Chapter 209. Autoinflammatory Disorders

Autoinflammatory syndromes, formerly known as periodic fever syndromes, are defined as recurrent attacks of often unprovoked systemic inflammation that are related to a lack of adequate regulation of the innate immune system.1-3 Unlike autoimmune diseases, these conditions are not generally marked by autoantibodies or autoreactive T cells. Many of these syndromes have a genetic etiology3,4 (eTable 209.1) involving the excessive production and activity of interleukin (IL)-1β.5 The conditions are no longer known as periodic fever syndromes, 6-8 because most are not truly periodic nor is fever a necessary feature.

As understanding of the pathogenesis of autoinflammatory syndromes increases, so does the spectrum of conditions that may be included within this category. Thus, systemic juvenile idiopathic arthritis, genetic inflammatory granulomatous diseases (early onset sarcoidosis and Blau syndrome) and Behçet disease (eTable 209.2) are now considered to be autoinflammatory disorders, although this chapter will be limited to conditions that do not fall into other diagnostic categories.

These syndromes should be suspected in patients, mainly young children, with recurrent fever unexplained by infections and/or with episodic symptoms in various systems, especially the skin, gastrointestinal tract, joints, and eyes. A complete history and physical examination are crucial, and often careful determination of the organ systems involved, age of onset, length of attacks, intervals between attacks, and triggering events will allow the correct diagnosis to be suspected before genetic tests are performed (Tables 209-1 and 209-2). It is very useful to examine patients during an attack or if not possible, to ask parents to record attacks carefully in a diary and send pictures of relevant physical findings.

Autoinflammatory syndromes also should be considered in patients with unexplained elevations of acute phase reactants, even in the absence of symptoms. It is also useful to measure markers of inflammation during and between attacks, as in some syndromes attacks are only the “tip of the inflammatory iceberg” and patients consistently have increased inflammatory indices. These patients are at higher risk of developing amyloid A (AA) amyloidosis, the major adverse outcome of the autoinflammatory syndromes (eTable 209.2). A family history often reveals relatives with similar symptoms, including unexplained cases of renal failure or amyloidosis. Specific autoinflammatory syndromes often show a predilection for certain ethnic groups.

Familial Mediterranean fever (FMF), first described in 1945, is the most common inherited autoinflammatory syndrome.9 It is an autosomal recessive disorder that results in recurrent attacks of fever, serositis, arthritis, and rash. Late complications of untreated FMF include the development of renal AA amyloidosis leading to the nephrotic syndrome and renal failure. The highest prevalence of FMF is in Sephardic Jews, Armenians, Arabs, and Turks. Because of the availability of genetic diagnosis, FMF is now recognized more frequently among Ashkenazi Jews, Greeks, and Italians as well.10,11 A national study in Turkey found a prevalence of 0.093%.12The prevalence of FMF among Sephardic Jews varies from 1:100 to 1:2000 (carrier rate of 1:5 to 1:45) and 1:87 to 1:1000 (carrier rate 1:7 to 1:32) among Armenians.13,14

Pathophysiology and Genetics

The familial Mediterranean fever gene (MEFV) has been localized to the short arm of chromosome 16.15-17 The product of this gene is a 781 amino acid protein termed pyrin (marenostrin in Europe). There may be a phenotype–genotype correlation with more severe disease and amyloidosis occurring in patients with the M694V, M694I, and M680I mutations.18 However, not all patients have homozygous or compound heterozygous pyrin mutations. In various series, between 30% to 70% of patients diagnosed with definitive familial Mediterranean fever by clinical criteria lack one or even both mutations, especially patients from Western Europe or the United States.19-21 In some families transmission of the condition appears to be autosomal dominant.22Mutations or polymorphisms in genes other than pyrin may impact the development of familial Mediterranean fever or the severity of the disease, including the development of amyloidosis.18,23

The pyrin protein consists of three main domains, the N-terminal 92 amino acid pyrin domain, the B-box, and the C-terminal B30.2 domain. Most mutations occur in exon 10 of the MEFV gene encoding the B30.2 domain.4 The pyrin protein plays a role in apoptosis and regulation of the innate immune response, mainly via the pyrin domain. Pyrin directly interacts with and binds to caspase 1 and inhibits the conversion of pro IL-1β to IL-1β.24,25 Mutations in the B30.2 region of pyrin, particularly those mutations considered more severe (positions 680 and 694) interfere in this binding process, thus contributing to increased levels of IL-1β and inflammation. Increased levels of IL-1β and inflammation with and without stimulation by exogenous stimuli have been demonstrated in mouse models and in people with pyrin mutations.4

