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Cited by 222Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy

Open access
Haanen, J., Ernstoff, M.S., Wang, Y., Menzies, A.M., Puzanov, I., Grivas, P., Larkin, J., Peters, S. +2 more·2020·Annals of Oncology
DOI 10.1016/j.annonc.2020.03.285
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Abstract

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids (CS) and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressant drugs (nSIs) could be replaced by specific selective immunosuppressant drugs (SI) following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that patients with cancer and preexisting active autoimmune diseases (ADs) should not be universally excluded from immune-checkpoint inhibitors (ICIs), because retrospective data suggest ICIs can be safe and effective in many such patients. It proposes a personalized two-step strategy: rotate off nonselective immunosuppressants to selective immunosuppressants before ICI initiation, then continue selective immunosuppression with ICIs under close multidisciplinary monitoring.

Key findings

  • Across retrospective studies, AD flares occurred in roughly 20%–40% of ICI-treated patients with preexisting ADs and were mostly manageable; in a 52-patient melanoma cohort, 38% flared at a median of 38 days, 85% of flares were grade 1/2, and response rates were similar with vs without flare (35% vs 31%).
  • Baseline immunosuppression was associated with worse outcomes: response was lower on immunosuppressants at ICI start (3/20, 15%) than without (14/32, 44%); baseline corticosteroids >10 mg prednisone were associated with poor outcome in NSCLC (odds ratio 0.42, P = 0.053; PFS HR 1.31, OS HR 1.66).
  • A systematic review of 123 patients with cancer and preexisting ADs found 41% had AD exacerbation, 25% had de novo irAEs, 17.1% permanently discontinued ICI, and 4.1% died; in 102 patients with preexisting IBD, GI adverse events occurred in 41% vs 11% without IBD, with no GI adverse event-related deaths.
  • In solid organ transplant recipients, a review of 39 ICI-treated patients reported allograft rejection in 41% (11 renal, 4 hepatic, 1 cardiac), median time to kidney rejection 21 days, and tumor response in 40% with rejection vs 52% without.

Methods

  • Design: narrative literature review and expert proposal, not a primary clinical study; it synthesizes retrospective cohorts, case reports, systematic reviews, and guideline-based AD treatments.
  • Data: PubMed search in English from 1 January 2008 to 30 December 2019 using terms including checkpoint inhibitor, immune-related adverse event, CTLA-4, PD-1, PD-L1, preexisting autoimmune diseases, and specific ADs and immunosuppressants.
  • Analysis: qualitative synthesis of safety/efficacy data and development of AD-specific two-step algorithms combining selective immunosuppressive therapy rotation before ICI with concomitant maintenance during ICI treatment.

Limitations

  • The paper states that key limitations of the underlying studies are their retrospective nature, heterogeneity in patient populations and oncological disease, and selection bias because treating oncologists were inclined to treat these patients; few had previous life-threatening or markedly symptomatic AD.
  • The paper states that prospective studies are lacking, no consensus guidelines exist for this population, and there is no means to determine individual risk–benefit ratios.
  • Evident from the text: the proposed algorithms are expert-opinion and extrapolation-based, go beyond current recommendations, and have not been prospectively validated; the authors call for an international registry and AD-specific prospective trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.annonc.2020.03.285

Cites

180 of 180 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 127 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    IL-6, transforming growth factor-b, and IL-1b are required for Th17 differentiation from naïve CD4+ T cells.

    “Importantly, IL-6, transforming growth factor-b, and IL-1b are required for Th17 differentiation from naïve CD4þ T cells.56,57”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Acosta-Rodriguez, 2007, Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells, Nat Immunol source

      Not checked in the free run.

    • cites [57] Volpe, 2008, A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses, Nat Immunol source

      Not checked in the free run.

  • Interpretationreasoning

    The SI rotation strategy resulted in the absence of severe AD exacerbation.

    “The clinical outcome benefit of this SI rotation strategy was twofold: optimal ICI activity under concurrent selective immunosuppression and the absence of severe AD exacerbation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A 2-4 week rotation phase is sufficient to achieve AD stability before ICI initiation.
  • Premisecitation

    High neutrophil to lymphocyte ratio and a low relative eosinophil count at 4 and 6 weeks were consistently associated with reduced benefit from ICIs.

    “Of note, high neutrophil to lymphocyte ratio and a low relative eosinophil count at 4 and 6 weeks were consistently associated with reduced benefit from ICIs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Fuca, 2019, Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors, ESMO Open source

      Not checked in the free run.

  • Interpretationreasoning

    Blocking IL-6 is particularly interesting given its dual advantage without potentially compromising the efficacy of ICIs.

    “In contrast to other systemic immunosuppressive drugs (anti-TNF-a or nSIs), blocking IL-6 is particularly interesting given this dual advantage without potentially compromising the efficacy of ICIs.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The data on modulation of peripheral blood immune cells suggest that early use of steroids may be the cause of worse clinical outcomes and not the consequence of poor-prognosis subgroups of patients who receive CS for palliative indications.

    “Consequently, these data about the modulation of peripheral blood immune cells suggest that the early use of steroids may be the cause of worse clinical outcomes and not the consequence of poor-prognosis subgroups of patients who receive CS for palliative indications.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 45
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Based on these data and by analogy with the treatment of classical ADs, patients with active ADs could be considered candidates for ICIs, even in the context of active immunosuppressive therapy.

