Periodic Fevers and Autoinflammatory Syndromes

Published by John Swope on


The autoinflammatory syndromes comprise a clinically distinct set of disorders unified by recurrent febrile episodes accompanied by inflammatory cutaneous, mucosal, serosal and osteoarticular manifestations (1-3). Although these rare disorders often have a striking onset and inflammatory features – they are without an infectious or autoimmune etiology.  Instead, many are unified by a genetically-driven dysregulated innate immune response with resultant activation of the inflammasome and cytokine excess.  Hence these disorders respond to interleukin-1 (IL-1), or tumor necrosis factor-a (TNF), and generally not to immunosuppressives.  Manifestations include periodic fevers, neutrophilic rashes or urticaria, serositis, hepatosplenomegaly, lymphadenopathy, elevated acute phase reactants, neutrophilia and a long term risk of secondary amyloidosis. 

The identification of the genetic origins underlying certain disorders has rapidly advanced our understanding of the immunopathogenesis of autoinflammatory disorders.  Affected individuals often have first- or second-degree relatives with similar features.   A monogenic defect has been identified for familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) and cryopyrin-associated periodic syndromes (CAPS) – which includes a spectrum of disorders – familial cold autoinflammatory disorder (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID).   Additional disorders also fall under the autoinflammatory umbrella, as they manifest similar inflammatory features but may or may not have an identifiable genetic cause.  Etiologic defects have been discovered for cyclic neutropenia, PAPA (pyogenic arthritis, acne, pyoderma gangrenosum), PASH (pyoderma gangrenosum, acne, suppurative hidradenitis) syndrome, DIRA (deficiency of the IL-1 receptor antagonist [IL-1Ra]) and DITRA (deficiency of the IL-36R antagonist).  Those without a known etiology include systemic-onset juvenile idiopathic arthritis (SoJIA), adult-onset Still’s disease, Marshall or PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenopathy) syndrome and the Schnitzler syndrome (1-5).

While these disorders are often rare, some are more frequently seen than others.  A federally funded German registry was established in 2009 and in a 9 month period they identified 117 patients (65 males, 52 females; age 1-21 years) with a diagnosis of FMF (n=84), SoJIA (n=22), clinically confirmed AID (n=5), TRAPS (n=3), CAPS (n=1), HIDS (n=1) and PFAPA (n=1) (6).   This review will focus on the distinguishing clinical features, onset, fever/flare duration, etiology and effective treatments – each of which is crucial to establishing an accurate diagnosis. 


Immune responses are either innate or adaptive.  The adaptive immune response recognizes self from non-self, generates antigen-specific cellular and cytokine responses and with activation driven autoantibody production the adaptive responses can establish immunologic memory or immune tolerance.  By contrast the innate immune response acts with immediacy to danger or pathogen signals termed pathogen-associated molecule patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs).  PAMPs and DAMPs activate intracellular inflammasomes to set forth an inflammatory cascade of effector molecules (3,4).  For example, the NLRP3 inflammasome is a cytosolic scaffold of proteins that are triggered by PAMP (microbial pathogens, monosodium urate, toxins) and DAMP (ATP, membrane disruption, oxygen radicals, hypoxia).  A disrupted, dysregulated innate immune system yields a proinflammatory state with the final common pathway being activation of the NLRP3 gene and the inflammasome with resultant unopposed cytokine excess .   Activation of the inflammasome yields increased production of proinflammatory cytokines such as IL-1, IL-18, TNF-α, IL-6, IL-17, type 1 interferons (IFN-α, IFN-β) and the complement system.  The inflammasome is a complex of proteins which, activates caspase-1 leading to cleavage inactive prointerleukin-1b to active IL-1b.   The critical role of the inflammasome in these disorders has led some to refer to the autoinflammatory disorders as “inflammasomopathies” (7).   


