Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity

INTRODUCTION — Autoinflammatory diseases are conditions of pathogenic chronic or recurrent inflammation mediated by antigen-independent hyperactivation of the immune system [1]. A broad spectrum of autoinflammatory diseases is now recognized, differing markedly from one another in pathogenesis and clinical manifestations. This topic review covers autoinflammatory diseases that originate in aberrant activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and related diseases involving the cytokine tumor necrosis factor (TNF). A general discussion of autoinflammatory diseases is available separately. (See "The autoinflammatory diseases: An overview".)

Additional topics cover other specific autoinflammatory diseases:

●(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

●(See "Cryopyrin-associated periodic syndromes and related disorders".)

●(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

●(See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

●(See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)

●(See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

●(See "Autoinflammatory diseases mediated by miscellaneous mechanisms".)

●(See "Deficiency of adenosine deaminase 2 (DADA2)".)

OVERVIEW OF NFkB — The term "nuclear factor kappa B" (NFkB) refers to a family of transcription factor complexes that participate in cell activation. The name derives from its discovery as a regulator of the immunoglobulin kappa light chain in B cells [2]. However, it has become clear that multiple distinct NFkB complexes play key roles in both immune and nonimmune cells [3,4].

NFkB dimers are formed from five proteins:

●p50

●p52

●RELA

●RELB

●c-REL

At least 13 different combinations have been identified, of which the best known are:

●p50:RELA

●p50:c-REL

●p52:RELB

Beyond the five NFkB proteins, additional proteins involved in regulation of NFkB activation include:

●Surface receptors and their signaling transduction partners (eg, TNFR-associated factor [TRAF] proteins)

●Proteins involved in regulation of NFkB complex formation via the addition and removal of ubiquitin (eg, NFkB regulator A20)

●At least eight distinct "brake" inhibitory proteins termed inhibitors of NFkB (IkB; eg, IkB-alpha, IkB-beta, and B cell lymphoma 3 [BCL3])

●The three members of the complex responsible for deactivating the IkB proteins, termed the IkB kinase (IKK) complex (IKK-alpha, IKK-beta, and IKK-gamma, also called the NFkB essential modulator [NEMO])

In resting cells, NFkB resides in the cytoplasm, translocating to the nucleus when cells receive appropriate stimulation to drive gene transcription. Genes regulated by NFkB include key proinflammatory mediators such as interleukin (IL) 1-beta and TNF [5], rendering NFkB central to systemic inflammation.

Nuclear translocation of NFkB occurs in two ways (figure 1). In the "canonical pathway" of NFkB activation, ligation of cell surface receptors (for example by IL-1-beta or bacterial lipopolysaccharide [LPS]) activates a kinase complex that phosphorylates a member of the IkB family that then retains NFkB in the cytoplasm. Phosphorylated IkB dissociates from the complex and is degraded, permitting nuclear entry of free NFkB dimer. Alternately, in the "noncanonical pathway" of NFkB activation, a different kinase cascade results in proteolytic processing of the inactive dimer formed by the p52 precursor protein p100 with RELB, allowing translocation of active p52:RELB to the nucleus. Noncanonical NFkB activation is initiated by the TNF receptor superfamily. These receptors also activate the canonical pathway, such that some stimuli (such as LPS and IL-1-beta) activate only one pathway while others (such as TNF) activate both [4,6].

Pathogenic mutations affecting this network disrupt normal NFkB function, giving rise to either immunodeficiencies or the NFkB-associated autoinflammatory diseases. The latter are sometimes termed the "relopathies" because all five NFkB proteins belong to the REL protein family [7]. NFkB not only activates cells but also protects them from apoptosis induced by TNF [8]. Enhanced susceptibility to apoptosis likely underlies to frequency of mucosal ulcers in affected patients and can also result in enhanced susceptibility to infection. (See "Inborn errors of immunity (primary immunodeficiencies): Classification", section on 'I. Immunodeficiencies affecting cellular and humoral immunity' and "Combined immunodeficiencies: Specific defects", section on 'Defects of transcription factors critical to T cell function'.)

As a core pathway of cell activation, both reduced and enhanced NFkB activity can lead to inflammatory diseases across the autoinflammatory-autoimmune spectrum. In the conditions discussed here, dysregulation of the NFkB pathway itself leads directly to antigen-independent inflammatory disease, although pathologic NFkB activation is usually not the only cause of disease, since many of the proteins affected have multiple cellular functions.

