Key points

Autoinflammatory syndromes and diseases are a group of disorders of innate immunity that are often inherited, sometimes acquired, characterized by febrile episodes, recurrent, of variable duration, seemingly unprovoked, and with multidistrict inflammation of variable severity. Unlike the classic autoimmune diseases in which the immunopathogenesis occurs primarily in lymphoid organs, that of the autoinflammatory disorders develops and occurs in the affected tissues, implying that tissue-specific factors in the target organs contribute to disease expression. A direct association between defective immune responses to bacterial components and these diseases has not been clearly established. Excessive or protracted signaling, or both, by cell surface or intracellular innate immune receptors is central to their pathogenesis.

Most classic autoinflammatory syndromes are generally dependent on germline or de novo gene mutations that cause or facilitate the assembly of a protein complex called inflammasome, capable of detecting cellular danger signals generated by infectious agents or metabolic stressors. Consequent production of proinflammatory cytokines, principally interleukin (IL)-1β, leads to the creation of autoamplifying feedback loops that explain their chronicity. These diseases and syndromes were initially cataloged as periodic fever syndromes.

Clinical classification of autoinflammatory diseases and syndromes is presented in Table 1 . A classification based on molecular insights garnered over the past decade was recently proposed; it is intended to supplant the classification shown in Table 1 , which is opaque to the genetic, immunologic, and therapeutic interrelationships that have become evident of late. Intrinsic inflammasomopathies represent molecular lesions in the constituent proteins of the inflammasome; extrinsic inflammasomopathies denote disorders of various upstream or downstream regulatory elements ( Table 2 ).

Clinical classification of the autoinflammatory syndromes and diseases

Clinical classification of the autoinflammatory syndromes and diseases

Molecular and biological components of autoinflammatory syndromes and diseases

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  IL-1: IL-1, a cytokine first cloned in the 1980s, rapidly emerged as a key player in the regulation of inflammatory processes. It is a powerful inducer of fever and inflammation, angiogenesis, tissue remodeling, and other features of the acute phase response. Highly conserved throughout evolution, IL-1 comprises 11 proteins (IL-1F1 to IL-1F11) encoded by 11 distinct genes. More than any other cytokine family, IL-1 is closely linked to the innate immune response as shown by the discovery that the cytoplasmatic domain of IL-1 receptor type I (IL1R1) is highly homologous to the cytoplasmatic domains of all toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as induction of cyclooxygenase type 2, overexpression of adhesion molecules, and nitric oxide synthesis are indistinguishable, whether triggered by IL-1 or TLR ligands; both nonspecifically affect antigen recognition and lymphocyte function. Although both families evolved to assist in host defense against infection, unlike the TLR family, the IL-1 family includes members that suppress inflammation. IL-1 acts on T-lymphocyte regulation and includes IL-1α and IL-1β, encoded by 2 separate genes. IL-1α or IL-1β rapidly increases the messenger RNA expression of hundreds of genes in multiple different cell types. IL-1 activities occur at 3 levels: (1) synthesis and release, (2) membrane receptors, and (3) intracellular signal transduction. Ligand binding to the receptor responds with a complex sequence of combinational phosphorylation and ubiquitination events resulting in activation of NF-kappaB signaling, Janus kinase (JNK), and p38 mitogen-activated protein kinase pathways, which cooperatively induce the expression of canonical IL-1 target genes (such as IL-6, IL-8, MCP-1, cyclooxygenase [COX]-2, IkappaB-α, IL-1α, IL-1β, MKP-1) by transcriptional and posttranscriptional mechanisms. Most intracellular components that participate in the response to IL-1 also mediate responses to IL-18, IL-33, and TLRs. Positive and negative feedback mechanisms are in place to amplify or terminate cellular responses to IL-1.

  
  
  
  
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    IL-1α: IL-1α is a cytokine with many metabolic, physiologic, and immunologic effects. Although produced by several cell types, it is characteristic of epithelial cells. Its synthesis in bulk by healthy keratinocytes is part of the immunologic function of the epidermis to maintain the cutaneous barrier and prevent entrance of pathogens. IL-1α interacts with several other cytokines; the most clinically relevant is its synergism with TNF.

    
    
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    IL-1β: IL-1β, a cytokine produced as a proprotein, is proteolytically activated by caspase-1 in macrophages. An important mediator of the inflammatory response, it is present in proliferation, differentiation, and apoptosis processes.

    
    
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    IL-1 receptor antagonist: IL-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 and an important negative regulator of the inflammatory response. A genetic deficiency of IL-1Ra was recently shown to be the cause of a severe inflammatory syndrome in humans. IL-10 activates the signal transducer and activator of transcription 3 (STAT-3) and modulates IL-1Ra transcription in lipopolysaccharide (LPS)-treated phagocytes by making IL-1Ra promoter accessible to readily available nuclear NF-kappaB.

    
    
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    IL-1 receptor type II: IL-1 receptor type II (IL-1 RII) is a naturally occurring inhibitor of IL-1. It binds to IL-1α and β and acts as a distractor, inhibiting the activity of such ligands. It is thought that IL-4 works as an antiinflammatory agent by activating IL-1RII, thus antagonizing IL-1 activity.

  
  
  
  
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  IL-17: IL-17, a cytokine produced by a subset of CD4+ T-helper cells called Th-17 that mount a protective immune response to several microbial pathogens, is implicated in a wide range of autoimmune, allergic, and autoinflammatory diseases such as eczema, RA, psoriasis, multiple sclerosis, IBD, and the enthesitis of psoriasis. Missense mutations of the gene encoding for NLRP3 are connected to excessive production of IL-1β, likely caused by a diminished inflammasome activation threshold resulting in neutrophilic infiltration and an IL-17 dominant response from augmented Th-17 cell differentiation. A major source of IL-17 is a T lymphocyte that constitutively expresses the IL-23 receptor, like splenic lymphoid tissue inducer-like (LTi-like) cells, which might contribute to the dynamic organization of secondary lymphoid organ structure and host defense.

  
  
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  TLR: TLRs are a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. Positive feedback loops triggering immune activation can occur when TLR signaling pathways stimulate host cells in an unchecked manner. On occasions, endogenous molecules such as heat-shock protein trigger specific immune responses that create a TLR-dependent autoamplification loop; this can lead to persistent immune activation.