The TNF receptor associated periodic syndrome is also known by the acronym TRAPS or familial Hibernian fever owing to a higher frequency of this syndrome in those of Irish, Scottish or Austrian or Northern European dissent.  Nevertheless, it has been described in other ethnic groups, including Mediterranean’s.  TRAPS differ from FMF and HIDS by having febrile attacks that last 1-3 weeks and occasionally up to 6 weeks.  Characteristic features include fever, arthralgia, myalgia, migratory rash, abdominal pain, pleuritis, conjunctivitis, periorbital edema, oral ulcers and scrotal swelling.  Skin manifestations included migratory macular erythematous rash or patches, ecchymoses, edematous dermal plaques, serpiginous or annular lesions and periorbital edema (5,8,9).  Limited skin biopsies showed perivascular and interstitial lymphocytic and mononuclear infiltrates without evidence of granulomatous or vasculitic change.

The genetics underlying this disorder was clarified by studies of a large Irish multiplex family who demonstrated an autosomal dominant syndrome characterized by recurrent fever, rash and abdominal pain.  Fevers last more than 5 days and less than 6 weeks. The vast majority (75-88%) have a childhood onset, usually as toddlers around age 3 years and most occurring before age 10 yrs.  Adult onset may occur.  Manifestations of TRAPS depend on the mutations for the gene encoding p55 TNF receptor type I (TNF-RI; CD120a).  There are 46 known missense mutations involving TNF-RI, all of which are localized to distal chromosome 12p.  The R92Q and P46L mutations are seen in 4% and 1% of the population respectively and tend to have low penetrance and less severe disease.  The R92Q and T61I polymorphisms may be found with an adult onset, and is often associated with RA, lupus or multiple sclerosis.   Effective treatment with etanercept which has been shown to reduce the frequency and severity of flares (9).  There reports of efficacy with anakinra and worsening with infliximab.

Hyper IgD syndrome

The Hyper IgD Syndrome (HIDS) is a rare disorder that begins early in life, usually before 2 yrs of age. Most reports have been seen in those of northern European, Dutch or French ancestry (1,2,10).   HIDS has inflammatory symptoms lasting 3–7 days with recurrent fever, chills, cervical lymphadenopathy, abdominal pain, hepatosplenomegaly, diarrhea, arthralgia or arthritis, aphthous ulcers, skin rash (usually palmar/plantar) and headaches.   Vaccinations may precipitate in inflammatory attacks in some patients.  High levels of ESR, CRP, serum amyloid A are seen and IgD levels > 100 IU/dl are sensitive but not specific for HIDS. In 1999, mevalonate kinase (MVK) gene mutations were found in patients with HIDS.  Currently tests for the MVK gene are the gold standard in diagnostic testing.  HIDS is an autosomal recessive disorder with defects in the gene encoding MVK, an enzyme central to cholesterol synthesis.  Although colchicines and steroids are sometimes effective, anakinra has become the drug of choice as it has been more uniformly beneficial in observational reports (1,10).

Familial Mediterranean Fever (FMF)

FMF is the most common of the ancestral or monogenic autoinflammatory disorders (1-6).  FMF preferentially affects Sephardic Jews, Armenians, Turks, North Africans, Arabs, Moroccans and others who familial origins can be traced to the Mediterranean basin.  While the vast majority of cases will have Mediterranean roots, ancestry should not exclude this diagnosis or the need for genetic testing if the clinical picture is suggestive, as many non-Mediterranean have been diagnosed with FMF.  The disorder often begins in childhood or adolescence, and up to 20% may have their first attack after the age of 20 yrs. Younger cases usually have more striking features and severity lessens with age.  FMF is characterized by febrile episodes accompanied by cutaneous, serosal or synovial/tenosynovial inflammation.  Fevers are usually 38oC or higher and may last 1-4 days, ending as abruptly as it began.  Bouts are unpredictable in their frequency and are usually without known triggers but may be provoked by infection, stress, exercise, or surgery.  Cutaneous features are distinctive, if not pathonomonic, and manifest as unilateral, more so than bilateral, erysipelas-like erythema, that is often painful and located on the extensor surface of the arms, legs or dorsum of feet.   Also distinctive is the occurrence of recurrent inflammatory, sterile, monarticular inflammatory joint effusions or tenosynovial swelling.  Less commonly myalgia, migratory arthritis and destructive/erosive arthritis may occur.  Serositis manifests as either pleuritis or peritonitis with abdominal pain and less frequently as pericarditis or scrotal swelling.  Rare manifestations include aseptic meningitis, orchitis and vasculitis.  Laboratory findings include leukocytosis and marked elevations of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) during the attacks.  Amyloidosis may complicate FMF with serum amyloid A (SAA) deposition in the kidney or other organs.  Amyloidosis is more common with M694V homozygocity, males and the alpha/alpha serum amyloid A1 gene.  Amyloidosis is unrelated to the severity of FMF and can be diagnosed by biopsy of the rectum, kidney, abdominal fat or bone marrow. 

