Pathophysiology

Familial Mediterranean fever (FMF) is the most prevalent AID worldwide, which is characterized by recurrent episodes of fever and serosal inflammation. It is generally considered an autosomal recessive disorder, and the pathogenic mutations are located in the MEFV gene on the chromosome 16. Four mutations, M694V, M694I, M680I, and V726A, account for most cases in the Mediterranean populations. The mutations in exon 10 of the MEFV gene tend to be associated with more severe disease as compared with variants found in exons 2 and 3. However, approximately 30% of patients who meet clinical diagnostic criteria for FMF have only one copy of MEFV mutations. Moreover, MEFV mutations are absent in up to 20% of patients who fulfill the clinical diagnostic criteria for FMF [7–9].

The MEFV gene, identified in 1997, encodes a protein of 781 amino acids, pyrin, which plays an important role in the innate immune system defending against external pathogens. In patients with FMF, the mutations in the MEFV gene result in the production of pyrin even in the absence of external triggers, leading to the formation of the NLRP3 inflammasome, which in turn causes the secretion of interleukin (IL)-1βand other inflammatory mediators, and eventually FMF attacks [7, 8].

Clinical Presentation

FMF mainly affects patients of Mediterranean descent, such as Turks, Armenians, North Africans, Jews, and Arabs, but it has also been reported in other parts of the world at a lower prevalence. Most patients experience the initial attack during early childhood, with 90% of patients exhibiting their first symptoms by the age of 20 years [7, 8].

Diagnosis

The major differential diagnoses for FMF include other autoinflammatory periodic fever syndromes, such as TRAPS, CAPS, MKD, and periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA). These diseases all present with periodic or episodic fevers, but the durations of fever vary. The attacks of TRAPS typically last 1–3 weeks, CAPS 1–2 days, HIDS 3–7 days, and PFAPA 3–7 days with a true periodicity of 3–4 weeks. Genetic testing is used to help distinguish these diseases clearly. Systemic juvenile idiopathic arthritis or Still disease usually may be differentiated from FMF by its typical quotidian or persistent fever. The etiologies for fever of unknown origin, for instance, rheumatic diseases, infection, and malignancy, should also be considered and excluded based upon their specific clinical features [11].

Treatment

The initial treatment for FMF is daily oral colchicine at doses of 1–2 mg/day to prevent acute attacks and the development and progression of amyloidosis [11]. Compliance is very important for its efficacy. Colchicine should generally be started at a low dose and gradually increased as tolerated to minimize the gastrointestinal toxicities, such as diarrhea, cramping, and bloating. Dose adjustment is necessary in patients with renal or liver impairment. Higher dosage above 2 mg/day is rarely used for long periods because of intolerance.

Regular safety monitoring should include measurements of blood cell counts for leukopenia, urinalysis for proteinuria, serum chemistries, and the acute-phase reactants [11]. The efficacy of colchicine in FMF has been proven in several double-blind, placebo-controlled trials. It can induce a near cessation of FMF attacks in about 70% of patients and provides at least some relief in more than 90%. In FMF patients with amyloidosis, colchicine could prevent the progression of nephrotic syndrome. Patients with elevated ESR, CRP, or SAA between attacks despite maximal colchicine are considered colchicine resistant because of the risk of amyloidosis.

For patients who are non-responders to colchicine (up to 15%) or those who are intolerant to colchicine (up to 5%), IL-1 inhibition is the preferred treatment. Concomitant colchicine at a tolerable dose should be given for the prevention of amyloidosis. Among the three IL-1 inhibitors, canakinumab, rilonacept, and anakinra, canakinumab is approved by FDA to treat the disease. TNF inhibitors or IL-6 receptor antagonist, tocilizumab, may be tried [11].

Pathophysiology

NLRP3-associated autoinflammatory disease (NLRP3-AID), formerly known as cryopyrin-associated periodic syndromes (CAPS) or cryopyrinopathies [6], consists of a clinical continuum of three overlapping disorders of increasing severity, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome. All three cryopyrinopathies are caused by mutations in the NLRP3 gene in chromosome 1, encoding a protein called cryopyrin (also known as NALP3, CIAS1, or PYPAF1). Thus, in 2018, it was proposed that a single name, NLRP3-associated autoinflammatory disease (NLRP3-AID), should be used, and adjectives mild, moderate, and severe phenotypes may be added instead of using the historical names FCAS, MWS, and NOMID/CINCA [6, 12, 13].

