Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease.

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

The emerging role of inorganic elements as potential antigens in sarcoidosis.

PURPOSE OF REVIEW: Previous studies mainly described a role for organic agents as possible triggers for sarcoidosis. In this review, we address recent studies suggesting a possible role for inorganic elements, such as metals or silica in sarcoidosis pathogenesis. RECENT FINDINGS: Several epidemiological papers suggest that inorganic agents, either by environmental exposures or occupational activities, could trigger sarcoidosis. Association between inorganics and sarcoidosis is also described in several recently published case reports and studies demonstrating immunological sensitization to inorganic agents in sarcoidosis patients.Studies comparing chronic beryllium disease (CBD) and sarcoidosis suggest that although antigenic triggers may differ, underlying processes may be comparable.Besides the fact that a growing number of studies show a possible role for inorganic triggers, it is also suggested that inorganic triggered sarcoidosis may result in a more severe phenotype, including pulmonary fibrosis. SUMMARY: We can use the knowledge already gained on CBD pathogenesis to conduct further research into role of inorganics, such as metals and silica as antigens in sarcoidosis. Given the importance of a lymphocyte proliferation test (LPT) in diagnosing CBD, it seems obvious to also implement this test in the diagnostic work-up of sarcoidosis to identify patients with an inorganic antigenic trigger of their disease.

Detection of Cutibacterium acnes in granulomas of patients with either hypersensitivity pneumonitis or vasculitis reveals that its presence is not unique for sarcoidosis.

Presence of C. acnes in granulomas is not unique to sarcoidosis but can also be found in patients with HP or EGPA. C. acnes may be involved in the pathogenesis of those granulomatous diseases in a mitogenic way. https://bit.ly/3pU0PeC.

Elevated Serum Amyloid a Levels Are not Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype.

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

Presence of Propionibacterium acnes in granulomas associates with a chronic disease course in Dutch sarcoidosis patients.

Several studies demonstrated that Propionibacterium acnes may be involved in sarcoidosis pathogenesis. Presence of P. acnes was found in granulomas of the majority of Japanese sarcoidosis patients. However, presence of P. acnes in tissue has never been related to sarcoidosis phenotypes and clinical outcome. Therefore, the aims of our study were to demonstrate whether P. acnes can be detected in granulomas of Dutch sarcoidosis patients and to investigate whether its presence is related to a clinical phenotype and/or course of disease. Sections of formalin-fixed paraffin-embedded tissue blocks of 76 sarcoidosis patients were examined by immunostaining with a P. acnes-specific monoclonal antibody (PAB antibody) using a Ventana BenchMark ULTRA. Clinical outcome status (COS) was determined and classified into two phenotype groups: A: resolved, minimal or persistent disease without treatment (COS 1-6) and B: persistent disease with need for treatment (COS 7-9). P. acnes was detected in samples of 31 patients (41%) and located within granulomas in samples of 13 patients (17%). The frequency of P. acnes detected in granulomas at diagnosis was significantly higher in patients with phenotype B compared to patients with phenotype A (29% versus 0%, p=0.021). Presence of P. acnes in granulomas can be confirmed in Dutch sarcoidosis patients. It is intriguing that presence of P. acnes in granulomas is more frequently found in patients with chronic disease requiring treatment. This adds to the rationale that a subgroup of sarcoidosis patients might benefit from antibiotic therapy.

Latent tuberculosis infection associates with cardiac involvement in patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic disease characterized by formation of non-caseating granulomas. About 5% of patients have symptoms of cardiac sarcoidosis. Identification of cardiac involvement is important since it is a major cause of death. Mycobacterial antigens have been linked to sarcoidosis pathogenesis. Previous findings suggest that a latent tuberculosis infection (LTBI) might associate with development of cardiac involvement in patients with sarcoidosis. The aim of the present study was to further evaluate these findings in another cohort of cardiac sarcoidosis patients. METHODS: Interferon release assays (IGRAs) or tuberculin skin tests (TST) were analysed in a cohort of cardiac sarcoidosis patients (n=103) and compared to non-cardiac sarcoidosis patients (n=153). RESULTS: In the cohort of patients with cardiac sarcoidosis, 7 could be diagnosed with a LTBI (6.8%) compared to only one of the non-cardiac patients (0.7%), p = 0.008. CONCLUSIONS: To conclude, we were able to show an association between a LTBI and cardiac involvement in patients with sarcoidosis. Future research is however required to unravel the mechanism involved in this association. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (3): e2020005).

Sarcoidosis in a patient clinically diagnosed with silicosis; is silica associated sarcoidosis a new phenotype?

A diagnosis of silicosis is made on the basis of exposure and typical radiological findings, according to the ILO's International Classification of Radiographs of Pneumoconiosis. Radiological patterns of silicosis can, however, resemble sarcoidosis. Sarcoidosis is a multi-systemic disorder of unknown etiology, although a role for initiating inorganic triggers such as metals or silica has been suggested. In this case report, we illustrate a patient previously diagnosed with silicosis based on exposure and radiological features, progressive under immunosuppressive treatment. In view of these findings, an open lung biopsy was performed and revealed sarcoidosis. The patient was effectively treated with infliximab. Further analysis showed the presence of silica in the granulomas. Sensitization to silica was also demonstrated, suggesting an association between silica exposure and sarcoidosis in this patient.