Chapter 134. Systemic Autoinflammatory Diseases

This chapter focuses on the clinical and immunologic description of the currently known monogenic autoinflammatory syndromes. Most of these syndromes present with predominantly neutrophilic skin eruptions and either fever or systemic inflammation, with elevation of acute-phase reactants during the attacks. Disease-specific organ inflammation often involves the skin, serosal surfaces, the eyes, the inner ear the meninges, the bones, the gastrointestinal tract, lymphadenopathy and more rarely, the vasculature. The characteristic clinical pattern of organ-specific inflammation in the various syndromes can, in most cases, be used to make a clinical diagnosis, which is then confirmed by genetic testing. The syndromes are summarized in this chapter.

 Autoinflammatory diseases are clinical disorders marked by episodic flares of abnormally increased systemic and organ-specific inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition.1 Historically, the term autoinflammatory diseases was first applied to two periodic fever syndromes that are caused by two single gene mutations encoding molecules involved in innate immune pathways. Both disorders lack the presence of antibodies or antigen-specific T cells, which are suggestive of an adaptive immune disorder such as an autoimmune disease. Mutations in MEFV1 encoding the protein, pyrin, cause familial Mediterranean fever2,3 and mutation in the p55 TNF receptor, TNFRSF1, cause the disease previously called familial Hibernian Fever, which prompted a disease name reflecting the molecular defect: TNF receptor-associated periodic syndrome (TRAPS).4 As both disorders also present as recurrent periodic syndromes, the term hereditary (periodic) fever syndromes was used synonymously with autoinflammatory syndromes. However, the genetic discovery of single gene mutations in innate immune regulatory genes that cause episodic inflammation in disorders that do not present with fevers has led to the preference of the more inclusive term of “autoinflammatory diseases.”

 Over the last decade the number of autoinflammatory disorders increased further and the currently known monogenic autoinflammatory disorders are listed in Table 134-1.

 In 1999, the same year of the discovery of the gene causing TRAPS, hyperimmunoglobulin D with periodic fever syndrome (HIDS), another periodic fever syndrome described in the Dutch population was found to be caused by mutations in mevalonate kinase, MVK.5,6 NOD2 mutations initially described in the autosomal dominant disorder Blau syndrome were also found to cause a sporadic form of the disease, early-onset sarcoidosis,7,8 both diseases are now referred to as pediatric granulomatous arthritis (PGA). Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) is caused by mutations in PSTPIP1.9 The discovery that mutations in NLRP3 (also called CIAS1, NALP3, PYPAF1) cause the spectrum of the cryopyrinopathies, including FCAS, MWS,10 and NOMID,11,12 has not only led to the recognition of a class of novel intracellular “receptor complexes,” the NOD-like receptors (NLRs) that sense intracellular danger, but also gave key insights in the activation and role of IL-1 in coordinating an immune response not only in the cryopyrinopathies but also a wider spectrum of inflammatory conditions in which the genetic cause of the disease has not yet been discovered.13 The discovery that deficiency of IL-1 receptor antagonist (DIRA) is a new neonatal syndrome caused by increased IL-1 signaling due to absence of the inhibitor of IL-1 signaling, the IL-1 receptor antagonist, IL1RN, has further expanded the clinical spectrum of IL-1-mediated organ inflammation.14,15 The pathogenic implications of mutations in LPIN2 causing Majeed's syndrome,16 an autoinflammatory bone disease,17 are less well understood. Recently, a novel cytokine pathway causing a systemic inflammatory disease in humans was added with the discovery that the absence of signaling of the anti-inflammatory cytokine IL-10, due to a loss of function mutation in the IL-10 receptor, IL10RA or IL10RB, can clinically present with severe early-onset enterocolitis.18

 The gene discovery led to an understanding of the pathogenesis of a wider spectrum of inflammatory conditions. Inflammation in its broadest sense is the response of living organisms to exogenous and endogenous “danger” that evolved to protect organisms from harmful environmental influences with the goal to maintain homeostasis.19 The molecular mechanisms of how organisms “sense” danger are remarkably conserved during evolution and involve receptors that sense harmful exogenous triggers, for example, bacterial cell walls, or viral RNA and DNA that are called pathogen-associated molecular patterns (PAMPs), and a growing number of endogenous triggers released from, for example, dying and stressed tissues that are referred to as damage-associated molecular patterns (DAMPs).19 These molecules get recognized and signal through extracellular (TLRs) and intracellular (NLRs) receptors.20,21

 CAPS and PGA are both caused by mutations in the regulatory domain of two intracellular NLR sensors, (1) NLRP3 and (2) NOD2, respectively, the mutations leading to increased sensitivity to danger triggers and increased “danger signaling.” NLRs also form multimolecular complexes that activate immune pathways. In the case of NLRP3 the complex can activate caspase-1, an enzyme that cleaves the inactive proinflammatory cytokines IL-1 and IL-18 into their active form. The IL-1 activating complexes are called inflammasomes, and have provided a molecular link from danger recognition to the activation of IL-1 as a pivotal proinflammatory “alarm” cytokine.

 The inflammasome can be activated by a number of triggers including uric acid crystals, which led to the exploration of the role of IL-1 in gout and a growing number of inflammatory conditions that currently have no known genetic cause.22 Proof of concept studies using IL-1 blockade to treat human disease have confirmed a role for IL-1 in causing gout,23–25 in glucose control in type 2 diabetes26 and a case of Behçet's disease.27 The role of IL-1 has also been demonstrated in systemic-onset Still's disease28 and more recently PFAPA, another periodic fever syndrome presenting with aphthous stomatitis, pharyngitis, and cervical adenopathy.

+++

Epidemiology and Etiology

The spectrum of cryopyrinopathies includes (1) the familial cold autoinflammatory syndrome (FCAS; OMIM #120100),29 (2) Muckle–Wells syndrome (MWS; OMIM #191900),30 and (3) the noninherited sporadic disease neonatal-onset multisystem inflammatory disease (NOMID) also called chronic infantile neurologic, cutaneous and arthritis (CINCA) syndrome (OMIM #607115).31 These three clinical disorders were initially described as distinct disorders, but the discovery that the familial disorders FCAS and MWS and the sporadic disease NOMID/CINCA are all caused by autosomal dominant gain of function mutations in NLRP3, which is also called NALP3, CIAS1 or PYPAF110–12 led to the recognition that these disorders form a disease spectrum with FCAS on the mild and NOMID on the most severe end of the spectrum.

The prevalence of CAPS is estimated to be between 1 and 2 patients per 1,000,000 people in Europe and the United States based on known cases in centers studying these patients, but actual epidemiologic studies to assess incidence and prevalence have thus far not been conducted.

+++

Pathogenesis

NLRP3/CIAS1 encodes the protein, cryopyrin, which belongs to a family of intracellular sensor molecules, the NLRs (NOD-like receptors). Cryopyrin can associate with adaptor proteins to form a multimolecular complex called the NLRP3 inflammasome that activates caspase-1, an enzyme that cleaves pro-IL-1β into its 17-kDa active IL-1 fragment.32 Mutations in cryopyrin result in an “overactive” inflammasome that leads to higher production of active IL-1.12,33–35 The inflammasome can be activated by a number of different triggers including bacterial triggers and molecules released during cell injury or stress [such as adenosine triphosphate (ATP) and uric acid], which leads to formation and activation of the NLRP3 inflammasome and activation of caspase-1, an enzyme that cleaves the proinflammatory cytokine IL-1β into its active form.

+++

 Current Hypothesis of Mechanism

 A current hypothesis is that wild-type cryopyrin is autoinhibited by a putative conformational interaction between the LRR domain and the NACHT domain. The majority of CIAS1 mutations are thought to disrupt the inactive closed ring conformation of wild-type cryopyrin and facilitate oligomerization of cryopyrin.36 However, about 50% of patients with clinical NOMID/CINCA and a much smaller percentage of FCAS and MWS patients do not have germ-line mutations in NLRP3 in DNA isolated from peripheral blood cells; they are, however, clinically indistinguishable from the NLRP3 mutation-positive patients and therefore a diagnosis of a CAPS should not be excluded on the basis of negative genetic testing. Somatic mosaicism of NLRP3 or the involvement of other genes in the disease pathogenesis has been suggested to account for at least some mutation-negative patients.37

+++

Clinical Findings

All CAPS patients present with episodes of fever, urticaria-like eruption, conjunctivitis (Fig. 134-1H), arthralgia, and elevations in acute-phase reactants, but differ in the spectrum of multiorgan disease manifestations and in long-term morbidity and mortality.