  
  
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  Regulatory B cells: Regulatory B cells (B-reg) are lymphocytes that produce antiinflammatory cytokines, like IL-10, and suppress Th1 and Th2 inflammatory responses. In some multiorgan inflammatory disorders with infiltration, where autoantibodies are not detected, B-regs seem to play a critical early role in T-cell priming or expansion.

  
  
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  Regulatory T cells: Regulatory T cells (T-reg) are lymphocytes that play a crucial role maintaining control of other leukocytes. Depletion may result in autoimmune disorders such as thyroiditis, gastritis, diabetes mellitus, and colitis, at the same time improving the response to antitumor vaccines. T-regs maintain peripheral tolerance in healthy individuals and suppress immune responses during infections to prevent tissue damage. To allow for effective infection elimination, T-regs themselves need to be regulated; the presence of pathogens is communicated to T-regs via TLRs, T-regs respond to ligands for TLR-2, 4, 5. Different TLRs have different effects on T-reg function, resulting in more or less suppression or abrogation.

  
  
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  Cytotoxic T-lymphocyte antigen 4: Cytotoxic T-lymphocyte antigen 4 (CTLA4, CD152), a costimulatory molecule expressed on activated T cells, plays a key inhibitory role during T-lymphocyte activation. The gene encoding for CTLA4 has been suggested as a candidate to confer susceptibility to autoinflammatory diseases and is associated with Behçet disease.

  
  
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  Antimicrobial peptides: Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection against skin infections; their expression further increases in response to microbial invasion. Defensins are a type of AMP first characterized for their antimicrobial properties and include the cathelicidins.

  
  
  
  
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    Cathelicidin: Cathelicidin is a unique AMP that protects the skin through direct antimicrobial activity and initiation of cellular responses resulting in cytokine release, angiogenesis, reepithelialization, and inflammation. Underexpression is a factor in Alzheimer disease; in rosacea, it is abnormally processed to forms that induce inflammation; in psoriasis, it converts self-DNA into a potent stimulus in an autoinflammatory cascade. Vitamin D ₃ is a major factor in the regulation of cathelicidin.

  
  
  
  
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  Caspase-1: Caspase-1 is a protein member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution phase of cell apoptosis. Activated by inflammasomes, caspase-1 processes the secretion and maturation of IL-1β and IL-18.

  
  
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  Danger receptors: Danger receptors are sensors of microbial invasion, cell stresses, and physiologic perturbations that can elicit inflammatory responses.

  
  
  
  
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    Nucleotide-binding oligomerization domain: Nucleotide-binding oligomerization domain (NOD) is a danger receptor that recognizes intracellular patterns capable of activating transcription of inflammatory cytokines.

    
    
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    Nucleotide-binding oligomerization domain-2: Nucleotide-binding oligomerization domain-2 (NOD-2) is a cytosolic innate receptor able to sense peptidoglycan from gram-positive and gram-negative bacteria, triggering receptor interacting protein-2 (RIP2)-mediated and NF-kappaB-mediated proinflammatory and antibacterial responses. Mutations in the gene encoding NOD-2 in humans have been associated with CD and Blau syndrome.

    
    
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    NOD-like receptor: NOD-like receptors (NLR) are intracellular microbial sensors; some sense nonmicrobial danger signals and assemble into inflammasomes, linking the sensing of microbial products and metabolic stresses to proteolytic activation of IL-1β and IL-18.

  
  
  
  
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  Putative nucleotide-binding (nucleoside triphosphatase) domain: The putative nucleotide-binding (nucleoside triphosphatase) domain (NACHT) is found with other domains in a variety of proteins involved in the regulation of inflammation and/or apoptosis. The acronym stands for: neuronal apoptosis inhibitor protein, major histocompatibility complex (MHC) class 2 transcription activator, incompatibility locus protein from Podospora anserina , and telomerase-associated protein.

  
  
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  Nucleotide-binding domain, leucine-rich repeat containing family: Nucleotide-binding domain, leucine-rich repeat containing family (NLR) include intracellular proteins, generally formed by a leucine-rich repeat (LRR) near the C-terminal and a NATCH. Several function in the innate immune system as sensors of pathogen components and participate in immune-mediated cellular responses via the caspase-1 inflammasome. The NLR network provided pivotal genetic and molecular insights into diseases previously regarded as autoimmune. NLR-related disorders include CAPS, CD, gout, and pseudogout, principally associated with increases in TNF or IL-1. The protein linked to their N-terminal differentiates NLRs. The largest group possesses a pyrin domain (PYD), known as NLRP (previously NALP). More than 14 subtypes of have been described.

  
  
  
  
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    Inflammasomes: Inflammasomes are large multimeric protein complexes linking sensing of microbial products and metabolic stresses (intracellular danger) to production of some proinflammatory cytokines. As a cytosolic sensor, it is the signaling platform required for the activation of IL-1β by proteolysis of prointerleukin (proIL)-β to the active form. The activation and mechanism of action varies depending on the components forming the complex. The first inflammasome described was named NLRP1.

    
    
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    Inflammasome NLRP3: Initially identified in a group of rare autoinflammatory conditions called CAPS, inflammasome NLRP3 has now been implicated in the pathogenesis of several common diseases including gout and gouty arthritis, Alzheimer disease, diabetes mellitus, silicosis, and some cancers. It was formerly known as NALP3, PYPAF1, or cryopyrin. Autoproteolytic maturation of caspase-1 zymogens, triggered by microbial ligands, danger-associated molecular patterns (DAMPs), and crystals, leads to secretion of IL-1β and IL-18. Different domains are responsible for the activation of the inflammasome depending on the aggressing agent.

  
  
  
  
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  Pyryn: Pyryn, a protein that plays an important role in modulating innate immune responses, is produced by the MEFV gene and usually downregulates inflammation. When defective, it is responsible for recurrent attacks of febrile polyserositis in FMF.

  
  
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  Cryopyrinopathies: Cryopyrinopathies are rare disorders associated with heterozygous mutations with gain-of-function of the gene that encodes NLRP3, which leads to inflammation driven by excessive production of IL-1β. The cryopyrinopathies include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile, neurologic, cutaneous, and articular (CINCA)/neonatal-onset multisystem inflammatory disease (NOMID) syndrome; initially considered separate entities, however, mutations of the same gene have been found in all 3 so they are now considered representatives in a continuum of subphenotypes.