    “Based on these data and by analogy with the treatment of classical ADs, patients with active ADs could be considered candidates for ICIs, even in the context of active immunosuppressive therapy.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Treatment of active ADs in cancer patients can be guided by analogy with the treatment of classical ADs.
    • Rests on an assumption: A 2-4 week rotation phase is sufficient to achieve AD stability before ICI initiation.

  • May combine two claims.

    Interpretationcitation

    The scarcity of safety and efficacy information for ICIs in patients with ADs represents a knowledge gap and limits the use of ICI therapy that could be considered in the estimated 20-50 million patients in the USA with ADs.

    “This issue represents a knowledge gap and limits the use of ICI therapy that could be considered in the estimated 20e50 million patients in the USA with ADs. 5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5]

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    The effectiveness of ICIs is not lowered in patients with preexisting ADs.

    “It appears that the effectiveness of ICIs is not lowered in this special population.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    At the time of treatment initiation in these studies, 82% of patients had no active symptoms of AD, and only 15%-20% were receiving immunosuppressive treatment of such conditions.

    “At the time of treatment initiation, 82% of patients in these studies had no active symptoms of AD, and only 15%e20% were receiving immunosuppressive treatment of such conditions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    At present, there are no consensus guidelines to treat this specific patient population, nor are there means to determine the risk-benefit ratio for individual patients.

    “At present, there are no consensus guidelines to treat this specific patient population, nor are there means to determine the riskebenefit ratio for individual patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In retrospective studies of patients with AD receiving ICIs, only a minority of patients (20%-40%) experienced exacerbation of their ADs, and these exacerbations were manageable.

    “In these studies, investigators reported that only a minority of patients (20%e40%) experienced exacerbation of their ADs, 11e15 which were manageable.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 11e15

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The development and resolution of ICI-related colitis is significantly associated with serum IL-17 fluctuations in ipilimumab-treated patients, suggesting a main role for Th17 cells.

    “The immunopathology underlying irAEs has not been fully described; based on accumulating evidence, the development and resolution of ICI-related colitis is significantly associated with serum IL-17 fluctuations in ipilimumab-treated patients, suggesting a main role for Th17 cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TCZ may be used as a second-line therapy for irAEs and for steroid-refractory irAEs; clinical improvement was observed in 79.4% of patients, with 52.9% requiring only a single dose for a symptomatic response.

    “Furthermore, it was demonstrated that TCZ may be used as a second-line therapy for irAEs and for steroid-refractory irAEs; clinical improvement was observed in 79.4% of patients, with 52.9% of patients requiring only a single dose for a symptomatic response.59”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Stroud, 2019, Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade, J Oncol Pharm Pract source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Prospective studies are lacking to determine the best strategy to deliver ICIs to patients with cancer and active or symptomatic AD.

    “Prospective studies are lacking to determine the best strategy to deliver ICIs to patients with cancer and active or symptomatic AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Overall, low-grade AD flares seem to occur more frequently and are manageable with standard treatment algorithms.

    “Overall, low-grade AD flares seem to occur more frequently and are manageable with standard treatment algorithms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Summarizing existing data on PD-1/PD-L1 and ADs, irAEs occur at an increased rate compared with patients in clinical trials without AD, and the excess morbidity appears largely confined to mild-moderate flares of ADs.

    “Summarizing the existing data on PD-1/PD-L-1 and ADs, we can conclude that (i) irAEs occur at an increased rate compared with patients in clinical trials without AD, and the excess morbidity appears largely confined to mild-moderate flares of ADs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In these retrospective studies, permanent discontinuation of ICIs was rare and tumor responses were seen.

    “Furthermore, permanent discontinuation of ICIs was rare and tumor responses were seen.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or refractory ICI-induced enterocolitis.

    “Based on two retrospective series, VDZ is an effective and well-tolerated therapeutic for steroid-dependent or refractory ICI-induced enterocolitis.69,70”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Bergqvist, 2017, Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis, Cancer Immunol Immunother source

      Not checked in the free run.

    • cites [70] Abu-Sbeih, 2018, Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study, J Immunother Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Baseline CS !10 mg of prednisone or equivalent dose was associated with poor outcome in patients with NSCLC treated with PD-1 axis inhibition (odds ratio 0.42, P=0.053), progression-free survival and overall survival (hazard ratio=1.31 and 1.66, P=0.03 and <0.001, respectively).

    “Importantly, baseline CS !10 mg of prednisone or equivalent dose was associated with poor outcome in patients with NSCLC treated with PD-1 axis inhibition (odds ratio 0.42, P ¼ 0.053), progression-free survival (PFS) and overall survival (hazard ratio ¼ 1.31 and 1.66, P ¼ 0.03 and <0.001, respectively).20,21”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Arbour, 2018, Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer, J Clin Oncol source

      Not checked in the free run.

    • cites [21] Hughes, 2019, Colitis after checkpoint blockade: a retrospective cohort study of melanoma patients requiring admission for symptom control, Cancer Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and Tim-3 expression.