Clinical Features

Clinical signs of familial Mediterranean fever develop by age 10 in 80% of patients and by age 20 in 90%.8,27,28 A typical attack of familial Mediterranean fever results in a 12- to 72-hour attack of fever, serositis, and monoarthritis of the knee or ankle, often accompanied by an erysipelaslike rash over the involved joint. Severe abdominal pain that may mimic peritonitis or appendicitis accompanies fever in nearly 90% of patients. Other symptoms related to serositis include pleuritis (30–45% of patients), pericarditis, and scrotal swelling. Acute arthritis is seen in 50% to 75% of patients and is characterized by massive neutrophilic effusions. It usually resolves within one week, though in 5% to 10% of cases the arthritis takes a chronic course, especially in the hip and sacroiliac joints.

Since the discovery of the genetic cause of familial Mediterranean fever, additional presentations of the condition have been recognized. These include recurrent abdominal pain of childhood, recurrent arthritis without fever, prolonged febrile myalgia, and exercise-induced myalgia.7,8 Less commonly, vasculitis may be a manifestation of an MEFV mutation, especially Henoch-Schonlein purpura or polyarteritis nodosa.28-30 For unclear reasons, the course of polyarteritis nodosa related to FMF is usually more benign than the idiopathic form. Children with frequent attacks and a chronic increase of inflammatory indices often have growth abnormalities and short stature. Splenomegaly is also common.

Amyloidosis

Prior to the discovery of colchicine as an effective therapy for familial Mediterranean fever by Goldfinger in 1972,31 amyloidosis was the major cause of morbidity and mortality. Amyloidosis usually presents with proteinuria and progresses to the nephrotic syndrome and renal failure within 3 to 5 years. Rarely familial Mediterranean fever can present with amyloidosis (“type II phenotype”). Later manifestations include signs of gastrointestinal involvement such as abdominal pain, diarrhea, malabsorption, and weight loss, as well as cardiomyopathy, macroglossia, joint stiffness, bleeding disorders, and peripheral neuropathies.

Risk factors for the development of amyloidosis include the particular genotype, especially patients homozygous for 694 and 680 mutations, family history of amyloidosis, geography of the patient (less amyloidosis in the United States), male gender, serum amyloid A genotype (there is an odds ratio of 7 for patients with an α/α genotype), and poor compliance with colchicine therapy.8,32

Amyloidosis should be suspected when regular screening urinanlysis demonstrates proteinuria. Renal biopsy then confirms the diagnosis, though less invasive diagnostic methods such as subcutaneous abdominal fat aspiration, rectal biopsy, and nuclear 123I labeled scan for serum amyloid P-component may be considered.33,34 The latter method can also be used to monitor the total body load of amyloid.34 Treatment once amyloidosis has developed is generally limited to minimizing its progression by controlling inflammation. A novel agent to decrease or inhibit fibril formation by blocking polymerization of serum amyloid A, eprodisate disodium, has recently been shown to slow the decrease in creatinine clearance, though very few patients actually have a marked improvement in their amyloidosis.35

Diagnosis

Diagnostic criteria for familial Mediterranean fever were described in 1997 based on the clinical pattern, ethnicity, family history, and response to colchicine.36 Laboratory tests are nonspecific and reflect elevated acute phase reactants. Elevations in the erythrocyte sedimentation rate, C-reactive protein, leukocyte count, fibrinogen, and serum amyloid A are usually present during attacks and frequently also between attacks. Serum amyloid A levels may be useful in monitoring treatment efficacy.37 The diagnosis should not rely only on genetic testing because at least 30% of familial Mediterranean fever patients are either heterozygote for the MEFV gene or do not show any mutations when tested in commercial laboratories.19-21 Questions regarding the testing of relatives of patients with genetically proven familial Mediterranean fever, and concerning the management of asymptomatic patients with homozygote genetic mutations, remain controversial.

Treatment

Treatment with colchicine (1–2 mg/day) is effective in preventing amyloidosis in nearly all patients and in preventing attacks in 60% to 70% of patients.31,38-42 However, 20% to 30% of patients are only partially responsive to maximal tolerated doses of colchicine, whereas 5% of patients are totally unresponsive and continue to have frequent attacks. Unresponsive patients may include those with more severe genetic mutations or patients with modifying genes that may inhibit the activity of colchicine, such as polymorphisms in MDR-1 P-glycoprotein pump transporter genes that result in lower intracellular concentration of colchicine.43 Good compliance is crucial; in some patients missing even one dose of colchicine can precipitate an attack.