Summary of the autoinflammatory syndromes and diseases

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  CAPS: CAPS are inherited autoinflammatory disorders caused by autosomal dominant gain-of-function mutations in the NLRP3 gene on chromosome 1q44. The following entities belong to the CAPS:

  
  
  
  
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    FCAS presents with recurrent episodes of fever, urticaria, articular symptoms, and conjunctivitis that may be triggered by cold. In some families, an association with reactive AA amyloidosis has been described.

    
    
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    MWS presents with urticaria, remitting fever, remitting coxitis, osteitis, bilateral anterior uveitis, sensorineural hearing loss, and increase in C-reactive protein (CRP) and serum amyloid A (SAA) levels. Amyloidosis is a serious complication affecting about 25% of patients, occasionally with fatal consequences. A report of an 8-year-old girl who responded remarkably to anakinra, with recovering of hearing loss, suggests that early diagnosis and treatment may reduce the long-term consequences of amyloidosis.

    
    
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    CINCA/NOMID is characterized by the triad of neonatal onset of cutaneous symptoms and signs resembling generalized urticaria, chronic meningitis, and recurrent fever. It presents with a distinctive osteoarthropathy, synovitis mainly of large joints, and overgrowth of epimetaphyseal cartilage, particularly of large bones. The term CINCA is used principally in Europe where it was first described; the term NOMID is more commonly used in the United States. Before the recognition of mutations leading to IL-1β overexpression and the development of targeted therapy, antiinflammatories were used but had limited benefit; treatment with anakinra and rilonacept has shown remarkable success.

    
    
    
    
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      Adult form: rare. Among 13 patients, 92% had headaches; of those, 77% had features of migraine, 54% had neurosensorial deafness, 69% had myalgias, 46% had papilledema, 15% had optic disc pallor, aseptic meningitis, amyloidosis, and renal failure. It responds to anti-IL-1 therapy.

      
      
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      Childhood form: cartilage overgrowth eventually causes osseous overgrowth particularly of large bones, deformities that persist beyond skeletal maturity and lead to limb length discrepancy, joint contracture, and early degenerative arthropathy. Blood tests may reveal neutrophilia, anemia, and increased levels of acute phase reactants. Twenty percent of patients die from a variety of complications before reaching adulthood. IL-1 receptor antagonist therapy may result in dramatic improvement, except of the arthropathy where it is questionable.

    
    

  
  
  
  
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  Familial Aicardi-Goutiéres syndrome: Familial Aicardi-Goutiéres syndrome (AGS) is characterized by chilblains, mouth ulcers, chronic unclassified inflammatory skin condition, microcephaly (or normal size head), mild or no mental retardation, spastic paraparesis, and chronic progressive deforming arthropathy of small and large joints with secondary contractures. AGS is an autosomal recessive condition associated with a defect in the 3′-repair exonuclease 1 (TREX1).

  
  
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  Tumor necrosis factor receptor-associated periodic syndrome: Arthralgia and nonerosive synovitis, nonspecific abdominal and cutaneous abnormalities are among the most common manifestations of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Chronic erosive joint disease progressing by flare ups and idiopathic recurrent pericarditis were recently added. TRAPS was recently reported in a 16 year old girl of short stature with dermatitis, myositis/fasciitis, delayed puberty with amenorrhea, no fever but increased inflammatory parameters on laboratory tests, particularly of amyloid A. Long-term etanercept administration gave her significant clinical improvement, reducing the erythrocyte sedimentation rate and the levels of CRP, IL-6, TNFα, and soluble TNFα receptor 1, but not of IL-12. Formerly known as familial Hibernian fever, it is caused by mutations in the type 1 TNF receptor superfamily member 1A (TNFRSF1A) gene, which may cause aberrant TNF-mediated intracellular signaling and be related to an error in transcription resulting in a defective membrane TNF receptor. NF-kappaB and p38 phosphorylation levels of monocytes, lymphocytes, and neutrophils stimulated with TNF are significantly low. For patients who fail with colchicine, etanercept may be a first choice ; but in a family of 9 patients all carrying a mutation in the TNFRSF1A gene, infliximab failed to cause a response, enhanced antiapoptotic activity and secretion of IL-1β, IL-6, IL-8, IL-12, and the IL-1 receptor was overexpressed; thus caution is advised when prescribing anti-TNFα therapy for these patients.

  
  
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  Chronic recurrent multifocal osteomyelitis: Chronic recurrent multifocal osteomyelitis (CRMO) involves inflammation with lytic, painful, bone lesions resembling osteomyelitis without an infectious origin; it usually starts during childhood although cases of adult onset have occurred. CRMO is a hereditary, autosomal recessive disease. It is currently treated with antiinflammatory drugs, mostly steroids. Recent studies suggest it may be a disorder of IL-1β regulation, suggesting new therapeutic options.

  
  
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  Majeed syndrome: CRMO plus dyserythropoietic anemia and an inflammatory neutrophilic dermatoses is known as Majeed syndrome. It is caused by a mutation on the LPIN2 gene, altering the regulation of oxidative stress in macrophages, which leads to tissue infiltration and cell damage. It occurs earlier than typical CRMO and responds well to antiinflammatory agents; it resolves spontaneously in most cases.

  
  
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  Recurrent hydatidiform mole: Recurrent hydatidiform mole is a benign trophoblastic tumor presenting as pregnancy without embryonic development and with cystic degeneration of chorionic villi. It has a strong genetic contribution. Multiple cases have been described within families. The first genetic cause was identified in the NLRP7 protein, similar in structure to NLRP3 and NLRP1, but unlike them, it acts as a negative regulator of IL-1β. It is induced by inflammatory cytokines as part of a negative feedback loop; NLRP7 was also expressed in target organs such as uterus, endometrium, and ovary, therefore dysregulation of inflammatory processes during pregnancy became the new hypothetical mechanism of disease. DNA methylation differences may be the consequence of tissue inflammation.

  
  
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  Deficiency of IL-1 receptor antagonist: Deficiency of IL-1 receptor antagonist (DIRA) was recently described in a patient with pustular rash, marked osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis, in whom genetic studies revealed a homozygous deletion on chromosome 2q13, which encompasses several IL-1 family members, including the gene encoding the IL-1-receptor antagonist (IL1-RN). LPS stimulation of mononuclear cells from the patient produced large amounts of proinflammatory cytokines. Treatment with anakinra completely resolved the condition. In the same issue of the New England Journal of Medicine , 9 children from 6 families with neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis were reported. All had mutations affecting IL-1RN allowing for unopposed action of IL-1 resulting in life-threatening systemic inflammation with skin and bone involvement.