FMF results from a recessive mutation of the MEFV (stands for MEditerranean FeVer) gene 16p13, located on the short arm of the chromosome 16.  The zygosity and type of mutation determines the severity of the disorder and age of onset in many.  In FMF there are over 80, mostly missense, mutations with the 5 most common genotypes (M694V, M6941, M680I, V726A, E148Q) accounting for nearly 80% of cases.  The dominant mutation depends on the population; V726A is common among Ashkenazi and Iraqi Jews, Druzes and Armenians; M680I is frequent in Armenians and Turks; M694I and A744S in Arabs; and R761H in Lebanese patients.  MEFV is found in neutrophils and myeloid cells, encodes an 86kDa protein called pyrin (or marenostrin).  Defective pyrin function leads to uncontrolled inflammation with elevated levels of interferon-γ (IFNγ) and circulating proinflammatory cytokines, including TNFα, IL-1, IL-6 and IL-8.   

Many patients with FMF respond favorably to colchicine.  Colchicine is effective in both aborting and preventing attacks and when used chronically decreases the risk of amyloidosis.  Most respond well with only a minority being refractory to colchicine – either because of dose-limiting gastrointestinal toxicity or more aggressive disease. Steroids may be effective but are seldom needed.   Refractory cases respond very well to IL-1 inhibition (with anakinra, canakinumab or rilonacept) (1,10).

The diagnosis of FMF should be a largely clinical one, based on recurrent 1-4 day bouts of fever with synovial, serosal or skin inflammation and high acute phase proteins.  Confirmation by MEFV testing may be necessary in atypical cases and those evidently not of Mediterranean ancestry.

CAPS (also known as the Cryopyrinopathies)

The cryopyrin-associated periodic syndromes (CAPS) are a distinct subset of autosomal dominant disorders etiologically connected by mutations of the NACHT domain of NLRP3, previously known as Cryopyrin (1-4, 12) .  NLRP3 (stands for (NOD-like receptor family pyrin domain 3) includes the cold-induced autoinflammatory syndrome-1 (CIAS1) gene and as such much of the literature suggests that these disorders are related to CIAS1.  CIAS1 encodes for cryopyrin, a protein similar to pyrin that is also expressed primarily in neutrophils and monocytes.  CAPS includes FCAS, Muckle-Wells syndrome and NOMID (otherwise known as chronic infantile neurologic cutaneous and articular syndrome [CINCA]).  The severity of disease is milder in FCAS and MWS but tends to be the most severe in NOMID with often devastating neurological complications [41].  Common features of CAPS, regardless of the specific clinical entity, include fever, urticarial-like rash, conjunctivitis, bone and joint symptoms, and elevated inflammatory markers such as CRP. There is little/no risk of amyloidosis with chronicity.   CAPS patients have uniformly responded well to IL-1 inhibition (anakinra, rilonacept, canakinumab) ( ).

FCAS begins in infancy and is unique by being provoked by cold-exposure with brief episodes (lasting < 24 hrs) of urticarial-like rash, fever, conjunctivitis, and joint/limb pain.  Although some patients have significant disability related to these attacks, long-term prognosis is favorable for most.

MWS has an older onset (adolescents and young adults) with fevers lasting up to 7 days.  Frequent attacks and chronicity may be accompanied by sensorineural hearing loss or deafness and a long term risk of amyloidosis (12).