Colchicine is generally well tolerated. The most common adverse effects include abdominal pain and diarrhea, especially in those receiving higher doses of colchicine and in patients with lactose intolerance.8,42 These effects are usually transient and respond to gradual dose changes, dividing the daily dose, lactose avoidance, and antidiarrheal and antibloating agents. Other rare adverse effects include myalgia/myositis, peripheral neuropathy, and bone marrow suppression. Colchicine dose not affect growth or development. Currently, there are no safe and effective alternatives for those who fail or do not tolerate colchicine. Corticosteroids are effective only for prolonged febrile myalgia and familial Mediterranean fever–related vasculitis.28

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), an autosomal recessive disease, was first described in 1984 in 6 Dutch patients.44 The mean age of onset is 6 months, with greater than 70% of patients having the first episode prior to 12 months of age.45 The disease is seen mainly in the Netherlands and Western Europe.

Pathophysiology and Genetics

HIDS is actually a metabolic disease caused by mutations in the MVK gene on the long arm of chromosome 12, encoding mevalonate kinase.46,47 The vast majority of patients have mutations in the V377I (founder gene) and I268T positions.48 Mutations result in an unstable enzyme that is less active than the wild type, particularly when patients are febrile. Hence attacks are often precipitated by infection and by vaccines that are pyrogenic.49 The cause of the fever and other symptoms is not clear, but it appears that a deficiency of geranylgeranyl and other isoprenoid substrates, rather than excessive mevalonate, is responsible for effecting inflammation.50 One theory is that this deficiency affects IL-1β processing through effects on R-type GTPase, dependent on prenylation. Total absence of MVK results in mevalonic aciduria, a syndrome characterized by severe neurologic sequelae in addition to febrile episodes (see Chapter 137).

Clinical Features

Attacks typically occur every 3 to 6 weeks and last for 3 to 7 days. Besides fever, patients develop a maculopapular, often mobiliform, rash, abdominal pain with vomiting and diarrhea, cervical lymphadenopathy, arthralgia or arthritis, and oral and genital ulceration (Fig. 209-1). Amyloidosis is a rare complication of HIDS (<3%).51

Diagnosis and Treatment

Acute phase reactants are elevated during attacks. IgD levels are usually elevated above 100 IU/ml, and IgA is elevated in 80% to 90% of patients. Mevalonate kinase activity is decreased and urinary mevalonic acid is elevated, mainly during attacks.52 Homozygous genetic mutations are present in 75% of patients.53 However, HIDS may be seen in patients without genetic mutations when tested commercially (termed “variant HIDS”). If clinical suspicion is high, serum IgD and either MVK genetic testing or urinary mevalonic acid should be obtained.8 False-positive causes of increased IgD levels (usually not to the degree in HIDS) include other autoinflammatory diseases, HIV, diabetes mellitus, smoking, and pregnancy. In patients younger than age 3, normal IgD levels may represent a false-negative test.

NSAIDs have some symptomatic benefit. Colchicine, thalidomide, and corticosteroids are ineffective. Simvastatin may reduce the number of febrile days but has no effect on the frequency of attacks.54 Case reports also suggest occasional benefit from montelukast, etanercept, and anakinra.55,56 Regardless of treatment, attacks usually decrease in severity and frequency over time.8

First described in 1982 as familial Hibernian fever, the gene mutation for the autosomal dominant disorder tumor-necrosis factor receptor associated periodic syndrome (TRAPS) was discovered in 1999.57,58 TRAPS is the most common autosomal dominant autoinflammatory disorder. Although initially described in patients of Irish or Scottish descent, TRAPS is found in all ethnic groups. TRAPS presents in 75% of cases during the first decade of life (median age 3), but it can present at any age. There is a slight male predominance (3:2).

Pathophysiology and Genetics

The TRAPS gene (TNFRSF1A) has been localized to the short arm of chromosome 12.58 The product of this gene is the 55 kDa TNF cell membrane receptor. There is a phenotype-genotype correlation with more severe disease and amyloidosis occurring in patients with cysteine residue mutations that alter protein structure.8 Milder mutations of low penetrance, including R92Q and P46L are frequently seen in normal controls (up to 9% of the population).4 These mutations may not be pathogenic by themselves but may contribute to other still unclear causes of increased inflammation. Decreased shedding of mutated membrane-bound TNF receptors was thought to explain the unopposed serum TNF effects observed in TRAPS.59

However, it is now clear that not all mutations result in defective shedding. The pathogenesis of TRAPS may involve defects in TNF induced apoptosis and stimulation of intracellular inflammatory pathways. This also may result in a decrease in the concentration of surface receptors.