  
  
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  Gout: Gout is an arthropathy characterized by increased levels of uric acid (UA) in the blood. The joint most commonly affected is that of the great toe; crystals of UA form and accumulate in the synovial fluids in less than 10% of hyperuricemic patients. Monosodium urate crystal deposition leads to acute inflammation, which resolves spontaneously. UA was identified as a danger signal that triggers the NALP3 inflammasome, activating IL-1, upregulating mediators such as cyclooxygenase, TNF, and IL-8, which in turn cause acute granulocytic inflammation. Colchicine, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and IL-1 blockers, seem effective in resolving flares. Once the attacks subside, control of UA metabolism is essential; this may be accomplished by diet, xanthine oxidase inhibitors such as allopurinol and febuxostat, and by probenecid-induced uricosuria.

  
  
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  Pseudogout: Pseudogout is an arthritis characterized by sudden painful swelling of 1 or more joints in episodes that last days or weeks. It typically occurs in older adults, most commonly affecting the knees but also the ankles, wrists, and elbows. It is also called calcium pyrophosphate deposition (CPPD) disease, which occurs when pyrophosphate crystals form in the fluid that lubricates joint linings, causing pain and inflammation. The underlying molecular mechanism is related to caspase-1 activating NALP3 resulting in the production of IL-1β and IL-18. Treatment of CPPD arthritis includes ice, rest, joint aspiration, and intra-articular injection of corticosteroids. Anakinra was used successfully in the treatment of resistant disease and in patients with renal failure.

  
  
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  Fibrosing disorders: Fibrosis is a pathologic manifestation in injured organs where there is excessive nonphysiologic synthesis and accumulation of extracellular matrix proteins from activated/differentiated fibroblasts. This results in the replacement of normal tissue components with inflammatory cells and connective tissue scar; it is seen in asthma, lung fibrosis, chronic kidney disease, liver fibrosis, vasculopathies such as atherosclerosis, and skin abnormalities such as keloids, hypertrophic scarring, and scleroderma. External insults such as asbestos, silica, bleomycin, and nephrogenic systemic sclerosis (induced by gadolinium in magnetic resonance contrast) have been identified as causes of organ fibrosis. IL-1 gene complex single nucleotide polymorphism has been associated with severe restrictive lung physiology in systemic sclerosis. NLRP3 inflammasome activation and IL-1β expression have a predominant role in establishing pulmonary inflammation and fibrosis; IL-23 and IL-17A have a similar role. IL-1 blockade reduced bleomycin-induced fibrosis in mice and intra-articularly in patients with refractory limited arthrofibrosis after knee surgery.

  
  
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  Type 1 diabetes: Type 1 diabetes is a metabolic condition with hyperglycemia in which destruction of pancreatic islets is evident at an early age; this leads to a marked reduction in insulin production. Most patients have autoantibodies against pancreatic B cells and increased IL-1β production. IL-1 blockade is efficacious in controlling and even reversing antibody-mediated destruction in animal models.

  
  
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  Type 2 diabetes: Type 2 diabetes is a common metabolic condition characterized by insulin resistance and uncontrolled glucose levels. Ultimately, chronic inflammation in the pancreas and adipose tissue causes impaired responsiveness to insulin and results in the development of disease. IL-1 signaling has a role in β-cell dysfunction and destruction via the NF-kappaB and mitogen activation protein kinase pathways leading to endoplasmic reticulum and mitochondrial stresses and apoptosis. Macrophages lacking adenosine triphosphate (ATP)–sensitive potassium channel (K _ATP ) subunits or ATP binding cassette transporters also activate the inflammasome. Glyburide prevents inflammasome activation in pancreatic cells. IL-1 blockers and IL-1Ra seem efficacious in controlling the inflammatory response, restoring insulin production in dysfunctional islets, and even allowing tissue regeneration.

  
  
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  Schnitzler syndrome: Schnitzler syndrome is characterized by simultaneous occurrence of monoclonal gammopathy, chronic urticaria, and either arthralgia, bone pain, fever of unknown origin, hepatomegaly or splenomegaly, lymphadenopathy, increased erythrocyte sedimentation rate, leukocytosis, thrombosis, and increased bone density. It is nonhereditary. Treatment with IL-Ra significantly inhibits IL-1β expression. Free circulating IL-18 is increased despite low expression in monocytes, suggesting constitutive activation of the inflammasome. Schnitzler syndrome responds well to anakinra.

  
  
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  Hereditary periodic fevers: Hereditary periodic fevers is a family of syndromes characterized by recurrent nonspecific systemic manifestations associated with increased acute phase reactants, with negative studies and no evidence of subjacent infection. It includes

  
  
  
  
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    Mevalonate kinase deficiencies (MKD):

    
    
    
    
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      Hyperimmunoglobulinemia D periodic fever syndrome (HIDS)

      
      
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      Mevalonic aciduria (MA)

    
    
    
    
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    FMF

    
    
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    CAPS

    
    
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    TRAPS

  
  
  
  
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  MKD: MKD is divided into 2 syndromes depending on severity: HIDS and the more severe form, MA, are both caused by autosomal recessive mutations in the gene encoding mevalonate kinase (MK), an enzyme leading to cholesterol pathway inactivation. Statins are potent inhibitors of the enzyme directly upstream of MK. Activated fibroblasts from patients with MKD secrete more IL-1β than those from healthy donors. All forms of MKD respond favorably to anti-IL-1 treatments.

  
  
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  HIDS: HIDS is characterized by recurrent inflammatory episodes clinically mimicking FMF. The most frequent signs and symptoms accompanying the febrile attacks include lymphadenopathy, abdominal pain, arthralgia, diarrhea, vomiting, skin lesions, and aphthous ulcers. The age of onset is less than 5 years, the first attack occurring around the age of 6 months (range 0–120 months) with attacks of joint pain of less than 14 days. Educational achievements, employment status, social functioning, general health perception, vitality, and other quality of life issues are affected. The frequency of attacks decreases with age but about half the patients continue to have them about 6 times a year after the age of 20 years. Amyloidosis happens in about 3% of cases and is a severe complication. The median serum IgD level is 400 U/ml, and may be normal in up to 25% of patients. It is a rare hereditary autosomal recessive condition. The biochemical pathway was uncovered by the discovery that HIDS results from mutations in MVK, which encodes an enzyme in the isoprenoid pathway. Some demonstrate good clinical responses to anakinra and etanercept, but prolonged febrile episodes with these drugs in a 10-year-old girl were recently reported.