NOMID is the most severe form of CAPS and differs from FCAS and MWS by being chronic, rather than episodic, in its manifestations.   It is characterized by a neonatal or infantile onset of chronic urticarial rash, low grade fever, otolaryngologic findings, sensorineural hearing loss, tinnitus and later, chronic aseptic meningitis may result in cerebral atrophy, seizures, hearing and vision loss, and mental retardation.   NOMID patients may develop a distinctive overgrowth of the epiphyses in the long bones with resultant deformity, leg length discrepancy, joint contractures or premature degenerative arthritis.  Late closure of the fontanel leads to frontal bossing. Amyloidosis is a known risk and mortality may be as high as 20%.   Prior to administration of IL-1 antagonistic therapy, the prognosis for patients with NOMID was poor.  

Still’s disease

Still’s disease is another name for systemic-onset juvenile idiopathic arthritis (SoJIA) and the adult continuum of the same disease, adult-onset Still’s disease (AOSD).  AOSD (and SoJIA) are considered under the autoinflammatory syndromes as they are often confused with these disorders, share many of the same clinical features and appear to be uniquely responsive to IL-1 (or IL-6) inhibition.  Still’s disease is a systemic inflammatory disorder of unknown etiology or genetics that typically affects children under 16 yrs of age (SoJIA) or young adults from ages 18-35 years (AOSD).  The classic triad includes quotidian (daily), spiking fevers (> 39oC), the JRA or “rheumatoid” rash, and polyarthritis (13,14). The cutaneous features associated with AOSD include pruritis and urticaria (<40%), salmon-pink evanescent (changes day to day) rash usually on the trunk, neck and extremities and almost never on the face, palms or soles.  Other characteristic manifestations include a prodromal sore throat (in adults, not children), arthralgias, myalgias, rapid weight loss, serositis (pleuritis or pericarditis), generalized lymphadenopathy, hepatomegaly (often with elevated hepatic enzymes) and splenomegaly.  Laboratory tests support the inflammatory nature of the disorder with neutrophilic leukocytosis, very high ESR and CRP, anemia of chronic disease, hypoalbuminemia, and serum rheumatoid factor and antinuclear antibodies are absent.  The importance of hyperferritinemia has been overstated by most as only 50% will have elevated ferritin levels (compared with >90% ESR or CRP elevations) and extreme elevations >2000 mg/dl are seen in 10-20% of patients with active systemic disease. These features are not intermittent (as they are in TRAPS or FMF), but instead are daily and quotidian with a regular periodicity to the fever, rash, myalgias and arthralgias.

The clinical course is marked by sporadic exacerbations of systemic inflammation (fever, rash, serositis, inflammatory labs) and/or chronic inflammatory arthritis.  There are no diagnostic clinical manifestations, serologic tests or histopathologic findings and thus, the diagnosis can be based on criteria by either Cush or Yamaguchi after exclusion of common infectious or neoplastic conditions (13,14).  Persistence of symptoms (eg, fever rash, polyarthritis, hepatosplenomegaly, etc) beyond 6 weeks is necessary to consider a diagnosis of AOSD. 

There is no known etiology for AOSD or SoJIA although several groups have noted polymorphisms in either the IL-18 or IL-1 genes.  A minority of patients may respond to antiinflammatory doses of nonsteroidal antiinflammatory drugs (NSAIDs) but most will require high-dose oral corticosteroids (ie, prednisone 40-60 mg/day) with or without methotrexate or azathioprine to achieve partial control of systemic inflammatory activity.  Refractory patients or those with recurrent systemic disease have shown a remarkable response to anakinra and other IL-1 inhibitors (canakinumab, rilonacept). TNF inhibitor therapy appears is effective in patients with chronic inflammatory polyarthritis, but is less successful in managing systemic manifestations (15, 16). 

Other Autoinflammatory Disorders

PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and adenopathy),  also known as Marshall syndrome,  affects children more so than adults (from 5-35 yrs) and is predictable in the periodicity febrile attacks that last an average of 4-5 days and recur approximately every 4 weeks (17).   In the interim patients are healthy and asymptomatic.  During febrile attacks, patients manifest aphthous stomatitis, pharyngitis, tender cervical lymphadenitis, abdominal pain, nausea, vomiting and fatigue.  There is no hearing loss or amyloidosis with the PFAPA syndrome.  Treatment may include a single dose of corticosteroid, chronic cimetadine use is effective in <25%, or surgical removal of tonsils.  Some have responded to anakinra.  There is no known cause.

PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome is an autosomal dominant disorder that affects children and adolescents with recurrent pyogenic, sterile arthritis with pustular skin lesions (eg, pyoderma gangrenosum and acne fulminans, cystic acne, pathergy) but no febrile episodes (6, 18, 19).  In some the arthritis may be severe, destructive or deforming.   PAPA is the results of a missense mutation in the adapter protein proline-serine-threonine phosphatase-interacting protein (PSTPIP1) gene.  The skin lesions of PAPA have responded to TNF inhibitors as well as  IL-1 inhibitors.

PASH: triad of pyoderma gangrenosum, acne, and suppurative hidradenitis is included as an autoinflammatory syndrome that affects adults and adolescents and is similar to PAPA, but differs by having hydraadenitis supprativa without pyogenic arthritis or fevers (18).  Early results suggest these patients may respond to IL-1 inhibitors.  Gene mutations for PAPA and other autoinflammatory disorders (eg,  PSTPIP1, MEFV, NLRP3, TNFRSF1A) have been absent.  The etiology is currently unknown.

Schnitzler syndrome: is a rare disorder of unknown etiology and is thought to be an acquired autoinflammatory disorder as it typically affects older individuals (40-60 yrs). Of the over 100 cases reported, few have been seen in the USA.  Typical manifestations include non-pruritic urticaria and a monoclonal gammopathy (usually IgM kappa) with at least two of the following: periodic fever, arthralgia or arthritis, bone pain, hepatosplenomegaly, lymphadenopathy, elevated erythrocyte sedimentation rate, leukocytosis and anemia.  Other features include weight loss and pancreatitis.   Dramatic responses have been seen with anakinra treatment.  There is a rare long term risk of developing a lymphoproliferative disorder (mainly Waldenström’s macroglobulinemia) (20).

DIRA (deficiency of the IL-1 receptor antagonist [IL-1Ra]).  DIRA is a rare, inherited disease that results from a deficiency of IL-1Ra and was initially described in patients from Newfoundland, Holland, Lebanon and Brazil (21).  Lack of the IL-1Ra leads to unopposed IL-1 activity and chronic pustular skin disease.   It begins in infancy and manifests as neutrophilic/pustular skin disease, pathergy, periostitis, multifocal osteomyelitis, oral mucosal lesions, nail dystrophy, and joint/bone pain.  Labs show elevated acute phase proteins.  Radiographic changes include osteitis of the ribs and long bones, heterotopic ossification with periarticualar soft-tissue swelling.  Treatment with anakinra leads to dramatic improvement and may abort significant morbidity and mortality if recognized early.

DITRA (deficiency of the IL-36R antagonist [IL-36Ra]) is a newly recognized entity wherein a mutation in the IL-35Ra gene results in either familial or sporadic cases of generalized pustular psoriasis that responds to IL-1 inhibition (21).  It is possible that this may be related to acrodermatitis continua of Hallopeau (ACH) that manifests as chronic, pustular eruptions involving the fingertips and nails.  

Cyclic Neutropenia.  Disorder with recurrent fevers that last 5-14 days and recurs every 21-35 days and coincides with episodic neutropenia (neutrophils < 500/mm3).  Common features include fatigue, pharyngitis, oral ulcers, stomatitis, cellulitis and lymphadenopathy (22).  Such patients are at risk for infection, sepsis and   This autosomal dominant disorder results from a mutation in the neutrophil elastase gene (ELA-2 or ELANE).  Cyclic neutropenia differs from congenital neutropenia which has more profound neutropenia and greater risk of infection.  Effective treatments include granulocyte colony stimulating factor (G-CSF),  steroids and in some cases cyclosporine.

