Autoinflammatory diseases are characterized by recurrent systemic inflammation due to abnormalities in the innate immune system, and some diseases are complicated by vasculitis. Among the autoinflammatory diseases caused by monogenic mutations, familial Mediterranean fever, in particular, develops various forms of vasculitis, with a high frequency of IgA-associated vasculitis and polyarteritis nodosa. Vasculitis is an important clinical manifestation in the recently defined A20 haploinsufficiency, Aicardi–Goutières syndrome, STING-associated vasculopathy with onset in infancy (SAVI), COPA syndrome and adenosine deaminase 2 deficiency. A20 haploinsufficiency resembles the vasculitis of Behcetʼs disease. Aicardi–Goutières syndrome, a type I interferonopathy, patients with SAMDH1 gene abnormalities have a higher incidence of vasculitis. SAVI causes severe skin lesions due to vasculitis. COPA syndrome causes diffuse alveolar hemorrhage due to pulmonary capillaritis. Adenosine deaminase 2 deficiency causes cerebral vasculopathy and cutaneous manifestations by polyarteritis nodosa-like vasculitis. Many clinical features overlap among autoinflammatory diseases, and the exact mechanism of vasculitis is unclear, but has been postulated to include direct damage to endothelial cells by IL-1β, type I interferon, and immune complexes. Therefore, attention should be paid to the complication of such vasculitis symptoms in autoinflammatory diseases, and appropriate diagnosis and treatment should be provided.
Primary immunodeficiency, also termed as inborn errors of immunity（IEI）, is characterized by not only susceptibility to infection but also malignancy, allergy, autoinflammation, and autoimmunity. Most of the patients with IEI manifest susceptibility to bacterial and viral infections. The mainstay of treatment for IEI includes 1）administration of antibiotics and prevention of bacterial, fungal, and viral infections and 2）immunoglobulin replacement therapy（IgRT）for antibody deficiency. The drug combination sulfamethoxazole-trimethoprim（ST）is used in a majority of patients with IEI to prevent infections. It is generally administered three times a week for the prevention of Pneumocystis pneumonia, whereas it must be administered daily for the prevention of bacterial infection. Chronic granulomatous disease is a phagocytic disorder and is sometimes associated with refractory infection. Most common pathogens include Staphylococcus aureus and Aspergillus; hence, ST and itraconazole are administered for prevention. Prednisolone is additionally administered to CGD patients with severe infections, such as a liver abscess. Patients with primary antibody deficiency are treated with in travenous or subcutaneous IgRT. Serum IgG trough levels should be maintained at >700 mg/dL. Treatment for the prevention of infections for IEI depend on disease specificities and patient conditions.
Cyclic GMP-AMP （cGAMP） synthase （cGAS） and stimulator of interferon genes （STING） are the two key molecules that trigger type I interferon reponse upon the emergence of cytosolic “non-self DNA”，such as the one from DNA viruses. Recent studies have shown that this pathway is also activated with “self-DNA” leaked out from the nucleus or mitochondria. Moreover，the cGAS-STING pathway is revealed to be associated with various autoinflammatory，autoimmune，and neurodegenerative diseases. In this review，we particularly focus on emerging issues regarding the regulation of STING activity by membrane traffic. The dysregulated membrane traffic of STING are recently shown by us and others to underly the pathogenesis of autoinflammatory diseases，SAVI （STING-associated vasculopathy with onset in infancy） and COPA （a monogenic autoinflammatory disease caused by missense mutations of coatomer protein complex subunit α （α-COP））.
Many subtypes with clinical symptoms similar to PAPA syndrome （pyogenic arthritis, pyoderma gangrenosum and acne syndrome）, which is one of autoinflammatory diseases, have been reported. It is called PSTPIP1-associated inflammatory diseases （PAID） because it is mostly due to variants in the PSTPIP1 gene. Since the PSTPIP1 molecule is involved in the activation of pyrin inflammasome and the regulation of the cytoskeleton, variants cause various clinical symptoms. In addition to PAPA syndrome, PAID currently has 6 syndromes （PASH, PAPASH, PsAPASH, PASS, PAMI, PAC）. We recently reported a new PAID, a case of pyoderma gangrenosum, acne and unclassified inflammatory bowel disease （PAB） syndrome. It was not ulcerative colitis but complicated with unclassifiable inflammatory bowel disease, which was different from PAC syndrome. In this paper, we introduced the structure and role of PSTPIP1 molecule, explanation of diseases of each PAID, and cases of PAB syndrome.
Familial Mediterranean fever （FMF） is a common autoinflammatory disease characterized by recurrent episodes of fever and serositis. The pathomechanism of the febrile attacks is still not fully understood, but clinically, various factors may trigger the attacks. In our study, menstruation was the most common trigger in female patients with FMF compared to other factors such as tiredness and psychological stress. We need to consider FMF in patients who have fever and serositis during every menstrual period. Menstrual-related patients had a younger age of onset, higher frequency of peritonitis, and higher rate of endometriosis. The mechanism by which menstruation is associated with attacks has been postulated to be the decrease in sex hormones during menstruation or the stimulation of the endometrial tissue by menstruation itself. Although colchicine is the first choice of treatment for FMF, there have been reports that sex hormone is effective in FMF patients in whom attacks are associated with menstruation. Therefore, this may be an option in the future for patients who are refractory or intolerant to colchicine treatment.
Adult-onset Still's disease（AOSD）is a rare disease, and the detailed disease mechanism is still unknown. Since serum ferritin and serum IL-18 are elevated, abnormal activation of monocyte lineage cells and their inflammasome has been assumed as one of the mechanisms. This review provides a comprehensive summary of previous findings on AOSD disease concepts, diagnosis, and treatment, as well as the upcoming relationship between AOSD and Gasdermin D, which play a central role in inflammasome-mediated inflammation.