In patients with FCAS the episodes are triggered by exposure to cold temperatures or air drafts and present with fevers, eruption, joint pain, conjunctivitis, and headaches. Typical episodes last for 12–48 hours and then resolve. The disease typically starts in early childhood.

Patients with MWS or NOMID typically present with urticaria-like eruptions at birth or within hours of birth; however, in some patients the first symptoms can present later. Patients with MWS have similar symptoms of fevers, urticaria-like eruption, joint pain, conjunctivitis, and headaches; however, in contrast to patients with FCAS, these symptoms can be continuous and are not typically precipitated by cold exposure. Episcleritis and optic disc edema are exceedingly uncommon in FCAS but are seen in some Muckle Wells patients; sensorineural hearing loss typically develops in the second to third decade of life in MWS patients.33 Patients with NOMID/CINCA present with the most severe phenotype. Often their initial presentation is thought to be neonatal sepsis as they present with fevers, urticaria-like eruption, leukocytosis, and high elevation of the acute-phase reactants around birth. Joint swelling and conjunctivitis can develop at birth but usually within the first months of life. CNS inflammation with aseptic leptomeningitis and neutrophilic pleocytosis in the cerebrospinal fluid are common. Severely affected children develop hydrocephalus (Fig. 134-1J), brain atrophy, and cognitive impairment. Patients typically develop sensorineural hearing loss within the first year of life (Fig. 134-1I), and on magnetic resonance imaging (MRI) cochlear enhancement is seen and suggests cochlear inflammation as the cause of hearing loss.35 Conjunctivitis, anterior and posterior uveitis, and subcorneal infiltrates can lead to retinal scarring, corneal clouding, and blindness. Arthralgia is common, true arthritis in most cases is very mild; however, between 50% and 70% of patients with NOMID develop characteristic bony overgrowth of the epiphyses of the long bones.38 Most commonly involved is the epiphyses of the distal femur and proximal tibia of the knee, which frequently leads to joint deformities and contractures. Other features include elevated inflammatory markers, short stature, and leukocytosis.

+++

Cutaneous Lesions

All CAPS patients present with an urticaria-like skin eruption (Figs. 134-1A and 134-1B). In most cases, the eruption is nonpruritic and is not associated with any particular sensation, but some patients describe the eruption as burning or stinging. The skin eruption is often the first noticeable disease manifestation particularly in the less severe cases and is typically considered to be allergic. The eruption is often present at birth or develops within hours of birth but in FCAS patients can also be discovered later in childhood. The eruption is migratory and nonscarring and can vary in severity from day to day and from patient to patient. A persistent livedoid or cutis marmorata pattern, in addition to the urticarial lesions that come and go, is often seen in older patients with long-standing disease. Other cutaneous manifestations can include soft, doughy palms, soles, fingers and toes (Fig. 134-1D) and clubbing of the finger (Fig. 134-1C) and toenails, without any evidence of pulmonary disease. In contrast to true familial and acquired cold urticaria, the ice cube test is negative in CAPS patients.39,40

+++

Dermatopathology

The histological features in FCAS, MWS, and NOMID are very similar and are discussed together. Histologically, the epidermis in CAPS is usually unaffected. There may be mild edema of the papillary dermis. The superficial dermal capillaries are dilated. A predominantly perivascular neutrophilic inflammatory infiltrate is present in the superficial dermis and middermis (Fig. 134-1E and 134-1F); however, there is no evidence of vascular destruction or true vasculitis and the number and appearance of mast cells is within normal limits.40–43 The eccrine glands are also surrounded and infiltrated by neutrophils (Fig. 134-1G). The histological finding of neutrophilic urticaria contrasts with the lymphocytic and eosinophilic infiltrate seen in classical urticaria and is an important clue to the diagnosis of CAPS.44

+++

Laboratory Tests and Special Tests (Including Imaging Studies)

Evidence of systemic inflammation is present with marked leukocytosis, thrombocytosis, and mild anemia of chronic disease. Elevated levels of acute-phase reactants, C-reactive protein, erythrocyte sedimentation rate and serum amyloid A (SAA) levels are typically seen. Eosinophilia can be present and is variable. Careful assessment of central nervous system disease in NOMID/CINCA is indicated. Lumbar punctures are performed in patients with NOMID to diagnose leptomeningitis and to monitor intracranial pressures and leukocytosis, which predominantly consists of neutrophils, and the elevation of protein in the cerebrospinal fluid when patients are on treatment. High-resolution gadolinium-enhanced MRI can show leptomeningeal and cochlear enhancement at various degrees in patients with NOMID. X-rays of the long bones indicate the location of epiphyseal lesions and are used to follow the bony overgrowth in patients with NOMID and MRIs of an individual lesion can be helpful to rule out bone tumors and to distinguish the presence of synovial inflammation which is usually fairly nonimpressive compared to the bony abnormalities in NOMID patients.38

Genetic testing for NLRP3/CIAS1 mutations confirms the diagnosis. Although almost all patients with FCAS and MWS are mutation positive, only 50%–60% of patients with NOMID have germ-line mutations that can be detected on genetic testing; therefore, a negative genetic test does not exclude the diagnosis of CAPS.

+++

Differential Diagnosis

In the neonate the differential diagnosis includes benign newborn eruptions, NOMID patients can present more dramatically, mimicking neonatal sepsis or congenital “TORCH” infections. Still's disease, systemic-onset juvenile idiopathic arthritis (SoJIA), and adult-onset Still's disease (AOSD) need to be considered in the differential diagnosis; although they typically do not present at birth. Patients with FCAS are often diagnosed with allergies or acquired cold urticaria. The bony lesions in NOMID patients can be painful and can initially resemble other benign or malignant bone tumors.

+++

Complications and Prognosis/Clinical Course

As treatment with IL-1 blocking agents has radically changed the outcome of these disorders, the prognosis in untreated and treated patients with CAPS differs significantly. In addition, the prognosis of the spectrum of CAPS depends on the disease phenotype. Untreated patients with FCAS usually have a good prognosis without hearing loss and the development of amyloidosis is rare. However, in a few families with cold-induced urticaria, the development of hearing loss and amyloidosis have been reported.45,46 The most severe complications of untreated MWS are hearing loss and the development of amyloidosis in up to 30% in European cohorts. Untreated NOMID/CINCA patients present with early-onset hearing loss usually in the first decade of life, develop mental retardation, progressive vision loss due to progressive optic nerve atrophy, hydrocephalus, cerebral atrophy, and children with severe bony overgrowth and the development of joint contractures can develop limb length discrepancies and severe physical disabilities.47

+++

Treatment and Prevention

Despite clinical heterogeneity, all patients with FCAS, MWS, and NOMID respond dramatically and invariably to IL-1 blockade. Studies have shown efficacy of anakinra (Kineret®, recombinant IL-1 receptor antagonist) and the long-acting drugs rilonacept (Arcalyst®, IL-1 Trap, a fusion protein of the IL-1 receptor and the Fc portion of IgG) and canakinumab (Ilaris®, IL-1β-blocking antibody) for the treatment of CAPS. All patients show rapid improvement in clinical and laboratory parameters with treatment.58–63

The drugs are generally well tolerated and these medications have now become the standard of care in the treatment of these conditions. Although anakinra has been used longer in the treatment of CAPS, rilonacept and canakinumab have undergone a development program for orphan diseases and are now FDA approved for the treatment of FCAS and MWS.48,49,64 Consistent with the clinical observations of the varied disease severity in FCAS, MWS, and NOMID/CINCA, increasing doses of IL-1-blocking agents such as anakinra are necessary to control more severe disease. Typically, subcutaneous injections of anakinra at 0.5–1.5 mg/kg/day is sufficient to suppress disease activity in FCAS patients. However, in NOMID patients doses up to 6 mg/kg/day or even 10 mg/kg/day50 have been administered to control disease.