Cryopyrin belongs to the NOD-like receptor (NLR) family that is intracellular sensors of molecular danger signals. It serves as a scaffold for the assembly of the NLRP3 inflammasome, a multimolecular complex activating the protease, caspase-1, which cleaves pro-IL-1β and pro-IL-18 to their biologically active forms. Nearly 200 disease-causing mutations of the NLRP3 gene have been reported in CAPS, and more than 75% of them are located in exon 3, which encodes the central regulatory NACHT domain of the cryopyrin protein. Point mutations in CAPS promote aberrant formation of the inflammasome and production of the active IL-1β, which leads to inappropriate inflammation. Phenotypic differences among the three cryopyrinopathies are thought to be caused by the different impact of mutations on the activity of the inflammasome, modulated by individual genetic background [12, 13].

Clinical Presentation [12, 13]

CAPS are rare autosomal dominant disorders with an incidence of 1/1,000,000 in the USA. The clinical features of the three subtypes of CAPS are described below.

FCAS, formerly known as familial cold autoinflammatory syndrome, is at the mildest end of the CAPS spectrum. The onset of symptoms typically occurs in early childhood, usually in the first year of life. FCAS flares are triggered by generalized cold exposure and present with a systemic inflammatory response including urticarial rash (100%), polyarthralgia (96%), and low-grade fever (93%). Patients may also experience conjunctivitis, which is rather distinctive among periodic fever syndromes, as well as fatigue, dizziness, headache, and nausea. Symptoms often develop within hours after cold exposure and last 12–48 h. FCAS rarely leads to secondary amyloidosis (<2%).

Muckle-Wells syndrome (MWS) is characterized by intermittent episodes of fever, urticarial rash, headache, conjunctivitis, and arthralgia/arthritis and may lead to severe sequelae such as progressive sensorineural hearing loss and renal amyloidosis. Febrile episodes are not typically precipitated by cold exposure. The self-limiting systemic inflammation may last between 12 h to days, and the intervals between attacks range from weeks to months. Patients who suffer from aseptic meningitis often complain of headache and may progress into increased intracranial pressure (ICP) with papilledema. Sensorineural hearing loss caused by chronic inflammation of inner ear typically develops in the late childhood or the early adulthood. Secondary amyloidosis has been described in 25–33% of untreated patients.

NOMID/CINCA is the most severe of the CAPS spectrum. In addition to the systemic symptoms similar to FCAS and MWS, such as urticarial rash, conjunctivitis, and fever, patients with NOMID/CINCA have characteristic abnormalities, including frontal bossing, protruding eyes, and saddle-shaped nose, generally manifesting at or near the time of birth. Focal exuberant cartilaginous proliferation at growth plates and epiphyses frequently leading to joint deformities is seen in up to 70% of patients, most commonly involving the epiphyses of the distal femur and proximal tibia and the patella. Chronic aseptic meningitis, presenting with irritability, headaches, nausea, and vomiting, can lead to increased ICP, papilledema, seizures, hydrocephalus, and cerebral atrophy. Other features include sensorineural hearing loss, uveitis, lymphadenopathy, hepatosplenomegaly, and arthralgia. NOMID/CINCA leads to growth retardation and cognitive disability and may cause premature death and secondary amyloidosis.

Laboratory findings in CAPS include leukocytosis with neutrophilia, thrombocytosis, and elevation of acute-phase reactants. Biopsies of urticarial rash show a marked perivascular infiltration of neutrophils, in contrast to the lymphocytic and eosinophilic infiltrate found in classical allergic urticaria. Lumbar punctures in patients with chronic meningitis may show increased ICP, neutrophilic leukocytosis, and elevation of protein. Radiographs of the long bones can demonstrate epiphyseal lesions.

Diagnosis

The diagnosis of CAPS should be suspected in patients with recurrent episodes of unexplained fever and/or urticarial rash, especially in patients with a positive family history. The diagnostic criteria for CAPS proposed by a multidisciplinary team of international experts in 2017 require one mandatory criterion plus ≥two of six CAPS typical signs/symptoms [14]. In patients with typical manifestations, the presence of NLRP3 mutations is confirmatory, but is not necessary to initiate therapy.

Treatment

Nearly all patients with CAPS respond dramatically to IL-1 blockade. Three IL-1 blocking agents are approved by the US Food and Drug Administration for the treatment of CAPS: anakinra, rilonacept, and canakinumab. Anakinra, an IL-1 receptor antagonist, is given subcutaneously on a daily basis. Rilonacept is a fusion protein consisting of a ligand-binding portion of the human IL-1 receptor linked to the Fc region of human IgG1. Rilonacept is given subcutaneously once a week. Canakinumab is a human anti-IL-1β monoclonal antibody, which is given subcutaneously every 8 weeks. Optimal treatment with these agents leads to complete resolution of symptoms in most cases [15].