  
  
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  IL-1 receptor-associated kinase-4 (IRAK-4) deficiency: IRAK-4 deficiency is characterized by recurrent infections by pyogenic bacteria with increased risk for infections with Streptococcus pneumoniae . It is a rare hereditary disease of primary immunodeficiency caused by a mutation in the IRAK-4 gene resulting in selective impairment of cellular responses to TLRs other than TLR3 and to most IL-1Rs, including IL-1R, IL-18R, and IL-33R.

  
  
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  Myeloid differentiation-factor 88 (MyD88) deficiency: MyD88 deficiency is a life-threatening, often recurrent, pyogenic bacterial infections (including invasive pneumococci); patients are otherwise healthy, with normal resistance to other microbes. Clinical status improves with age, not due to cellular leakiness in MyD88 deficiency but to compensation and maturation of the adaptive immune system. Autosomal recessive primary immunodeficiency is phenotypically indistinguishable from IRAK-4.

  
  
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  CD: CD and ulcerative colitis (UC) are the 2 most common forms of IBD; clinical and genetic features distinguish them. In CD, the inflammation is typically transmural and discontinuous throughout the gut, whereas in UC it primarily affects the mucosal and submucosal layers of the rectum and colon in a continuous pattern. NOD2 seems to be a genetic discriminating factor as a locus only associated with CD. A mutation inappropriately activates the immune system against intestinal flora. Some anti-TNFα antibodies (infliximab, adalimumab, etanercept) may be efficacious in improving and remitting CD and UC.

  
  
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  Blau syndrome: Blau syndrome is characterized by the clinical triad of granulomatous dermatitis, symmetric polyarthritis, and recurrent uveitis. It is a chronic, autosomal dominant condition and onset occurs before 4 years of age it is caused by mutations in the NOD-2 gene leading to constitutive NF-kappaB activation. The NOD-2 pathway possibly interacts with either the TLR2 or TLR4 pathways. Impaired production of the proinflammatory and antiinflammatory cytokines TNF-α, IL-10, granulocyte-colony stimulating factor G-CSF, and interferon (IFN)-γ may be responsible for the chronic inflammation. IL-1 production by mononuclear cells is not increased, hence it is not surprising that anakinra was ineffective.

  
  
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  Guadeloupe periodic fever: Guadeloupe periodic fever (FCAS2) was first described in 2 families from the Guadeloupe archipelago. Week-long episodic fevers triggered by exposure to cold are associated with arthralgia, myalgia, and other constitutional symptoms. Two affected members of 1 family had sensorineural hearing loss. Although clinically similar to FCAS or MWS, mutational screening of NLRP3 and other known periodic fever genes was negative; because of its similar presentation, it became known as FCAS2.

  
  
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  Enthesitis: Enthesitis is characterized by inflammation where tendons and ligaments attach onto bones (entheses). It is associated with adjacent osteitis or bone and synovial inflammation. Imaging, histologic, and genetic findings mitigate against the view that in psoriasis the cause is autoimmune and directed against a common autoantigen expressing in the skin and joints. In clinically normal joints, microscopic damage and inflammation may be observed. In distal interphalangeal psoriatic arthritis, inflammation envelops the nail root connected to the subjacent periostium by interdigitating fibers, the extensor, and the collateral tendons. Current thinking is that minor trauma and tissue-related factors have an innate immune drive not involving dysregulation of T-cell function, at least initially. A randomized, placebo-controlled study of etanercept demonstrated statistically significant and clinically relevant benefit in refractory heel enthesitis in patients with ankylosing spondylitis.

  
  
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  Psoriasis: Psoriasis is a multisystemic disease that primarily affects the skin and the joints, principally characterized by erythematous and scaly plaques. A main cause of cutaneous lesions seems to be dysregulated cytokine production orchestrated by activated Th-1 and Th-17 cells, heavily regulated at transcriptional level. Biological drugs against TNFα, IL-12 and IL-23 are effective in controlling and reducing progression; etanercept, infliximab, adalimumab, and ustekinumab are indicated in psoriasis and psoriatic arthritis that does not respond to conventional treatment.

  
  
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  Psoriasiform eruptions: Treatment with anti-TNFα agents may cause palmoplantar pustulosis and plaquelike psoriasiform lesions histologically suggesting psoriasis or lichenoid, eczematoid reactions. In a report of 13 patients, MxA, a protein specifically induced by type 1 interferons, was strongly produced and closely associated with recruitment into the skin of CXCR3+ lymphocytes bearing markers of cytotoxic capacity.

  
  
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  RA: RA is an autoimmune disease that presents at any age, most frequently in women; it often affecting joints symmetrically; the wrists, fingers, knees, feet, and ankles are the sites most commonly involved. Biological agents for RA primarily aim to neutralize circulating and cell-bound proinflammatory cytokines, interfere with the interaction of antigen-presenting and T lymphocytes, eliminate circulating B lymphocytes, or interfere with intracellular signaling in immune-competent cells that cause inflammation.

  
  
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  Ankylosing spondylitis: Ankylosing spondylitis is a systemic disease manifesting chronic arthritis of the spine and sacroiliac joints, leading to loss of spinal mobility. Extra-articular manifestations include uveitis, aortitis, enthesitis, dactylitis, restrictive lung disease, and consequent pulmonary hypertension. Its susceptibility link to HLA-B27 is one of the strongest known HLA-disease associations. Genetic analyses implicate the IL-1 cluster on chromosome 2q13 as an important susceptibility locus. IL-1 is upregulated in spondyloarthropathies, and IL-1 polymorphism in association with ankylosing spondylitis is claimed. IL-1 blockade treatment in patients with ankylosing spondylitis demonstrates a sustained response. Newer long-lasting IL-1Ra monoclonal antibodies should provide a new option.

