Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis

Damsky, William; Wang, Alice; Kim, Daniel; Young, Bryan D.; Singh, Katelyn; Murphy, Michael J.; Daccache, Joseph; Clark, Abigale; Ayasun, Rüveyda; Ryu, Changwan; McGeary, Meaghan K.; Odell, Ian D.; Fazzone-Chettiar, Ramesh; Pucar, Darko; Homer, Robert J.; Gulati, Mridu; Miller, Edward J.; Bosenberg, Marcus W.; Flavell, Richard A.; King, Brett

doi:10.1038/s41467-022-30615-x

Cited by 66 publications

(39 citation statements)

References 59 publications

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“…However, the number of patients with extra-cutaneous disease were small and the end points were poorly described. Nevertheless, this was an important validation of the original case reports ( 305 ).…”

Section: Studies With a Focus On Extra-pulmonary And Multi-organ Sarc...supporting

confidence: 72%

“…Damsky et al ( 305 ) recently published an open-label study of ten patients with cutaneous sarcoidosis. The authors found that treatment led to significant improvement of skin lesions using the previously validated cutaneous sarcoidosis activity and morphology instrument (CSAMI) scoring system.…”

Section: Studies With a Focus On Extra-pulmonary And Multi-organ Sarc...mentioning

confidence: 99%

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Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches

et al. 2022

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Sarcoidosis is a systemic granulomatous inflammatory disease of unknown etiology. It affects the lungs in over 90% of patients yet extra-pulmonary and multi-organ involvement is common. Spontaneous remission of disease occurs commonly, nonetheless, over 50% of patients will require treatment and up to 30% of patients will develop a chronic progressive non-remitting disease with marked pulmonary fibrosis leading to significant morbidity and death. Guidelines outlining an immunosuppressive treatment approach to sarcoidosis were recently published, however, the strength of evidence behind many of the guideline recommended drugs is weak. None of the drugs currently used for the treatment of sarcoidosis have been rigorously studied and prescription of these drugs is often based on off-label” indications informed by experience with other diseases. Indeed, only two medications [prednisone and repository corticotropin (RCI) injection] currently used in the treatment of sarcoidosis are approved by the United States Food and Drug Administration. This situation results in significant reimbursement challenges especially for the more advanced (and often more effective) drugs that are favored for severe and refractory forms of disease causing an over-reliance on corticosteroids known to be associated with significant dose and duration dependent toxicities. This past decade has seen a renewed interest in developing new drugs and exploring novel therapeutic pathways for the treatment of sarcoidosis. Several of these trials are active randomized controlled trials (RCTs) designed to recruit relatively large numbers of patients with a goal to determine the safety, efficacy, and tolerability of these new molecules and therapeutic approaches. While it is an exciting time, it is also necessary to exercise caution. Resources including research dollars and most importantly, patient populations available for trials are limited and thus necessitate that several of the challenges facing drug trials and drug development in sarcoidosis are addressed. This will ensure that currently available resources are judiciously utilized. Our paper reviews the ongoing and anticipated drug trials in sarcoidosis and addresses the challenges facing these and future trials. We also review several recently completed trials and draw lessons that should be applied in future.

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Section: Studies With a Focus On Extra-pulmonary And Multi-organ Sarc...supporting

confidence: 72%

Section: Studies With a Focus On Extra-pulmonary And Multi-organ Sarc...mentioning

confidence: 99%

Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches

et al. 2022

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“…On the other hand, IFN-γ is a T-helper cell type 1 (Th1) cytokine, previously demonstrated to be an efficient inducer of LGCs from human monocytes [23, 53]. In vivo , IFN-γ is found in human tuberculosis and leprosy granulomas [7, 54] and in non-infectious granulomatous disease such as sarcoidosis [55, 56] and Blau syndrome [57]. All these conditions are associated with the presence of LGCs and T cells (either Th1 or Th17) within the granulomas.…”

Section: Discussionmentioning

confidence: 99%

Multinucleation resets human macrophages for specialized functions at the expense of mononuclear phagocyte identity

Ahmadzadeh

Pereira

Vanoppen

et al. 2022

Preprint

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Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. While osteoclast multinucleation is a prerequisite for vertebrate bone homeostasis, the effector function resulting from LGC and FBGC multinucleation is less well-defined. More generally, how multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrated comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced down-regulation of mononuclear phagocyte identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, only B7-H3 (CD276)-expressing human LGCs can form granuloma-like clusters in vitro, suggesting that LGC multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.

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“…Interestingly, many of the listed cytokines implicated in sarcoidosis pathogenesis, including IFN-g and IL-2, IL-23, IL-4, and IL-13, act via the JAK-signal transducer and activator of transcription (STAT) pathway. As a confirmation, JAK-STAT pathway activation has been reported in patients with sarcoidosis [ 39 ], and JAK inhibitors represent one of the new therapeutic options for long-standing sarcoidosis [ 40 ].…”

Section: Immunopathology Of Sarcoidosis and Covid-19 Shared Mechanismsmentioning

confidence: 99%

Sarcoidosis and COVID-19: At the Cross-Road between Immunopathology and Clinical Manifestation

Tana,

Cinetto,

Mantini

et al. 2022

Biomedicines

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Coronavirus disease 2019 (COVID-19) has been associated with dysregulation of the immune system featuring inappropriate immune responses, exacerbation of inflammatory responses, and multiple organ dysfunction syndrome in patients with severe disease. Sarcoidosis, also known as Besnier–Boeck–Schaumann disease, is an idiopathic granulomatous multisystem disease characterized by dense epithelioid non-necrotizing lesions with varying degrees of lymphocytic inflammation. These two diseases have similar clinical manifestations and may influence each other at multiple levels, eventually affecting their clinical courses and prognosis. Notably, sarcoidosis patients are at high risk of severe COVID-19 pneumonia because of the underlying lung disease and chronic immunosuppressive treatment. In this narrative review, we will discuss interactions between sarcoidosis and COVID-19 in terms of clinical manifestations, treatment, and pathogenesis, including the role of the dysregulated renin–angiotensin system, altered immune responses involving increased cytokine levels and immune system hyperactivation, and cellular death pathways.

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Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis

Cited by 66 publications

References 59 publications

Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches

Sarcoidosis: Updates on therapeutic drug trials and novel treatment approaches

Multinucleation resets human macrophages for specialized functions at the expense of mononuclear phagocyte identity

Sarcoidosis and COVID-19: At the Cross-Road between Immunopathology and Clinical Manifestation

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