periodic fever

What is periodic fever syndrome

Periodic fever syndromes are a group of diseases characterized by recurrent episodes of fever with healthy intervals between febrile episodes 1). Periodic fever syndromes are self-limited and improve spontaneously without specific therapy. Episodes of fever are usually associated with presence of inflammation in different parts of the body such as peritoneum, pleural spaces, testis, etc. with elevated serum acute phase reactants level 2). These diseases should be differentiated from infections, malignancies and other autoimmune disorders 3). Existence of family history of periodic fever and prolonged illnesses are diagnostic clues of periodic fever syndrome. Arthritis or arthralgia, abdominal or chest pain due to serositis, skin rash, and oral ulcers are other common presentations of periodic fever syndromes, although these symptoms can be found in infectious diseases with prolonged or recurrent fever 4). Headache, seizure, aseptic meningitis, development delay as well as adenopathy, organomegaly and cardiac involvement are uncommon findings in periodic fever syndrome. Renal involvement is uncommon but in some types, renal failure due to amyloidosis may occur.

Periodic fever is named when there are 3 episodes of fever in at least 3-6 months with 7 days asymptomatic period between each episode 5). Rarely, periodic fever syndrome without fever has been reported 6). In this situation, one of the other symptoms is repeated periodically. For this reason, experts believe that periodic fever should be considered as a diagnosis in a patient, who shows similar problem repeatedly. Some periodic fever syndromes occur in regular intervals especially periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) and cyclic neutropenia, however, Familial Mediterranean Fever (FMF) and hyperimmunoglobulin D (hyper IgD) generally have regular patterns. On the other hand, auto-inflammatory syndromes in infancy such as chronic infantile neurologic cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome, familial cold urticaria and tumor necrosis factor receptor–associated periodic syndrome (TRAPS) usually have irregular patterns 7).

The first manifestation of periodic fever syndromes are present in childhood and adolescence, but infrequently it may be presented in young and middle ages. Genetic base has been known for all types of periodic fever syndromes except periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). Common periodic fever disorders are Familial Mediterranean fever (FMF) and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). In each patient with periodic fever, acquired infection with chronic and periodic nature should be ruled out.

At least eight hereditary periodic fever syndromes have been known so far which are common in fever with cutaneous manifestations, and musculoskeletal involvement 8), each of them having specific characteristics. Fever and symptoms occur due to the increment of inflammation which is caused by mutation in genes. Most of these disorders result from gene mutations that cause defect in production of some proteins which have important role in control of inflammation and apoptosis.

Usually there are symptoms of the disease for a long time prior to the definite diagnosis. Mostly fever attacks start during childhood, but sometimes they may start in adolescence or in adulthood. Clinical examinations are helpful for diagnosis which is confirmed by specific genetic testing 9).

Periodic fever syndrome causes

Periodic fever syndrome disorders are categorized under the term monogenic auto-inflammatory syndromes. The characteristic of these disorders is episodic attacks of systemic inflammations without presence of infection or auto-antibodies 10). The pathogenesis of periodic fever syndrome disorders is disregulation of inflammation control due to mutations of genes coding for some proteins with regulation role 11). It has been believed that dysregulation of innate immune response and abnormalities in activity of interleukin-1 and pro-inflammatory cytokines may contribute to fever production and systemic inflammation 12). Innate immune cells such as macrophages, neutrophils, and monocytes are involved 13). Unlike adaptive immunity, innate immunity is programmed genetically 14) and most of these diseases are caused by mutation in genes which make proteins participant in inflammatory response 15).

It is thought that mutate proteins lead to increased or prolonged secretion of pro-inflammatory cytokines 16). Activation of caspase-1 and the release of IL-1β are the end point of pathophysiologic cycle of these disorders 17). Treatment with anti-IL1 drugs is mandatory 18).

Table 1. Characteristics of classic periodic fever and cryopyrin associated periodic syndromes (CAPS)

Autoinflmatory disorderCharacteristics
Hyper IgD
  • Hereditary periodic fever syndromes with good prognosis.

  • Clinical presentation is not specific and diagnosis is based on detection of gene mutation.

  • Recurrent fever with migratory muscle spasms with or without transient blanching erythematous skin lesions.

  • Genetic assessment is necessary for definite diagnosis.

  • Recurrent fever, relapsing arthritis, urticaria, chronic meningitis and brain atrophy.

  • Anti interlukine-1 drugs control the symptoms effectively

  • Fever, limb pain, recurrent urticaria-like lesions, conjunctivitis and deafness.

  • Canakinumab was very effective in patients (complete remission).

