The classification of auto-inflammatory diseases is complicated, Professor Li Caifeng clarified in an article!

Auto-inflammatory diseases (AlDs) are a group of diseases
that cause changes in the proteins encoded by single gene mutations, inherent immune disorders, and eventually lead to a multi-organ inflammatory response in the body.
AlDs usually begins in childhood and presents with a variety of clinical manifestations, including recurrent inflammatory reactions
such as fever, rash, serositis, synovitis, or certain specific organs.

AIDs are mainly divided into the following categories according to pathogenesis: inflammatory body signaling pathway disease, interferon (IFN) signaling pathway disease, nuclear transcription factor (NF-κB) signaling pathway disease, in addition, protein folding disorder disease, other cytokine-mediated diseases and other diseases with unclear classification
.

Recently, the 9th Children's Rheumatic Immunization Summit Forum and the 15th National Children's Rheumatic Immunological Disease Study Class were held
online.
Professor Li Caifeng of Beijing Children's Hospital affiliated to Capital Medical University introduced the disease according to the pathogenesis of AlDs, bringing full of dry goods
.

Inflammatory microbody signaling pathway disease

Common clinical features of inflammatory microbody signaling pathway disorders are:

• Fever;

• Neutrophil rash: erysipelas-like rash, impetigo, urticaria, gangrenous pyoderma;

• Anti-interleukin-1 (Anti-IL-1) therapy is effective
  .
  

At the meeting, Professor Li Caifeng mainly introduced the following four types of inflammatory microbody signaling pathway diseases
.

(1) Cryopyrin-related cycle syndrome (CAPS)

CAPS is a group of autoinflammatory diseases caused by the function-acquired consolidation of the gene NLRP3 encoding cryopyrin, inherited in an autosomal dominant manner
.

CAPS contains diseases (from mild to severe): familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and CINCA syndrome
.
Its clinical features are mainly fever, arthralgia and urticaria, which can affect the skin, muscles, bones, joints, eyes, ears and central nervous system, and IL-1 receptor antagonists can effectively control the progression of
the disease.

(2) Familial Mediterranean fever (FMF)

FMF is an autoinflammatory disease caused by an acquired mutation in the MEVF function of the gene encoding the pyrin protein, inherited in an autosomal recessive manner
.

The clinical features of FMF are fever, chest pain, abdominal pain, serositis, erysipelas-like erythema, a brief but obvious inflammatory response at the time of the attack, and a recessive inflammatory response
between attacks.
Notably, recurrent inflammatory attacks significantly increase the risk of AA amyloidosis and eventually lead to end-stage renal disease (ESRD
).

Colchicine is effective in most patients with FMF, can effectively prevent cyclical fever and amyloidosis, and patients who do not respond to colchicine therapy (about 10%) can be treated
with IL-1 receptor antagonists.

(3) Purulent aseptic arthritis - gangrene pyoderma - acne syndrome (PAPA)

PAPA is a group of autoinflammatory diseases caused by heterozygous mutations in the PSTPIP1 gene, inherited in an autosomal dominant manner
.

Typical triad of PAPA includes purulent aseptic arthritis, gangrene pyoderma, acne, and some patients may present with a pathogenic aseptic abscess at the injection site and pyoderma
gangrene.
Joint involvement is characterized by aseptic oligoarthritis, which gradually resolves
over the course of the disease.

(4) High IgD with periodic fever syndrome (HIDS/MKD)

HIDS is an autoinflammatory disease caused by a mutation in the mevalonate kinase gene (MVK) loss of function and is inherited in an autosomal recessive manner
.

HIDS often begins in childhood, with 90% of patients developing
within the first year of life.
Clinical manifestations include: recurrent fever with maculopapular rash, lymphadenopathy, abdominal pain, and elevated serum IgD, each lasting 3 to 7 days, the interval between asymptomatic attacks usually lasts 1 to 2 months, leukocytes and neutrophils may occur at the time of the attack, and inflammation may be elevated in the acute stage; Increased urinary mevalonic acid; Serum lgD (>100 IU/ml) and lgA levels are elevated in more than 80% of patients, well and remain elevated between episodes
.

Interferon pathway disease

Common clinical features of interferon pathway disease are:

• Cutaneous vascular manifestations (erythema nodosum, frostbite-like rash, reticulated blue spots, gangrene/ulceration of the extremities, vasopathic changes);

• Adiponitis, lipodystrophy;

• manifestations of the central nervous system (basal ganglion calcification, leukodyma);

• pulmonary involvement (interstitial lung disease, pulmonary fibrosis);

• Muscular-muscular manifestations (contractures, non-invasive arthritis, myositis
  ).
  

