Autoinflammatory diseases mediated by miscellaneous mechanisms

INTRODUCTION — Autoinflammatory diseases are conditions of pathogenic chronic or recurrent inflammation mediated by antigen-independent hyperactivation of the immune system [1]. Most represent inborn errors of immunity. 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 via mechanisms beyond those covered in other specific topics:

●(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 NFkB and/or aberrant TNF activity".)

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

A general discussion of autoinflammatory diseases is available separately, as are topics on classification and genetic diagnosis of inborn errors of immunity:

●(See "The autoinflammatory diseases: An overview".)

●(See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

●(See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

OVERVIEW OF PATHOGENESIS — Normal immune function requires that inflammatory pathways are activated when needed for host defense, but that activation is limited to the intensity, location, and duration required to clear the threat in order to minimize damage to healthy tissues. To achieve this end, multiple negative regulatory loops are in place to constrain and ultimately shut down proinflammatory pathways. Dysfunction in these mechanisms can result in autoinflammation. Examples discussed elsewhere include variants in MEFV that render the protein pyrin resistant to control through phosphorylation, leading to familial Mediterranean fever (see "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis"); variants in ubiquitin-specific peptidase 18 (USP18) that intensify interferon (IFN) receptor signals, resulting in an interferonopathy termed pseudo-TORCH (toxoplasmosis, other [syphilis], rubella, cytomegalovirus, herpes simplex virus) syndrome (see "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'Pseudo-TORCH syndrome'); and aberrant activation of proinflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) through deficiency of the key regulatory protein A20. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Haploinsufficiency of A20'.)

Here, we discuss autoinflammatory disorders that do not fit comfortably into any of the broad autoinflammatory disease categories or define their own. These disorders arise from deficiency of adenosine deaminase 2 (ADA2), defects in vesicle trafficking (COPA syndrome), and pathogenic variants affecting phospholipase C gamma 2 (PLCG2), or transfer RNA (tRNA) nucleotidyltransferase, CCA-adding 1 (TRNT1).

SPECIFIC AUTOINFLAMMATORY DISORDERS

COPA syndrome — Pathogenic variants in the coatomer protein complex, subunit alpha gene (COPA) result in a syndrome featuring interstitial lung disease, pulmonary hemorrhage, and inflammatory arthritis (see "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Genetic testing') [2,3]. Patients may have autoantibodies including rheumatoid factor, anti-cyclic citrullinated peptide (CCP), antinuclear antibody (ANA), and antineutrophil cytoplasmic antibody (ANCA). Peripheral blood analysis reveals an interferon gene signature [4]. How this signature arises remains unclear.

COPA helps to transport vesicles from the Golgi apparatus to the endoplasmic reticulum. This vesicular movement, retrograde with respect to the normal flow of protein synthesis and secretion, limits endoplasmic reticulum accumulation of the protein stimulator of interferon genes (STING), a key molecule in the detection of intracellular DNA viruses. Deficiency of COPA results in excess STING signaling and thereby aberrant production of type I interferons [5]. This close relationship between COPA and STING helps explain the clinical similarity between COPA syndrome and STING-associated vasculopathy with onset in infancy (SAVI). More generally, aberrant vesicular trafficking promotes inflammation through inadequate protein processing, triggering the cell's unfolded protein response [2]. Studies in an animal model implicate defects in T cell education in the thymus, as well as defects in regulatory T cells, resulting in lung damage mediated directly by pathogenic T cells and blurring the border between autoinflammation and autoimmunity [6]. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)", section on 'STING-associated vasculopathy with onset in infancy (SAVI)'.)

Response to Janus kinase (JAK) inhibitor treatment is reported, and glucocorticoids and other immunosuppressive agents provide some benefit [7-10].

PLAID/APLAID — Autoinflammation and phospholipase C gamma 2 (PLCG2) associated antibody deficiency and immune dysregulation (APLAID) and PLAID (also called familial cold autoinflammatory syndrome 3 [FCAS3], a form of familial atypical cold urticaria) are caused by different heterozygous pathogenic variants of the PLCG2 gene [11,12]. (See "Cryopyrin-associated periodic syndromes and related disorders" and "Cold urticaria", section on 'Atypical forms of cold urticaria'.)

The autoinflammation in PLAID manifests as pruritic erythema with urticaria and sometimes angioedema elicited by evaporative cooling (eg, exposure to cold air or wind) rather than touching cold objects or water [11]. Neonatal skin findings include ulcers and other lesions in cold-sensitive regions (nose, fingers, toes, cheeks) and granulomatous lesions that spare warm regions (flexural areas, skin folds) [13]. Cold-induced leukocyte activation is also seen. Autoimmunity and immunodeficiency (antibody/B cell and natural killer [NK] cell defects) are each present in approximately one-half of patients.

APLAID is characterized by recurrent blistering skin lesions, ocular inflammation, enterocolitis, bronchiolitis, arthralgia, and mild immunodeficiency [12].