The resolution of symptoms and the achievement of inflammatory remission not only in the blood but also in the specific organs with treatment by IL-1 inhibitors are an important proof of concept that the systemic and organ-specific inflammation seen in these disorders is dependent on IL-1β. Notably, only bony overgrowth changes progress on treatment with IL-1-blocking agents which suggests that the continuation of lesional bone growth is likely independent of IL-1.65

+++

 Epidemiology and Etiology

 DIRA (OMIM #612852) is an autosomal recessive disorder caused by loss of function mutations of the IL-1 receptor antagonist (IL1RN).14,15 The mutations in IL1RN are founder mutations that have so far been described in Newfoundland, the Netherlands, the Middle East (Lebanon), and the northern part of Puerto Rico around Arecibo. The allele frequency for the mutation could be estimated in the founder populations in Newfoundland and Northern Puerto Rico, with the allele frequencies being 0.2% in Newfoundland and 1.3% in Northern Puerto Rico.14 Therefore, in some regions of Puerto Rico the incidence of DIRA may be as high as 1 in 6,300 births.

+++

 Pathogenesis

 IL-1 receptor antagonist (IL-1Ra) competes with the proinflammatory cytokines IL-1α and IL-1β for binding sites on the IL-1 type I receptor. While IL-1α and IL-1β lead to the formation of a functional signaling complex and transmission of a signal, IL-1Ra prevents the formation of a signaling complex and acts as a negative regulator blocking IL-1 signaling. The homozygous 3′-truncation mutants of IL1RN and the genomic deletion, including the IL1RN locus seen in patients with DIRA, lead to the production of a nonfunctional IL-1 receptor antagonist protein or the absence of the protein, respectively.

 Stimulation of patients’ cells with IL-1 leads to increased production of a number of proinflammatory cytokines and chemokines including IL-6, IL-8, MIP-1-α, and TNF suggesting that IL-1 signaling cannot be blocked in these patients. The patients’ parents and healthy siblings who are heterozygous for the mutation express about half the amount of IL-1Ra compared to healthy controls but do not seem to have a clinical phenotype.

+++

 Clinical Findings

 All currently reported patients with DIRA (n = 10) presented with disease at birth or within 2.5 weeks of age. Fetal distress was present in six of ten reported patients. Pustular eruption, joint swelling, oral mucosal lesions, and pain with movement were common initial disease manifestations. The major clinical findings include pustular skin lesions (eFigs. 134-1.1A and 134-1.1B) and characteristic bone manifestations. Characteristic radiographic findings include balloon-like widening of the anterior rib ends (in all ten patients), periosteal elevation of multiple long bones, and multifocal osteolytic lesions. Less common are heterotopic ossification of the proximal femurs (eFig. 134-1.1C), widening of the clavicles (in two patients), metaphyseal erosions of the long bones (in two patients), and multiple osteolytic skull lesions. Cervical vertebral fusion secondary to collapsing vertebral osteolytic lesions as well as C1, C2 instability due to odontoid nonfusion requiring surgical stabilization were seen. One patient who had developed seizures had a magnetic resonance imaging (MRI) lesion suggesting CNS vasculitis and one patient presented with multiple episodes of thrombosis following placement of a central line. One patient developed bony overgrowth of the epiphyses of the long bones including distal and proximal tibia and femurs distal and proximal radius and humerus reminiscent of lesions seen in NOMID, these lesions remained unchanged on anakinra therapy.

+++

 Cutaneous Lesions

 The severity of the skin findings can vary widely. Cutaneous pustulosis can range from normal skin with rare individual pustules over discrete crops of pustules (eFig. 134-1.1A) to generalized severe pustulosis or ichthyosiform lesions (eFig. 134-1.1B). Oral mucosal vesicular or aphthous ulcers early in life were seen in some patients but do not seem to recur later in life. Nail changes including onychomadesis and pits were also seen in four patients.

+++

 Dermatopathology

 Histologically, the epidermal changes in DIRA are characterized by the presence of intraepidermal neutrophils and neutrophilic pustules (eFig. 134-1.1D). Marked papillary dermal edema is commonly present and may be associated with subepidermal vesiculation (eFig. 134-1.1E). An intense neutrophilic inflammatory infiltrate is present throughout the dermis and may extend to involve the superficial subcutis (eFig. 134-1.1F). Changes of frank vasculitis are absent in most patients; however, vasculitis was observed in the connective and fat tissue adjacent to bone in one patient.14

+++

 Laboratory Tests and Special Tests (Including Imaging Studies)

 Inflammatory markers including ESR and CRP in untreated patients are very elevated accompanied by leukocytosis and thrombocytosis. A skeletal survey looking for periosteitis and osteolytic bone lesions should be performed in suspected cases and bone scans may be needed. A skin biopsy can reveal characteristic neutrophilic lesions and genetic testing confirms the diagnosis.

+++

 Differential Diagnosis

 The differential diagnosis in the perinatal period includes septic osteomyelitis, DIRA can mimic congenital ichthyosiform conditions associated with immunodeficiencies, or resemble mutation-negative NOMID; however, hearing loss, conjunctivitis or other forms of eye inflammation have not yet been observed. One patient developed interstitial lung disease. The bone lesions can resemble the benign, often self-limited cortical hyperostosis.51,52 Based on skin findings, the disease has been mistaken as pustular psoriasis, which typically does not present in newborns.53

+++

 Complications and Prognosis/Clinical Course

 In untreated patients the mortality is high in the newborn period. If immunosuppressive therapy is not initiated, patients can develop a severe inflammatory response syndrome leading to multiorgan failure and death. Another patient died of cardiopulmonary complications due to chronic lung disease.14

+++

 Treatment and Prevention

 Treatment with anakinra can be life saving. Anakinra is a recombinant IL-1 receptor antagonist, the recombinant form of the protein these children are missing. In all patients, response to anakinra was immediate, leading to the resolution of clinical symptoms, including eruption and osteolytic lesions and normalization of the acute-phase reactants.14,15 Prenatal diagnosis, within areas where the disease might be common, may be indicated in order to prepare the families and care team for the diagnosis which can prevent costly and invasive workup and lead to timely treatment.

+++

Epidemiology and Etiology

Familial Mediterranean fever (FMF; OMIM #249100) is an autosomal recessive disease caused by mutations in MEFV (MEditerranean FeVer), the gene encoding the protein pyrin.2,3 FMF is the most common monogenic autoinflammatory disease. FMF is most common among populations around the Mediterranean Sea. Clinical symptoms of FMF present in most patients before the age of 20 and therefore the diagnosis is mainly made by pediatricians.

+++

 Molecular Genetics

 More than 70 mutations have been described in FMF but five founder mutations: (1) E148Q in exon 2 and (2) M680I, (3) M694V, (4) M694I, and (5) V726A in exon 10, account for 70%–80% of cases occurring in patients of Mediterranean ancestry.54 The prevalence of clinical cases with FMF varies widely but is most frequent in non-Ashkenazi Jews (~1:248 to 1:1,000),55 Armenians (~1:500), and populations of Arab (~1:2,600) and Turkish ancestry (~1:1,000).56 The carrier rate for the four most common mutations in the Jewish populations is estimated to be between 0.06 and 0.22,57 and in the Turkish population is 0.2.58,59 The high frequency of the carrier rate in some populations has led to suspicions of a selective advantage of the carrier state to a broad class of bacterial pathogens.60 Although at a much lower prevalence, FMF has been described in populations different from the classically affected ones such as Anglo-Saxons and Germans,61 Afghans,62 Indians and Chinese,61 Italians,63–65 Spanish,66 French, Greeks64,67 and Cypriots.68 The male–female ratio is about 1.5 to 2.0:1 and the higher prevalence in males is thought to be partially due to less access to medical care and a higher rate of misdiagnosis in women in some countries with the highest disease prevalence.69,70 Although single heterozygous mutation in MEFV do not typically cause disease in most patients, recent reports suggest that a number of patients with clinically typical FMF have only one identifiable mutation in MEFV and should be treated appropriately.71,72