Familial Cold
  • Mildest disease of CAPS, clinical symptoms occur after exposure to cold.

  • Fever, arthralgia, conjunctivitis, non-itching urticarial like rash, and headache.

  • Treatment with anakinra before exposure to cold may be effective in prevention of inflammatory symptoms

Abbreviations: IgD = Immunoglobulin D; TRAPS = Tumor Necrosis Factor Receptor–Associated Periodic Syndrome; CINCA = Chronic Infantile Neurologic Cutaneous and Articular Syndrome; NOMID = Neonatal Onset Multisystem Inflammatory Disease; CAPS = Cryopyrin Associated Periodic Syndromes

[Source 19) ]

Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) or recurrent hereditary polyserositis is the most common disease among hereditary periodic fever syndromes, and it is an autosomal recessive disorder 20).

Familial Mediterranean Fever is seen most frequently in people from Mediterranean area such as Jews, Arabs, Turks and Armenians, but it is sometimes reported from all over the world. Prevalence of familial mediterranean fever is 1:200 to 1:1000 21). Although familial mediterranean fever is a autosomal receive disorders, positive family history is present in less than 50% of patients 22). Familial Mediterranean Fever is slightly more common in women perhaps due to the influence of sex hormones. Sometimes fever attacks disappear in pregnancy and return after delivery. Rarely infertility may occur due to defect in ovulation and adhesion in pelvic peritoneum. Some complications of familial mediterranean fever such as renal amyloidosis are more common in males 23).

Familial Mediterranean Fever (FMF) is characterized by periodic fever that occasionally occurs at regular intervals, usually with neutrophil induced serositis. The responsible gene for the disease is MEFV that is located on short arm of chromosome 16 24). This gene produces a protein called Pyrin or Marenostrin that is found in neutrophils and plays an important role in reduction of inflammation 25). Mutation in this gene leads to defection in production of these proteins and onset of inflammatory cycle. In addition to gene mutation, environmental factors are important and in many patients there is a trigger factor such as emotional stress, infection, extreme physical exercise, fatigue, trauma and menses 26).

Familial Mediterranean Fever Treatment

The drug of choice for Familial Mediterranean Fever (FMF) is colchicine that is also used for prevention. It is recommended to use this drug for a long time. A minority group of patients do not respond to colchicine may be due to non-adherence 27). Starting dose is 1mg/day and it may be increased to 1.5 to 2 mg/day until remission is achieved 28). Based on weight or body surface area, the colchicine dose is 0.03±0.02 mg/kg/day and 1.16±0.45 mg/m2/day, respectively[8]. In children younger than 5 years, higher doses of colchicine, 0.07 mg/kg/day or 1.9 mg/m2/day, may be required 29). The most common side effects of colchicine are diarrhea and nausea which are seen rarely. Fetal malformation from colchicine has not been reported 30).

In colchicine resistance cases interferon-alpha may be helpful 31). In patients with incomplete remission with colchicine, or in whom amyloid A level is high despite treatment with colchicine, IL1 blockade (Anakinra) may be effective 32). Other drugs such as NSAIDs and corticosteroids have limited indication for treatment of FMF. Myalgia responds to treatment with corticosteroids, but not colchicines. NSAIDs are used for treatment of arthralgia 33). Febrile attacks do not respond to and are not preventable by NSAIDs or steroids.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA)

Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA) is a syndrome that consists of recurrent episodes of fever, sore throat, mouth sores and swelling of the glands in the neck. The frequency of PFAPA is not known, but the disease appears to be more common than originally thought, and may be the most common recurrent fever (autoinflammatory) syndrome that does not come from an infection. Both males and females and all ethnic groups can develop PFAPA. Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA) usually starts in early childhood, between the ages of two to five years. Occasionally PFAPA may develop at an older age, including rare cases in adults.

Clinical criteria of Periodic Fever, Aphthus stomatitis, Pharyngitis, Cervical Adenitis (PFAPA)

  1. Regulatory recurring fevers with an early age of onset (<5 years of age)
  2. Symptoms in the absence of upper respiratory tract infection with at least one of the following clinical signs:
    • a) aphthous stomatitis
    • b) cervical lymphadenitis
    • c) pharyngitis
  3. Exclusion of cyclic neutropenia, completely asymptomatic interval between episodes, normal growth and development.

It is not yet known what causes Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis (PFAPA). No gene defect has yet to be found in PFAPA, although sometimes more than one family member has the disease and a history of a tonsillectomy (surgical removal of the tonsils) may be reported among family members. No infection has been found in PFAPA, and it is not a contagious disease. It is clear that the inflammatory process is active during episodes, but it is not clear why this happens.