SPECIFIC DISEASES

Haploinsufficiency of A20 — Encoded by the TNF-alpha-induced protein 3 (TNFAIP3) gene, A20 is an enzyme that can both add and remove ubiquitin, regulating protein function as well as clearance by the proteasome. Its targets include the NFkB regulatory protein NFkB essential modulator (NEMO) and other components of the NFkB activation cascade. A20 also regulates the NATCH domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) inflammasome, leading to excess production of interleukin (IL) 1-beta and IL-18 [9-12]. Autosomal dominant loss-of-function TNFAIP3 variants enhance translocation of NFkB to the nucleus, leading to the disorder haploinsufficiency of A20 (HA20, also called familial Behçet-like autoinflammatory syndrome; MIM #616744) [9,13]. (See "Clinical manifestations and diagnosis of Behçet syndrome".)

Patients experience recurrent, painful oral, genital, and/or gastrointestinal ulcers, resembling Behçet syndrome. Most patients present before 10 years of age. As an autosomal dominant disorder, affected family members are common.

Other clinical manifestations are highly variable and can include:

●Episodic fever

●Gastrointestinal symptoms (eg, abdominal pain, bloody diarrhea, bowel perforation)

●Cutaneous findings (eg, rashes and abscesses)

●Autoimmunity (eg, thyroiditis, systemic lupus erythematosus)

●Musculoskeletal symptoms (eg, polyarthritis)

●Recurrent viral and bacterial infections

●Ocular findings (eg, anterior uveitis, retinal vasculitis)

●Neurologic involvement (eg, central nervous system vasculitis)

●Cardiac involvement (eg, pericarditis with effusion, venous thrombi)

Laboratory findings include elevated acute-phase reactants (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) and, in many patients, the presence of autoantibodies including antinuclear antibody (ANA) and anti-double-stranded deoxyribonucleic acid (dsDNA).

Patients are often erroneously diagnosed initially with periodic fever with aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome; seronegative or seropositive inflammatory arthritis; inflammatory bowel disease; or systemic lupus erythematosus [14,15]. Presentation with inflammation and lymphadenopathy resembling autoimmune lymphoproliferative syndrome (ALPS) also has been reported [16]. (See "Clinical manifestations and diagnosis of Behçet syndrome" and "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)" and "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

Some patients respond to colchicine, while others benefit from mono- or combination therapy with immunosuppressive agents, including systemic glucocorticoids plus nonsteroidal antiinflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; eg methotrexate), and biologic DMARDs (bDMARDs) that inhibitor TNF, IL-1, or IL-6 [13,15].

NFkB essential modulator (NEMO) C terminal deletion — Deletion of the C terminus of NEMO results in inability to interact with its inhibitor A20 [17]. Patients demonstrate enhanced NFkB activation and present early in life with erythroderma and colitis presenting as malabsorption, together with systemic inflammation. Some patients also experienced recurrent bacterial infections. Steroids, infliximab, and transplantation have been reported as effective in some cases [18,19]. Recurrent infections are managed as they are for NEMO deficiency, of which this autoinflammatory condition represents a subset. (See "Toll-like receptors: Roles in disease and therapy", section on 'NEMO defects' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'NEMO deficiency' and "Combined immunodeficiencies: An overview".)

RELA haploinsufficiency — Heterozygous deficiency of the NFkB component RELA was first identified in a three-year-old child presenting with recurrent episodes of fever and recurrent acute ileitis, together with oral and vaginal ulcers [20]. The patient's mother and siblings also experienced recurrent mucocutaneous ulcers beginning in the first years of life. These patients were diagnosed with early-onset Behçet syndrome prior to identification of RELA haploinsufficiency. Patient cells exhibited reduced NFkB signaling and increased apoptosis upon exposure to TNF. Murine studies confirmed the sensitivity of epithelial cells to TNF-mediated apoptosis, even in the presence of a genetically normal hematopoietic compartment. Treatment with the TNF inhibitor infliximab resulted in resolution of mucosal ulceration, illustrating both the importance of NFkB beyond the immune system and how reduced as well as enhanced function of NFkB can manifest as autoinflammation.

