Diagnosis And Treatment Of Type I Interferon Disease

Objective:1.To summarize and analyze the clinical characteristics of patients of monogenic type I interferonopathies in China.2.To evaluate the effects and adverse reactions of Janus kinase(JAK)inhibitors in the treatment of type I interferonopathies.3.To explore the relationship between the loss of-function mutations of SAMD9L(Sterile alpha motif domain-containing 9 like)and type I interferonopathies.Method:1.Analyze the clinical datas of patients of type I interferonopathies,including 21 patients in our department and the Department of Rheumatology and Immunology of Shenzhen Children's Hospital and 31 cases who have been reported in China,and describe their clinical characteristics statistically.2.Analyze the effects of JAK inhibitors during the treatment for patients with type I interferonopathies in our department.3.Collect clinical datas and genetic datas of a patient who carried a frameshift mutation of SAMD9L.She had a clinical phenotype similar to type I interferonopathies.Sanger sequencing and Real time-PCR was conducted to explore the relationship between the SAMD9L and type I interferonopathies.Result:1.A total of 52 patients were enrolled,including 14 cases of Deficiency of adenosine deaminase 2(DADA2),20 cases of Aicardi-Goutieres syndrome(AGS),15 cases of STING-associated infantile-onset vasculopathy(SAVI),and 3 cases of Spondyloenchondro-dysplasia with immune dysregulation(SPENCDI).We identified 69.2%of the patients presented before the age of 3 years.The most vulnerable organs include skin(67.3%),nervous system(59.61%),pulmonary interstitial(40.38%),blood system(39.58%),thyroid(32%).The percentages of elevated ESR and positive autoimmune antibody were 69.44%,62.85%respectively.Except for DADA2,the expressions of ISGs in patients with the other three diseases were increased significantly.DADA2 mainly manifests as reticularis(57.14%)and early-onset cerebral infarction(57.14%).While the main clinical features of AGS were chilblain-like rash(55%),intracranial calcification(100%),growth retardation(68.42%),positive autoimmune antibodies are(63.64%).And the major symptoms of SAVI were lung interstitial disease(100%)and positive autoimmune antibodies(84.6%).Three cases of SPENCDI patients all manifested as vertebral dysplasia and intracranial calcification.2.A total of 6 patient with interferonopathies received the treatment with JAK inhibitors,including 2 cases of AGS,2 cases of SAVI and 2 cases of SPENCDI.The follow-up time was 3-30 months.Clinical symptoms,such as chilblain rash,respiratory symptoms,cytopenia,raised transaminase could be partially or completely relieved.Acute phase reactants(APR)of four cases were elevated,only APR of one case returned to normal.All the imaging manifestations of intracranial calcification,leukodystrophy and interstitial lung disease did not change significantly before and after treatment with JAK inhibitors.Expressions of ISGs of three cases were monitored dynamically,and two expressions of ISGs of the cases declined significantly.The levels of expressions of ISGs were inconsistent with clinical manifestations and severity of inflammation.3.A 2-month-old female patient manifested as hepatosplenomegaly,chilblain-like rash,growth retardation,epilepsy,increased APRs,decreased pancytopenia,increased transaminase,and decreased B cells,intracranial calcification.According to the results of WES,we anchored the candidate gene to SAMD9L.The de novo heterozygous mutation of SAMD9L was identified by Sanger sequencing.The mutation was c.26422729del/insTCCTGT,p.K881Ifs*2,which can lead to truncated protein.The expression of ISGs and SAMD9L were significantly higher than healthy control.After the treatment with JAK inhibitor,the clinical symptoms and laboratory indicators were significantly improved,and the level of expression of ISGs and SAMD9L decreased.Conclusion:1.If the disease starts before the age of 3 year,accompanied by one or more of the following clinical symptoms,including rash(chilblain rash,livedo reticularis),neurological symptoms(cerebrovascular events,intracranial calcification,leukodystrophy),interstitial lung disease,developmental backwardness,abnormal thyroid function and positive autoimmune antibodies,the possibility of type ? IFN disease should be considered.If the patient's main manifestations are vasculitis(livedo reticularis,early-onset cerebrovascular events),the possibility of DADA2 should be considered,and detection of ADA2 enzyme activity can be used to support the diagnosis.If the patient mainly performs with chilblain-like rash,neurological symptoms(intracranial calcification,leukodystrophy),the possibility of AGS should be considered.If the patient has interstitial lung disease as the main manifestation,the possibility of SAVI should be considered.Narrowing of the spine vertebral body is a relatively specific manifestation of SPENCDI.2.The effects of JAK inhibitors in the treatment of type ? interferonopathies are not uniform among our patients.JAK inhibitors may be partially or completely effective for the symptoms of systems,but the anti-inflammatory of JAK inhibitors is not significant.The level of expressions of ISGs does not represent the severity of clinical manifestations and inflammation.7.SAMD9L is a negative regulator of IFN-I,loss of function mutations of SAMD9L may cause continuous activation of the type I IFN signaling pathway.The CANDLE-like phenotype(Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature)caused by SAMD9L loss of function mutations may be a monogenic type I interferonopathies.