There are no laboratory tests specific for diagnosing PFAPA. The disease is diagnosed based on symptoms and physical examination. White blood cell counts and markers of inflammation including the sedimentation rate and the C-reactive protein, all of which can be measured with a blood test, increase during episodes. It is important to exclude all other diseases that may present with similar symptoms (especially a Streptococcus infection) before confirming the diagnosis. The dramatic response to treatment with steroids also helps diagnose PFAPA. In cases without a classic presentation it may be necessary to exclude other causes of recurrent fever (see other patient sheets on this topic), especially if symptoms start in the first year of life and markers of inflammation are increased also between episodes.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis Treatment

The aim of the treatment will be to control symptoms during the episodes of fever, to shorten the duration of the episodes, and to prevent episodes from occurring. The fever usually does not respond well to acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil or Motrin). A single dose of steroids (usually prednisone or prednisolone), given when the symptoms first start, dramatically shortens, and often even ends, the episode. However, the time between episodes also may be shortened with this treatment, and the next episode may occur earlier than expected.

Medications like cimetidine and colchicine, when used regularly, may prevent future episodes in about a third (cimetidine) to half (colchicine) of the children. Several studies have found that a tonsillectomy (removing the tonsils by surgery) cures PFAPA in the majority of patients (more than 80%) but the role and timing of surgery in treating PFAPA has still not been fully clarified. Alternatives to steroids should be considered in patients needing steroids more frequently than once every three – four weeks.

Hyperimmunoglobulin D syndrome

Hyperimmunoglobulin D syndrome or mevalonate kinase deficiency is a hereditary periodic fever syndrome that occurs in unpredictable intervals[2-4]. Dutch-type periodic fever is another name for this autosomal recessive disorder 34).

First cases of hyperimmunoglobulin D syndrome were reported in Dutch population in 1984 but later several patients were reported from other countries and in other races 35). Hyperimmunoglobulin D syndrome usually starts in childhood and 70% of patients are younger than 1 year old at the beginning of the disease 36). Sometimes fever attacks are stimu-lated with immunization, trauma, and stress 37).

Hyperimmunoglobulin D syndrome results from a mutation in a gene which is located on chromosome 12q24 and encodes mevalonate kinase (MVK) enzyme 38). Mevalonate kinase (MVK) enzyme contributes to cholesterol synthesis and it has an anti-inflammatory effect 39). Mutated enzyme has a decreased function with a pro-inflammatory response 40).

The typical symptoms of hyperimmunoglobulin D syndrome are fever, malaise, chills, cervical lymphadenopathy, and diarrhea. Abdominal pain, arthritis or arthralgia, skin rash, and hepatosplenomegaly are other signs 41). Fever and other symptoms resolve after 3 to 7 days with an afebrile interval lasting 6-8 weeks, but skin rash and arthritis may last longer 42). Arthritis in hyperimmunoglobulin D syndrome is transient and non-destructive 43).

Hyperimmunoglobulin D syndrome treatment

There are no absolutely effective drugs for treatment of hyperimmunoglobulin D syndrome, thalidomide, etanercept (anti-tumor necrosis factor), and corticosteroids are used successfully in some patients, but efficacy of these drugs is doubt-ful 44). Anti interleukine-1 (IL-1) (anakinra or canakinumab) has been effective in severe cases unresponsive to other treatments 45).

Prognosis of hyperimmunoglobulin D syndrome is excellent even without treatment 46) and amyloidosis is very rare in these patients 47). Episodes of fever decreases by aging 48).

Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS)

Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) or familial Hibernian fever  49), is an autosomal dominant disease that occurs in irregular intervals and is characterized by episodes of fever, pain in muscle groups and painful skin lesions on trunk or extremi-ties 50).

For the first time, TRAPS was described in a large Irish family, but then it was reported in all countries 51). The male to female ratio is 3:2 52) or 1:1 53) and Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) is more common in Caucasians and Arabs but less common in Indians[20]. This syndrome has been reported in patients 2 weeks to 53 years of age 54).

The cause of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) is mutation in the gene that encodes the type 1 TNF receptor 55). The gene is TNFRSF1A and is located on chromosome 12p13.2 56). TNFR1 is a trans-membrane receptor and the main mediator of signaling by TNF-α 57). As binding of TNF-α to mutate TNFR1 lessens, as a result, TNF induced apoptosis decreases 58). Consequently, following increase the activity of TNF, inflammatory response enhances 59).