+++

 Pathogenesis

 MEFV encodes the protein pyrin, which is composed of a PYRIN, B-box, coiled–coiled, and the B30.2 (PRYSPRY) domain. Pyrin also belongs to the human tripartite motif (TRIM) family that comprises 70 members that all share the PRYSPRY domain. The most severe mutations in FMF (M680L, T681I, and M694V/L/I) are located in exon 10 and mapped to conserved Fc-containing residues that form conserved hot spots within the B30.2 (PRYSPRY) domain.73 A similar area on TRIM5α, another member of this family, confers viral restriction to HIV and murine leukemia virus.74,75 Interestingly, the FMF mutations in some cases represent a retro-change to an ancestral haplotype seen in other species which has led to speculations that pyrin may have a role in the recognition of pathogens.76 However, the inflammatory pathways induced by mutated pyrin in FMF are not fully understood. In a murine pyrin-knockout model, increased interleukin (IL)-1 secretion is observed and the transfection of wild-type murine pyrin back into murine monocytes suppresses IL-1β production,60 which led to the hypothesis that wild-type pyrin may be anti-inflammatory. Pyrin may also act as a transcription factor as pyrin has two nuclear localization motifs.2,77 Pyrin can be cleaved by caspase-1 and cleaved pyrin can translocate to the nucleus.78 The N-terminal fragment may activate NF-κB through increased calpain-mediated degradation of IκB-α. Pyrin is also found in the cytoplasm of monocytes where it colocalizes with microtubules79 that may explain why colchicine, which can destabilize microtubules, is so effective in the treatment of FMF.80 Pyrin also interacts with ASC, the apoptosis-associated speck-like protein with a caspase-recruitment domain (CARD)—a molecule involved in the formation of an inflammasome through homotypic interactions with pyrin through its pyrin domain and with NLRP proteins and inflammatory caspases through the CARD domain.21 Pyrin's binding to ASC may lead to sequestration of ASC or its direct binding to caspase-1 may prevent formation of other functional NLR inflammasome complexes81; in both instances, the interaction would lead to a reduction of IL-1 production. Most of the disease-causing mutations in the MEFV gene have been found in the caspase-binding area of the B30.2/PRYSPRY domain, and lead to decreased pyrin binding to ASC. One hypothesis assumes that when pyrin is mutated, ASC is not sequestered and is available to assemble with cryopyrin to form the NALP3 inflammasome, which then leads to increased secretion of proinflammatory cytokines. Another hypothesis suggests that wild-type pyrin may be proinflammatory by forming an IL-1β-activating platform similar to the NLRP3 inflammasome.82 Mutant pyrin in that setting would have a further increased role of inflammasome activation. In addition, wild-type pyrin that is overexpressed in HeLa cells increases ASC speck formation and, paradoxically, increase the survival of these cells.83

+++

Clinical Findings

FMF typically presents with 1–3-day episodes of fever with serositis, which typically consists of sterile peritonitis, but pleuritis, arthritis, and eruption can also be present. The arthritis attacks can last up to 1 week. The frequency of the attacks can vary from once weekly to once every few years. Physical exertion and emotional stress can induce these attacks, but in many instances there are no obvious triggers associated with the onset of attacks. In infants, particularly children under the age of 2, fever alone can be the initially presenting feature which typically progresses to more classic features within 3 years,84 which may be complicated by the development of amyloidosis.22 Abdominal pain is the second most common clinical finding in FMF presenting at some time in over 90% of patients. The peritonitis can be severe and mimic a surgical abdomen with a rigid abdominal wall, rebound tenderness, and absent bowl sounds. Not uncommonly, FMF patients have a history of a nondiagnostic exploratory laparoscopy and/or laparotomy. Small peritoneal effusions can be seen on abdominal CT and likely present an inflammatory exudate. Pleurisy is also common and is usually unilateral. A sharp chest pain, worse on inspiration and coughing, can give a clue to the diagnosis.

Symptomatic pericarditis during the attacks occur but are rare,85,86 but on echocardiogram small, nonclinically significant effusions can be present during attacks.

Other rare clinical features of FMF include, protracted febrile myalgia, which presents with up to 6-week episodes of debilitating muscle pain, fever and elevation of acute-phase reactants but normal CK levels.87 Inflammation of the tunica vaginalis, an embryological remnant of the peritoneal membrane,88 can lead to severe scrotal pain and ischemic testicular necrosis and rarely aseptic meningitis have been seen.89

+++

Cutaneous Lesions

Erysipeloid erythema is the most characteristic eruption of FMF, but it is rarely present in isolation.90 These lesions appear on the lower limbs, usually below the knee. They tend to affect the dorsum of the foot and ankle and lower extremity. They consist of warm, tender, swollen erythematous plaques, 10–15 cm in diameter, with well-defined borders (Fig. 134-2A). The lesions may be bilateral, may be initiated by prolonged walking, and subside within 24–48 hours. Other cutaneous manifestations described in FMF include a localized edema affecting the upper or lower limbs, face, or neck, and subcutaneous nodules.91 In children, episodic scattered nonspecific purpuric papular lesions that affect the face, trunk, or extremities are more frequently observed.92 A higher incidence of vasculitic purpura, including Henoch–Schönlein purpura, has also been described in FMF patients in some case series.69

+++

Dermatopathology

Biopsies of erysipeloid skin eruptions are rarely reported; on biopsies, a perivascular and interstitial inflammatory infiltrate composed of predominantly neutrophils and lymphocytes in the dermis, with prominent edema of the papillary dermis and dilatation of superficial dermal capillaries, can be seen. The epidermal changes may include mild hyperkeratosis and acanthosis90,91 (Fig. 134-2B). In one series, direct immunofluorescence studies show deposition of complement C3 in the vessel wall of the small superficial dermal vessels in all cases and deposition of fibrinogen and IgM in some case.

+++

Laboratory Tests and Special Tests

During the inflammatory attacks nonspecific markers of inflammation, the acute-phase reactants, ESR, CRP, and SAA levels are typically elevated.93 Mild hypergammaglobulinemia including elevation of IgD, mostly in patients who are homozygous for the M694V mutations, can be seen during as well as in between attacks.94 In between the febrile attacks, elevation of the acute-phase reactants can persist—a finding that has also been observed in heterozygous carriers for the mutation.95,96 Similar to many other autoinflammatory diseases, autoantibodies to ANA, RF, and ANCA are typically not found, which initially led to the hypothesis that these disorders are caused by an innate immune defect.

+++

Differential Diagnosis

In patients with peritonitis, acute appendicitis may be suspected; however, spontaneous resolution of fever is a clue to the diagnosis of FMF. Hereditary angioedema may present with abdominal pain but usually does not cause fever. Hypertension and a pattern of dominant inheritance help to differentiate porphyria from FMF in patients with abdominal pain and fever. In children, systemic-onset juvenile idiopathic arthritis (SOJIA) is a consideration; however, an evanescent eruption, quotidian fever pattern, lymphadenopathy, and polyarthritis and the absence of abdominal pain are suggestive of SoJIA. FMF needs to be distinguished from the other familial fever disorders.

+++

Complications and Prognosis/Clinical Course

The most common and severe complication of FMF is the development of AA amyloidosis.22 Before the use of colchicine, renal failure secondary to amyloidosis was the most common cause of death in patients with FMF. Acquired amyloidosis in patients with inflammatory conditions, including FMF, is caused by deposition of a degradation product of SAA, which is an acute-phase reactant that is released during inflammation by the liver. Although AA amyloid is deposited in kidneys, the GI tract, lungs, testes, thyroid, and adrenal glands can also be affected, but the renal involvement usually dominates the clinical course.97 Amyloidosis usually presents in patients with a long-standing history of febrile attacks, it rarely can be a first manifestation of FMF.98–100

All patients with FMF should be monitored for the development of amyloidosis by following the development of proteinuria in between the febrile attacks. Renal failure typically develops 3–5 years after the onset of proteinuria. SAA levels are a sensitive measure for predicting progression of renal dysfunction in patients with amyloidosis and the therapeutic goal should be normalizing SAA levels or decreasing them at least below 10 mg per liter97 (see Chapter 133).

