澤幡 美千瑠

BACKGROUND: We investigated the association between the development of sarcoidosis and personal or family medical history, with a focus on immune-mediated inflammatory diseases (IMIDs), in a Japanese population. METHODS: In this exploratory case-control study, self-administered questionnaires were completed by 164 patients with newly diagnosed sarcoidosis (64 men, 100 women) who visited public health centres in 7 prefectures between 2018 and 2020 to apply for medical expense subsidies (cases) and by 1779 community-dwelling controls (641 men, 1138 women) undergoing municipal health checkups (controls). The questionnaire collected information on personal and family medical histories, including IMIDs. Logistic regression analyses adjusted for age and sex were used to identify risk factors associated with onset of sarcoidosis. RESULTS: A history of IMIDs was associated with a greater likelihood of sarcoidosis (adjusted odds ratio [aOR] 3.05, 95 % confidence interval [CI] 1.79-5.21). Increased risk was observed for rheumatoid arthritis (aOR 2.63, 95 % CI 1.06-6.53), Sjögren's syndrome (aOR 14.39, 95 % CI 4.30-48.10), and hypothyroidism (aOR 4.91, 95 % CI 2.20-10.97). Some conditions, such as asthma, lymphoma, and insulin use, showed possible associations, with wide CIs including 1.0. Additionally, a family history of sarcoidosis was strongly associated with disease occurrence (aOR 21.30, 95 % CI 3.86-117.68), supporting a potential genetic predisposition consistent with previous epidemiological findings. CONCLUSIONS: This study suggests that sarcoidosis may be associated with IMIDs in the Japanese population. However, its findings should be interpreted with caution, given its exploratory design and limited statistical power.

Established fibrosis in pulmonary sarcoidosis is typically not progressive. However, progressive fibrosis similar to interstitial pneumonia occasionally occurs. We herein report a 49-year-old woman who was histologically diagnosed with sarcoidosis. She also had honeycomb-like manifestations in the lower lobes that resembled idiopathic pulmonary fibrosis on computed tomography, whereas pathological findings of a surgical lung biopsy suggested interstitial lung disease associated with rheumatoid arthritis. However, the patient did not develop clinical rheumatoid arthritis even after 17 years of follow-up. Notably, she showed progressive fibrosis and was treated with anti-fibrotic therapy. It is thus important to recognize progressive fibrosis in pulmonary sarcoidosis, although it is rare.

BACKGROUND: This study investigated the association between the development of sarcoidosis and environmental factors, focusing on the childhood hygiene environment. METHODS: This case-control study used a questionnaire administered to patients with sarcoidosis and residence-matched controls (age 18 to <90 years) in 7 prefectures between 2018 and 2020. Logistic regression analysis was performed to identify risk factors, including adulthood lifestyle history, childhood hygiene environment, and history of infections. RESULTS: One hundred sixty-four patients with sarcoidosis and 1779 controls (641 men, 1138 women) were enrolled. Multivariate analysis showed that smoking history during adulthood was associated with developing sarcoidosis (odds ratio [OR], 2.09; 95 % confidence interval [CI], 1.16-3.75). For the childhood hygiene environment, attending nursery school (OR, 2.76; 95 % CI, 1.57-4.84) and use of well water (OR, 2.89; 95 % CI, 1.65-5.07) at age 0-2 years were associated with developing sarcoidosis. The OR of attending nursery school at age 3-6 years (OR, 1.79; 95 % CI, 0.89-3.61) was lower than that at age 0-2 years, but the OR of use of well water at age 3-6 years (OR, 2.89; 95 % CI, 1.59-5.26) was still high. By contrast, the risk of developing sarcoidosis was lower for being breastfed (OR, 0.36; 95 % CI, 0.15-0.88). Development of sarcoidosis was associated with history of tuberculosis (OR, 5.82; 95 % CI, 1.28-26.53). CONCLUSIONS: Both adulthood lifestyle history and childhood hygiene environment were associated with sarcoidosis. Daily direct exposure to diverse microorganisms during childhood may increase the likelihood of antigens for granuloma formation entering the body and also modify susceptibility to sarcoidosis.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, is characterized by the formation of non-caseating granulomas affecting multiple organs. Accumulating evidence implicates Cutibacterium acnes (C. acnes; formerly Propionibacterium acnes) as a potential microbial trigger. The consistent detection of C. acnes within sarcoid granulomas, along with associated Th1-polarized immune responses, indicates that latent intracellular persistence and reactivation of this commensal bacterium may drive granulomatous inflammation. This bacterium can persist intracellularly within macrophages and dendritic cells and, upon reactivation, may induce Th1/Th17-dominant immune responses in genetically and immunologically susceptible individuals. Immune dysregulation, including deficient C. acnes-specific regulatory T cell (Treg) responses, may underlie the unchecked effector activity that sustains inflammation. Enhanced C. acnes-specific T-cell reactivity, including elevated interferon-γ and interleukin-2 production, is observed in some patients, supporting this hypothesis. Although direct evidence for C. acnes-specific Tregs and antigen-specific T-cell responses is limited, immune dysregulation involving impaired tolerance is thought to contribute to the heterogeneity of sarcoidosis, which ranges from spontaneous remission to chronic fibrotic progression. Recent advances in diagnostic tools, including P. acnes-specific monoclonal antibody immunostaining and T-cell assays specific to C. acnes, offer promising approaches for detecting microbial involvement. These developments highlight the importance of etiology-driven treatment strategies. As sarcoidosis likely comprises a spectrum of underlying causes, etiology-specific interventions are particularly warranted upon the identification of a defined trigger, such as C. acnes. This review explores the potential pathogenesis of sarcoidosis, focusing on latent microbial reactivation, immune dysregulation, and their diagnostic and therapeutic implications, and highlights opportunities for precision medicine.

BACKGROUND: Severe pulmonary sarcoidosis is less common in Japan than in other countries, and the actual clinical situation of systemic steroid use in Japan requires clarification. METHODS: This study analyzed 65 patients with histologically diagnosed sarcoidosis who initially received systemic steroids for pulmonary lesions and made regular outpatient visits to Hokkaido University Hospital, JR Sapporo Hospital, or JR Tokyo General Hospital in September 2017. RESULTS: Median age at diagnosis was 35 (interquartile range [IQR] 26-48) years. Thirty-four patients (52.3%) were men. Median time from diagnosis to steroid initiation was 5 (IQR, 1-9) years. Median maximum steroid dose was prednisolone (PSL) 30 (range 5-60) mg/day. Immunosuppressants were used in 19 patients (29.2%). Twenty-one patients (32.3%) received PSL ≤ 10 mg/day and 7 (10.8%) received 5 mg/day. The PSL ≤ 10 mg/day group included a significantly lower proportion of men than the group treated with higher doses (33.3% vs. 61.4%, p = 0.034). Most cases were effectively treated, but some required long-term steroid administration. Even when steroid inhalation therapy was ineffective, systemic administration of PSL 5 mg/day effectively resolved chest imaging findings and respiratory symptoms. The successful steroid withdrawal rate was 18.5% overall, increasing to 23.8 and 42.9% in the PSL ≤ 10 mg/day and 5 mg/day groups, respectively. CONCLUSION: Approximately one-third of patients received an initial steroid dose of PSL ≤ 10 mg/day for pulmonary sarcoidosis. This was mostly effective and the withdrawal rate was relatively high. Our results support that some Japanese patients with pulmonary sarcoidosis may successfully receive an initial dose of PSL ≤ 10 mg/day.