(1) STING-related vascular disease with onset in infancy (SAVI)

SAVI is an autoimmune disease caused by a functionally acquired mutation in the gene encoding STING (TMEM173) in an autosomal dominant manner
.

Patients with SAVI often develop early infancy, and clinical features include rashes (telangiectasia, pustules, and/or vesicles) on the face, hands, and feet, worsening with cold exposure, ulcers; Interstitial lung disease, pulmonary fibrosis; Some patients may also experience perforation
of the nasal septum.

(2) Aicardi-Goutières syndrome (AGS)

AGS is a rare group of genetic disorders with neurological and cutaneous involvement
.
Clinical features include multiple intracranial calcifications, leukoles, chronic lymphocytosis of the cerebrospinal fluid (CSF), and frostbite-like lesions
.
Some children have a normal number of CSF lymphocytes early in the course of the disease, and a few may also show autoimmunity, autoinflammation, abnormal vascular network at the base of the skull, or intracranial macrovasculitis
.

(3) Proteasome-associated autoinflammatory syndrome (PRAAS)

PRAAS is a group of autoinflammatory diseases caused by mutations in genes encoding 20S core granosome subproteasome or proteasome chaperone proteins, causing increased IFN production, and is inherited in an autosomal recessive manner
.

Clinical features of PRAAS include frostbite-like purple nodular lesions (neutrophilic dermatosis), alipositis with progressive lipodystrophy and muscle atrophy, and joint contractures
with limb deformities.

(4) Chronic atypical neutrophil dermatitis with lipodystrophy and hyperthermia (CANDLE)

The age of onset of CANDLE < June (mostly 2-4 weeks), which is mainly manifested by recurrent fever, purplish-red macules (recurrent attacks, residual purpura), periorbital edema and erythema, and lipodystrophy<b10>.
Laboratory tests may be: elevated CRP/ESR; Early increase in leukocytes and decrease in later stages; ANCA antibody, CANCA, ANA positive; Cytokines IL-6 and IP-10 are elevated
.
Pathological examination reveals atypical myeloid monocyte infiltration in the perivascular and interstitial regions, including non-vasculitic inflammatory responses
involving mature neutrophils and partial monocytes.

NF-κB signaling pathway-mediated AIDs

Common clinical features of NF-κB signaling pathway-mediated AIDs are:

• granulomas / mouth sores;

• Rainbow eyelash;

• Immunodeficiency
  .
  

(1) Granulomatous arthritis in children (Blau syndrome)

Blau syndrome is an autoimmune disease caused by a mutation in the NOD2/CARD15 gene, in which the family onset is Blau syndrome and the sporadic is early-onset sarcoidosis
.
The mode of inheritance is autosomal dominant
.

The clinical manifestations of Blau syndrome are characterized by a triple sign of rash, arthritis, and iridocyclitis, with macrovasculitis, granulomatous interstitial nephritis, and granulomatous changes
of hepatosplenic granuloma.
Laboratory anemia, elevated ESR, CRP, ANA and RF negative; Plain joint x-rays on imaging often show decreased bone density, but joint disruption or narrowing
is rare.

(2) Familial Behcet-like autoinflammatory response syndrome (HA20)

HA20 is an autoimmune disease caused by mutations in the TNFAIP3 gene encoding protein A20 and is inherited in an autosomal dominant manner
.

HA20 is more common in women (78%), the age of onset is small, with oral ulcers, genitals, gastrointestinal ulcers, and elevated acute reactants as the main clinical features, most of which are accompanied by skin pain, arthritis, and recurrent infections
.
At present, the main application of hormones and anti-TNF is used to treat HA20
.

Other AIDs disorders

(1) Tumor necrosis factor (TNF) receptor-related periodic syndrome (TRAPS)

TRAPS is a periodic febrile syndrome caused by mutations in the TNFRSF1A gene encoding the TNF receptor, inherited in an autosomal dominant manner with peptozoinity
.

TRAPS tends to begin in childhood (before the age of 10 years) and is characterized by recurrent prolonged fever, myalgia, periorbital edema, and migratory rash, and persistent inflammation may lead to secondary amyloidosis
.
Their ESR and CRP are elevated during and between episodes
.
Skin biopsy shows infiltration
of superficial and deep lymphocytes and monocytes.