Pathophysiology

NLRP12-associated autoinflammatory disease (NLRP12-AID) is also known as familial cold autoinflammatory syndrome 2 (FCAS 2), and it is a rare autosomal dominant disease that is characterized by recurrent fever and musculoskeletal symptoms associated with the mutations in the NLRP12 gene.

Studies have shown that NLRP12 is closely related to the inflammasome scaffold, NLRP3. While the precise function of NLRP12 is debatable, it forms inflammasome or regulates inflammasome function. NLRP12 is reported to regulate inflammation by activation of caspase-1 via inflammasome, leading to the processing and secretion of IL-1β. Meanwhile, caspase-1 induces cell apoptosis and attenuates the negative regulation of NF-κB signaling induced by TNF [16, 17].

Clinical Presentation and Diagnosis

NLRP12-AID can occur in multiple ethnic groups, sporadically in both children and adults. The clinical features of NLRP12-AID are similar to NLRP3-AID, notably FCAS, including periodic fever, rash (primarily urticaria), myalgia, polyarthralgia/arthritis, abdominal pain/diarrhea, thoracic pain, headache, sensorineural deafness, lymphadenopathy, and splenomegaly. Most patients report cold exposure as a trigger. Elevated acute-phase reactants are common in episodes. The NLRP12 gene variant, F402, is the most frequent, and some other rare NLRP12 gene variants have been reported as well. NLRP12-AID is diagnosed based on the characteristic clinical phenotype and genotype [16, 18–20].

Treatment

Therapeutically, glucocorticoids and antihistamine drugs are largely effective in the majority of patients with NLRP12-AID. IL-1 inhibitors may be beneficial. However, it has been reported that some patients albeit initially responsive eventually developed resistance to anakinra within a few months of treatment. Unlike their definite therapeutic roles in FCAS, IL-1 antagonists may be further evaluated for its potential efficacy in the treatment of the disease [19, 20].

Pathophysiology

TRAPS is caused by mutations in the TNFRSF1A gene in chromosome 12p13 which encodes the 55-kD, the TNF receptor 1 (TNFR1) for TNF-α. Most mutations associated with TRAPS (94%) are single-nucleotide missense variants within exons 2, 3, 4, and 6. The pathogenic mechanism of TRAPS is not fully understood. Studies suggest that TRAPS mutations might result from impaired metalloprotease-dependent cleavage of TNFRSF1A, producing soluble “shed” receptors. TNFR 1 on the cell surface does not neutralize TNF perhaps due to mutant TNFR1 protein misfolding and endoplasmic reticulum retention. In vitro studies show possible causative links between TRAPS-associated TNFRSF1A mutations and impaired TNF-α binding, abnormal apoptosis, and altered NF-kB pathway, as well as defective receptor trafficking to the cell surface [21].

Clinical Presentation

TRAPS often occurs in childhood (age 3) and causes variable and heterogeneous clinical manifestations. The disease is characterized by recurrent fever attacks, typically lasting from 1 to 3 weeks. Febrile attacks recur either spontaneously or after minor triggers (local injury, minor infection, stress, exercise, and hormonal changes) at varying intervals and usually initiate with muscle cramps or myalgia underlying the rash that migrate in a centrifugal pattern. Skin lesions usually start as painful and warm macules and papules, which progressively expand at the periphery, subsequently coalescing into large patches or plaques. Skin biopsies usually show dermal perivascular lymphocytic and monocytic infiltrates. Other less common skin lesions may include erysipelas-like erythema and urticarial rash. Eye involvement can include peculiar periorbital edema, conjunctivitis, and/or uveitis. Arthralgia occurs during febrile attacks in about two-thirds of patients, including mono- or oligo-arthralgia. Arthritis is less common, and joint effusion may occur. Serositis is also common, and amyloidosis can occur as a long-term complication of TRAPS [22, 23].

Diagnosis

TRAPS is diagnosed based on clinical ground and genetic confirmation of specific TNFRSF1A mutations. Patients with TRAPS should be regularly screened for proteinuria from renal amyloidosis [21].

Treatment

Patients gain some symptomatic relief from nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, while colchicine or immunomodulators such as methotrexate, cyclosporine, and thalidomide produce very little benefit. TNF-α blockers, such as etanercept, can be used. IL-1 inhibitor, canakinumab, has been approved by FDA to treat the disease [21].