Clinical Features

Attacks typically last 1 to 6 weeks, and occur 2 to 6 times per year, commonly triggered by exercise.60-63 They are marked by fever as well as serositis (abdominal, chest and testicular pain), conjunctivitis, arthralgia and myalgia. Two unique features are periorbital edema and a painful, distally migrating, erythematous rash (Fig. 209-1B). This rash represents a mononuclear perivascular infiltrate of the subcutaneous fascia and occasionally panniculitis. Patients with certain mutations, particularly R92Q, may develop a shorter and milder attack, with involvement of the pharynx and oral ulcerations. Less common manifestations include recurrent pericarditis and central and focal neurologic abnormalities. Amyloidosis develops in 14% to 25% of patients, particularly those with cysteine mutations and a family history of amyloid (Fig. 209-1B).8

Diagnosis and Treatment

Unlike other autoinflammatory diseases in which genetic abnormalities are only supportive of the diagnosis, the identification of TRAPS is based on finding a genetic mutation in the TNFRSF1A gene. Amyloidosis develops in 14% to 25% of patients, particularly those with cysteine mutations and a family history of amyloid.8

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective for mild attacks. Corticosteroids are often beneficial for severe attacks, but escalating doses are often required as the efficacy tends to decrease over time. Colchicine is not effective.

In view of the role of defective shedding of the TNF receptor in the pathogenesis of TRAPS, researchers hypothesized that etanercept, a soluble TNF fusion protein receptor developed for the treatment of inflammatory arthritis, would be beneficial. Initial case reports supported this hypothesis.63,64 However, follow-up indicates that etanercept is not effective in all patients, and in others it loses effectiveness over time. Anti-IL-1 medications such as anakinra may be effective in such cases.65 In general, aggressive therapy with the TNF receptor binding antagonist etanercept or anti-IL-1 agents such as anakinra should be reserved for patients with severe disease or those at increased risk of developing amyloidosis.

Three autosomal dominant syndromes that constitute the cryopyrin-associated periodic syndromes (CAPS). All are caused by single base mutations on the CIAS1/NALP3 gene located on the long arm of chromosome 1 encoding the protein cryopyrin.66,67 Some mutations are specific to one of the syndromes and some mutations overlap among all three syndromes (eTable 209.1).65,66 Often, especially in patients with neonatal-onset multisystem inflammatory disease, no mutations are found. Thus, as with other autoinflammatory syndromes, it is clear that other factors influence the development and severity of CAPS.68

The cryopyrin protein contains an N-terminal pyrin domain and has an important role in regulation of the assembly of the inflammasome (Fig. 198-1). This is a group of proteins that, once assembled, activates caspase-1, leading to cleavage of pro-IL-1β to active IL-1β. Mutations of cryopyrin protein probably increase the rate of spontaneous inflammasome assembly.68,69 Cryopyrin is present mainly in neutrophil cells and chondrocytes, explaining the target organs of these diseases.

The three diseases that compose CAPS are considered variants of the same process, varying by severity of symptoms, systems involved and outcome.68,70 All respond dramatically to anti-IL-1 therapy.

Familial Cold Autoinflammatory Syndrome (FCAS)

Familial cold urticaria familial cold autoinflammatory syndrome (FCAS), the mildest of the CAPS, was first described in 1940 and the genetic mutation discovered in 2001.71 Most FCAS patients are located in the United States. Almost all patients have a genetic mutation in the CIAS1/NALP3 gene. FCAS often starts at birth and is apparent in 95% of the patients by 6 months.

Typically, the attack starts 2 to 3 hours after generalized cold exposure (as opposed to the direct contact that triggers cold-induced urticaria). Patients develop an urticarial like rash that starts on the extremities and spreads to the trunk, low-grade fever, arthralgia, conjunctivitis, nausea, extreme thirst, sweating and headaches. The attack peaks at 6 to 8 hours and lasts up to 24 hours. The frequency of attacks is variable, but they may occur with debilitating regularity. The rash is not true urticaria (mast cells), rather there is a perivascular polymorphonuclear cellular infiltrate in the dermis. Amyloidosis is a rare complication of FCAS (2–4%).