Similar to other periodic syndromes, fever is the main symptom in children, in adults attack may be without fever 60). Fever duration in Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) usually is longer than in other periodic fever syndromes such as Familial Mediterranean Fever (FMF) or in hyperimmunoglobulin D syndrome and it may last up to 3 weeks 61).

Interval between fever episodes has variable frequency but in average it occurs every 5 to 6 weeks 62). The onset of the disease occurs along with fever and muscular spasm 63). No known triggers for the onset of the illness are identified 64). The muscle pain is migratory and affected muscles are tender in palpation and warm 65). This finding is usually associated with erythematous patches that are warm and tender and are resolved with pressure 66). Other symptoms of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) are abdominal pain (due to inflammation in peritoneal cavity or muscular cramp in abdominal wall) that is seen in 92% of patients, conjunctivitis or periorbital edema, which is a characteristic for TRAPS and is seen in over 80% of patients, chest pain (in 57% of patients), and arthralgia. Other less common symptoms are arthritis, scrotal pain and lymphadenopathy 67).

Tumor Necrosis Factor Receptor–Associated Periodic Syndrome Treatment

Non steroidal anti inflammatory drugs (NSAIDs) are used for treatment of fever but musculoskeletal and abdominal pain do not respond to NSAIDs, so they should be treated with corticosteroids; neither of these drugs can prevent episodes 68). Etanercept is an anti-TNF agent that decreases severity, duration, and frequency of the attacks 69). Treatment with anakinra, which is an IL-1 blocker, may be also effective 70). Treatment with infliximab, an anti-TNF antibody, may lead to paradoxical inflammatory reactions, so it should not be used 71).

The most severe complication of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) is amyloidosis that occurs in less than 25% of untreated patients and manifests with dysfunction of involved organs 72). So, prognosis of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) is related to subsequent amyloidosis 73). Risk of amyloidosis increases in mutation that affects cysteine amino acids 74).

Cryopyrin Associated Periodic Syndromes (CAPS)

Cryopyrin Associated Periodic Syndromes (CAPS) refer to a group of diseases which have similar phenotypes all of which result from mutation in the CIAS1 (cold-induced autoinflammatory syndrome) gene, which encodes cryopyrin 75). This protein regulates generation of pro-inflammatory cytokines[2,29]. Chronic infantile neurologic cutaneous and articular syndrome (CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS), which will be explained respectively, belong to cryopyrin associated periodic syndromes (CAPS). These syndromes usually have overlapping symptoms the severity of which are affected by other genetic mutations and environmental factors 76).

After ruling out infection and malignancies, auto-inflammatory disorders should be considered. However, physician needs to reevaluate each patient with periodic disorder for non-inflammatory syndromes.

Chronic infantile neurologic cutaneous and articular syndrome

Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is the most severe one among the cryopyrin associated periodic syndromes[30]. These syndromes occur in all ethnic groups without any superiority 77). Chronic infantile neurologic cutaneous and articular (CINCA) syndrome that is also named neonatal onset multisystem inflammatory disease (NOMID) is a congenital inflammatory disorder that starts in neonatal period and it has various symptoms such as recurrent fever, central nervous system (brain and spinal cord) involvement, cutaneous manifestations, chronic arthropathy, and morphologic feature 78). Skin manifestations which are the first presentation at birth in 75% of patients, are similar to urticaria and vary during the day 79). Urticaria is stimulated with cold. Central nervous system involvement exists in almost all patients and hydrocephalus and ventriculomegaly may be present prenatally 80). Neurologic manifestations result from chronic meningitis and brain atrophy, and include seizure, sensory organ involvement such as ocular manifestations, progressive sensory neural hearing loss, and headache. Mental retardation exists in some patients 81) but it is not an initial manifestation 82). Relapsing joint involvement is also seen in CINCA patients 83) and severity of arthropathy is related to the age of onset, i.e. patients with a later onset have milder manifestations without destruction 84). Knees are the most common involved joints and then ankles, feet, and elbows 85). Patients with CINCA have a typical morphology. They have a short stature, macrocephalus, hoarseness, saddle nose, short extremities, and clubbing 86).

Diagnosis of CINCA is based on the above mentioned specific features 87). Triad of continuous rash, CNS involvement, and relapsing joint involvement is helpful for diagnosis but this syndrome should be differentiated from other hereditary periodic fever syndromes such as Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS), and hyperimmunoglobulin D syndrome.