Another patient with RELA haploinsufficiency had variants in other genes affecting immune response in addition to RELA haploinsufficiency [21]. He was initially diagnosed at five years of age with ALPS due to presence of refractory autoimmune cytopenias, splenomegaly, and lymphadenopathy. This patient also had episodic aseptic meningitis and severe headaches but did not have mucocutaneous ulcerations or inflammatory intestinal disease.

Dominant-negative RELA deficiency — Heterozygous pathogenic variants in RELA that result in truncated proteins that have loss of function or are hypomorphic and cause a dominant-negative effect on wild-type proteins were found in patients with a monogenic, early-onset, Behçet syndrome-like condition [22]. These patients appear to have a more severe phenotype than RELA haploinsufficiency, with autoinflammatory and autoimmune manifestations in addition to mucocutaneous ulcers (oral, genital, and perianal) and autoimmune hematologic disorders (eg, immune thrombocytopenia [ITP], neutropenia) [22-25].

Clinical manifestations are variable depending upon the pathogenic variant but can be different even in patients with the same mutation, and incomplete penetrance is reported [22-25]. Additional described features include:

●Constitutional symptoms (periodic fever, night sweats, fatigue, failure to thrive)

●Lymphadenopathy

●Musculoskeletal (arthralgia, myalgia, arthritis, tendonitis, scoliosis)

●Gastrointestinal (diarrhea, esophagitis, peritonitis, pancreatitis)

●Endocrine (hypothyroidism)

●Cutaneous (erythema nodosum, panniculitis, acneiform rash, pustulosis, atopic dermatitis, folliculitis, leukocytoclastic vasculitis)

●Ocular (increased intraocular pressure, thinning of the optic nerve, severe allergic conjunctivitis, episcleritis)

●Neurologic (headaches, brain fog, hypotonia, muscle weakness)

●Recurrent infections (pneumonia, otitis media, cellulitis, croup, respiratory syncytial virus, periodontitis)

●Autoimmune disorders (inflammatory bowel disease, juvenile idiopathic arthritis, and neuromyelitis optica)

Previous diagnoses patients have carried include Behçet syndrome, Sjögren's disease, systemic lupus erythematosus, and hyperimmunoglobulin E (IgE) syndrome.

Some patients have elevated acute-phase reactants (ESR, CRP) during flares or positive ANAs [22,24]. Elevated immunoglobulins have also been reported. Truncated RELA results in defective NFkB signaling that leads to elevated levels of TNF and enhanced TNF-induced apoptosis. Excessive production of type I and II interferons (IFNs) is driven by enhanced expression of Toll-like receptor 7 (TLR7) [22].

Most patients have at least partial response to topical corticosteroids and oral glucocorticoids. There are case reports of patients whose disease manifestations have improved on colchicine, rituximab (anti-CD20), a TNF inhibitor (infliximab, adalimumab, etanercept), IL-1 inhibitors (anakinra, canakinumab), or apremilast (phosphodiesterase 4 [PDE-4] inhibitor) [23-25]. Other case reports have noted lack of responsiveness to methotrexate, tocilizumab, azathioprine, hydroxychloroquine, and cimetidine. Janus kinase (JAK) inhibitors are a proposed option in patients with refractory disease [22]. One patient with refractory ITP was successfully treated with hematopoietic cell transplantation (HCT). In some patients, symptoms spontaneously improved with age [23,24].

ALPK1 gain-of-function defects (ROSAH syndrome) — Alpha kinase 1 (ALPK1) plays a role in innate immune activation through its function as a sensor for bacterial sugars that triggers signaling through the NFkB pathway [26]. Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) syndrome is an autosomal dominant disorder caused by gain-of-function heterozygous missense variants in ALPK1 that cause spontaneous NFkB activation [27,28].

The clinical presentation of ROSAH syndrome is variable, although penetrance is complete in all affected family members. In addition to the syndrome-defining features noted above, nearly all patients have at least one inflammatory feature, including noninfectious recurrent fever, episodic malaise, gastrointestinal symptoms (episodic abdominal pain, gastroesophageal reflux disease, dysphagia, constipation, ileus), arthralgias, arthritis that can be deforming, AA amyloidosis, transient cytopenias, and uveitis with retinal vasculitis [28]. Other features include hyposalivation with dry mouth, enamel defects, and multiple dental caries. Abnormalities on brain magnetic resonance imaging (MRI) are common and include meningeal enhancement and premature mineralization of the basal ganglia and brainstem (substantia nigra and red nuclei) reminiscent of the interferonopathies. Laboratory abnormalities include lymphopenia, transient neutropenia, and episodic elevation of C-reactive protein (CRP) and proinflammatory cytokines and chemokines (only TNF persistently elevated). Immunoglobulin levels are typically normal, and high-titer autoantibodies are lacking. Cerebrospinal fluid (CSF) findings are consistent with central nervous system (CNS) inflammation. Signal transducer and activator of transcription 1 (STAT1) phosphorylation, NFkB signaling, and IFN gene expression are increased.