NSAIDs and antihistamine therapies are not effective. Corticosteroids may alleviate symptoms but the magnitude and frequency of effective doses may result in significant adverse effects. Anti-IL-1 agents are very effective in alleviating symptoms. In a recent controlled trial, rilonacept a fusion protein soluble IL-1 receptor, has been shown to be effective.72,73

Muckle-Wells Syndrome (MWS)

Muckle-Wells syndrome (MWS), the CAPS of intermediate severity, was described in 1962 and the genetic mutation was found together with that of FCAS in 2001.66,74 MWS starts later in life than FCAS and can appear at any age. Most cases are in Europe. Genetic mutations in the CIAS1/NALP3 gene are found in 65% to 75% of patients.

Attacks are usually not triggered by cold exposure. A typical attack includes fever, rash, arthralgia, arthritis, myalgia, headaches, conjunctivitis, episcleritis and uveitis. Attacks are more persistent than those of FCAS, lasting up to 3 days. Fifty to seventy percent of patients develop sensorineural hearing loss that typically starts in adolescence. Amyloidosis develops in 25% of patients with MWS.74,75 MWS also responds dramatically to anti- IL-1 therapy.75,76

Neonatal-Onset Multisystem Inflammatory Disease (NOMID)

Neonatal-onset multisystem inflammatory disease (NOMID), in Europe called chronic infantile neurologic, cutaneous, articular syndrome (CINCA), is the most severe of the CAPS. It was first described in 1981, and the association with the CIAS1/NALP3 gene was reported in 2002.67,77 However, only about 50% to 60% of patients have mutations in this gene.

The onset of NOMID is at or within several weeks of birth.69,78,79 Up to half of affected infants are born prematurely. Patients present with an urticaria like rash and fever, often occurring daily. They also have symptoms related to chronic aseptic meningitis such as headaches, irritability and vomiting. Late neurologic complications include hydrocephalus, developmental delay, mental retardation, and hearing loss. Ocular findings include conjunctivitis, uveitis, and papillitis of the optic nerve, resulting in visual loss. By about age 2, 50% of patients have developed a severe arthropathy, consistently mainly of cartilage growth abnormalities leading to severe pain, metaphyseal and epiphyseal overgrowth, ossification irregularities, deformities, and disabilities. There is little synovial inflammation in NOMID. Patients have typical morphological changes including short stature, frontal bossing, macrocephaly, saddle nose, short, thick extremities with clubbing of fingers, and wrinkled skin. About 20% die by age 20 and others develop amyloidosis.

NSAIDs, antihistamines, corticosteroids, colchicine, methotrexate, and other immunosuppressive medications are marginally effective and do not change the disease course. One case report showed that etanercept was effective, mainly for the arthropathy.80 Anakinra, a recombinant IL-1 receptor antagonist, is dramatically effective in treating the rash, fever, and meningitis of NOMID, with normalization of acute phase reactants and a steroid-sparing effect.81-83 However, existing joint damage and mental retardation are not reversible. Early recognition and treatment are crucial in preventing long-term damage and disability.

Pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome PAPA was first described in 1997 and has been reported mainly in Europe.84 PAPA usually presents in the first decade of life, but can become manifest at any age. It is the result of mutations on the long arm of chromosome 15 in the PSTPIP1 gene encoding the CD2 antigen-binding protein.85 This cytoskeleton protein also binds to pyrin, thereby enabling its function.86 Similar to FMF, mutations in PSTPIP1 may affect IL-1 activity. The protein also inhibits apoptosis.

Clinical Manifestations84

Attacks are often triggered by minor trauma, resulting in fever, and massive neutrophilic joint effusion primarily affecting large joints. Patients also may develop pyoderma gangrenosum, severe acne (mainly during adolescence) and diabetes mellitus.

Treatment and Outcome

Intra-articular corticosteroid injections and surgical drainage do not affect outcome. Case reports suggest that anti-TNF agents and anakinra may be effective.87,88

If incompletely controlled, PAPA results in progressive destructive arthritis, skin scarring from acne, and significant depression from the severe sequellae of the disease. Longevity often depends on whether diabetes develops.

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) is probably the most common periodic fever syndrome in childhood and was initially described in 1987.89 The etiology in unknown. Although no specific genetic mutations have been found, familial cases of PFAPA are known and many Middle Eastern patients have heterozygous FMF mutations.