Risk factors for the development of amyloidosis were evaluated in a survey that collected data from 14 countries on genetically confirmed cases of FMF. The prevalence of renal amyloidosis in these patients was 11.4%. The country of recruitment—Armenia, Turkey, and Arab countries—conferred the highest risk of amyloidosis followed by homozygosity for M694V. The infant mortality rate, which can be used as a sensitive proxy indicator of population health and hygiene,101 correlated with the risk for amyloidosis suggesting an environmental impact on the development of amyloidosis. These data were strengthened by the fact that one-third of the patients currently living in countries with the lower risk of renal amyloidosis (Israel and “other” including the US) were Arabs, Turks, or Armenians, who were from ethnic groups originating from high-risk countries.102 Another factor associated with the risk of developing AA amyloidosis is an allelic variant in the SAA1 gene encoding for SAA.103,104 Deterioration of amyloid deposits was seen in patients with a median of 28 mg per liter and regression of amyloid deposits was seen in 60% of patients with a median SAA concentration of less than 10 mg per liter.

+++

Treatment and Prevention

Antipyretics are typically administered during the acute febrile attacks to lower the fever and prevent the development of febrile seizures. Colchicine is first-line treatment and is very effective in the treatment of most patients in preventing amyloidosis.105 Daily use of colchicine results in near complete remission in three-fourths of patients, with 95% noting a marked improvement. Recently, the similarity between symptomatic patients who present with two versus one mutation has been noted. Patients with only one mutation but typical disease require and respond to treatment with colchicine.106 Daily oral colchicine doses of 1.2–1.8 mg are often required for clinical effect in most adults and children over 5 years107 and younger children can be treated with lower doses. Commonly, colchicine causes diarrhea, but gradual uptitration of the dose helps to overcome this problem. Bloating and abdominal pain can also be caused by lactose intolerance that may develop in patients on colchicine. Elderly patients or those with renal impairment treated with colchicine may develop a myopathy or neuropathy.108 In patients with persistent disease, IL-1- and TNF-blocking therapies are used to treat the disease.

+++

Epidemiology and Etiology

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) (OMIM #260920) and mevalonic aciduria (OMIM #610377) are autosomal recessive disorders caused by mutations in MVK, the gene which encodes mevalonate kinase an enzyme involved in the cholesterol and isoprenoid biosynthesis pathway.5,109 The discovery that HIDS is caused by mutations in the mevalonate kinase gene led to the recognition that MA, a “classic” metabolic disorder that had previously been associated with autosomal-recessive mutations in MVK, are indeed similar disorders along a severity spectrum with HIDS on the milder and MA on the most severe side of the disease spectrum.110,111 Most patients with HIDS are of Western European (particularly Dutch and French) ancestry, suggesting a founder gene effect in these populations.109

HIDS mutations are evenly distributed along the coding region of the MVK gene, in contrast to mutations causing MA, which cluster between amino acids 243 and 334.112 Most patients carry two missense mutations and V377I which is the most common mutation in patients with HIDS, followed by mutations in I268T; these two mutations accounted for 65%–80% of the cases in two case series,112,113 including a recent cohort of 103 genetically defined patients.113 The male–female ratio was 1.5:1 and the prevalence of the disease is not known. In the recent case study, patients were contributed from 13 countries and three continents but the majority came from the Netherlands.113 The carrier frequency for the common mutation V377I mutation is 0.6% in the Dutch population and the marked underrepresentation of homozygotes for this mutation suggests that homozygotes may have a milder clinical phenotype or no clinical phenotype.114,115

+++

Pathogenesis

The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, can be examined in the patient's fibroblasts, lymphocytes, and lymphoblasts. Residual enzyme function is associated with the severity of the clinical phenotype. In most patients with MA, the enzyme activity is below the level of detection, while patients with the HIDS phenotype still have residual mevalonate kinase enzyme activity between 1% and 8% of the activities measured in normal controls.116 The metabolite mevalonic acid accumulates at higher levels in plasma, urine, and tissues in patients with the MA phenotype and no enzyme function and to low-to-moderately increased levels in patients with the HIDS presentation and residual enzyme activity. During febrile attacks, the MVK activity in peripheral blood mononuclear cells of HIDS patients drops two- to eightfold, which suggests that minor elevations in body temperature can trigger a chain of events, leading to a temporary deficiency of products which cannot be produced because of the enzyme block.117 Mevalonate kinase is the rate-limiting step in the conversion from mevalonate to mevalonate phosphate and end products of this pathway include cholesterol and a number of isoprenoids, molecules that participate in cellular processes related to cell growth and differentiation, cytoskeletal function, and vesicle trafficking.118 In peripheral blood, mononuclear cells from patients with HIDS, but not from normal controls, and the shortage of isoprenoid end products, but not the excess of mevalonate, contribute to increased IL-1β production.119 IL-1 secretion can be lowered by the addition of geranylgeranyl, suggesting that isoprenoids have an anti-inflammatory role and their lack of production during an attack further aggravates the disease.120

+++

Clinical Findings

The median disease onset ranges from the first week of life to 10 years. Episodes may occur once or twice per month and typically last 3–7 days. Prodromal symptoms such as malaise, headache, and chills are found in two-thirds of patients. A rapid rise in temperature, often over 40°C, typically follows. In 63% of cases, childhood vaccinations induce the first attack; other nonspecific triggers are physical and emotional stress. Painful lymphadenopathy accompanies the fever in 90% of patients. Axillary and inguinal lymphadenopathies are less frequent and splenomegaly occurs in one-third of patients. Gastrointestinal symptoms, including abdominal pain, vomiting, and/or diarrhea, are present in over 90% of patients, and the severity may prompt exploratory surgery, leading to the discovery of residual adhesions from past episodes of aseptic peritonitis.113 Articular symptoms are seen in over 80% of patients, and predominantly affect the large joints and metacarpophalangeal and proximal interphalangeal joints of the hands.113 Similar to HIDS, patients with MA present with febrile episodes and systemic inflammation, but other features include severe failure to thrive, lymphadenopathy, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic facies (microcephaly), cerebellar ataxia, as well as diarrhea and malabsorption.

+++

Cutaneous Lesions

Two-thirds of patients with HIDS have an eruption with the fevers. Erythematous macules, papules, and nodules ranging from 0.5 to 2.0 cm in diameter, which may be confluent or solitary in distribution, are frequently observed during attacks121 (Fig. 134-3). Petechiae and purpura are also seen during attacks.122 Oral aphthous ulcers with or without genital lesions occur in 48.5% of patients and may mimic Behçet's disease.113 MA is much more severe then HIDS, but the cutaneous manifestations are similar.122

+++

Dermatopathology

Biopsies of lesional skin reportedly show a perivascular neutrophilic and lymphocytic inflammatory infiltrate with slight leukocytoclasis and fibrinoid changes of vessel walls, consistent with leukocytoclastic vasculitis. Perivascular deposits of IgD and C3 in a granular staining pattern can be detected on direct immunofluorescence studies of skin biopsies from some of the patients.123 Sweet syndrome-like or cellulitis-like findings and deep vasculitis have also been reported. Erythema elevatum diutinum have been reported in association with HIDS.124,125

+++

Laboratory Tests and Special Tests

The diagnosis of HIDS is usually suspected clinically, but the definitive diagnosis is made by genetic testing. During the attacks, patients usually have elevated acute-phase reactants. Most patients have a persistently elevated serum IgD level (>100 U/mL), and in 82% of cases the serum IgA was likewise elevated121 with median concentrations for IgD being 400 U/mL.113 Between attacks some patients continue to have elevations of the acute-phase reactants. Although the elevation of IgD is not specific for HIDS and can be normal in genetically proven cases, it is often a helpful clue in considering the diagnosis.