Observational data suggest that immunomodulation with anticytokine therapy can improve autoinflammatory disease manifestations. In one case series, all four patients treated with anti-TNF therapy (adalimumab) had improvement in fatigue, headache, or arthralgia when present, and CRP normalized in three [28]. All six patients treated with anti-IL-1 therapies (anakinra or canakinumab) noted some improvement in subjective symptoms, but episodic CRP elevation remained. Two patients treated with IL-6 blockade (tocilizumab) who did not have advanced retinal disease had significantly improved intraocular inflammation. Additional studies are needed to determine the best choice of therapy and whether earlier treatment can prevent development of disease manifestations.

Defects of linear ubiquitination — Ubiquitination is a form of post-translational modification that targets proteins for proteasome degradation. Attachment of linear chains of ubiquitins also regulates the function of intracellular signaling complexes, including the TNF receptor and its downstream mediators, including NFkB. The protein complex responsible for ubiquitination is the linear ubiquitin chain assembly complex (LUBAC) [8,29]. Maintenance of proper levels of LUBAC requires the presence of OTU deubiquitinase with linear linkage specificity (OTULIN) that limits LUBAC autoubiquitination [30,31]. Ubiquitin-like modifier-activating enzyme 1 (UBA1) is a ubiquitin-activating enzyme (E1) that initiates ubiquitination.

OTULIN deficiency — Patients with homozygous deficiency of OTULIN demonstrate enhanced NFkB signaling and a clinical syndrome characterized by fevers, systemic inflammation, diarrhea, panniculitis, and arthritis beginning in infancy, termed alternately OTULIN-related autoinflammatory syndrome (ORAS); autoinflammation, panniculitis, and dermatosis syndrome (AIPDS); or otulipenia (MIM#617099) [32,33]. Patients may respond to TNF inhibition or bone marrow transplantation [31].

LUBAC deficiency — Patients with linear ubiquitin chain assembly complex (LUBAC) deficiency due to homozygous deletions affecting one of its component proteins, heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1) or HOIL-1 interacting protein (HOIP), also present with autoinflammation, manifesting as fever lasting up to 15 days, invasive bacterial infection with organisms such as Streptococcus pneumoniae or Haemophilus influenzae, hepatosplenomegaly, and amylopectinosis (a glycogen storage disease) [34,35]. NFkB signaling in these patients is reduced rather than increased, although enhanced responsive to IL-1-beta is observed, such that disease pathogenesis remains uncertain. (See "Toll-like receptors: Roles in disease and therapy", section on 'HOIL-1/HOIP deficiency'.)

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome — Although classified here with the NFkBopathies, the VEXAS phenotype probably reflects cellular aberrancy that extends well beyond the NFkB pathway. In the initial report of this syndrome, a myeloid-restricted, somatic missense mutation in codon 41 of UBA1, an X-linked gene that encodes the enzyme that initiates ubiquitination, was identified in 25 men from the United States and the United Kingdom with severe, late-adult onset autoinflammatory disease [36]. There was significant phenotypic variation despite all patients having a pathogenic variant affecting the same amino acid (p.Met41Val, p.Met41Thr, or pMet41Leu) that led to production of catalytically deficient cytoplasmic UBA1 and activation of multiple innate immune pathways. In a Spanish cohort of 30 patients, two were found to have a splice acceptor site pathogenic variant, not a p.Met41 variant [37]. Additionally, UBA1 mosaicism was detected in both hematopoietic and nonhematopoietic tissues, indicating that the mutational event occurs during early embryonic development not adulthood as was previously suspected. In an unselected patient population screened for pathogenic UBA1 variants, 1 in 13,591 unrelated persons, 1 in 4269 males >50 years, and 1 in 26,238 females >50 years were identified [38].