Diagnostic Approach to Periodic Febrile Disorders

Advances in our understanding of the pathogenesis and genetics of these disorders have lead to testing which may ultimately diagnose one of these rare disorders.  However, in order to pursue genetic testing clinicians need to have sufficient clinical grounds for ordering such tests.   Hence a complete clinical evaluation is necessary to characterize features that are most diagnostic.   It should be noted that while autoinflammatory disorders may have markedly elevated acute phase reactants, anemia of chronic disease, neutrophilic leukocytosis, nonspecific perivascular inflammation on skin biopsy,  negative serologic tests for autoantibodies or a clinical response to steroids, colchicines or IL-1 inhibition – these findings are nonspecific.   If a periodic fever or autoinflammatory condition is suspected, it is important to exclude possible infectious, neoplastic or autoimmune disease based on the manifestations and pattern of organ involvement.   Common adult causes of fever of unknown origin (FUO) include polymyalgia rheumatic, giant cell arteritis and other systemic necrotizing vasculitides, lupus, tuberculosis and occult infections, lymphoma, leukemia or inflammatory bowel disease.   Once these are excluded, an autoinflammatory disorder can be considered. 

The clinical features that are most predictive in making a diagnosis are : 1) the age of onset; 2) the presence, magnitude and duration of fever; 3) the duration of “attacks”; 4) rash or urticaria; 5) distinguishing features (Table 1 – eg, serositis, arthritis, organomegaly, ocular or neurologic involvement);  5) ethnicity; and 6) family history of similar illness.   Figure 1 details an algorithmic approach to patients with undiagnosed periodic fevers; initially focusing on the duration of febrile attacks and the age of the individual at onset.  Once a differential diagnosis is considered, confirmation may ensue by either an empiric trial of known effective therapy or the identification of a genetic mutation with commercially available tests.  The down-side of genetic testing is that not all patients with an apparent autoinflammatory disorder will prove to have an identifiable known genetic anomaly.  Moreover, widespread batteries of tests or screening for multiple gene mutations have not been shown to be either cost-effective or diagnostically prudent.


The autoinflammatory disorders can pose a significant challenge to pediatricians, internists, primary care physicians, dermatologists, rheumatologists and infectious disease specialists.   Affected individuals often have either dramatic clinical presentations of  FUO or puzzling episodic febrile/cutaneous disease without evidence of infection of malignancy.  The diagnosis of an autoinflammatory disorder can be made based on clinical features and supported by either genetic testing or response to IL-1 inhibition or other specific therapy.


  1. Zeft AS, Spalding SJ. Autoinflammatory syndromes: Fever is not always a sign of infection Cleve Clinic J Med 2012; 79: 569
  2. Fietta P.  Autoinflammatory diseases: the hereditary periodic fever syndromes. Acta Bio Medica Ateneo Parmense 2004; 75; 92-99
  3. Ozkurede VU, Franchi L. Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes. Clin Exp Immunol. 2012 Mar;167(3):382-90
  4. Menu P, Vince JE.  The NLRP3 inflammasome in health and disease: the good, the bad and the ugly. Clinical and Experimental Immunology, 166: 1–15
  5. Long SS. Distinguishing among prolonged, recurrent, and periodic fever syndromes: approach of a pediatric infectious diseases subspecialist.  Pediatr Clin North Am. 2005 Jun;52(3):811-35
  6. Lainka E, Bielak M, Lohse P, Timmann C, Stojanov S, von Kries R, Niehues T, Neudorf U.  Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population.  Eur J Pediatr. 2012 Dec;171(12):1775-85.
  7. Smith EJ, Allantaz F, Bennett L, Zhang D, Gao X, Wood G, Kastner DL, Punaro M, Aksentijevich I, Pascual V, Wise CA.  Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review. Curr Genomics. 2010 Nov;11(7):519-27.
  8. Toro JR, Aksentijevich I, Hull K, Dean J, Kastner DL. Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations. Arch Dermatol. 2000 Dec;136(12):1487-94.
  9. Bulua AC, Mogul DB, Aksentijevich I, Singh H, He DY, Muenz LR, Ward MM, Yarboro CH, Kastner DL, Siegel RM, Hull KM. Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study.  Arthritis Rheum. 2012 Mar;64(3):908-13.
  10. van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, Simon A; International HIDS Study Group.Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome.   Medicine (Baltimore). 2008 Nov;87(6):301-10.
  11. Hoffman H, Patel D. Genomic-based therapy: Targeting interleukin-1 for autoinflammatory diseases. Arthritis Rheum 2004;50:345-9.
  12. Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, Hansmann S, Plontke SK, Koitschev C, Koetter I, Angermair E, Benseler SM. Hearing loss in Muckle-Wells syndrome.  Arthritis Rheum. 2013 Mar;65(3):824-31
  13. Cush JJ.  Adult onset Still’s disease. Bull Rheum Dis 2000; 49(6):1-4
  14. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, Kashiwazaki S, Tanimoto K, Matsumoto Y, Ota T, et al. Preliminary criteria for classification of adult Still’s disease.  J Rheumatol. 1992 Mar;19(3):424-30.
  15.  Petryna O, Cush JJ, Efthimiou P.  IL-1 Trap rilonacept in refractory adult onset Still’s disease. Ann Rheum Dis. 2012 Dec;71(12):2056-7
  16. EfthimiouP, PetrynaO,  Mehta B,. Kontzias A, Cush J. Successful use of canakinumab in adult-onset Still’s disease refractory to short acting IL-1 inhibtors.  EULAR 2012;THU0401
  17. Kyvsgaard N, Mikkelsen T, Korsholm J, Veirum JE, Herlin T.  Periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis.  Dan Med J. 2012 Jul;59(7):A4452.
  18. Lindor NM, et al. A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc. 1997 Jul;72(7):611–5
  19. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T.  Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)–a new autoinflammatory syndrome distinct from PAPA syndrome.  J Am Acad Dermatol. 2012 Mar;66(3):409-15
  20. Besada E, Nossent H. Dramatic response to IL1-RA treatment in longstanding multidrug resistant Schnitzler’s syndrome: a case report and literature review. Clin Rheumatol. 2010 May;29(5):567-71.
  21. Cowen EW, Goldbach-Manksky R. DIRA, DITRA, and new insights into pathways of skin inflammation: What’s in a name?Arch Dermatol. 2012 March ; 148(3): 381–384
  22. Dale DC, Welte K.   Cyclic and chronic neutropenia.  Cancer Treat Res. 2011;157:97-108.