The majority of these syndromes occur sporadically 88) but there is a mutation in the CIAS1 (now named NLRP3) gene on chromosome 1q44 89) that encodes the cryopyrin protein in 60% of patients 90). However, this mutation can be found in two other syndromes including Muckle-Wells Syndrome (MWS) and Familial Cold Autoinflammatory Syndrome (FCAS) 91).

Treatment with anti IL-1 drugs especially with anakinra is effective in CINCA and results in significant improvement in symptoms of the disease 92). Nonsteroidal anti-inflammatory drugs and glucocorticosteroids are effective on fever and pain but not on skin lesions 93).

Muckle-Wells Syndrome

Muckle-Wells Syndrome (MWS) also called urticarial deafness amyloidosis syndrome, is a rare autosomal dominant syndrome 94). It is of middle severity between Cryopyrin Associated Periodic Syndromes (CAPS). Episodes of this syndrome are presented with fever, limb pain, recurrent or sub-chronic urticaria-like lesions and conjunctivitis. Episcleritis and optic disc edema are other eye related findings 95). Fever is usually mild and disappears in 12 to 36 hours 96). Two-thirds of patients have sensory neural hearing loss that usually starts in the second decade of life 97). Amyloidosis occurs in one-fourth of patients which can lead to renal failure[36] and peripheral neuropathy that occurs later than renal amyloidosis 98). Unlike other Cryopyrin Associated Periodic Syndromes (CAPS), urticarial rash is not always stimulated with cold 99). The time of onset is during infancy and sometimes in adolescence. Lifelong arthralgia and non-erosive arthritis may exist[34]. There is a mutation in NLRP3 gene in MWS as in other CAPS, but some mutations are typically found in Muckle-Wells syndrome 100). Incidence of CAPS syndromes is not subject to sex 101).

Three anti-IL-1 drugs including anakinra (an IL-1 receptor antagonist), rilonacept (an IL-1 soluble receptor), and canakinumab (a human monoclonal antibody against IL-1β) are effective on CAPS. Canakinumab and rilonacept have FDA approval for treatment of Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) 102). Treatment with canakinumab was very effective and in 96% of patients complete remission was achieved 103). Studies show that treatment cannot eradicate existing damages but hearing loss may return 104).

Familial Cold Autoinflammatory Syndrome

Familial Cold Autoinflammatory Syndrome (FCAS), formerly called familial cold urticaria, is the mildest CAPS disease 105). As other Cryopyrin Associated Periodic Syndromes (CAPS), FCAS is inherited in an autosomal dominant fashion 106). Familial Cold Autoinflammatory Syndrome (FCAS) usually begins before 6 months of age 107) and in 60% of patients symptoms are seen during the first days of life 108). Clinical symptoms occur within 8 hours 109) after generalized exposure to cold 110) and last for 12 to 48 hours 111). Fever, arthralgia, conjunctivitis, non-itching urticarial like rash, and headache are indicators of familial cold autoinflammatory syndrome (FCAS) 112). There are no signs of CNS involvement 113). Audiology symptoms and deafness is absent 114). Localized exposure to cold is not a trigger in this disease and it distinguishes familial cold autoinflammatory syndrome from acquired cold urticaria 115).

Treatment with anakinra before exposure to cold may be effective in prevention of inflammatory symptoms 116). Moving to warm places is recommended to these patients 117). In all three diseases of CAPS, treatment with anakinra is effective 118). Rilonacept and canakinumab as long acting IL1 blockers have been approved by FDA for treatment of familial cold autoinflammatory syndrome and Muckle-Wells syndrome 119). Long time prognosis of familial cold autoinflammatory syndrome is good and amyloidosis is uncommon 120).

Autoinflammatory Bone Disorders

Autoinflammatory Bone Disorders are a group of autoinflammatory disorders with sterile bone inflammation as a hallmark finding. Some of the disorders of this group are monogenic such as pyogenic arthritis, pyoderma gangraenosum and acne (PAPA) syndrome, the deficiency of IL-1 receptor antagonist (DIRA) and Majeed syndrome (or familial chronic multifocal osteomyelitis). Some other sterile osteitises have polygenic background or are without specific genetic basis, so these disorders are classified as sporadic group,. In which chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are also classified 121).

Pyogenic arthritis, Pyoderma gangaenosum and Acne (PAPA) syndrome

Pyogenic arthritis, Pyoderma gangaenosum and Acne (PAPA) syndrome is a rare autosomal-dominant disease that characterizes with sterile inflammation in joints and cutaneous manifestation. The cause of the disease is mutation in PSTPIP1 (proline/serine/threonine phosphatase–interacting protein 1) located on chromosome 15q24-25 122). This gene produces a protein that mostly exists in hematopoietic cells and regulates T cell activation, cytoskeletal organization and releases of interleukin-1B (IL-1B). Mutation in this gene leads to dysregulation of IL-1B production 77 and macrophages. Pyogenic arthritis, Pyoderma gangaenosum and Acne (PAPA) syndrome patients have impaired invasive motility 77 and might have dysregulated apoptosis 123).