The common clinical features are recurrent fevers; systemic inflammation involving the skin, lung, cartilage, and/or vasculature; elevated acute-phase reactants including ESR and ferritin; and progressive hematologic abnormalities including cytopenias and dysplastic bone marrow with vacuolization of myeloid and erythroid precursor cells [36,37,39-43]. Diseases reported in the initial cohort and others include relapsing polychondritis, neutrophilic dermatoses such as Sweet syndrome, polyarteritis nodosa, giant cell arteritis, venous thromboembolism, myelodysplastic syndrome, and multiple myeloma. The presentation and clinical course of myelodysplastic syndrome seen in VEXAS are distinct from typical clonal hematopoiesis [44]. Some patients with myelodysplastic syndrome progressed to acute myeloid leukemia in an Italian cohort [40]. In patients identified by genetic screening in an unselected health care system cohort, two phenotypes were found: the classic, highly inflammatory phenotype and a "pauci-inflammatory" phenotype with only hematologic and rheumatologic features [38].

In a French cohort of 124 patients, 74 (60 percent) were found to have an increased risk of serious infections, primarily bacterial and viral (52 and 30 percent, respectively) but also including invasive fungal and atypical infections that occurred despite antimicrobial prophylaxis [39]. Pulmonary infections were the most common (59 percent), with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Legionella pneumophila, and Pneumocystis jirovecii the main pathogens identified. Treatment with JAK inhibitors was most strongly associated with serious infection compared with other therapies, but 16 percent of severe infections occurred in patients who were not on immunosuppressive therapy and whose glucocorticoid dose was ≤10 mg daily, suggesting an intrinsic immunodeficiency. Age >75 years and p.Met41Val mutation were also associated with increased risk of serious infections.

The mortality rate is high, ranging from 12 to 40 percent [36,37,39,40]. Most deaths are due to infection and progression of myelodysplastic syndromes [41]. Inflammatory manifestations typically improve on higher doses of glucocorticoids, but patients usually are unable to wean off them. Variable rates of response in small numbers of patients are reported for several other classes of medications including targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) such as JAK inhibitors, bDMARDs such as monoclonal antibodies to IL-6 receptor (eg, tocilizumab) and IL-1-beta (eg, canakinumab), and csDMARDs such as IL-1 receptor antagonists (eg, anakinra) [37,39-41,45]. Several patients with hematologic manifestations, primarily severe autoinflammatory manifestations refractory to multiple therapies or myelodysplastic syndromes, have been treated successfully with hypomethylating agents (eg, azacitidine, decitabine) or HCT [45,46].

Blau syndrome — Blau syndrome (MIM #186580) is an autosomal dominant condition characterized by granulomatous inflammation of the skin, eye, and joints [47]. The syndrome arises through gain of function in nucleotide-binding oligomerization domain protein 2 (NOD2, also called caspase recruitment domain-containing protein 15 [CARD15]), an intracellular sensor for the bacterial cell wall component muramyl dipeptide (MDP) [48,49]. NOD2 bound to MDP oligomerizes to form a signaling complex that triggers classical NFkB activation [50]. Human cells bearing Blau-associated NOD2 mutations do not exhibit either spontaneous NFkB activation or enhanced sensitivity to MDP, but instead trigger NFkB with exposure to otherwise insufficient stimuli including interferon gamma, resulting in enhanced production of multiple proinflammatory cytokines [51]. NOD2 variants also confer risk of inflammatory bowel disease, but these mutants impair rather than enhance NFkB function [49,52]. Asymptomatic carriers of Blau-associated mutations have been reported [53].

Patients with Blau syndrome exhibit a papular erythematous rash, sometimes only transiently. Arthritis develops in the first decade of life, often as minimally symptomatic and minimally erosive swelling in wrists, ankles, knees, and/or elbows with progressive flexion contractures of the fingers. Biopsy of joints and skin can reveal noncaseating granulomas; indeed, mutations in NOD2 underlie most cases of what had previously been termed early-onset sarcoidosis [54-56]. Uveitis may lead to glaucoma and blindness [57,58]. Less common manifestations include fever, cranial neuropathies, arteritis, and granulomatous involvement of visceral organs [57,59]. Treatment with methotrexate, TNF inhibitors, and mycophenolate mofetil can be effective [58,60]. IL-1 or IL-6 blockade have been effective in some patients [61,62]. A role of JAK inhibitors such as tofacitinib has been observed at an anecdotal level but has not been studied formally [63].