Clinical Features

The onset of PFAPA is usually in early childhood (<5 years).90-92 This is the only autoinflammatory syndrome that is truly periodic with attacks occurring usually every 21 to 28 days and fever lasting 5 to 7 days. Patients usually report a prodrome of feeling unwell several hours before the start of an attack. Pharyngitis and cervical adenopathy are present in 80% to 100% of patients and aphthous stomatitis in 60% to 70%. Patients also frequently have abdominal pain, nausea/vomiting, arthralgia, and headaches.

Diagnosis and Treatment

Diagnostic criteria have been defined for children with typical clinical features. In addition, patients must be completely asymptomatic between attacks, exhibit normal growth and development, and not have cyclic neutropenia.90 Other autoinflammatory syndromes, particularly TRAPS or HIDS, need to be considered in patients with atypical features or in those who are not completely well between attacks. Patients have increased acute phase reactants during attacks, which normalize between attacks. Some patients have a mild increase in IgD and some have heterozygous mutations of other autoinflammatory genes, especially MEFV.91

A single dose of prednisone (0.6–2 mg/kg) at the onset of symptoms usually aborts that attack,90-92 though it may also decrease the intervals between attacks. Cimetidine is effective as a prophylactic agent in about 33% of patients (40 mg/kg/day, in 2 divided doses),90,93 although it usually does not abort attacks. Recent reports suggest that tonsillectomy is curative in nearly all patients.94,95

The natural course of PFAPA in untreated patients is benign. The frequency and severity of attacks diminish over time, and PFAPA usually resolves fully during the second decade of life.90,91,95 Amyloidosis is not a complication of PFAPA.

Chronic recurrent multifocal osteomyelitis (CRMO) was first described in 1972.96 The disease is usually sporadic and the etiology unknown. The median age of onset is 10 years. Several related autoinflammatory bone disorders have been found to have a genetic etiology.97 A rare autosomal recessive disorder of CRMO with congenital dyserythropoietic anemia (Majeed syndrome) is associated with mutations in the LPIN2 gene.98,99 Cherubism, an autosomal dominant chronic inflammatory disease of excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, is associated with mutations in the SH3BP2 and possibly PTPN11 genes.100 A mouse model of CRMO with mutations in the PISPIP2 gene has been described.101

Patients with CRMO develop recurrent episodes of bone pain and fever. Bone lesions include osteolytic lesions surrounded by sclerotic bone, especially in the metaphysis of long bone. Any bone may be involved, particularly the clavicle and ribs, and asymptomatic lesions may be demonstrable on technetium bone scan. Bacterial cultures of biopsies are negative. Other associated clinical findings may include synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO syndrome), isolated palmoplantar pustolosis, psoriasis, sacroiliitis, inflammatory bowel disease, and pyoderma gangrenosum.102

The natural history of CRMO is waxing and waning symptoms, often with spontaneous remissions and healing of lesions followed by relapses. In the past patients were thought to have a good long-term prognosis, but recent studies have found chronic disease in about 50% of patients. Without treatment, chronic bone deformities, leg length inequality, and disability are common.103,104

Antibiotics are usually not effective. Some patients respond to NSAIDs. Others may benefit from corticosteroids, methotrexate, sulfasalazine, azithromycin, interferon, infliximab, or bisphosphanates, especially pamidronate. No markers predicting the optimal agent for an individual patient have been reported.

Schnitzler syndrome, first described in 1972, is characterized by a chronic urticarial eruption with a monoclonal IgM gammopathy.105,106 Other findings include intermittent fever, joint, and/or bone pain with radiologic evidence of osteosclerosis, lymphadenopathy, hepatosplenomegaly, and elevated acute phase reactants. The etiology is still unknown. The disease pursues a chronic course, without remission. Traditional NSAID, colchicine, dapsone, and antihistamine therapy is usually not effective. Late evolution to a lymphoproliferative malignancy, often Walderstom macroglobulinemia, occurs in at least 15% of patients. Amyloidosis has been reported in some cases. Recently, one patient was reported to respond dramatically to anakinra.107

There are rare cases of FMF+TRAPS, HIDS+TRAPS, and CAPS+TRAPS.108,109 Often these patients have the R92Q TNFRSF1A and E148Q MEFV mutations. These overlap cases may express more severe manifestations of autoinflammatory disease with “mixed” characteristics.

Autoinflammatory gene mutations also may play a role in the severity and clinical presentations of other diseases including Behçet disease, inflammatory bowel disease, juvenile idiopathic arthritis, and palindromic arthritis.110-113 Most recently, reports have suggested that these gene mutations may affect the outcome of septic shock and may increase the risk of secondary amyloidosis and the development of atherosclerotic plaque.114,115