Sarcoid-like Granulomatosis Associated with Immune Checkpoint Inhibitors in Melanoma

We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on 18 melanoma patients with histologically proven ICI-induced granulomatosis over a 12-year period in a single center, as well as on 67 similar cases reported in the literature, was conducted. Results indicate ICI-induced granulomatosis is an early side effect (median time to onset: 2 months). Its clinical presentation, with predominant (90%) thoracic involvement, histopathological appearance and supposed underlying biology (involving the mTOR pathway in immune cells, Th17 polarization and TReg dysfunction) are indistinguishable from those of sarcoidosis. Moreover, it appears to be associated with ICI benefit (>65% objective response rate). Evolution is generally favorable, and symptomatic steroid treatment and/or ICI discontinuation are rarely necessary. ICI-associated granulomatosis is critical to explore for several reasons. Practically, it is essential to differentiate it from cancer progression. Secondly, this “experimental” sarcoidosis brings new elements that may help to address sarcoidosis origin and pathophysiology. Its association with ICI efficacy must be confirmed on a larger scale but could have significant impacts on patient management and biomarker definition

High-sensitivity cardiac troponin T is a biomarker for atherosclerosis in systemic lupus erythematous patients: a cross-sectional controlled study

Abstract Background Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematous (SLE) patients. The Framingham score underestimates the risk for CVD in this population. Our study aimed to determine whether serum high-sensitivity cardiac troponin T (HS-cTnT) might help to identify SLE patients at risk for CVD. Methods The presence of carotid plaques was prospectively assessed by ultrasound in 63 consecutive SLE patients asymptomatic for CVD and 18 controls. Serum HS-cTnT concentration was measured using the electrochemiluminescence method. Factors associated with carotid plaques were identified and multivariate analysis was performed. Results Framingham score was low in both SLE patients (median 1 (range 1–18%)) and controls (1 (1–13%)). Nevertheless, 23 (36.5%) SLE patients, but only 2 (11.1%) controls (p = 0.039), had carotid plaque detected by vascular ultrasound. In the multivariate analysis, only age (p = 0.006) and SLE status (p = 0.017) were independently associated with carotid plaques. Serum HS-cTnT concentration was detectable (i.e. >3 ng/L) in 37 (58.7%) SLE patients and 6 (33.3%) controls (p = 0.057). Interestingly, 87% of SLE patients with carotid plaques, but only 42.5% of SLE patients without plaques (p < 0.001), had detectable HS-cTnT. Conversely, 54.5% of SLE patients with detectable HS-cTnT, but only 11.5% with undetectable HS-cTnT (p < 0.001), had a carotid plaque. In the multivariate analysis, only body mass index (p = 0.006) and HS-cTnT (p = 0.033) were statistically associated with carotid plaques in SLE patients. Overall, the risk of having a carotid plaque was increased by 9 (odds ratio 9.26, 95% confidence interval 1.55–90.07) in SLE patients in whom HS-cTnT was detectable in serum. Conclusion Serum HS-cTnT level is high and associated with carotid plaques in SLE patients who are at an apparently low risk for CVD according to the Framingham score. HS-cTnT may be a useful biomarker for SLE-associated atherosclerosis

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

International audienceCD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients

Osseous sarcoidosis: a multicenter case-control study

International audienceObjective: To describe the clinical presentation, distribution of lesions, treatment, and outcomes of osseous sarcoidosis.Methods: A French retrospective multicenter study of patients with biopsy-proven sarcoidosis analyzed patients with 1) a biopsy-proven granuloma without caseous necrosis, and either 2) osseous clinical manifestations, or 3) abnormal osseous imaging. Sarcoidosis patients with osseous involvement (cases) were compared with 264 age- and sex-matched sarcoidosis patients with no osseous manifestations (controls).Results: In the osseous sarcoidosis group (n = 88), forty-two (48%) patients had osseous-related symptoms involving the axial (69%) and/or appendicular (58%) skeleton. On imaging, the most commonly affected bones were in the spine (52%), pelvis (42%), hands (22%) and femur (19%). Compared with controls, cases had higher rates of mediastinal (93% vs. 47%) and extra-thoracic lymph node involvement (66% vs. 21%), pulmonary (90% vs. 65%) and cutaneous involvement (44% vs. 23%) (all P < 0.0001), and hypercalcemia (8.5% vs. 2%, P = 0.014). Spleen/liver and gastrointestinal involvement were less frequent in the osseous sarcoidosis group (29% vs. 45%, and 1% vs. 17%, respectively, P < 0.0001). Response rates to with glucocorticoids alone, glucocorticoids plus methotrexate or glucocorticoids plus hydroxychloroquine were 23/44 (52%), 9/13 (69%) and 4/6 (67%), respectively.Conclusion: In patients with osseous sarcoidosis the spine and pelvis were the most commonly affected bones. Compared with controls, cases with osseous sarcoidosis have higher rates of thoracic and extra-thoracic lymph node involvement, pulmonary and cutaneous involvement, and hypercalcemia. Most patients with osseous sarcoidosis had a good response to glucocorticoids in combination with methotrexate or hydroxychloroquine

Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case–control study

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