    “Contrarily, other published reports showed evidence in mouse models that anti-TNF-a enhances the antitumor activity of combined anti-PD-1 and anti-CTLA-4 immunotherapy, 61 reinforces both CD8 T-cell-dependent immunity and anti-PD-1 therapy, by preventing anti-PD-1-induced cell death of tumor infiltrating lymphocytes as well as PD-L1 and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Perez-Ruiz, 2019, Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature source

      Not checked in the free run.

    • cites [62] Bertrand, 2017, TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma, Nat Commun source

      Not checked in the free run.

    • cites [63] Bertrand, 2015, Blocking tumor necrosis factor alpha enhances CD8 T-cell-dependent immunity in experimental melanoma, Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking the IL-6 and PD-1/PD-L1 axes simultaneously provides synergistic antitumor effects on multiple levels, and the lack of IL-6 in the tumor microenvironment augments Th1 immunity and increases the efficacy of ICIs.

    “Intriguingly, blocking the IL-6 and PD-1/PD-L1 axes simultaneously provides synergistic antitumor effects on multiple levels, and the lack of IL-6 in the tumor microenvironment augments Th1 immunity and increases the efficacy of ICIs.51e53”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 51e53

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    ICIs could be considered reasonable to use in patients with advanced cancer and preexisting minimally active or asymptomatic ADs.

    “Overall, ICIs could be considered reasonable to use in patients with advanced cancer and preexisting minimally active or asymptomatic ADs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IL-6 is a major acute inflammatory phase mediator with pro-tumorigenic properties.

    “Interestingly, IL-6 is a major acute inflammatory phase mediator with pro-tumorigenic properties.49,50”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Horisberger, 2018, A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy, J Immunother Cancer source

      Not checked in the free run.

    • cites [50] Fisher, 2014, The two faces of IL-6 in the tumor microenvironment, Semin Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CS promote M2 macrophage polarization, induce T regulatory cell recruitment and expansion, Th1 to Th2 phenotype skewing, and apoptosis in lymphocytes, thereby blunting a proliferative burst of CD8-positive T cells needed in cancer response to PD-1/PD-L1 blockade.

    “CS, the most widely used immunosuppressants, promote M2 macrophage polarization, 36 induce T regulatory cells recruitment and expansions, 37 Th1 to Th2 phenotype skewing, 38 and apoptosis in lymphocytes, 39 thereby blunting a proliferative burst of CD8-positive T cells needed in cancer response to PD-1/PD-L-1 blockade.40”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] Sica, 2012, Macrophage plasticity and polarization: in vivo veritas, J Clin Invest source

      Not checked in the free run.

    • cites [37] Edward, 2017, Selective expansion of human regulatory T cells in nasal polyps, and not adjacent tissue microenvironments, in individual patients exposed to steroids, Clin Immunol source

      Not checked in the free run.

    • cites [38] Libert, 2014, How steroids steer T cells, Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Flares often do not require therapy discontinuation and are manageable with standard treatment algorithms.

    “(ii) flares often do not require therapy discontinuation and are manageable with standard treatment algorithms”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with preexisting autoimmune disorders (ADs) or those receiving systemic immunosuppression for organ transplantation have been universally excluded from clinical trials.

    “In order to limit the risk of severe immune-related adverse events (irAEs) or exacerbation of underlying autoimmune or inflammatory disease, patients with preexisting autoimmune disorders (ADs) or those receiving systemic immunosuppression for organ transplantation have been universally excluded from clinical trials.3,4”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Hodi, 2010, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med source

      Not checked in the free run.

    • cites [4] Robert, 2015, Pembrolizumab versus Ipilimumab in Advanced Melanoma, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many studies reported that patients receiving immunosuppressive therapy at ICI initiation had worse clinical outcomes and shorter progression-free survival, which was confirmed in multivariable analysis.

    “Similarly, many studies reported that patients receiving immunosuppressive therapy at ICI initiation had worse clinical outcomes and shorter PFS, which was confirmed in multivariable analysis.23e25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 23e25

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunosuppressive treatment options for antisynthetase syndrome-associated interstitial lung disease are limited with low efficacy, even in highly immunosuppressed patients with nonselective immunosuppressants, and the specific use of additional immunosuppressive agents is empirical.

    “Unfortunately, immunosuppressive treatment options for ASS-ILD are limited with low efficacy, even in highly immunosuppressed patients with nSI, and the specific use of additional immunosuppressive agents is empirical.117”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Wilkes, 2005, Treatment of antisynthetase-associated interstitial lung disease with tacrolimus, Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infliximab treatment is associated with more colitis recurrence than vedolizumab, with confounding by overall fewer infusion doses compared with vedolizumab.

    “Moreover, infliximab treatment is associated with more colitis recurrence than VDZ, with the confounding factor of overall less infusion doses compared with VDZ.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Abu-Sbeih, 2019, Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis, J Immunother Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNF antagonists allow corticosteroid tapering and are highly efficacious in patients with severe/refractory sarcoidosis, with success rates in skin (80%), neurologic (95%), hepatic (50%), cardiac (88%), bone (67%), and ocular sarcoidosis (86%).

    “TNF antagonists allow CS tapering and are highly efficacious in patients with severe/refractory SX with success rates in skin (80%), neurologic (95%), hepatic (50%), cardiac (88%), bone (67%), and ocular SX (86%).103,104”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] Jamilloux, 2017, Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients, Semin Arthritis Rheum source

      Not checked in the free run.

