to more than one syndrome). The final combined score of both panels assigns a rank of likelihood of the disorders, and helps in determining the correct subsequent diagnostic tests. This algorithm is not evidence based, but is solely derived from expert opinion. Lines are dotted or solid for clarity only both are worth one point. Abbreviations: CAPs, cryopyrin associated periodic syndromes; FMF, familial Mediterranean fever; HiDs, hyper igd syndrome; PFAPA, periodic fever, adenitis, pharyngitis and aphthous stomatitis; TrAPs, TNF receptor associated periodic syndrome. Adapted with permission from elsevier simon, A. et al. Familial Autoinflammatory syndromes. in Kelley s Textbook of Rheumatology, 8th edn, Ch. 113 (eds Firestein, G. s. et al.) (saunders, Philadelphia, 2008). 56 Review criteria we searched PubMed for original articles published between 1970 and 2008 focusing on recurrent febrile syndromes. The search terms we used were periodic fever, autoinflammatory, familial Mediterranean fever, hyper igd syndrome, mevalonate kinase, tumor necrosis factor associated periodic syndrome, cryopyrin, CiAs1, NALP3, NLrP3, MeFv, PFAPA and amyloidosis. we also searched the reference lists of identified articles for further relevant papers. 1. McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kda TNF receptor, TNFr1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, (1999). 2. samuels, J. 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 (Baltimore) 77, (1998). 3. Livneh, A. et al. The changing face of familial Mediterranean fever. Semin. Arthritis. Rheum. 26, (1996). 4. Drenth, J. P. H. & van der Meer, J. w. M. Hereditary periodic fever. N. Engl. J. Med. 345, (2001). 5. international FMF Consortium. Ancient missense mutations in a new member of the roret gene family are likely to cause familial Mediterranean fever. Cell 90, (1997). 6. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, (1997). 7. Lidar, M. & Livneh, A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth. J. Med. 65, (2007). 8. van der Hilst, J. C. et al. Long term follow up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 87, (2008). 9. Houten, s. M. et al. Mutations in MvK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat. Genet. 22, (1999). 10. Drenth, J. P. H. et al. Mutations in the gene encoding mevalonate kinase cause hyper igd and periodic fever syndrome. international Hyper igd study Group. Nat. Genet. 22, (1999). nature reviews rheumatology volume 5 may

8 11. Houten, s. M., Frenkel, J., & waterham, H. r. isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation. Cell. Mol. Life Sci. 60, (2003). 12. Hoffmann, G. et al. Mevalonic aciduria an inborn error of cholesterol and nonsterol isoprene biosynthesis. N. Engl. J. Med. 314, (1986). 13. Feldmann, J. et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 71, (2002). 14. Hoffman, H. M. et al. Mutation of a new gene encoding a putative pyrin like protein causes familial cold autoinflammatory syndrome and Muckle wells syndrome. Nat. Genet. 29, (2001). 15. Hawkins, P. N. et al. spectrum of clinical features in Muckle wells syndrome and response to anakinra. Arthritis Rheum. 50, (2004). 16. Hoffman, H. M., wanderer, A. A. & Broide, D. H. 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J. et al. effect of etanercept and anakinra on inflammatory attacks in the hyper igd syndrome: introducing a vaccination provocation model. Neth. J. Med. 63, (2005). 55. Gattorno, M. et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor associated periodic syndrome. Arthritis Rheum. 58, (2008). 56. simon, A., van der Meer, J. w. M. & Drenth, J. P. H. Familial Autoinflammatory syndromes. in Kelley s Textbook of Rheumatology, 8th edn, Ch. 113 (eds Firestein, G. s. et al.) (saunders, Philadelphia, 2008). acknowledgments H. M. Hoffman is supported by the National institute of Allergy and infectious Diseases and the Ludwig institute of Cancer research. A. simon is supported by a ZonMw veni grant. 256 MAY 2009 volume 5