  
  
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  Still disease: Autoimmune arthritis that, depending on the age of onset, is classified as idiopathic juvenile arthritis (JIA) or adult-form Still disease (ASD):

  
  
  
  
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    Pediatric form: JIA is the commonest cause of chronic arthritis in children. Studies of specific genes have been modeled on the premise of shared autoimmunity wherein genetic variants that predispose to other autoimmune phenotypes confer susceptibility to JIA. Genome-wide association studies accelerated the detection of non-HLA susceptibility loci in other autoimmune phenotypes and are likely to uncover novel JIA-associated variants.

    
    
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    Systemic JIA is a rare systemic inflammatory disease considered to be a subtype of JIA. Besides arthritis, it is characterized by rash, spiking fevers, serositis, and hepatosplenomegaly. IL-1, IL-6 and IL-18, neutrophils, and monocytes/macrophages (rather than lymphocytes) play a major role in its pathogenesis, distinguishing it from other JIA subtypes. Strongly associated with MAS, systemic JIA should be viewed as an autoinflammatory rather than a classic autoimmune disease. Remarkable improvement has been observed with anti-IL-1 and -IL-6 therapies.

    
    
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    Adult form: ASD is rare. The diagnosis is solely clinical and often difficult. It must be considered in patients with high spiking fever, transient rash, arthralgia, oligo or polyarticular arthritis, leukocytosis, sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and high serum ferritin level.

  
  
  
  
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  SLE: SLE is a disease of unknown cause with female predominance. Clinical criteria as well as immunologic characteristics (eg, autoantibodies) are necessary for diagnosis. Its variable course may be characterized by remissions and relapses. New symptoms like those produced by infection often challenge the differential diagnosis. Patients have 5 times the mortality of the normal population, the main reasons being infection and cardiovascular events rather than disease manifestations. Defective immune regulation and uncontrolled lymphocyte activation as well as expansion of local immune responses, increased antigen-presenting cell maturation, and tissue infiltration by pathogenic cells are all influenced by cytokines and cause organ damage. Deposition of circulating immune complexes do not fully explain the tissue specificity; skin-specific autoinflammatory processes in combination with autoimmune complexes likely play a role in exacerbating or amplifying skin manifestations. IL-6 plays a critical role in the immunopathology, B-cell hyperactivity, and maintenance of the autoinflammatory loop. Blocking IL-6 inhibits anti-dsDNA production in vitro and benefited all lupus models tested.

  
  
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  Epidermal growth factor receptor (EGFR) antagonist-induced autoinflammatory condition: This condition is characterized by acneiform reactions associated with sterile inflammation, sometimes severe, triggered by pharmacologic inhibition of EGFR signaling in oncologic therapy. The pathogenesis involves the action of IL-1 on the hair follicle.

  
  
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  Pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome: PAPA syndrome is characterized by sterile pyogenic arthritis, pyoderma gangrenosum (PG), and acne. The onset of acne coincides with puberty. Sterile skin abscesses may be encountered. PAPA syndrome is inherited as autosomal dominant. The pathogenesis involves alteration of the protein PSTPIP-1 (proline, serine, threonine, phosphatase interactive protein), which colocalizes with pyrin in neutrophils. Mutations in its encoding gene produce hyperphosphorylated PSTPIP-1, which binds avidly to pyrin, reducing its inhibition of inflammasome activation.

  
  
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  Periodic fever, aphthous stomatitis, and adenitis (PFAPA) syndrome: PFAPA syndrome starts typically in childhood and is one of the most common causes of periodic fever of unknown origin in that age group. Febrile episodes are intermittent, last 3 to 5 weeks, and are accompanied by oral and pharyngeal aphthous lesions. During attacks, complement (C1QB, C2, SERPING1), IL-1–related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes are significantly overexpressed, but T-cell–associated transcripts (CD3, CD8B) are downregulated. Treatment based on evidence of IL-1β activation in a study of 5 patients led to prompt clinical response to IL-1Ra antagonist therapy in all patients.

  
  
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  PG, acne, and suppurative hidradenitis (PASH) syndrome: Two patients with a clinical presentation similar to, yet distinct from, PAPA syndrome were described recently. Both had PG and acute or remittent acne conglobata, but lacked pyogenic arthritis. Instead, they had suppurative hidradenitis. Mutations in PSTPIP1 exons 1 to 15 were excluded. In the promoter region, increased repetition of the CCTG microsatellite motif was present on 1 allele in both patients. Alterations of the most commonly affected exons of the MEFV, NLRP3, and TNFRSF1A genes were not detectable. One patient was treated with anakinra and responded well, although without complete remission, implying that IL-1β may be pathogenic.

  
  
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  Atypical hemolytic uremic syndrome (aHUS): Atypical hemolytic uremic syndrome (aHUS) is characterized by Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure. The typical form is caused by Escherichia coli (O157:H7), which produces a verotoxin similar to the shigga toxin that creates thrombotic microangiopathies leading to erythrocyte fragmentation, platelet consumption, and glomerular hypoperfusion. Except for diarrhea, the clinical symptoms of the typical and atypical variants are practically identical, but aHUS is caused by an inherited mutation in the gene that codes for complement factor H (CFH) and a membrane cofactor protein that binds to complement component 3b (C3b) preventing activation of the complement cascade. Unregulated activity of C3 leads to the production of anaphylatoxins C3a and C5, chemotactans for neutrophilic infiltration and inflammation. Endothelial damage by neutrophils releases thrombin and starts the microangiopathic cascade. Eculizumab, a monoclonal humanized anti-C5 antibody, has shown success in patients with aHUS.

  
  
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  Age-related macular degeneration: Age-related macular degeneration, the leading cause of blindness in developed countries, is caused by a variation on CFH. The substitution of histidine for tyrosine in the Y402H gene causes a 7-fold increase in the risk of developing the disease. Proteins and immune complexes deposit around the macula and retina producing progressive loss of vision. Increased levels of complement-activating molecules including C5a are found in serum. C5a promotes IL-22 and IL-17 expression by CD4+ T cells. The possible inactivation of IL-22 and IL-17 may herald a novel approach.