Table 1.  Autoinflammatory Syndromes: Acronyms, Meanings, Overview

Acronyms Meanings Clinical Overview
AOSD adult-onset Still’s disease Quotidian fevers >39oC, polyarthritis, rash, serositis, lymphadenopathy, organomegaly
CAPS cryopyrin-associated periodic syndromes Includes FCAS, MWS, NOMID/CINCA
CINCA  chronic infantile neurologic cutaneous and articular syndrome (same as NOMID) Severe form of CAPS with infantile onset, chronic urticaria, neurologic involvement
DIRA deficiency of the IL-1 receptor antagonist Pustular lesions, periostitis, osteomyelitis, mucosal lesions
DITRA deficiency of the IL-36R antagonist Chronic pustular psoriasis
FCAS familial cold autoinflammatory disorder Infants with cold induced fever, urticaria, conjunctivitis, joint/bone pain
FMF familial mediterranean fever Periodic fevers, red painful rash, serositis
HIDS hyperimmunoglobulinemia D syndrome Recurrent fever, cervical lymphadenopathy, abdominal pain, hepatosplenomegaly, arthralgia or arthritis, aphthous ulcers
MWS Muckle-Wells syndrome Adolescents/Adults with fever, urticaria, sensorineural hearing loss, tinnitus
NOMID neonatal-onset multisystem inflammatory disease Severe form of CAPS with infantile onset, chronic urticaria, neurologic involvement
PAPA pyogenic arthritis, acne, pyoderma gangrenosum Recurrent pustular skin lesiosn (pyoderma gangrenosum) with recurrent pyogenic, sterile arthritis
PASH pyoderma gangrenosum, acne, suppurative hidradenitis Same as PAPA without the pyogenic arthritis
PFAPA periodic fever, aphthous stomatitis, pharyngitis and adenopathy Children with monthly fevers (lasts 4 days),  aphthous stomatitis, pharyngitis, cervical lymphadenopathy, abdominal pain
SoJIA systemic-onset juvenile idiopathic arthritis Children (3-16 yrs) with quotidian fevers >39oC, polyarthritis, rash, serositis, lymphadenopathy, organomegaly
TRAPS TNF receptor associated periodic syndrome Toddlers with recurrent fever (>1 week), arthralgia, myalgia, migratory rash, abdominal pain, pleuritis, conjunctivitis, periorbital edema