Pathophysiology

Mevalonate kinase deficiency (MKD) , also known as hyperimmunoglobulin D syndrome (HIDS), is a rare monogenic disorder characterized by recurrent febrile attacks associated with rash, lymphadenopathy, abdominal pain, and elevated serum immunoglobulin D (IgD). HIDS can be divided into classic and variant forms. If the genetic defect is known, it is called the classic form, which accounts for 75% of cases. The variant form has similar clinical symptoms, but there is unclear genetics.

The classic HIDS is an autosomal recessive disorder, caused by loss-of-function mutations in the MVK gene which lead to mevalonate kinase (MK) deficiency. The most common mutation found in classic HIDS is the V377I mutation. The MK protein, encoded by the MVK gene in the chromosome 12, is an enzyme in the cholesterol synthesis pathway. Mutations in MVK that cause a mild to moderate reduction (normal 5–15%) in the enzymatic activity of MK lead to the periodic fever syndrome, HIDS, whereas mutations that cause more severe reduction or loss of MK activity result in a potentially fatal condition with marked developmental delay and mevalonic aciduria. The diminished activity of MK results in accumulation of its substrate mevalonic acid in serum and urine. However, the pathophysiologic mechanism underlying MK deficiency and self-limiting inflammation is still unclear. The cause of the characteristic high concentration of IgD in this syndrome is unclear. It has been suggested that neither elevated level of IgD nor accumulated mevalonic acid is responsible for the pathogenesis in HIDS [24–26].

Clinical Presentation [24–26]

HIDS occurs almost exclusively in childhood, and 90% of patients experienced the first attack within the first year of life, with a median age of 6 months. HIDS affects female and male equally. Most patients reported are of Dutch or French ancestry.

The potential triggers for HIDS attacks include vaccinations, minor trauma, surgery, or stress. Symptom-free intervals between attacks usually last 1–2 months without obvious periodicity. The durations of interval vary greatly and may become longer with increasing age. HIDS attacks are characterized by the rapid onset of moderate to high fever, which typically lasts 3–7 days. The prodrome may include nasal congestion, sore throat, fatigue, backache, and headache. More than 90% of patients have diffuse lymphadenopathy, mostly cervical, during febrile attacks. Palpable splenomegaly is found in 50% of patients. Abdominal pain is reported in 85% of patients, which is often accompanied by vomiting and/or diarrhea; the severity of pain may suggest acute abdomen. Skin rashes are noted in over 80% of patients, and erythematous macular rash is the most common type. Aphthous ulcers may occur in 50% of patients. Polyarthralgia/polyarthritis develops in 80% of patients during febrile episodes. Larger joints are involved more commonly and often in a symmetrical pattern. Secondary amyloidosis is rare.

Laboratory findings during HIDS attacks include leukocytosis with neutrophilia; elevation of acute-phase reactants such as ESR, CRP, SAA, ferritin, and fibrinogen; and increase in urinary mevalonate. The acute-phase reactants commonly return to normal or are only mildly elevated between attacks except for SAA, which may remain elevated in 50% of patients. Elevated serum IgD (>100I U/mL) and IgA levels are seen in over 80% of patients and remain elevated between attacks; elevated serum IgD levels are nonspecific.

Diagnosis

The diagnosis of HIDS should be entertained in patients with early-onset recurrent fever lasting 3–7 days, accompanied by a combination of characteristic clinical findings, such as lymphadenopathy, splenomegaly, arthralgia/arthritis, abdominal pain, and rash. The Eurofever clinical diagnostic/classification criteria may be used [27]. If the diagnostic cutoff score of ≥42 is reached, serum IgD should be measured to confirm the HIDS diagnosis. Clinical suspicion of the diagnosis in normal serum IgD can be corroborated by genetic testing [27].

Treatment

Most patients with HIDS have a normal lifespan and carry a good prognosis. However, if the attacks are frequent and severe, the quality of life will be significantly affected. The goal of treatment is to improve quality of life and to minimize the risk of drug adverse effects. NSAIDs and/or short courses of oral glucocorticoid may be used; IL-1 inhibitors can be used, and canakinumab is approved by FDA to treat the disease [24–26].

Pathophysiology

Blau syndrome (BS) is characterized by an early-onset clinical triad of arthritis, dermatitis, and uveitis, and it is a rare autosomal dominant autoinflammatory granulomatous disorder. It is caused by gain-of-function mutations in the nucleotide-binding domain of the nucleotide-binding oligomerization domain protein 2 (NOD2), also called caspase recruitment domain-containing protein 15 (CARD15) gene in chromosome 16. In 2018, an international expert committee proposed that a general name, NOD2-associated granulomatous disease, should be used to encompass BS, early-onset sarcoidosis, and familial Crohn disease due to the fact that all the disorders are linked to NOD2 mutations. Similar to NLRP3 protein, NOD2 protein is also a member of the NOD-like receptor family, which plays important roles in innate immune system. Mutations in BS are predominantly located in exon 4 of the NOD2 gene. The two most common mutations are two missense mutations, R334Q and R334W.