    • cites [104] Maneiro, 2012, Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish registry of biologics BIOBADASER and a systematic review, Semin Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 plays a key role in the immune-pathogenesis of giant cell arteritis and was identified as a potential target for its treatment.

    “IL-6 plays a key role in the immune-pathogenesis of GCA and was identified as a potential target for the treatment of GCA.95”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Dasgupta, 1990, Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis, Br J Rheumatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Interstitial lung disease in antisynthetase syndrome is often severe and rapidly progressive and is the major determinant of morbidity and mortality, occurring in >70% of patients.

    “ILD is often severe and rapidly progressive and is the major determinant of morbidity and mortality, which occurs in >70% of patients.117”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Wilkes, 2005, Treatment of antisynthetase-associated interstitial lung disease with tacrolimus, Arthritis Rheum source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intravenous and subcutaneous tocilizumab have been approved for the treatment of adults with moderate to severe active rheumatoid arthritis.

    “Intravenous and s.c.TCZ have been approved for the treatment of adults with moderate to severe active RA.111,112”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Gabay, 2013, Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial, Lancet source

      Not checked in the free run.

    • cites [112] Burmester, 2016, Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial, Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tocilizumab is a humanized monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptor and inhibits IL-6R-mediated signaling.

    “TCZ, a humanized mAb, binds to both soluble and membrane-bound IL-6R and inhibits IL-6R-mediated signaling.96”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Scheinecker, 2009, Tocilizumab, Nat Rev Drug Discov source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tocilizumab is also effective and safe for polymyalgia rheumatica treatment.

    “TCZ is also effective and safe for PMR treatment.114,115”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [114] Izumi, 2015, Tocilizumab is effective against polymyalgia rheumatica: experience in 13 intractable cases, RMD Open source

      Not checked in the free run.

    • cites [115] Devauchelle-Pensec, 2016, Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study, Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ICI-related eosinophilia was described initially with ipilimumab and later with PD-1/PD-L1 inhibitors; it was frequently associated with a favorable response to ICIs.

    “ICI-related eosinophilia was described initially with ipilimumab 120 and later with PD-1/PD-L1 inhibitors; additionally, it was frequently associated with a favorable response to ICIs.121e123”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [120] Moreira, 2017, Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy, Immunotherapy source

      Not checked in the free run.

    • cites 121e123

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    ICI-related eosinophilia is a rare immune-related adverse event with an estimated frequency of approximately 2%-3%.

    “ICI-related eosinophilia is a rare irAE (estimated frequency of approximately 2%e3%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with persistent SLE may benefit from belimumab; those more likely to respond have high disease activity (e.g., SLE disease activity index >10), prednisone dose >7.5 mg/day, and serological activity (low C3/C4, high anti-dsDNA titers), with cutaneous, musculoskeletal, and serological manifestations responding the most.

    “Patients with persistent disease may benefit from BLM; more likely to respond are patients with high disease activity (e.g.SLE disease activity index >10), prednisone dose >7.5 mg/day, and serological activity (low C3/C4, high anti-dsDNA titers), with cutaneous, musculoskeletal, and serological manifestations responding the most.73e77”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 73e77

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD20 is aberrantly expressed in subsets of melanoma cells with stem-cell properties.

    “CD20 is also aberrantly expressed in subsets of melanoma cells with stem-cell properties.87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Fang, 2005, A tumorigenic subpopulation with stem cell properties in melanomas, Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with ICI-related eosinophilia appear to remain asymptomatic, and none have developed any organ damage secondary to this eosinophilia.

    “Patients appear to remain asymptomatic, and none have developed any organ damage secondary to this ICI-related eosinophilia.121”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Bernard-Tessier, 2017, Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies, Eur J Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-5 is one of the main pathogenesis players of hypereosinophilic syndrome.

    “Consequently, IL-5 is one of the main pathogenesis players of hypereosinophilic syndrome (HES).125”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Sutton, 2005, Anti-IL-5 and hypereosinophilic syndromes, Clin Immunol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tumor-associated B cells in melanoma are involved in drug resistance and retain a pro-tumorigenic property in part through insulin-like growth factor-I secretion.

    “Moreover, tumor-associated B cells in melanoma are involved in drug resistance and retain a pro-tumorigenic property in part through insulin-like growth factor-I secretion.86”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Somasundaram, 2017, Tumor-associated B-cells induce tumor heterogeneity and therapy resistance, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One randomized controlled trial reported a significant reduction in reported extraglandular manifestations and improvement of musculoskeletal features at weeks 12 and 36 (P=0.029) and vasculitis at week 24 (P=0.03).

    “One RCT 132 reported a significant reduction in reported extraglandular manifestations and improvement of musculoskeletal features at weeks 12 and 36 (P ¼ 0.029) and vasculitis at week 24 (P ¼ 0.03).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Meijer, 2010, Effectiveness of rituximab treatment in primary Sjogren's syndrome: a randomized, double-blind, placebo-controlled trial, Arthritis Rheum source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    B-cell targeted therapies (with belimumab or rituximab) may be considered in patients with severe, refractory systemic disease (ESSDAI score >14, or high activity in any of the ESSDAI domains).

    “Immunosuppressive agents should be mainly used as CSsparing agents, with no evidence supporting the choice of one agent over another and that B-cell targeted therapies (with BLM or RTX) may be considered in patients with severe, refractory systemic disease (ESSDAI score >14, or high activity in any of the ESSDAI domains).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most deaths in systemic sclerosis are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes.