Two major manifestations of Pyogenic arthritis, Pyoderma gangaenosum and Acne (PAPA) syndrome are erosive arthritis and cutaneous syndromes both of which start in childhood. Joints involvement is recurrent, sterile and destructive and may develop spontaneously or after minor trauma. Skin symptoms of the disease are severe acne, recurrent non healing sterile ulcer called pyoderma gangraenosum and pathergy.

For treatment, the disease responds well to TNFα blockers such as Infliximab, adalimumab and anakinra. Some new immunosuppressive drugs may also be used to treat PAPA syndrome.

Majeed Syndrome

Majeed Syndrome is an autosomal recessive disease caused from a mutation in LPIN243. Majeed Syndrome was firstly reported in 1989 124). Majeed syndrome is a chronic disease which affects the whole life and is characterized by early onset of multifocal osteomyelitis. Other features of Majeed syndrome are congenital anemia and transient inflammatory dermatosis which result from infiltration of neutrophils into dermis and is called Sweet syndrome. Diagnosis is suspected based on clinical manifestations and is confirmed with genetical studies 125). Treatment of the disease includes non-steroidal anti-inflammatory drugs eventually in combination with corticosteroids or interferon-α.

Deficiency of the Interlukin-1 Receptor Antagonist

Deficiency of the IL-1 receptor antagonist (DIRA) is a new TNF-receptor-associated periodic syndrome which was primarily described in 2009 126). Deficiency of the IL-1 receptor antagonist (DIRA) results from mutation in the IL1RN (2q14) 127). It is an autosomal recessive disease. Signs of the disease usually start in prenatal period and include systemic inflammation, multifocal osteolytic lesions, periostitis, and a pustular rash. Other manifestations are heterotopic bone formation around the proximal femur, thrombosis, and rarely vasculitis. Some manifestations which are seen in Neonatal Onset Multisystem Inflammatory Disease (NOMID) but not in deficiency of the Interlukin-1 Receptor Antagonist (DIRA) are meningitis, cochlear inflammation, hearing loss, and conjunctivitis or uveitis. Deficiency of the interlukin-1 receptor antagonist (DIRA) patients have a good response to treatment with the recombinant interlukin-1 receptor antagonist anakinra 128).

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome or Chronic Recurrent Multifocal Osteomyelitis (CRMO)

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome and Chronic Recurrent Multifocal Osteomyelitis (CRMO) are chronic nonbacterial or sterile osteomyelitises due to an auto-inflammatory process. Some authorities believe this disorders are different diseases with similar pathway and they have common clinical, radiological and maybe histological findings 129). Innate immune system is involved and any auto-antibodies or autoreactive T-cells have not been fouind in these disorders. SAPHO is usually described in adult patients with similar symptoms of spondylarthropathies 130). Vertebral bone is the most common site of involvement and it may lead to vertebral collapse. In SAPHO syndrome, skin involvement such as acne and pustulosis is prominent. CRMO is suggested to be a variant of SAPHO syndrome in children 131), but in CRMO skin manifestations are rare findings 132). Exacerbations and remissions of the inflammation is a hallmark for differentiation of these disorders from similar disorders. Increasing number of lesions over the time and self-limiting course without major sequelae are other characteristics. The patients present symptoms of CRMO at school age that include bone lesions. One fourth of the patients had spinal involvement and half of them developed vertebral deformities 133).

Treatment is based on NSAIDs and/or corticosteroids. In cases with resistance to these drugs methotrexate, sulfasalazine, and TNF inhibitors are used. CRMO is usually self-limited but a large number of patients experience a prolonged disease 134). In patients with bone lesions, treatment with bisphosphonates and pamidronate may be helpful and pain resolves 3 months after treatment 135). MRI is the most sensitive way of diagnosing bone lesions and finding those lesions that are not observed in a simple radiography.