Table 2. Distinctive Features among the Autoinflammatory Disorders

Disease Genetics, mutation Onset age Fever/ flare duration Muco-Cutaneous Musculoskeletal Other Significant  Findings Effective Therapy$
TRAPS* (Hibernian fever) Autosomal dominant, TNFR1 Infants, rarely adults Usually 1-3 wks Erthematous rash or dermal plaques on extremities Myalgia Arthralgia (erosive synovitis is rare) Serositis, abdominal pain, conjunctivitis periorbital edema Etanercept Anakinra
FMF* Autosomal Recessive, MEFV gene < 20 yrs in 80% of patients >39oC 1-3 days Erysipelas- like Recurrent monarthritis, tenosynovitis, arthralgias, myalgia Abdominal pain, serositis, scrotal swelling Colchicine Anakinra Rilonacept
Hyper IgD Autosomal recessive, mevalonate kinase gene < 2 yrs. 3-7 days Palmar/ plantar rash. aphthous ulcers Arthralgia Arthritis Cervical adenitis, abdominal pain, Anakinra
FCAS Autosomal dominant, NLRP3   < 1 yr. < 24 hrs Urticaria Arthralgias Cold-induced conjunctivitis Avoid cold Anakinra Rilonacept Canakinumab
Muckle-Wells* Autosomal dominant, NLRP3 Variable; infants, teens,  young adults Low-grade fever 1-3 days Erythematous rash, urticaria (sometimes cold-induced) Myalgias, arthralgias, arthritis Conjunctivitis, uveitis, sensorineural hearing loss, fatigue Anakinra Rilonacept Canakinumab
NOMID* Sporadic, NLRP3 < 1 yr Mild fevers, constant Chronic urticarial-like skin rash Arthralgia, arthritis, Bony overgrowth of epiphysis, bony hypertrophy/deformity; frontal bossing Chronic uveitis Conjunctivitis,  chronic aseptic  meningitis, sensorineural hearing loss, headaches, papilledema, optic atrophy, visual loss,  mental retardation Anakinra Rilonacept Canakinumab
AOSD & SoJIA Acquired; No known genetic link 3-35 yrs >39oC,  daily quotidian fevers Evanescent pink rash, 30-40% pruritic or urticarial Polyarthritis Polyarthralgia Myalgia Carpal anklyosis Prodromal sore throat, serositis, lymphadenopathy, hepatosplenomegaly Steroids Methotrexate Anakinra (IL-1 inhibitors)
PFAPA Unknown 5-35 years q4 wks; lasting 4-5 days Aphthous ulcerations None Pharyngitis cervical adenitis, abdominal pain Tonsillectomy Single steroid dose Cimetadine Anakinra
PAPA Autosomal dominant, PSTPIP1gene Children adolescents adults None Acne Pyoderma gangrenosum Pathergy Inflammatory arthritis mostly large joints (some erosive or deforming)   TNF inhibitors IL-1 inhibitors
Cyclic Neutropenia Autosomal dominant, Neutrophil elastase (ELA-2 or ELANE) Child to Adult 10-14 days of low grade fevers; recurs q4-6 wks oral ulcers gingivitis periodontitis recurrent cellulitis or furunculosis None Malaise, pharyngitis, lymphadenopathy, LN,ST G-CSF, Steroids

$adapted from Hoffman et al (10)

* Associated risk for amyloidosis

Abbreviations: familial mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) and cryopyrin-associated periodic syndromes (CAPS) – which includes a spectrum of disorders – familial cold autoinflammatory disorder (FCAS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID), syndrome, PAPA (pyogenic arthritis, acne, pyoderma gangrenosum), PASH (Pyoderma gangrenosum, acne, suppurative hidradenitis) syndrome, DIRA (deficiency of the IL-1 receptor antagonist [IL-1Ra]), DITRA (deficiency of the IL-36R antagonist), systemic-onset juvenile idiopathic arthritis (SoJIA), adult-onset Still’s disease (AOSD), PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenopathy)

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