    “Most deaths are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes.143”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Allanore, 2016, Treatment of systemic sclerosis: is there any hope for the future?, RMD Open source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 2019 EULAR recommendations propose that the treatment of systemic disease should be tailored to organ-specific severity using the ESSDAI definitions.

    “The new 2019 EULAR recommendations 142 propose that the treatment of systemic disease should be tailored to organ-specific severity using the ESSDAI definitions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Immunosuppressive agents should be mainly used as corticosteroid-sparing agents.

    “Immunosuppressive agents should be mainly used as CSsparing agents, with no evidence supporting the choice of one agent over another and that B-cell targeted therapies (with BLM or RTX) may be considered in patients with severe, refractory systemic disease (ESSDAI score >14, or high activity in any of the ESSDAI domains).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An open-label trial showed a reduction in the mean ESSDAI score from 8.7 to 5.7 at week 28 (P<0.0001), with a decrease of at least four points in 40% of cases and improvements in parotid swelling in 77% of cases, in patients with primary Sjögren syndrome treated by belimumab.

    “An open-label trial showed a reduction in the mean ESSDAI score from 8.7 to 5.7 at week 28 (P < 0.0001), with a decrease of at least four points in 40% of cases and improvements in parotid swelling in 77% of cases, in patients with pSS treated by BLM.140”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Mariette, 2015, Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study, Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The safety and effectiveness of immune-checkpoint inhibitor therapy in solid organ transplantation recipients are unknown.

    “Thus, the safety and effectiveness of ICI therapy in this special population are unknown.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Johnson, 2017, Immune checkpoint inhibitors in challenging populations, Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One randomized controlled trial reported statistically significant placebo differences at week 36 (P=0.03) and a statistically significant trend at week 48 (P=0.07) in the log-transformed ESSDAI score.

    “Moreover, one RCT 138 reported statistically significant placebo differences at week 36 (P ¼ 0.03) and a statistically significant trend at week 48 (P ¼ 0.07) in the logtransformed ESSDAI score.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Bowman, 2017, Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren's syndrome, Arthritis Rheumatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several published studies reported efficacy of rituximab in primary Sjögren syndrome.

    “Several published studies reported efficacy of RTX in pSS.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Meijer, 2010, Effectiveness of rituximab treatment in primary Sjogren's syndrome: a randomized, double-blind, placebo-controlled trial, Arthritis Rheum source

      Not checked in the free run.

    • cites 133e135

      Not checked in the free run.

    • cites 134e137

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this report, tumor response was documented in 40% of patients who experienced allograft rejection and 52% of those who did not.

    “Noteworthy, in this report tumor response was documented 40% of patients who experienced allograft rejection and 52% of those who did not.155,156”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

      Not checked in the free run.

    • cites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    According to EULAR recommendations, cyclophosphamide should be considered for treatment of systemic sclerosis-associated interstitial lung disease, in particular for patients with progressive interstitial lung disease, based on two high-quality randomized controlled trials.

    “According to EULAR recommendations, 145 in view of the results from two high-quality RCTs 146,147 and despite its known toxicity, CYC should be considered for treatment of SSc-ILD, in particular for patients with SSc with progressive ILD.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [145] Kowal-Bielecka, 2017, Update of EULAR recommendations for the treatment of systemic sclerosis, Ann Rheum Dis source

      Not checked in the free run.

    • cites [146] Tashkin, 2006, Cyclophosphamide versus placebo in scleroderma lung disease, N Engl J Med source

      Not checked in the free run.

    • cites [147] Hoyles, 2006, A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma, Arthritis Rheum source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The use of antimalarial drug hydroxychloroquine should be restricted to patients with active systemic disease (clinic ESSDAI score ≥1).

    “Otherwise, the use of antimalarial drug (HCQ) should be restricted to patients with active systemic disease (clinic ESSDAI score !1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Ramos-Casals, 2020, EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies, Ann Rheum Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    B cells have a central pathophysiologic role in primary Sjögren syndrome, illustrated by autoantibodies against SS-A/Ro and/or SS-B/La, elevated rheumatoid factor, hypergammaglobulinemia, and elevated circulating and salivary gland tissue levels of BAFF.

    “The involvement of B cells as a central pathophysiologic role for B cells is illustrated by the presence of autoantibodies against SS-A/Ro and/or SS-B/La, elevated levels of rheumatoid factor (RF), hypergammaglobulinemia, and elevated levels of circulating and salivary gland tissue levels of BAFF.131”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Jonsson, 2005, Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren's syndrome, J Clin Immunol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Systemic sclerosis is frequently associated with malignancy.

    “Importantly, SSc is frequently associated with malignancy.144”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Tyndall, 2010, Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database, Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent systematic review and institutional experience report including 39 ICI-treated transplant recipients (23 renal, 11 hepatic, 5 cardiac) reported allograft rejection in 41% of patients [11 renal (48%), 4 hepatic (36%), 1 cardiac (20%)] with very similar rates between anti-PD-1 versus anti-CTLA-4 agents (40% versus 36%).