Clinical Presentation

The disease onset of BS typically occurs before the age of 4 years. Three typical sites affected by granulomatous inflammation are joints, eyes, and skin. Joints are affected in over 90% of patients. The chronic granulomatous arthritis is almost always polyarticular, presenting as minimally symptomatic swelling involving the wrists, ankles, and knees. Arthritis of proximal interphalangeal joints of hands can lead to progressive flexion contractures of the fingers (camptodactyly). Symmetric hypertrophic tenosynovitis develops in up to 40% of patients, resulting in the typical periarticular “boggy” appearance, especially about the knees. Granulomatous uveitis is frequent (80%) and usually chronic and persistent. Acute anterior uveitis can be a presenting feature and often extends to panuveitis. Most patients have bilateral ocular involvement, leading to cataracts, glaucoma, and even blindness. Ocular involvement is the most significant morbidity in BS. The BS-associated dermatitis is typified by ichthyosis-like popular-nodular erythematous rash. The typical clinical triad of dermatitis, arthritis, and uveitis is seen in up to 80% of patients, usually in a consecutive fashion. Other manifestations include lymphadenopathy, vasculitis, cranial neuropathies, and granulomatous involvement of visceral organs. Fever and abdominal pain can occur infrequently.

Laboratory findings include leukocytosis, thrombocytosis, and elevation of acute-phase reactants such as ESR and CRP. Biopsies of synovium and skin show noncaseating granulomas in typical cases.

Diagnosis

The diagnosis of BS is based upon characteristic clinical phenotype. Histological findings of granulomas are the most supportive of the disease in the proper clinical setting. Molecular testing for the NOD2 mutations provides more definitive diagnosis.

Treatment

Optimal therapy for BS has not been well defined. NSAIDs can be used for mild clinical manifestations, and severe symptoms are often treated with systemic glucocorticoids. Immunosuppressants such as methotrexate and cyclosporine are used as glucocorticoid-sparing agents. Biologic agents such as TNF-α blockers (infliximab and adalimumab) can be used. IL-1 and IL-6 inhibitors were anecdotally reported. Uveitis should be managed with both topical and systemic therapies. Early diagnosis and proper management is crucial to avoid long-term ocular complications.

Pathophysiology

Yao syndrome (YAOS, OMIM 617321), formerly called NOD2-associated autoinflammatory disease (NAID), is a polygenic AID characterized by periodic fever, dermatitis, arthritis, swelling of the distal extremities, as well as gastrointestinal and sicca-like symptoms. The disorder has a genetic association with certain NOD2 variants [31].

The pathogenesis of YAOS remains elusive, and it is postulated that the interplay between the NOD2 defect as a risk factor and environmental factors may play a role. It has been recently reported that NOD2 transcript level was significantly elevated in the peripheral blood mononuclear cells from IVS8⁺¹⁵⁸ YAOS patients. Moreover, these patients’ cells had elevated basal IL-6 secretion. In contrast, NF-κB activity and TNF-α secretion were uniquely suppressed in haplotype IVS8⁺¹⁵⁸/R702W patients. Specific NOD2 genotypes may result in distinct NOD2 expression and cytokine profiles. Further study is needed to dissect its pathomechanism [32, 33].

Clinical Presentation and Diagnosis [31, 34, 35]

YAOS is a multisystem inflammatory disease. Recurrent fever occurs in >60% of patients, and typically each febrile episode lasts several days. The fever occurs at varying intervals ranging from several weeks to several months. Intermittent dermatitis is common, manifesting as erythematous patches and plaques on the face, trunk, and limbs. Skin biopsies are usually consistent with spongiotic dermatitis, and other types of dermatitis can be present. Granulomatous changes are extremely rare. Arthritic symptoms are common with oligo- and polyarticular involvement. Some patients (25%) have distal lower extremity swelling involving the ankle and foot with unilateral distribution often. Recurrent or intermittent abdominal pain and/or diarrhea of varying degrees occurs in about two-thirds of patients. Sicca-like symptoms occur in 60% of patients. Other less common manifestations include recurrent chest pain with pleuritis and/or pericarditis, headache, oral ulcers, lymphadenopathy, and sore throat. The diagnosis criteria for YAOS are listed in Table 16.2. YAOS is diagnosed if two major criteria, one or more minor criteria, and the molecular and exclusion criteria are fulfilled.

Table 16.2

The diagnostic criteria for Yao syndrome

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