  
  
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  Behçet disease: Behçet disease is characterized by chronic inflammatory vasculitis leading to painful ulcerations on the oral mucosa resembling canker sores; genital lesions that may be painful and ulcerate (particularly on the scrotum and vulva); acneiform lesions; tender skin nodules particularly on the legs; uveitis and retinal vasculopathy; arthropathy with swelling and pain mostly in the knees, ankles, elbows, or wrists; inflammation of arteries, including large arteries, and veins, leading to swellings on the arms and legs and thrombotic events; abdominal pain, diarrhea, and bleeding; headaches; fever; disorientation; poor balance; and strokes. Serum soluble cytotoxic lymphocyte antigen 4 (sCTLA4) levels may be low, especially in patients with single nucleotide polymorphisms of the promoter and exon regions on the CTLA4 gene, suggesting that sCTLA may be related to the immunologic abnormalities and clinical expressions. A recent study found that a marked increase in Th-17 cells and a decreased frequency of CD4+ and T-regs in peripheral blood induced by IL-21 correlate with activity. IL-21 and IL-17A–producing T cells were present within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels in patients with active Behçet disease and central nervous system involvement. IL-21 blockade with an IL-21R-Fc restored the Th17 and T-reg homeostasis.

  
  
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  Cherubism: Cherubism is characterized by fibrous and bone hyperplasia of the jaw during infancy. It is a hereditary autosomal dominant disease caused by a mutation on the SH3BP2 gene leading to production of an overly active protein that disrupts critical signaling pathways associated with maintenance of bone tissue and some immune system cells, causing inflammation of the jaw bones and triggering production and activation of osteoclasts.

  
  
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  Chediak-Higashi syndrome: Chediak-Higashi syndrome is characterized by oculocutaneous albinism, immunodeficiency, and thrombophilia. A defect in microtubule polymerization leads to diminished phagocytic capacity. Autosomal recessive mutation in the lysosomal trafficking regulator (LYST) gene seems to be involved in abnormal membrane fusions. Treatment includes cyclosporine and rituximab for the accelerated phase, followed by allogeneic marrow transplant for the hematologic and immunologic symptoms.

  
  
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  Griscelli syndrome: Griscelli syndrome is characterized by albinism and immunodeficiency, and is usually fatal during infancy. It is a rare autosomal recessive entity. Three types exist, based on genetic and molecular features. A mutation in the RAB27A gene leads to dysfunction of an enzyme involved in exocytosis of cytotoxic vesicles and melanosomas.

  
  
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  X-Linked lymphoproliferative (XLP) syndrome: XLP syndrome is characterized by severe febrile episodes after exposure to Epstein-Barr virus (fulminating mononucleosis). It is a hereditary immunodeficiency that only affects males due to a mutation in the SH2D1A gene, which affects the CD8 cytotoxic and NK response. Some patients present severe hypogammaglobulinemia and increased risk for hematologic neoplasms.

  
  
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  Hermansky-Pudlak syndrome: Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, hemorrhagic diathesis from thrombocytopenia due to platelet storage-pool deficiency and, in some cases, pulmonary fibrosis, granulomatous colitis, and renal failure as a result of cellular accumulation and deposition of ceroid lipofuscin. It is an autosomal recessive syndrome caused by mutations in the HPS1-HPS8 and AP3B1 genes that code for a protein that participates in vesicle formation.

  
  
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  Familial hemophagocytic lymphohistiocytosis: Familial hemophagocytic lymphohistiocytosis (HLH) is characterized by prolonged fever, splenomegaly, and pancytopenia with evidence of hemophagocytosis (erythrocytes phagocytized by macrophages in bone marrow, spleen, lymph nodes, and cerebrospinal fluid) accompanied by hypertriglyceridemia and hypofibrinogenemia that are reversible with treatment. It is a potentially fatal hereditary disease caused by a mutation of important cytotoxic T-cell and NK function genes, a suppression of CD8+ T cells, which normally deter viral replication during infection that leads to perpetuation of macrophage antigenic activation and decreased macrophage-mediated and cytokine-mediated apoptotic signaling. Initial treatment based on dexamethasone, cyclosporine A, and etoposide is designed to reduce the hypercytokinemia. There are reports of successful treatment with the anti-CD25 antibody daclizumab, the anti-CD52 antibody alemtuzumab, and drugs directed at TNF. Anti-IFN-γ antibody is a promising treatment modality.

  
  
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  Secondary hemophagocytic lymphohistiocytosis: Secondary hemophagocytic lymphohistiocytosis commonly occurs in infancy and is associated with complications of rheumatic diseases and viral processes. It is clinically similar to primary HLH, and in the dysfunction of NK and cytotoxic T cells. Unlike HLH, the patients have neither a basic immunodeficiency nor a genetic component.

  
  
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  Atherosclerosis: Atherosclerosis is significant contributor to mortality worldwide through complications such as stroke and myocardial infarction. IL-1β plays multiple direct, local roles in the formation and stability of atheroma by eliciting inflammatory responses by macrophages, endothelial cells, and smooth muscle cells. Apolipoprotein E–deficient mice develop accelerated atherosclerotic disease; treatment with an IL-1 receptor antagonist inhibited the formation of atheroma comparable with complete genetic ablation of IL-1β or IL-1R1.

  
  
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  Familial atypical cold urticaria: Lifelong symptoms of familial atypical cold urticaria (FACU) begin in early childhood with pruritus, erythema, and urticaria after exposure to cold. Angioedema with or without syncope occurs in 255 to 75% of patients. Attacks may be triggered by atmospheric conditions, aquatic activities, handling cold objects, or ingesting cold foods and beverages. Skin biopsies demonstrate mast cell infiltrates and postchallenge degranulation. This hereditary autosomal dominant condition thus differs from acquired cold urticaria (ACU) and from FCAS by timing of symptoms and the absence of fever, chills, and joint pains. ACU is usually self-limiting, sporadic, and the cold stimulation test is positive, whereas it is negative in FACU. [This newly described syndrome seems not to be autoinflammatory and is included here for differential purposes only.]

  
  
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  Neutrophilic urticarial dermatosis: Neutrophilic urticarial dermatosis is characterized by an urticarialike rash with pale, flat, or slightly raised nonpruritic macules, papules, and plaques. Skin histology consists of a neutrophilic infiltrate that is perivascular and interstitial, with intense leukocytoclasia but without vasculitis or dermal edema. In a report of 9 patients, 1 had dermographism, 6 had fever, 7 had polyarthritis, and 6 had leukocytosis. Purpura and angioedema are not seen, which differentiates it from neutrophilic urticaria and an associated systemic disease, mainly Schnitzler syndrome, adult-onset Still disease, SLE, and hereditary autoinflammatory fever syndromes, is strongly indicated.