    “Interestingly, a recent systematic review and institutional experience report 155 that included 39 ICI-treated transplant recipients (23 renal, 11 hepatic, 5 cardiac) reported allograft rejection in 41% of patients [11 renal (48%), 4 hepatic (36%), 1 cardiac (20%)] with very similar rates between anti-PD-1 versus anti-CTLA-4 agents (40% versus 36%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    There is still much to learn about how to treat this special population with the best selective immunosuppressive therapy without compromising ICI effectiveness and without exposing patients to a life-threatening risk from autoimmune disease exacerbations or from graft rejection.

    “there is still much to learn about how to treat this special population with the best selective immunosuppressive therapy without compromising ICI effectiveness and without exposing patients to a life-threatening risk from AD exacerbations or from graft rejection.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    The risk in transplant recipients may be due to alloimmunity and acute rejection of the allograft, rather than an ICI-induced immune-mediated adverse event.

    “So far, they consider whether the risk in transplant recipients may be due to alloimmunity and acute rejection of the allograft, rather than an ICI-induced imAE.155”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    We are still in the learning phase regarding the best use of ICIs in patients with cancer and preexisting active autoimmune diseases.

    “We are still in the learning phase regarding the best use of ICIs in patients with cancer and preexisting active ADs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Another monocentric study reported a rate of graft rejection of 28.6%, which is very similar to the 33.3% graft rejection rate reported in previous case reports that received PD-1 inhibitors.

    “Another monocentric study reported a rate of graft rejection of 28.6%, which is very similar to the 33.3% graft rejection rate reported in previous case reports that received PD-1 inhibitors.158”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] DeLeon, 2018, Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience, J Gastrointest Oncol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The authors searched PubMed for papers published in English between 1 January 2008 and 30 December 2019 using specified search terms.

    “We searched PubMed for papers published in English between 1 January 2008, and 30 December 2019, using the terms 'checkpoint inhibitor ICI', 'immune-related adverse event', 'CTLA4', 'PD-1', 'PD-L1', preexisting autoimmune diseases, Antisynthethase syndrome, Azathioprine, Connective tissue disease, Cyclophosphamide, Cyclosporine, Inflammatory bowel disease, ICI-related diarrhea and colitis, Interst”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Allograft preservation strategies in these special patients follow general acute rejection guidelines, with i.v. solumedrol 250-500 mg daily for 3 days being the most common first-line strategy.

    “In general, allograft preservation strategies in these special patients follow general acute rejection guidelines, with i.v.solumedrol 250e500 mg daily for 3 days being the most common first-line strategy.156,174”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

      Not checked in the free run.

    • cites [174] 2009, KDIGO clinical practice guideline for the care of kidney transplant recipients, Am J Transplant

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Concomitant treatment with ICI and calcineurin inhibitor was associated with a lower antitumor response; in a recent review of nine patients who were left on full dose of calcineurin inhibitor during ICI therapy, rejection was not observed but objective tumor response was seen in only one of nine patients.

    “Concomitant treatment with ICI and calcineurin inhibitor (CNI), which is an anti-T-cell-specific drug, used widely for maintenance graft regimen, was unfortunately associated with a lower antitumor response; in a recent review of nine patients who were left on full dose of CNI during ICI therapy, rejection was not observed but objective tumor response was seen in only one of nine patients.165,166”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [165] Kittai, 2017, Immune checkpoint inhibitors in organ transplant patients, J Immunother

      Not checked in the free run.

    • cites [166] Grant, 2018, Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations, Melanoma Manag source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The addition of sirolimus resulted in ongoing antitumor efficacy while promoting allograft tolerance in melanoma patients with organ rejection and colitis induced by anti-PD-1 therapy.

    “Recently, it was reported that the addition of sirolimus resulted in ongoing antitumor efficacy while promoting allograft tolerance in melanoma patients with organ rejection and colitis induced by anti-PD-1 therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Esfahani, 2019, Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation, Nat Commun source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Authors suggest a possible difference in immune mechanisms mediating the occurrence of immune-related adverse events and allotransplantation immunity because they observed an irAEs rate similar to the cohort exempt from rejection and to the classical rate obtained in non-SOT recipients.

    “Authors also suggest a possible difference in immune mechanisms mediating the occurrence of irAEs and allotransplantation immunity because they observed an irAEs rate similar to the cohort exempt from rejection and to the classical rate obtained in non-SOT recipients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Abdel-Wahab, 2019, Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature, J Immunother Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The median time to rejection reported in previous case reports is 8 days with a range of 5-63 days.

    “The median time to rejection reported in previous case reports is 8 days with a range of 5e63 days.27,159e164”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 27,159e164

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many possible therapies for antibody-mediated rejections have been reported in patients without cancer including plasma exchange, IVIG, anti-CD20 antibodies, and anti-T-cell antibodies.

    “Concerning antibody-mediated rejections, many possible therapies have been reported in patients without cancer including plasma exchange, IVIG, anti-CD20 antibodies, and anti-T-cell antibodies.156,174”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

      Not checked in the free run.

    • cites [174] 2009, KDIGO clinical practice guideline for the care of kidney transplant recipients, Am J Transplant

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Graft rejection appears to be an early PD-1 inhibitor adverse event and occurs earlier than most other immune-related adverse events.

    “Globally, graft rejection appears to be an early PD-1 inhibitor adverse event and occurs earlier than most other irAEs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The most important risk factors leading to graft rejection are not well defined.