Aberrant TNF activity — TNF is a canonical proinflammatory cytokine, produced by innate immune lineages such as macrophages but also by T cells [64,65]. The cytokine is expressed on the cell surface as a membrane-bound trimer that is then released by cleavage mediated by TNF-alpha-converting enzyme (TACE). Both membrane-bound and soluble TNF can interact with specific receptors. TNF receptor 1 (TNFR1), expressed broadly across lineages, recognizes either form of TNF. TNF receptor 2 (TNFR2) is expressed in a more restricted fashion, including on monocytes and regulatory T cells, and recognizes principally the membrane-bound form of TNF. Both receptors signal via pathways that include NFkB. TNFR1 also prominently engages mechanisms that, unless antagonized, trigger cell death (apoptosis, necroptosis). When ligated, membrane-bound TNF can itself signal via pathways including NFkB. This diversity of signaling provides multiple opportunities for pathologic genetic variants in the TNF pathway to induce inflammation.

TNF receptor 1-associated periodic syndrome (TRAPS) — TRAPS (MIM #142680) was the second autoinflammatory disease for which the genetic defect was described, after familial Mediterranean fever [66]. Formerly known as familial Hibernian fever or familial periodic fever, TRAPS is inherited in an autosomal dominant fashion with incomplete penetrance. The genetic defect resides in the gene encoding the 55 kDa receptor for TNF (TNF receptor 1 [TNFRSF1A]), resulting in aberrant activation of NFkB and other inflammatory pathways.

Patients may present from infancy to the 40s and beyond, although more than half develop symptoms in the first decade of life. The first patients identified were of Irish (Hibernian) descent, but other ethnicities are also represented. Flares last for at least five days and often continue for more than two weeks. They are typically accompanied by conjunctivitis and periorbital edema in addition to focal migratory myalgias, rash, abdominal pain, and occasionally monoarthritis. The rash may take a relatively characteristic form, with single or multiple erythematous patches that spread distally down an extremity.

The genetics, clinical manifestations, pathogenesis, prognosis, and treatment of TRAPS are discussed in detail elsewhere. (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

TRAPS11 — Three patients have been described with a tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) like presentation and mutations affecting TNFRSF11A, encoding receptor activator of NFkB (RANK) [67]. One patient had an extensive duplication encompassing this gene, and two were a mother-daughter dyad sharing a one base-pair deletion resulting in a frame shift. Patients presented with recurrent episodes of fevers and systemic inflammation lasting several days to several weeks, together with abdominal pain and arthralgia. Glucocorticoids and colchicine were partially effective. Termed TRAPS11 for its clinical similarity to TRAPS, the pathogenesis of this condition remains unknown.

Deficiency of adenosine deaminase 2 (DADA2) — Homozygous deficiency of the enzyme ADA2 results in an autoinflammatory syndrome termed DADA2 [68,69]. Patient presentation is highly variable, both in systems affected and in age of presentation [70,71]. Cardinal manifestations include vasculitis often presenting in childhood and manifesting as ischemic or hemorrhagic stroke, livedo reticularis, immunodeficiency, bone marrow failure, and systemic inflammation. While the pathogenesis of DADA2 is incompletely understood, it is included here because TNF blockade is remarkably effective for the prevention of recurrent vasculitic episodes, although this therapy is less effective for cytopenias and may complicate the immunodeficiency [72,73]. DADA2 is discussed in greater detail separately. (See "Deficiency of adenosine deaminase 2 (DADA2)".)

DIAGNOSIS — As with other autoinflammatory diseases, NFkB-mediated autoinflammatory diseases should be considered in patients who present with inflammatory episodes that recur or persist over months or years in the absence of other causes. Unusual infections and malignancy are first excluded. The evaluation then proceeds with an attempt to identify a clinical pattern consistent with one of the known autoinflammatory disorders (table 1). Genetic testing remains the mainstay of diagnosis, either targeted to a single gene or more commonly to a panel of autoinflammation-associated diseases. Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations that can be missed by conventional sequencing and may require sequencing of myeloid cells, deep sequencing, or droplet digital polymerase chain reaction (ddPCR) testing. Classification criteria incorporate the results of such genetic testing, considering both unambiguously pathogenic mutations and variants of indeterminate significance, although these criteria are intended to guide research rather than diagnosis [74]. Clinical criteria, in the absence of genetic data, have been developed for the diagnosis and classification of the NFkB-driven disease TNF receptor-1 associated periodic syndrome (TRAPS) (table 2) [75]. Deficiency of adenosine deaminase 2 (DADA2) can be diagnosed by measurement of adenosine deaminase 2 (ADA2) activity [73]. The diagnosis of TRAPS is discussed in greater detail separately. (See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)", section on 'Diagnosis'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis is discussed in detail elsewhere but is mentioned briefly here. (See "The autoinflammatory diseases: An overview", section on 'Differential diagnosis'.)