+++

Differential Diagnosis

The diagnosis of HIDS is often delayed by a median of 9.9 years after onset of symptoms. The differential diagnoses include other forms of hereditary fever syndromes including FMF. However, FMF does not present with lymphadenopathy or oral ulcers, and HIDS attacks do not respond to colchicine. In patients with prominent oral and genital ulcers, the disease can mimic Behçet's disease. Other erroneous diagnoses include adult-onset Still's disease, juvenile idiopathic arthritis, rheumatic fever, and chronic infection.113 MVK deficiency can mimic congenital infections, myelodysplastic syndromes, or chronic leukemia, and emphasizes the importance of considering a broad differential in patients with hematologic abnormalities.126

+++

Complications and Prognosis/Clinical Course

Long-term consequences of inadequately treated disease included amyloidosis in less than 3%, joint contractures, abdominal adhesions in ~10%. School children with HIDS miss more school days and adults have higher rates of discharges from their jobs and a higher rate of unemployment in comparison to the control population.113

+++

Treatment and Prevention

NSAIDs are administered for fever and arthralgia. Short courses of corticosteroids may be effective in some patients, but colchicine is ineffective. Based on the assumption that mevalonate accumulation is pathogenic, simvastatin, an HMG-CoA reductase inhibitor, was given to six patients, of whom five had a nonstatistically significant decrease in the number of febrile days.127 In 80% of patients in whom anticytokine therapy with either anti-IL-1 or anti-TNF agents was offered, benefit was observed. One patient with severe MA was treated with an allogeneic bone marrow transplant and achieved complete inflammatory remission.128

+++

Epidemiology and Etiology

Pyogenic arthritis, pyoderma gangrenosum and cystic acne (PAPA) syndrome (OMIM #604416) is a very rare autosomal dominant disorder characterized by pyogenic arthritis, pyoderma gangrenosum and cystic acne, and is caused by mutation in CD2BP1, a gene on chromosome 15q24.129

+++

Pathogenesis

PAPA syndrome is caused by mutations in CD2BP1 that encodes proline-serine-threonine-phosphatase-interacting protein 1 (PSTPIP1). PSTPIP1 undergoes phosphorylation by PTP-PEST, a protein tyrosine phosphatase. In its phosphorylated form, PSTPIP1 cannot bind to pyrin. Mutations in PSTPIP1 prevent its phosphorylation and lead to a prolonged binding to pyrin. It is hypothesized that mutations in the CD2BP1 gene result in production of a hyperphosphorylated protein that binds excessively to pyrin, and that the PSTPIP1/pyrin complex prevents the inhibitory function of pyrin on the NLRP3 inflammasome, which would lead to increased IL-1β production and inflammation.9,82,130,131

+++

Clinical Findings

The clinical manifestations of this disorder include pyoderma gangrenosum, cystic acne, and pyogenic sterile arthritis.9 Arthritis first begins in the first decade of life and may be triggered by episodes of mild trauma; the arthritis can be progressively destructive. Pyoderma gangrenosum lesions often occur at sites of injury. Nodulocytic acne can cause scarring if untreated. The recurrent sterile arthritis usually occurs after minor trauma, but may also occur spontaneously. PAPA attacks can be self-limiting or chronic, which can then lead to joint destruction and joint deformities.129

+++

Cutaneous Lesions

Dermatologic manifestations include pyoderma gangrenosum (Fig. 134-4A) and acne conglobata (nodulocystic acne of the face and trunk) (Fig. 134-4B). The acne begins in childhood or adolescence and persists into adulthood.131 The pyoderma gangrenosum lesions start as violaceous nodules, usually on the legs, resulting in poorly healing ulcers with undermined rolled edges.

+++

Dermatopathology

Biopsies of lesional skin of pyoderma gangrenosum show a predominance of neutrophilic inflammatory infiltrate in the dermis and superficial ulceration. Biopsies of acne conglobata are characterized by burrowing and interconnecting abscesses and scars.

+++

Laboratory Tests and Special Tests

Elevations of acute-phase reactants are seen during the acute attacks and can be persistently elevated in patients with more chronic lesions. The diagnosis is established by genetic testing. Cultures of the skin and joint lesions from these patients are sterile.

+++

Differential Diagnosis

Pyoderma gangrenosum is primarily a clinical diagnosis, after excluding other causes of ulcers such as infection. The histologic differential for pyogenic granuloma may include infectious causes of abscesses and other diseases with neutrophils in the dermis such as Sweet syndrome.

+++

Treatment and Prevention

Treatment of pyoderma gangrenosum is challenging since it is not responsive to antibiotics and only responds partially to systemic glucocorticosteroids and immunosuppressive therapies. Treatment with infliximab132,133 or anakinra134 has been effective in treating the skin and joint findings in these patients.

+++

 History

 Large families of Irish–Scottish ancestry with an autosomal dominant periodic fever condition complicated by amyloidosis were initially described in 1982; the disease was then called familial Hibernian Fever. However, as there were other smaller families with autosomal dominant conditions of other Northern European ancestry that were confirmed to have the same disease with the discovery of genetic mutation in TNFRSF1A, the disease was then called TRAPS indicating its molecular origin. TNFRSF1A mutations have since been found in patients of diverse ethnic backgrounds including Swedish, German, Finnish, Dutch, Austrian, African-American, Puerto Rican, Belgian, Dutch, Portuguese, Italian, Arabic, Czech, and Mexican.135

+++

Epidemiology and Etiology

TNF receptor-associated periodic syndrome (TRAPS) (OMIM #191190) is an autosomal dominantly inherited disease caused by mutations in TNFRSF1A, the gene located on chromosome 12p13 that encodes the 55-kDa TNF receptor 1.4 The reported incidence is 5.6 per 10,000,000 person-years.136 Male to female ratio is 1.5:1.135

+++

Pathogenesis

More than 50 mutations in TNFRS1A have been described in patients with clinical disease. Most are missense mutations, leading to cysteine substitutions in the extracellular domain of the TNF receptor.137–139 Mutations resulting in loss of a cysteine residue correlate with clinically more severe disease and a higher risk of amyloidosis.141

Most of the mutations are single nucleotide missense mutations occurring within exons 2, 3, and 4. The TNF type 1 receptor or p55 receptor is expressed on leukocytes and endothelial cells. The extracellular domain of the receptor is composed of four cysteine-rich domains (CRD), each containing six cysteine residues that form three intradomain disulfide bridges in each CRD.140 Nearly all TRAPS mutations are found in the first two CDRs at the N-terminal region of the receptor. The interpretation of noncysteine substitutions in TNFRSF1A has been more difficult, as some substitutions such as the P46L variant occur in up to 20% of clinically asymptomatic individuals in a West African population, which suggests that this variant in this population represents a polymorphism rather than a disease-causing mutation. The presence of another TNFRSF1A variant, R92Q, did not correlate with the TRAPS phenotype, although it was associated with heterogeneous clinical inflammatory symptoms suggesting a reduced penetrance variant that may play a role in a wider clinical spectrum of inflammatory disorders.142,143 Despite the known genetic defect, the mechanism of disease pathogenesis remains incompletely understood. In some patients, delayed TNF receptor cleavage from cells may account for an increased signaling through the TNF receptor; however, the majority of patients do not have receptor shedding defects,143,144 which led to the search for other pathways. Interestingly, most mutations in the TNF receptor affect receptor folding and trafficking, resulting in the retention of misfolded TNF receptor complexes in the endoplasmic reticulum and the presence of only the wild-type receptor on the cell surface.145,146 This phenomenon was examined in a mouse knockin model confirming that the mutant TNFR1 receptor can no longer oligomerize with wild-type receptor molecules but rather forms disulfide-linked homooligomers that can bind TNF with high affinity but not on the cell surface. Mutant receptors accumulate in the endoplasmic reticulum within the cells and LPS stimulation of these cells leads to enhanced activation of mitogen-activated protein kinases (MAPKs) and secretion of proinflammatory cytokines upon stimulation with the bacterial cell wall component, lipopolysaccharide (LPS).147 The presence of an intact TNF receptor on the cell surface is necessary in this model to from an autocrine loop between mutated TNFR1 signaling in the endoplasmic reticulum and wild-type TNF receptor on the cell surface receiving a TNF signal.147 These findings provide a rationale as to why the disease is inherited in an autosomal dominant manner and also offer an explanation regarding the partial response to TNF blockade.148 In one report, NF-κB activation may in fact be decreased in response to TNF stimulation of leucocytes from patients with TRAPS.151 This was not seen in response to LPS or IFN-γ suggesting that there may be an alternative stimulus other than TNF that is responsible for the previously observed activation of NF-κB.