    “It is likewise not well defined the most important risk factors leading to graft rejection.156”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    It is unknown whether ICI treatment directly prompts allograft rejection or whether it is the consequence of diminished immunosuppression or some other factor.

    “It stays unknown whether ICI treatment directly prompts allograft reflection or whether it is the consequence of diminished immunosuppression or some other factor.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    ICIs could be beneficial in solid organ transplantation patients or patients with active preexisting autoimmune diseases.

    “and because ICIs could be beneficial in such patients”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Solid organ transplantation patients or patients with active preexisting autoimmune diseases have been universally excluded from clinical trials with ICIs.

    “Because SOT patients or patients with active preexisting ADs have been universally excluded from clinical trials with ICIs”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cotreatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated regulatory T cell numbers in the peripheral blood were maintained.

    “Cotreatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Esfahani, 2019, Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most transplant recipients without cancer respond to the high-dose corticosteroid approach, but it is unclear whether the same is true in the ICI-rejected solid organ transplantation population.

    “Although most transplant recipients without cancer respond to the highdose CS approach, 174 it is unclear whether the same is true in the ICI-rejected SOT population.156”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [174] 2009, KDIGO clinical practice guideline for the care of kidney transplant recipients, Am J Transplant

      Not checked in the free run.

    • cites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Numbers of IFN-g+ CD4+ T cells and serum IFN-g levels increased with the addition of sirolimus treatment, likely promoting ongoing anti-PD-1 efficacy.

    “Interestingly, numbers of IFN-gþ CD4þ T cells and serum IFN-g levels increased, with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy.168”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Esfahani, 2019, Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation, Nat Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It remains unclear which immunosuppression regimen is most efficacious at reducing the risk of graft rejection without completely compromising ICI efficiency.

    “It remains unclear which immunosuppression regimen is most efficacious at reducing the risk of graft rejection without completely compromising ICI efficiency.156”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [156] Shirali AC. Minimizing the impact of imAEs and maximizing efficacy: renal toxicities. Medscape 2019.

      Not checked in the free run.

72 of 72

  • The authors state this as an assumption.

    Treatment of active ADs in cancer patients can be guided by analogy with the treatment of classical ADs.

    “Based on these data and by analogy with the treatment of classical ADs, patients with active ADs could be considered candidates for ICIs, even in the context of active immunosuppressive therapy.”

  • The paper relies on this without support.

    A 2-4 week rotation phase is sufficient to achieve AD stability before ICI initiation.

    “ICI treatment can be introduced after 2e4 weeks of AD stability under SIs, or alternatively concomitantly to the introduction of SIs in patients with rapid disease pace.”

  • The paper relies on this without support.

    Standardized risk assessment for IBD exacerbation from ICI treatment is still lacking.

    “Standardized risk assessment for IBD exacerbation from ICI treatment is still lacking.”

  • The paper relies on this without support.

    Patients with severe baseline IBD activity without active IBD treatment at the time of ICI treatment will be more likely to have IBD exacerbation and its related complications.

    “In general, we usually anticipate that patients with severe baseline IBD activity without active IBD treatment at the time of ICI treatment will be more likely to have IBD exacerbation and its related complications.”

  • The paper relies on this without support.

    The use of prednisone <10 mg/day or hydroxychloroquine at 5-7 mg/kg/day is tolerated.

    “The use of PDN < 10 mg/day or hydroxychloroquine (HCQ) at 5e7 mg/kg/day is tolerated.”

  • The paper relies on this without support.

    During tocilizumab therapy, C-reactive protein and erythrocyte sedimentation rate will be completely normalized.

    “During TCZ therapy, we recommend avoiding the use of C-reactive protein and erythrocyte sedimentation rate as biomarkers for GCA activity because they will be completely normalized under TCZ.”

  • The paper relies on this without support.

    IL-17 inhibitors may exacerbate or induce inflammatory bowel disease.

    “IBD is of special interest when using IL-17 inhibitors since these agents may exacerbate or induce IBD, although real-life data are very reassuring.”

  • The paper relies on this without support.

    Effective treatment of arthritis immune-related adverse events requires a prolonged treatment period.

    “Because effective treatment of arthritis irAEs requires a prolonged treatment period, in this case, an anti-TNF-a inhibitor may potentially dampen the antitumor benefit of ICI therapy.”

  • The paper relies on this without support.

    Antisynthetase syndrome is associated with a higher prevalence of interstitial lung disease than dermatomyositis and polymyositis.

    “In contrast to other IIMs, ASS is associated with a higher prevalence of ILD than dermatomyositis (DM) and polymyositis (PM), representing IIMs with which it shares many features.”

  • The paper relies on this without support.

    The place of tocilizumab in spondyloarthritis is not yet clear, with inconsistent or mixed responses.

    “The place of TCZ in this indication is not yet clear with inconsistent or mixed responses.”

  • The paper relies on this without support.

    Optimal dosing of mepolizumab in patients with corticosteroid-refractory hypereosinophilic syndrome is variable depending on HES subtype but globally ranges from 300 mg to 750 mg monthly.

    “Optimal dosing in patients with GS-refractory disease requires further study; it seems to be variable depending on HES subtype but globally ranges from 300 mg to 750 mg monthly.”

  • The paper relies on this without support.