(2) Adenosine deaminase 2 deficiency (DADA2)

DADA2 is an autoimmune disease caused by mutations in the ADA2 gene and is inherited in an autosomal recessive manner
.

24% of patients with DADA2 had onset age < 1 year, 77% had onset within 10 years of age, and the latest age of onset was 59 years<b10>.
Its clinical manifestations are fever, nodular arteritis, reticulobruis, and early-onset stroke, with a variety of manifestations and different degrees, with a mortality rate of 8%, and the common causes of death are stroke and infection
.

Diagnosis and treatment of AIDs

Professor Li Caifeng stressed that patients with the following clinical manifestations need to consider the possibility of AIDs:

1.
The age of onset is small;

2.
Unexplained recurrent fever, with or without asymptomatic intervals;

3.
Recurrent systemic symptoms such as rash or arthralgia / arthritis;

4.
Multi-system inflammation (inflammatory manifestations of synovium, serous membrane, eye, skin, nervous system, etc.
);

5.
Family history of similar diseases;

6.
The reactants in the acute phase are elevated during the attack, while the asymptomatic period can be normal;

7.
Long-term complications of the inflammatory response of the whole body;

8.
No clear infection, tumor and other diseases that need to be identified are found in the course of the disease
.

There are two main tests for AIDs, laboratory tests for inflammatory indicators and genetic testing for
genetic diseases.
For those with high clinical suspicion of AIDs, genetic testing is the key and foundation
to assist in the final diagnosis and the development of appropriate treatment plans.
The analysis and interpretation of genetic test results must be discussed
by the clinician, the genetic pathologist and the testing party.

Current therapeutic options for AIDs include targeted drugs and traditional drugs, and the key is to quickly control inflammation early and reduce disability and mortality
.

AIDs are a group of inflammatory genetic diseases with inherent immune disorders caused by genetic mutations, with complex and diverse clinical manifestations and significantly elevated
acute onset of inflammatory indicators.
Clinically, for those with a high suspicion of AIDs, genetic testing may be used to assist in the final diagnosis
.
Therapeutic drugs for AIDs include targeted drugs and traditional medicines, which require early and rapid control of systemic inflammation and improved prognosis
.

• Chief physician, professor, doctoral student/postdoctoral supervisor
• Director of the Department of Rheumatology, Beijing Children's Hospital, Capital Medical University
• Head of the Department of Rheumatology, Capital Medical University
• Standing Committee Member of Chinese Society of Rheumatology
• Vice Chairman of Beijing Society of Rheumatology
• Standing Committee Member of the Rheumatology Specialist Committee of the Chinese Medical Doctor Association and leader of the Children's Rheumatology Group
• Vice President of the Rheumatology and Immunology Branch of the Beijing Medical Doctor Association
• He is the leader of the rheumatology group of the Chinese Pediatric Association and the vice chairman of the Pediatric Humanities Construction Committee
• Honorary Vice President, Standing Committee Member and Chairman of the Pediatric Branch of the Cross-Strait Medical and Health Exchange Association
• Chairman of the Rheumatology and Immunology Professional Committee of Futang Children's Medical Development Research Center
• Vice Chairman of the First Committee of the Rheumatology and Immunology Branch of Beijing Medical Education Association
• Standing Committee Member of the Rheumatic Immunological Disease Drug Research Professional Committee of the Chinese Association of Chinese Medicines
• He is a member of the Standing Committee of the First Committee of the Rheumatology and Immunorehabilitation Professional Committee of the Chinese Rehabilitation Medical Association
• Standing Committee Member of the First Rheumatic Immunology Committee of the Chinese Association of Women Physicians
• He is a member of the second session of the Pediatrics Branch of the China Association for the Promotion of International Healthcare Exchange
• Member of the International Research Organization for Pediatric Rheumatology (PRINTO) and General Coordinator of China
• Member of the Pediatrics Group of the Asia-Pacific Federation of Rheumatology Societies (APLAR).
  

[1] Shen Min,Qing Yufeng,Shi Xiaofei,Fan Ping,Zhang Wen,Li Caifeng,Zhao Yan.
Diagnostic norms for autoinflammatory diseases[J].
Chinese Journal of Internal Medicine,2021,60(12):1129-1138.

[2] Rheumatology Group of Pediatrics Branch of Chinese Medical Association, et al.
" Expert consensus on the diagnosis and treatment of autoinflammatory diseases in children.
" Chinese Journal of Practical Pediatrics 37.
03(2022):161-172.

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