Treatment of PLAID and APLAID is not well established. PLAID symptoms can be ameliorated partially through avoidance of evaporative cooling (eg, by toweling off rapidly after exercise or showering) as well as antihistamines [14]. Environmental triggers for APLAID are not well defined. Glucocorticoids improve APLAID-associated inflammation, but usage is limited by side effects. Partial response to interleukin (IL) 1 blockade was reported in one family but not in another [12,15].

SIFD syndrome — Congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) is caused by hypomorphic biallelic variants in the tRNA nucleotidyl transferase 1 (TRNT1) gene, encoding the enzyme tRNA nucleotidyltransferase, CCA-adding 1, that lead to dysregulation in protein clearance pathways [16,17]. TRNT1 is ubiquitously and constitutively expressed. Patients with SIFD have increased levels of IL-6 and interferon (IFN) gamma in the serum and TNF and IL-1-beta in tissue biopsies. Mitochondrial dysfunction is also seen.

The spectrum of clinical features is broad and includes [16,18-21]:

●Fever that typically lasts five to seven days

●Mucocutaneous (oral ulcers, cellulitis) manifestations

●Musculoskeletal (arthralgias, arthritis, dactylitis) manifestations

●Sideroblastic or aplastic anemia

●Immunodeficiency of variable severity (hypogammaglobulinemia most common; B cells low, with decreased mature cells, to normal; T and NK cells also low to normal; serious bacterial and viral infections rare)

●Enteropathy

●Vision and sensorineural hearing loss

●Developmental delay, neurodegeneration, seizures, and cerebellar abnormalities

●Failure to thrive

Severity can range from profound anemia, severe immunodeficiency, hemophagocytic lymphohistiocytosis, and metabolic abnormalities with death in early childhood to milder forms with retinitis pigmentosa and more moderate hematologic and immunologic defects. Median survival is 48 months. Complete deficiency of TRNT1 is embryonic lethal. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (TRNT1 mutation)'.)

Several patients have been successfully treated with TNF inhibitors (infliximab or etanercept), with suppression of fevers, improvement in other clinical manifestations, and normalization of elevated acute-phase reactants and proinflammatory cytokines and chemokines [22].

DIAGNOSIS — 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.

The disorders considered in this topic should be considered for patients who develop some combination of the following symptoms, especially beginning in childhood:

●Coatomer protein complex subunit alpha (COPA) syndrome – Interstitial lung disease, pulmonary hemorrhage, arthritis, autoantibodies

●PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) – Cold-induced urticaria, acral blistering lesions, humoral immunodeficiency, tissue-focused inflammation

●Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) – Fever, anemia, retinitis, skin and joint inflammation

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of the autoinflammatory diseases reviewed here includes other autoinflammatory diseases, for example, mediated through inflammasomes, interferon, or nuclear factor kappa B (NFkB)/tumor necrosis factor (TNF) (table 1). (See "The autoinflammatory diseases: An overview", section on 'Diagnosis'.)

Other inflammatory diseases to be considered include multicentric Castleman disease and autoimmune lymphoproliferative syndrome (ALPS). (See "HHV-8-negative/idiopathic multicentric Castleman disease" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

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 "The autoinflammatory diseases: An overview", section on 'Differential diagnosis' and "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".)

TREATMENT — Treatment of the autoinflammatory diseases discussed here varies with condition (see discussions on each specific autoinflammatory disorder above). Therapies for coatomer protein complex subunit alpha (COPA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID), and sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) are less well established, and patients respond variably to glucocorticoids, tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, or other interventions.

SUMMARY

●Overview – The autoinflammatory diseases (table 1) constitute a family of disorders characterized by aberrant activation of inflammatory pathways in the absence of antigen-directed autoimmunity. Most forms of autoinflammatory disease represent inborn errors of immunity. (See 'Introduction' above.)

●Pathogenesis and specific disorders – Some autoinflammatory diseases are mediated by mechanisms that do not fall comfortably within the major families of autoinflammatory disorders. These include coatomer protein complex subunit alpha (COPA) syndrome, PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID), and sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). (See 'Overview of pathogenesis' above and 'Specific autoinflammatory disorders' above.)

●Diagnosis – 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. After excluding unusual infections and malignancy, the next step is to attempt to identify a clinical pattern consistent with one of the known autoinflammatory disorders (table 1). Genetic testing remains the mainstay of diagnosis. (See 'Diagnosis' above and "The autoinflammatory diseases: An overview", section on 'Diagnosis'.)

●Differential diagnosis – The differential diagnosis of autoinflammatory diseases 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 'Differential diagnosis' above and "The autoinflammatory diseases: An overview", section on 'Differential diagnosis'.)

●Treatment – Treatments for COPA syndrome, PLAID/APLAID, and SIFD are not well established. (See 'Treatment' above.)