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Abstract
Autoinflammatory diseases (AIDs) refer to a broad range of genetically mediated conditions characterized by recurrent attacks of systemic inflammation with typical manifestations of fever, rash, serositis, lymphadenopathy, and musculoskeletal symptoms. The discovery of genetic basis for these conditions have led to the understanding of novel intracellular receptors for infectious and noninfectious danger signals in innate immunity. Innate immunity has a key role in the development of AIDs, in contrast with autoimmune disease, which arise from problems in adaptive immunity. Advances in understanding the molecular mechanisms of intracellular inflammatory cascades have led to renewed interest in its role in the pathogenesis of more common non-genetic autoinflammatory rheumatic conditions, such as Behcet's disease, gouty arthritis, Adult onset Still's diseases, and systemic onset juvenile arthritis. The characterization of cryopyrin (inflammasome) and its significant role in the activation of proinflammatory cytokines, such as IL-1β and TNF-α in the development of AIDs, has provided rational targets of anti-cy-tokine biologic treatment for some of these conditions.
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Figure 1.
The schematic pathway of inflammasome activation and secretion of Interleukin-1 (IL-1). PAMP: pathogen associated molecular pattern, DAMP: damage associated molecular pattern, LRR: leucin repeat region, PYD: pyrin domain, ASC: apotosis-associated speck-like protein containing CARD (A: dashed box shows detailed structure of pyrin domain).
Figure 2.
Molecular targets of monogenic autoinflammatory syndromes. Mutated proteins are marked as stars. PAMP: pathogen associated molecular pattern, DAMP: damage associated molecular pattern, LRR: leucin repeat region, PYD: pyrin domain (dashed box shows detailed structure of pyrin domain).
Table 1.
Classification of pattern-recognition receptor
| Secreted | Transmembrane | Cytosolic |
|---|---|---|
| Collectin | Toll-like receptor (TLR) | RIG-I-like receptor (RIR) |
| Ficolin | C-type lectin | NLR* |
| Pentraxin | Absent in melanoma 2 (AIM2) | |
| Interferon-inducible protein 16 (IFI16) |
Table 2.
Classification of monogenic autoinflammatory diseases by clinical features
FMF: Familial Mediterranean fever, MKD: Mevalonate kinase deficiency, TRAPS: TNF receptor-associated periodic syndrome, AD: autosomal dominant, AR: autosomal recessive, FCAS: familial cold autoinflammatory syndrome, MWS: Muckle-Wells syndrome, CINCA: chronic infantile neurological cutaneous and articular syndrome, PAPA: pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome.
Table 3.
Drug treatment for various autoinflammatory diseases
| Disease | Drugs | Evidence | |
|---|---|---|---|
| periodic/recurrent fever | FMF | Colchicine | +++ |
| Anti-IL-1 | ++ | ||
| Anti-TNF | + | ||
| MKD | Systemic steroids | ++ | |
| Anti-IL-1 | + | ||
| Anti-TNF | + | ||
| TRAPS | Systemic steroids | ++ | |
| Etanercept | ++ | ||
| Infliximab | - | ||
| Anakinra | + | ||
| Cryopyrinopathies | FCAS, MWS | Anti-IL-1 (anakinra, rilonacept, canakinumab) | ++ |
| CINCA | |||
| Granulomatous disorders | Blau's syndrome | Systemic steroids | + |
| Cyclosporin A | + | ||
| Methotrexate | + | ||
| Anti-IL-1/anti-TNF | + | ||
| Pyogenic disorders | PAPA syndrome | Systemic steroids | ++ |
| Anti-IL-1 | + | ||
| Anti-TNF | + | ||
| DIRA | Anakinra | +++ | |
| Systemic rheumatic diseases | Behcet disease | Colchicine | +++ |
| Cyclosporin A | ++ | ||
| Anti-TNF | + | ||
| AOSD* | Systemic steroids | +++ | |
| Anakinra | ++ | ||
| JIA† | Anti-TNF | ++ | |
| Anti-IL-1 | + | ||
| Gout | Colchicine | +++ | |
| Anti-IL-1 | ++ | ||
| SAPHO‡ | Anti-TNF | ++ | |
| Anakinra | + |
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