The differential diagnosis of the NFkB-mediated autoinflammatory diseases includes other autoinflammatory diseases, for example, those mediated through inflammasomes or interferon. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)" and "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

The differential diagnosis also includes unusual infections such as relapsing fever, malignancy and premalignant states (Schnitzler syndrome), cyclic neutropenia, and rheumatic diseases including systemic juvenile idiopathic arthritis (sJIA)/adult-onset Still's disease (AOSD). (See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation" and "Fever of unknown origin in adults: Etiologies" and "Fever of unknown origin in adults: Evaluation and management".)

Patients with NFkB-mediated diseases may also present with recurrent infections and thus with immunodeficiency rather than autoinflammation as the dominant disease feature. (See "Toll-like receptors: Roles in disease and therapy", section on 'NEMO defects' and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'NEMO deficiency' and "Combined immunodeficiencies: An overview".)

TREATMENT — Glucocorticoids directly suppress NFkB activation by enhancing expression of the inhibitor of NFkB (IkB) proteins and other counterregulatory proteins and by direct binding of the glucocorticoid receptor complex to NFkB itself, along with other pathways [76,77]. Glucocorticoid therapy is thus effective in the NFkB-mediated autoinflammatory diseases, although often at the expense of unacceptable toxicity.

Blockade of mediators such as TNF, interleukin (IL) 1, and IL-6 (cytokines that are induced by NFkB and that in turn trigger further NFkB activation by binding to their surface receptors) can be helpful. TNF antagonists are particularly effective in conditions such as Blau syndrome, haploinsufficiency of RELA, and the vasculitic and inflammatory manifestations of deficiency of adenosine deaminase 2 (DADA2) (see 'Blau syndrome' above and 'RELA haploinsufficiency' above and 'Deficiency of adenosine deaminase 2 (DADA2)' above). IL-1 blockade is particularly effective in TNF receptor 1-associated periodic syndrome (TRAPS) [78]. Colchicine, an inhibitor of microtubules and the NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) inflammasome, can be helpful in haploinsufficiency of A20 (HA20). Janus kinase (JAK) inhibitors may be effective in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Nonsteroidal antiinflammatory drugs (NSAIDs) can play ancillary roles.

SUMMARY AND RECOMMENDATIONS

●Definition – The autoinflammatory diseases constitute a family of disorders characterized by aberrant activation of inflammatory pathways in the absence of antigen-directed autoimmunity. (See 'Introduction' above.)

●Pathogenesis – Some autoinflammatory diseases are mediated by the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB). Normally sequestered in the cytoplasm, mutations affecting NFkB regulatory proteins result in aberrant translocation to the nucleus, where NFkB drives transcription of proinflammatory genes such as interleukin (IL) 1-beta and tumor necrosis factor (TNF). Although classified with the NFkBopathies, the vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) phenotype probably reflects cellular aberrancy that extends well beyond the NFkB pathway. (See 'Overview of NFkB' above.)

●Clinical manifestations and diagnosis – NFkB-mediated autoinflammatory disease include haploinsufficiency of A20 (HA20), VEXAS, Blau syndrome, TNF receptor 1-associated periodic syndrome (TRAPS), and deficiency of adenosine deaminase 2 (DADA2). Clinical features vary widely but can include fever, oral ulcers, rash, uveitis, and colitis. DADA2 can present as stroke in children, whereas VEXAS is due to somatic mutations and has a late-adult onset. Diagnosis is typically by genetic testing. (See 'Specific diseases' above and 'Diagnosis' above.)

●Treatment – Treatment typically begins with glucocorticoids. Data on other treatments for the NFkB-mediated autoinflammatory disease are limited due to the rarity of these diseases, but inhibitors of cytokines including TNF, IL-1, and IL-6 may provide substantial relief to some patients. (See 'Treatment' above.)