Cytokines other than TNF have also been implicated in the disease. Patients with TRAPS have increased NF-κB activation, the major signaling molecule involved in the secretion of proinflammatory cytokines; they also have higher than expected levels of functional TNFR1 at the cell surface.149 Interestingly, some TRAPS patients have an exaggerated inflammatory response to treatment with infliximab.150

+++

Clinical Findings

The median age of onset is 3 years with initial presentation ranging from 2 weeks to 53 years of age.135 TRAPS attacks present with fever, disabling myalgia, skin eruption, serositis (pleuritic and abdominal pain), arthritis, and eye involvement. Attacks last on average 21 days per month and occur every 5–6 weeks; however, there is considerable variability in the length and the time between attacks. An early sign of an impending attack often is a “deep” muscle cramping that increases in severity over 1–3 days and then remains severe for more than 3 days before the symptoms gradually resolve. A minority of patients present with daily symptoms that vary in severity. Although the actual trigger for an attack is often unknown, physical and emotional trauma and menstruation can be associated with attacks. Pregnancy may be associated with amelioration. Fevers of between 38°C and 41°C for more than 3 days usually precede other inflammatory symptoms. Fever is invariably seen in pediatric patients but may be absent during some attacks in adults.

The involved areas often move centrally and the tissues over the involved muscles are warm, tender to palpation, and erythematous. Other findings include arthralgia and frank synovitis. The arthritis is nonerosive, asymmetric, and monoarticular, and affects primarily large joints including the hips, knees, or ankles. Tenosynovitis of flexor and extensors also occurs and is not confined to febrile episodes.

Abdominal pain is present in more than 90% of patients. Often, fever and abdominal pain are the only manifestations of a clinical attack of TRAPS. Patients can present with vomiting and constipation, suggestive of bowel obstruction, and the abdominal findings can present as an acute abdomen leading to laparotomy and appendectomy without histologic evidence of inflammation. The presence of intra-abdominal adhesion on laparotomy and a mononuclear infiltrate on tissue biopsies from resected bowel suggest peritonitis and some mucosal inflammation.

More than 80% of patients present with conjunctivitis and/or periorbital edema. Lymphadenopathy, if observed, is usually limited to a single anatomical location. Severe uveitis and iritis may be seen. Chest pain may be either musculoskeletal or pleuritic and was present in 57% in one large cohort.135

+++

Cutaneous Lesions

Over 80% of patients present with skin eruptions during the attacks. Patients often present with periorbital edema (Fig. 134-5A). The most characteristic cutaneous manifestation is a centrifugal migratory, erythematous patch (Figs. 134-5B and 134-5C), which typically migrates from the periphery to the center of the body. The tissue overlying the local area of myalgia is often tender to palpation, warm and erythematous and blanchable.152 Some patients present with diffuse erythema of cheeks and confluent salmon-pink-colored macules and papules or mottled erythema of the chest, abdomen, and extremities.153

+++

Dermatopathology/Histopathology

Microscopic evaluation of lesional skin shows a mild perivascular lymphocytic inflammatory infiltrate in the dermis and edema of the upper dermis, and may reveal slight C3 and C4 deposition around the small vessels in the dermis.153 A fascia/muscle biopsy shows normal myofibril architecture without evidence of inflammation, but extensive acute and chronic inflammation of the surrounding connective tissue, including panniculitis, fasciitis, and perivascular chronic inflammation.154

+++

Laboratory Tests and Special Tests

Elevations of acute-phase reactants are seen during the acute attack, including elevation of erythrocyte sedimentation rate, C-reactive protein, haptoglobin, fibrinogen, and ferritin. A large percentage of patients also demonstrate an elevated acute-phase response between clinically symptomatic attacks. Anemia of chronic disease is seen in patients with long-standing elevation of acute-phase reactants and most patients demonstrate a polyclonal gammopathy. MRI of affected muscle groups reveals focal areas of edema in discrete muscular compartments and intramuscular septa myalgia.154 As seen with the other diseases, autoantibodies, including antinuclear antibodies and rheumatoid factor, are typically negative.

+++

Differential Diagnosis

TRAPS can mimic other autoinflammatory disorders and the diagnosis needs to be made by genetic testing. TRAPS can also mimic SoJIA or AOSD, but the characteristic migratory, erythematous eruption with underlying myalgia and periorbital edema seen in TRAPS are not seen in SoJIA or AOSD. The quotidian fever pattern observed in SoJIA/AOSD has also not been seen in TRAPS.

+++

Complications and Prognosis/Clinical Course

Similar to descriptions in the FMF section, systemic AA amyloidosis and the development of renal failure is the most severe complication of TRAPS (Figs. 134-5D–134-5F). As in FMF, all patients, particularly those with cysteine mutations, need to be closely monitored for the development of proteinuria. The majority of patients with kidney involvement develop nephritic syndrome and ultimately renal failure.

Amyloidosis is common among families with the C30R, C52F, and C88R mutations and is uncommon in patients from families with the C33Y, T50M, and C88R mutations.135,143

+++

Treatment and Prevention

Nonsteroidal anti-inflammatory drugs may be sufficient to treat mild attacks. Corticosteroids suppress the attacks, but the steroid requirement may increase over time and is associated with considerable side effects. Colchicine is not effective in treating TRAPS symptoms nor in the prevention of amyloidosis. Etanercept, the p75 TNF receptor fusion protein, suggests a favorable clinical response.135,155–158 In patients at risk of amyloidosis, tailoring the dose of anticytokine therapy to lower SAA levels in an attempt to prevent the development of amyloidosis is indicated. Anakinra has been reported to be successfully used in some therapy-resistant cases and is often considered before using anti-TNF agents.159,160

+++

 Epidemiology and Etiology

 Pediatric granulomatous arthritis (OMIM #186580) is a unifying term for either Blau syndrome (OMIM #186580),161,162 a familial form, and early-onset sarcoidosis, a sporadic form.163,164 Both begin in early childhood, are characterized by arthritis, recurrent uveitis, and a typical skin eruption, and result from mutations in NOD2.165,166 The disease affects young children of both genders without ethnic or racial predilection.161,165,166

+++

 Pathogenesis

 Blau syndrome and early-onset sarcoidosis are NOD2-gene-associated chronic autoinflammatory diseases. The NOD2 gene is located on chromosome 16q12 and is highly expressed in antigen-presenting cells.167 The downstream responses of NOD2 activation are incompletely characterized but include activation of NF-kB and mitogen-activated protein kinase (MAPK), both signaling pathways that upregulate levels of antimicrobial peptides, proinflammatory cytokines, and chemokines.8

+++

 Moelecular Pathogenesis

 The NOD2 gene encodes a protein belonging to the family of intracellular NLR receptors with an NACHT and leucine-rich repeat (LRR) domain involved in pathogen recognition and innate immune responses.168 Patients with Blau syndrome and early-onset sarcoidosis have mutations in the NACHT domain (exon 4) of the NOD2 gene.7,8,163,169,170 In vitro NOD2 can be triggered by peptidoglycan components from the cell wall of Gram-positive and Gram-negative bacteria, such as muramyl dipeptide. Similar to the pathogenic model of mutations in the NACHT domain of NLRP3 in CAPS, mutations in the NACHT domain of NOD2 are postulated to cause constitutive activation of the NOD2 inflammasome. Most patients with PGA have the R334W and R334Q encoding mutations. Others described in the cohort include E383K, R587C, C495Y, and W490L.164