SWEET’s Syndrome

In 1964, Sweet described a syndrome with fever and neutrophilic dermatitis 136). Three types of disease were described by Cohen and Kurzrock 137). Malignancy-associated form can be associated with hematologic malignancy (such as acute leukemia) and solid tumors. It can be first manifestation of a malignant disorder or first presentation of recurrent malignancy. Second form is classical form which usually is seen following a respiratory or gastrointestinal infection, pregnancy or rheumatologic disorders (such as irritable bowel disease, systemic lupus erythematosus, Behcet’s disease, FMF and Sarcoidosis) 138). Third form of Sweet’s syndrome is drug induced following antibiotics (trimethoprim-sulfamethoxazole, nitrofurantoin), NSAIDs (celecoxib and diclofenac), antiepileptics (diazepam and carbamazepine), antihypertensives (hydralazine), oral contraceptives, propylthiouracil and retinoids 139).

Pathogenesis of this syndrome is unknown. Some Cytokines (such as Interleukin 1, TNF-alpha, IL-8, IL-17), human leukocyte antigen serotypes have a possible role in the pathogenesis of this syndrome 140). The innate immune is involved in this syndrome, so recently it is classified as a autoinflmmatory disorder 141).

Clinical features of this syndrome are a recurrent and acute illness with high fever, peripheral neutrophillia, and skin involvement such as erythematous plaques, erythema nodosum and ulcers. Other manifestations are general malaise, headache, and myalgia, arthralgia, and conjunctivitis 142). Central nervous system (aseptic meningitis), kidneys, intestines, liver, heart, and lungs may be involved 143). Diagnostic criteria for classic and drug-induced Sweet syndrome is shown in Table 2. Criteria for malignancy-associated Sweet’s syndrome are similar to classic Sweet’s syndrome.

In histopathology, diffuse and neutrophil-rich infiltrate is seen in the dermis 144). There is usually no evidence of vasculitis (fibrin deposition or neutrophils) in the vessel wall 145).

There are some reports on successful treatment of Sweet’s syndrome with antibiotics, oral potassium iodide, NSAIDs and colchicines; oral corticosteroids or metylprednolone pulse is very useful in patients with refractory disease 146). Other treatments are infusion of intravenous immunoglobulin and biologic agents such as anakinra and anti TNF-α agants 147).

Table 2. Diagnostic criteria for classic and drug-induced Sweet’s syndrome

Classical Sweet’s syndrome
Major Criteria (both are mandatory)

  • Abrupt onset of painful erythematous plaques or nodules.

  • Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis.

Minor Criteria

  • Pyrexia: Temp>38°C.

  • Association with an underlying hematologic or visceral malignancy, inflammatory disease, pregnancy, or preceded by an upper respiratory or gastrointestinal infection or vaccination.

  • Excellent response to treatment with systemic corticosteroids or potassium iodide.

  • Abnormal laboratory findings (3 of 4):

ESR>20mm/hr / positive CRP / WBC>8000 /Neutrophilia > 70%.

  • Abrupt onset of painful erythematous plaques or nodules.

  • Histopathologic evidence of a dense neutrophilic infiltrate.

  • Pyrexia: T>38°C.

  • Temporal relationship between drug ingestion and clinical presentation, or temporally related recurrence after oral challenge.

  • Temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.

Footnote: Diagnosis of classic Sweet’s syndrome is confirmed by 2 major criteria and two of the four minor criteria but for diagnosis of drug-induced Sweet’s syndrome all five criteria are mandatory.

Blau Syndrome

Blau syndrome or “juvenile systemic granulomatosis” 148) or early onset sarcoidosis 149) was reported for the first time in 1985 150). It is a rare disease related to mutation in the CARD15/NOD2 gene localized on chromosome 16q12 151). The disease is autosomal dominant and begins in early childhood usually before 4 years of age 152).

The first episode of Blau syndrome is in the first 2 years of age with continuous attack 153). The most common sites of this syndrome are skin, joints and eyes but not lungs or hilar lymph nodes. Skin lesions which are rarely seen in sarcoidosis in adults include brown colored scaly maculopapules with tapioca-like appearance which are lichenoid-like. Another skin manifestation is erythema nodosum 154). Destructive arthritis and tendinitis are other manifestations of musculoskeletal involvement 155). Pneumonitis, eye involvement (uveitis and iritis) and involvement of other organs such as liver and kidney is seen in this syndrome 156). Characteristic feature of the disease is non-caseating granulomatous lesions involving joints, skin and eyes that lead to symmetric polyarthritis and cataract in 50% of patients. Differentiation of Blau syndrome from sarcoidosis based on histological findings is difficult but clinical symptoms are clearly different 157).

Treatment options for Blau syndrome are corticosteroids, immunosuppressant drugs (such as methotrexate and cyclosporine), infliximab or anakinra 158).