  
  
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  Nakajo-Nishimura syndrome: Nakajo-Nishimura syndrome is an autosomal recessive inflammatory and wasting disease that usually begins in early infancy with a perniolike rash. Patients develop periodic high fever and nodular erythemalike eruptions, gradually progressive lipomuscular atrophy on the upper body, mainly the face and upper extremities, characteristic long clubbed fingers with joint contractures. It is caused by a homozygous mutation of the PSMB8 gene, encoding the β5i subunit of the immunoproteasome. Accumulation of ubiquitinated and oxidated proteins as a result of deficiency of proteasome activities cause hyperactivation of p38 MAPK and overproduction of IL-6 and IFNγ-induced protein 10 (IP-10) in patient cells in vitro and in vivo, which may account for the inflammatory response and periodic fever.

  
  
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  Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome: CANDLE syndrome is characterized by early-onset recurrent fevers, annular violaceous plaques, persistent violaceous swelling of the eyelids, low weight and height, lipodystrophy, hepatomegaly, and a range of visceral inflammatory manifestations. It is caused by nonsense mutations in the PSMB8 gene. Laboratory abnormalities include chronic anemia and increased levels of acute phase reactants liver enzymes. Histopathology of skin lesions shows atypical mononuclear infiltrates of myeloid lineage and mature neutrophils. Patients express increased levels of IP-10, MCP-1, IL-6, and IL-1Ra. IFN-γ and cytokine blockade may be useful.

  
  
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  Joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy (JMP) syndrome: JMP syndrome is characterized by childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Variable features include hypergammaglobulinemia, hepatosplenomegaly, seizures, and basal ganglia calcification. It is an autosomal recessive disorder believed to be caused by mutations in the PSMB8 gene, which affects MHC class I antigen-processing resulting in activation of inflammatory cytokine pathways.

  
  
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  Vasculitis: Studies in children suggest that inflammatory disorders such as FMF and other autoinflammatory diseases may predispose to vasculitis, the most common being Henoch-Schonlein purpura and Kawasaki disease (KD). Patients with KD demonstrate increased transcription of IL-1 genes suggesting that it or its receptor may be targets for therapy, particularly for patients resistant to intravenous high-dose immunoglobulin. In patients with ANCA-associated vasculitis, serum IL-17 and IL-23 levels were significantly increased in acute flares, and they remained increased in a proportion of convalescents in whom significant increases in IFN-γ were detected.

  
  
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  Alopecia areata: Alopecia areata is characterized by a loss of hair in patches (areata), rarely diffuse, with progression in some to total loss of scalp hair (totalis) or to loss of all body hair (universalis). It is hypothesized to be an inflammatory disease with a major genetic component that affects 1% to 2% of the population; perifollicular T-cell infiltrates and local cytokine production play an important part in its pathogenesis. The IL-1 system has major effects on hair growth regulation in vitro, with the inhibitory actions of IL-1α and IL-1β opposed by the receptor antagonist IL-1Ra. Polymorphism of the IL-1Ra gene is associated with more severe clinical outcomes in several chronic inflammatory diseases, including alopecia areata. IL-Ra agonists could be an option for patients who are refractory to conventional therapy.

  
  
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  Rosacea: Rosacea is a common chronic skin condition affecting the face, characterized by flushing, redness, pustules, and dilated blood vessels. The eyes are often involved; thickening of the skin with enlargement (phymas), especially of the nose, occur in some. Cathelicidin dysfunction emerged as the central factor in the pathogenesis of the inflammation and vascular response. Doxycycline reduces production of TNF-α and IL-1β; its antiinflammatory effect is believed to explain its efficacy.

  
  
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  Vitiligo: Vitiligo is characterized by achromic patches on the skin, hair, and mucosa due to autoimmune or autoinflammatory loss of melanocytes from the involved areas. It may be part of a broad, genetically determined diathesis as suggested by familial clustering. It was recently demonstrated that chromosome 17 harbors the gene coding for NALP1. A study has shown various levels of expression of NALP1 gene in patients with vitiligo, higher in those with whole-body involvement. NALP1 at low levels is widely expressed, but at higher levels in immune cells, particularly T cells and Langerhans; different patterns are seen that are consistent with the particular involvement of NALP1 in skin autoimmunity.

  
  
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  Melanoma: Melanoma is characterized by pigmented melanocytic malignancies that progress from macules to tumors and metastasize readily beyond a certain invasion level. Late-stage human melanoma cells spontaneously secrete active IL-1β via constitutive activation of NALP3 and IL-1R signaling. In contrast, NALP3 functionality in intermediate-stage melanoma cells requires activation of the IL-1R by muramyl dipeptide to secrete IL-1β. In vitro, angiogenesis in melanoma is prevented by inhibitors of caspase-1 and caspase-5 or IL-1 receptor blockade. IL-1 is implicated in the development and progression of human melanoma suggesting that inhibiting the inflammasome pathway or reducing IL-1 activity could be therapeutic. New targets for the treatment of metastatic melanoma are emerging; IL-6 and IL-10 blockade are potential strategies. Treatment of in-transit metastatic melanoma with intralesional IL-2 resulted in 76% lesional clearance.

  
  
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  Alzheimer disease: Neuroinflammation is a complex innate response of neural tissue to diverse stimuli such as pathogens, damaged cells, and irritants. Inflammatory mediators including cytokines, chemokines, and prostaglandins are increased in the cerebrospinal fluid and brain tissue of patients with a history of neuroinflammatory conditions and neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and multiple sclerosis. The microglia and astrocytes express pattern recognition receptors (PRRs), which are always on high alert for pathogens or other inflammatory triggers and participate in the assembly and activation of the inflammasome to produce IL-1β, IL-18, and IL-33, influencing the release of toxins from glial and endothelial cells thus promoting or inhibiting neurodegenerative processes. Modulating the inflammasome may be a plausible strategy for many neuroinflammatory conditions.

  
  
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  Procalcitonin: Procalcitonin is a laboratory inflammation biomarker of higher sensitivity and specificity than traditional markers (CRP, erythrocyte sedimentation rate, and leukocytosis) to differentiate the causes of fever, particularly in autoimmune, autoinflammatory, and malignant diseases.