+++

 Clinical Findings

 Patients typically present before 4 years of age with a tan, scaly, ichthyosiform eruption and symmetric polyarticular arthritis (eFig. 134-5.1B) or tenosynovitis. Ocular findings, including recurrent bilateral uveitis, conjunctivitis, synechiae, cataracts, and glaucoma, and can be seen later in the course of the disease. In one series of 45 mutation-positive patients, 88% of affected patients displayed the classic dermatitis, whereas 41% had severe visual impairment.170 On physical examination, lymphadenopathy, hepatosplenomegaly, and salivary gland involvement have been reported. Mild-to-moderate fever episodes occur in ~15% of patients. Other rare disease manifestations include pneumonitis, acute pulmonary embolism, acute pericarditis, asymptomatic arterial hypertension, granulomatous glomerulonephritis, chronic renal insufficiency, and cranial neuropathy.164,171

+++

 Cutaneous Lesions

 Skin lesions most commonly described as a scaly, erythematous, maculopapular eruption covering much of the trunks and extremities (eFig. 134-5.1A); this pattern is rarely seen among adult sarcoidosis patients.172,173 Individual lesions appears as small (1–2 mm) red–brown to pinkish tan, flat-topped papules that are closely grouped in oval clusters and linear arrays.174 Panniculitis in the form of erythema nodosum and leukocytoclastic vasculitis was also reported in some patients with early-onset sarcoidosis.8,164

+++

 Dermatopathology/Histopathology

 A skin biopsy is required to confirm the diagnosis of sarcoidosis. Biopsy of the skin papule shows nonnecrotizing well-demarcated granulomas in the dermis with relatively few lymphoid cells around the epithelioid histiocytes and with negative tests for microorganisms (eFig. 134-5.1D). The granulomas are composed of multinucleated histiocytes admixed with scattered inflammatory cells.174 Histologically, it is difficult to distinguish these diseases from sarcoidosis. The histologic differential for sarcoidosis includes various causes of granulomatous dermatitis such as lupus vulgaris, granulomatous inflammatory reaction to foreign body, granulomatous rosacea, late secondary syphilis, and tuberculoid leprosy. Nonnecrotizing granulomatous have been reported in lymph nodes and liver biopsies.164

+++

 Laboratory Tests and Special Tests

 Serum and blood tests show persistent leukocytosis with a predominance of polymorphonuclear cells, moderate thromobocytosis, and increased erythrocyte sedimentation rate and acute-phase protein plasma levels.171 There is no specific test for sarcoidosis; it is a diagnosis of exclusion, especially after excluding infectious causes of granulomas. Genetic testing for NOD2 mutations should be performed in suspected cases to confirm the diagnosis.

+++

 Differential Diagnosis

 The differential diagnoses include sarcoidosis, various granulomatous inflammatory processes such as infection, foreign body granulomas, and granulomatous rosacea. Early in life, patients are often misdiagnosed as oligoarticular juvenile idiopathic arthritis (JIA); however, an early clue is the absence of antinuclear antibodies that is often present in young JIA patients with severe eye manifestations.

+++

 Complications and Prognosis/Clinical Course

 Chronic synovitis can lead to progressive camptodactyly and other joint contractures. Chronic uveitis, if untreated, can lead to the development posterior synechiae and vision loss. Visual impairment in Blau syndrome seems to be more associated with R334W mutations.175

+++

 Treatment and Prevention

 The less severely affected patients may respond to NSAIDS, methotrexate, and cyclosporine,171 whereas the more severely affected patients may require systemic corticosteroid treatment.161 Positive responses to anti-TNF therapy165,171,176 have also been reported; however, the treatment of ocular disease can be challenging and worsening uveitis has been reported in patients on anti-TNF therapy.165 More recently, interleukin-1 (IL-1)-blocking agents, such as anakinra, have successfully been used to treat individual cases of PGA.171 In some cases, thalidomide has been useful in controlling the disease.177

+++

 Epidemiololy and Etiology

 Majeed syndrome (OMIM #609628) is a rare, autosomal-recessive autoinflammatory disorder first reported in 1989. The original report described members of a consanguineous Arab family presenting with chronic recurrent multifocal osteomyelitis (CRMO), congenital dyserythropoietic anemia (CDA), and neutrophilic dermatosis.178 The syndrome is very rare and the reported families are so far all from the Middle East. Majeed syndrome results from mutations in the LPIN2 gene, encoding the protein lipin-2.

+++

 Clinical Findings

 Majeed syndrome is a rare infantile form of chronic recurrent multifocal osteomyelitis (CRMO). In contrast to other patient with CRMO, Majeed syndrome patients also present with congenital dyserythropoietic anemia (CDA) that presents as hypochromic, microcytic anemia, and the severity can range from mild to transfusion-dependent.

+++

 Cutaneous Lesions

 Inflammatory dermatosis can manifest as Sweet syndrome (neutrophilic dermatosis), psoriasis, and pustulosis. Patients can also develop erythematous plaques with small vesicles on the face, trunk, and extremities. Skin lesions range in size between 0.5 and 4 cm, were itchy, and had a serosanguineous discharge. The surface of the large lesions was studded with vesicles.178

+++

 Dermatopathology

 Biopsy of inflammatory skin lesions usually shows neutrophilic infiltrate in the dermis with edema of the papillary dermis similar to biopsies of Sweet syndrome and no histologic evidence of vasculitis.182

+++

 Laboratory Tests and Special Tests

 Laboratory testing is not specific. Cultures from blood, bone marrow, and skin are always negative for microorganisms. Routine complete blood count (CBC) is used to diagnose and follow the anemia. Molecular testing mutations in LPIN2 gene in those patients who meet the clinical diagnostic criteria can be useful to confirm or establish the diagnosis in a proband. Radiographs show osteolytic lesions with surrounding sclerosis. Bone biopsies are necessary to exclude infectious osteomyelitis; however, bone and blood cultures are typically sterile.

+++

 Differential Diagnosis

 The differential diagnoses include infectious osteomyelitis as well as bone tumors. The histologic differential may include neutrophilic dermatoses such as Sweet syndrome, leukocytoclastic vasculitis, or infection.

+++

 Treatment and Prevention

 CRMO can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), or with corticosteroids if nonresponsive to NSAIDs. Bisphosphonates and anti-TNF agents have been used in other patients with CRMO.179 CDA can be treated with red blood cell transfusion if clinically indicated.

+++

 Epidemiology and Etiology

 IL-10 receptor deficiency is a rare disease and so far has only been described in four patients, two siblings of Turkish, one patient of Lebanese, and one patient of German origin. The incidence and prevalence of this disease is unknown. The disease is caused by homozygous missense mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins that form a functional IL-10 receptor.18

+++

 Pathogenesis

 Interleukin-10 is an anti-inflammatory cytokine that is secreted by a wide variety of cells, and has immunoregulatory effects on T cells, B cells, myeloid cells, and other cell types.180 IL-10 limits the secretion of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-12. IL-10 signals through the IL-10 receptor, which consists of two components (IL10R1 or IL10Ra and IL10R2 or IL10Rb also CRFB4)181 The IL10R2 subunit of the IL-10 receptor is also a subunit for the interleukin-22 and interleukin-26 receptors.182,183 The described missense mutations lead to loss of function of the IL-10 receptor and therefore IL-10 cannot signal, which leads to increased production of the proinflammatory cytokines including TNF-α; interleukin-1α, -1β, -2, and -6; and chemokines RANTES; MIP-1α and MIP-1β. Mice deficient in either interleukin-10 receptor 1 or interleukin-10 receptor 2 also present with severe enterocolitis.184

+++

 Clinical Findings

 All described patients presented before the age of 12 months with severe enterocolitis and enteric fistulas, perianal abscesses, proctitis and abscesses in the perianal region, developed early in life. The enterocolitis responds poorly to treatment with corticosteroids, TNF inhibitors, azathioprine, and surgical resection. Heterozygous carriers for the mutations did not have a clinical phenotype.18

+++

 Cutaneous Findings and Histopathology

 The patients can also present with early-onset folliculitis, enterocutaneous fistulas, or perianal abscess and anocutaneous fistulas.18

+++

 Laboratory Tests and Special Tests

 In patients with the suspected diagnosis, genetic testing should be performed.

+++

 Treatment and Prevention

 Treatment modalities to treat Crohn's disease have been used and one severely affected child went into complete remission after and allogeneic bone marrow transplant. The folliculitis and inflammatory anal fistulas resolved shortly after allogeneic hematopoietic stem-cell transplantation.18