Periodic fever syndrome symptoms

Periodic fever syndromes are a group of diseases characterized by episodes of fever with healthy intervals between febrile episodes. These disorders are self-limited and improve spontaneously without specific therapy. Episodes of fever are usually associated with presence of inflammation in different parts of the body such as peritoneum, pleural spaces, testis, etc. with elevated serum acute phase reactants level. Periodic fever syndromes should be differentiated from infections, cancers and other autoimmune disorders 159).

Periodic fever syndrome diagnosis

In a patient with periodic fever, acquired infection with chronic and periodic nature should be ruled out. It depends on epidemiology of infectious diseases. Malaria and borrelliosis can be ruled out by evaluation of peripheral blood smear and brucellosis and Lyme disease can be excluded by serological studies or blood culture. In children, urinary tract infection may present as a periodic disorder, so urine analysis and culture are mandatory in a child with periodic symptoms 160). Some malignancies such as leukemia and tumoral lesions should be excluded in patients with periodic syndromes and weight loss in any age and weight gain disorder or malaise in children 161). For this reason, abdominal ultrasound and chest X-ray are necessary and bone marrow aspiration in selected patients is recommended. Table 2 shows paraclinical evaluation in suspected patients with periodic fever syndromes.

After ruling out infection and malignancies, auto-inflammatory disorders should be considered. However, physician needs to reevaluate each patient with periodic disorder for non-inflammatory syndromes. Hyper IgD, Chronic Infantile Neurologic Cutaneous and Articular Syndrome (CINCA syndrome), Tumor Necrosis Factor Receptor–Associated Periodic Syndrome (TRAPS) and other auto-inflammatory syndromes are other causes of periodic fever disorders. Figure 1 and Figure 2 show clinical approach to periodic fever patients, based on the epidemiology of periodic fever in the country.

To establish diagnosis in autoinflammatory disorders is very difficult because there are no definite diagnostic criteria or a gold standard, so it depends on both clinical findings and genetic study to get the diagnosis confirmed (Table 1) 162). All patients usually have a history of repeated hospitalizations and antibiotic therapy. It is due to similar symptoms and signs in autoinflammatory disorders and infectious diseases, immuno-deficiency and/or hematologic disorders. So in each patient, these disorders, especially infectious diseases, should be ruled out 163).

Table 3. Laboratory tests for patients with periodic fever

Study IndicationTime
CBC, ESR, CRPAll patientsAt least 2 times in febrile and afebrile period
Chest X-rayAll patientsIn febrile period
Abdominal ultrasoundAll patientsIn febrile period
Serum IgsAll patientsNo difference
Wright, Coombs-WrightIn endemic regionAt least once in febrile period
EBV serologyAll patients with sore throat and lymphadenopathyIn febrile period
Peripheral blood smearIn endemic regionAt least once in febrile period
Blood cultureAll patientsAt least once in febrile period
Throat cultureAll patients with sore throatIn febrile period
Urine analysis and cultureAll childrenAt least once in febrile period
Stool examAll childrenAt least once, no difference
Bone marrow aspirationIn selected patients with cytopenia, bone pain, weight loss, abdominal and/or mediastinal adenopathyNo difference
Liver function testsAll patientsAt least once in febrile period
FANAAll childrenAt least once, no difference

Abbreviations: CBC = Complete Blood Cells; ESR = Erythrocyte Sedimentation Rate; CRP: C = Reactive Protein; Ig: Immunoglobulin; EBV = Epstein Barr Virus; FANA = Fluorescent Antinuclear Antibody Test

[Source 164) ]

Figure 1. First step to diagnosing Periodic Fever

First step to diagnosing Periodic Fever

Abbreviations: CBC = Complete Blood Cells; ESR = Erythrocyte Sedimentation Rate; CRP = C-Reactive Protein

[Source 165) ]

Figure 2. Second step to diagnosing Periodic Fever

Second step to diagnosing Periodic FeverSecond step to diagnosing Periodic Fever

Abbreviations: FMF = Familial Mediterranean Fever; PFAPA = Periodic Fever, Aphthus stomatitis, Pharyngitis, Cervical Adenitis; U/A = Urinaly sis; BUN = Blood Urea Nitrogen; Cr = Creatinine; ESR = Erythrocyte Sedimentation Rate; CRP = C – Reactive Protein; IgD = Hyperimmunoglobulin D; TRAPS = Tumor Necrosis Factor Receptor–Associated Periodic Syndrome; CINCA = Chronic Infantile Neurologic Cutaneous and Articular Syndrome

[Source 166) ]

Periodic fever syndrome treatment

Treatment options depend on the underlying cause of the periodic fever.

References   [ + ]