    300 mg subcutaneous monthly mepolizumab is likely to be effective in most patients with corticosteroid-refractory hypereosinophilic syndrome.

    “Other emerging data suggest that 300 mg s.c.monthly is likely to be effective in most of these subjects.”

  • The paper relies on this without support.

    The mechanisms of immune-related adverse events and autoimmune diseases are similar enough that treatments for primary autoimmune diseases can be extrapolated to ICI-treated patients with preexisting autoimmune diseases.

    “based on current immuno-pathophysiological knowledge and on extrapolations from treatment options for primary ADs”

  • The paper relies on this without support.

    Selective immunosuppressive therapy can prevent autoimmune disease exacerbations or graft rejection without compromising ICI effectiveness.

    “without compromising ICI effectiveness”

  • The paper relies on this without support.

    The proposed treatments (e.g., mepolizumab, benralizumab, rituximab, belimumab) are safe and effective in ICI-treated patients with autoimmune diseases.

    “we recommend preferentially the introduction of concomitant mepolizumab 300 mg once monthly or benralizumab 30 mg once monthly preventatively for asymptomatic patients with AEC > 5 G/l”

  • The paper relies on this without support.

    Cytokine profile and specific active immune cell types can guide personalized choice of selective immunosuppressive therapy.

    “personalized choice of the best SIT is one of the most promising future directions and should be based on precision medicine strategies, according to the cytokine profile and specific active immune cell types involved in the AD of individual patients.”
16 of 16

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A detrimental effect on survival has been suggested when corticosteroids are used for cancer-related symptoms or for the management of a pre-existing autoimmune disease (AID).

    “Conversely, a detrimental effect on survival has been suggested when used for cancer-related symptoms or for the management of a pre-existing AID”

    From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [51]

    The Introduction reports shorter overall survival associated with corticosteroid use in patients with NSCLC receiving immune-checkpoint inhibitors and discusses patients receiving steroids for palliative indications. It also reports poorer ICI outcomes among patients on immunosuppressants, including a pre-existing autoimmune-disease cohort, but does not specifically establish a survival effect from corticosteroids used to manage autoimmune disease. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A growing body of evidence indicates that ICPis may be safe and effective in patients with pre-existing autoimmune diseases.

    “However, a growing body of evidence indicates that ICPis may be safe and effective in these patients [51,52].”

    From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [51]

  • Following immune checkpoint inhibition, T cells and other immune cells are activated, resulting in production of pro-inflammatory cytokines which may lead to off-target inflammation and autoimmunity.

    “One important explanation may be that following immune checkpoint inhibition, T cells and other immune cells are activated, resulting in the production of pro-inflammatory cytokines which may lead to off-target inflammation and autoimmunity [51].”

    From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [51]

  • High-dose steroids can theoretically reverse the anti-cancer benefit of ICPi treatment.

    “because high-dose steroids can theoretically reverse the anti-cancer benefit of ICPi treatment [51,62].”

    From Graves’ Disease during Immune Checkpoint Inhibitor Therapy (A Case Series and Literature Review) (2021) · cites this paper as [51]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Psoriasis recommendations disagree on the next choice after anti-IL-12/23

    Major

    The main text ranks anti-IL-23 second and anti-IL-17 third, while the Figure 2 description recommends anti-IL-17 when the preferred anti-IL-12/23 treatment is unavailable.

  • GCA monitoring algorithm includes biomarkers the text says to avoid

    Minor

    The GCA section recommends avoiding CRP and ESR as activity biomarkers during tocilizumab therapy, but its monitoring algorithm includes both in regular biological evaluation.

  • IBD prevalence differs between the NSCLC cohort description and table

    Minor

    The description of the 56-patient NSCLC cohort reports IBD in 11%, whereas its Table 1 entry lists IBD in 20%.

3 of 3

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1 of the 181 references couldn’t be matched to a known paper.

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Related

Authors
Haanen, J., Ernstoff, M. S., Wang, Y., Menzies, A. M., Puzanov, I., Grivas, P., Larkin, J., Peters, S., Thompson, J. A., & Obeid, M.
Affiliations
  • The Netherlands Cancer Institute (NL)
  • Roswell Park Comprehensive Cancer Center (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Sydney (AU)
  • Seattle Cancer Care Alliance (US)
  • Royal Marsden NHS Foundation Trust (GB)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • National Institutes of Health (US)
ORCID
Venue
Annals of Oncology
Publisher
Elsevier BV
Published
2020-06
Volume
31
Issue
6
Pages
724-744
ISSN
0923-7534 (ISSN-L)
DOI
10.1016/j.annonc.2020.03.285
OpenAlex
W3012088984
Semantic Scholar
5e78d5415abd2243bf554d5aaa83402c7acf9cc5
Cited by
222
References
181
Citations by year
2026: 17 · 2025: 30 · 2024: 50 · 2023: 34 · 2022: 33 · 2021: 42 · 2020: 16
FWCI
11.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • Sanofi
  • Fondation Leenaards
  • Neos Therapeutics
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
autoimmune disease, immune checkpoint inhibitors, cancer immunotherapy, immunosuppressants, corticosteroids, drug efficacy, adverse events, treatment algorithm, patient selection, international registry
MeSH terms
Immune Checkpoint Inhibitors, Autoimmune Diseases, Humans, Neoplasms, Prospective Studies, Retrospective Studies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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