Granulomatosis With Polyangiitis in a Patient on Programmed Death-1 Inhibitor for Advanced Non-small-cell Lung Cancer

BackgroundRheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management.MethodsFirst, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed.ResultsThe overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies.ConclusionThese statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

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“… 114 The first case of granulomatosis with polyangiitis with a high anti-PR3 ANCA titre was reported in 2019. 115 …”

Section: Resultsmentioning

confidence: 99%

“…114 The first case of granulomatosis with polyangiitis with a high anti-PR3 ANCA titre was reported in 2019. 115 Recently, patients experiencing rapid bone loss with CPI leading to multiple fractures were reported, raising the question of a potential influence of immune activation on bone metabolism. 116 on July 13, 2020 by guest.…”

Section: Points To Considermentioning

confidence: 99%

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors

et al. 2020

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“…Various forms of vasculitis affecting large vessels have been reported, and the corresponding diagnoses include GCA [33,56,57] or periaortitis [58]. Additionally, medium or small vessels can be affected, with cases of granulomatosis with polyangiitis (GPA) [59,60], eosinophilic granulomatosis with polyangiitis (EGPA) [61] and cryoglobulinemic vasculitis [62] having been reported. Cutaneous granulomatous [63,64] and leukocytoclastic vasculitides [65] have also been described.…”

Section: Vasculitismentioning

confidence: 99%

Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors

Μελισσαρόπουλος

Klavdianou

Filippopoulou

et al. 2020

IJMS

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Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. Their clinical efficacy is well-documented, but the side effects associated with their use are still under investigation. These drugs cause several immune-related adverse events (ir-AEs), some of which stand within the field of rheumatology. Herein, we present a literature review performed in an effort to evaluate all publicly available clinical data regarding rheumatic manifestations associated with ICIs. The most common musculoskeletal ir-AEs are inflammatory arthritis, polymyalgia rheumatica and myositis. Non-musculoskeletal rheumatic manifestations are less frequent, with the most prominent being sicca, vasculitides and sarcoidosis. Cases of systemic lupus erythematosus or scleroderma are extremely rare. The majority of musculoskeletal ir-AEs are of mild/moderate severity and can be managed with steroids with no need for ICI discontinuation. In severe cases, more intense immunosuppressive therapy and permanent ICI discontinuation may be employed. Oncologists should periodically screen patients receiving ICIs for new-onset inflammatory musculoskeletal complaints and seek a rheumatology consultation in cases of persisting symptoms.

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“…The development of autoimmune small-vessel vasculitis has been observed after checkpoint inhibitor therapy ( 21 – 24 ), indicating a relevant role of immune checkpoint molecules in the disease process. However, no molecular alterations of such molecules in the immune system of patients with AAV have been reported so far.…”

Section: Discussionmentioning

confidence: 99%

“…In parallel, increasing reports of immune-related adverse events were noted (irAEs) ( 20 ). In fact, several forms of vasculitis have been reported to develop or re-activate after checkpoint inhibitor therapy, including AAV ( 21 – 24 ).…”

Section: Introductionmentioning

confidence: 99%

CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1

et al. 2021

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ObjectivesANCA-associated vasculitides (AAV) affect small- and medium-sized blood vessels. In active disease, vessel wall infiltrates are mainly composed of monocytes and macrophages. Immune checkpoint molecules are crucial for the maintenance of self-tolerance and the prevention of autoimmune diseases. After checkpoint inhibitor therapy, the development of autoimmune vasculitis has been observed. However, defects of immune checkpoint molecules in AAV patients have not been identified yet.MethodsMonocytes and monocyte-derived macrophages from AAV patients and healthy age-matched controls were tested for surface expression of immunoinhibitory checkpoint programmed cell death ligand-1 (PD-L1). Using in vitro co-culture approaches, the effect of monocyte PD-L1 expression on CD4+ T cell activation and proliferation was tested.ResultsMonocytes from AAV patients displayed lower PD-L1 expression and a defective PD-L1 presentation upon activation, an effect that was correlated with disease activity. Lower PD-L1 expression was due to increased lysosomal degradation of PD-L1 in AAV monocytes. We identified a reduced expression of CMTM6, a protein protecting PD-L1 from lysosomal breakdown, as the underlying molecular defect. PD-L1low AAV monocytes showed increased stimulatory capacity and induced T cell activation and proliferation. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1, thus normalizing the pro-stimulatory behavior of AAV monocytes.ConclusionsThis study identifies a defect of the immunoinhibitory checkpoint PD-L1 in monocytes from patients with AAV. Low expression of CMTM6 results in enhanced lysosomal degradation of PD-L1, thus providing insufficient negative signaling to T cells. Correcting this defect by targeting lysosomal function may represent a novel strategy to treat AAV.

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Granulomatosis With Polyangiitis in a Patient on Programmed Death-1 Inhibitor for Advanced Non-small-cell Lung Cancer

Cited by 16 publications

References 24 publications

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors

Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors

CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1

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