Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation

Braaten, Tawnie; Brahmer, Julie R.; Forde, Patrick M.; Le, Dung T.; Lipson, Evan J.; Naidoo, Jarushka; Schollenberger, Megan D.; Zheng, Lei; Bingham, Clifton O.; Shah, Ami A.; Cappelli, Laura C.

doi:10.1136/annrheumdis-2019-216109

Cited by 173 publications

(168 citation statements)

References 31 publications

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“…65 In ICI-IA, however, there is a large subgroup of patients with persistent disease up to several months to years after the ICI is stopped. 66 In one study, 49% of patients with follow-up at 6 months post-ICI cessation still had active IA. Interestingly, as in traditional reactive arthritis, patients with a reactive arthritis phenotype after ICI have had a self-limited course.…”

Section: Disease Course and Prognosismentioning

confidence: 98%

“…Some irAEs affecting other organ systems, such as the gastrointestinal tract, are monophasic and self‐limited, resolving after ICI cessation and/or corticosteroid or brief courses of immunomodulatory therapy . In ICI‐IA, however, there is a large subgroup of patients with persistent disease up to several months to years after the ICI is stopped . In one study, 49% of patients with follow‐up at 6 months post–ICI cessation still had active IA.…”

Section: Clinical Features and Epidemiology Of Ra Spa And Ici‐iamentioning

confidence: 99%

“…Thus far, most reports are from small case series or single‐center cohort studies and the assays used to detect seropositivity are not uniform between studies. Despite these limitations, aggregation of the data from multiple studies reveals a low rate of seropositivity among patients developing IA following treatment with ICI therapy with 5.5% (12/217; range 0%‐36%) positive for RF and 5% (11/217; range 0%‐11%) positive for ACPAs . In a study comparing ICI‐IA patients to ethnically matched counterparts with RA, 7.7% of ICI‐IA patients were positive for RF or ACPAs, whereas 64.6% of RA patients were positive for ACPAs and 56.7% positive for RF, with 49.3% being positive for both .…”

Section: Serologymentioning

confidence: 99%

“…While ANA is not specific for a particular subgroup, it does correlate with an increased incidence of JIA‐associated uveitis, particularly iridocyclitis . Aggregate analysis of ANA positivity in patients with ICI‐IA, as defined by a titer greater than 1:40, from several published studies revealed that 15.3% (32/209; range 0%‐89%) of patients were positive for ANA . In addition, antibodies against specific nuclear antigens, dsDNA, Ro, and La (usually seen in patients with systemic lupus erythematosus or Sjögren's syndrome), have been detected in ICI‐IA patients .…”

Section: Serologymentioning

confidence: 99%

“…Despite these limitations, aggregation of the data from multiple studies reveals a low rate of seropositivity among patients developing IA following treatment with ICI therapy with 5.5% (12/217; range 0%-36%) positive for RF and 5% (11/217; range 0%-11%) positive for ACPAs. 30,31,33,36,[57][58][59]66,[109][110][111][112][113][114][115] In a study comparing ICI-IA patients to ethnically matched counterparts with RA, 7.7% of ICI-IA patients were positive for RF or ACPAs, whereas 64.6% of RA patients were positive for ACPAs and 56.7% positive for RF, with 49.3% being positive for both. 116 Although these results indicate that the prevalence of seropositivity in ICI-IA is much lower than in RA, it is unknown if seropositivity is increased in patients who develop RA-like disease following ICI therapy.…”

Section: Ici-ia Autoantibodiesmentioning

confidence: 99%

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Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

Cappelli¹,

Thomas²,

Bingham³

et al. 2020

Immunological Reviews

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The development of inflammatory arthritis in patients receiving immune checkpoint inhibitor therapy is increasingly recognized due to the growing use of these drugs for the treatment of cancer. This represents an important opportunity not only to define the mechanisms responsible for the development of this immune‐related adverse event and to ultimately predict or prevent its development, but also to provide a unique window into early events in the development of inflammatory arthritis. Knowledge gained through the study of this patient population, for which the inciting event is known, could shed light into the pathogenesis of autoimmune arthritis. This review will highlight the clinical and immunologic features of these entities to define common elements for future study.

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Section: Disease Course and Prognosismentioning

confidence: 98%

Section: Clinical Features and Epidemiology Of Ra Spa And Ici‐iamentioning

confidence: 99%

Section: Serologymentioning

confidence: 99%

Section: Serologymentioning

confidence: 99%

Section: Ici-ia Autoantibodiesmentioning

confidence: 99%

See 3 more Smart Citations

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

Cappelli¹,

Thomas²,

Bingham³

et al. 2020

Immunological Reviews

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Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-risk Resected Melanoma

et al. 2021

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IMPORTANCEAgents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined.OBJECTIVE To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTSThis retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included.MAIN OUTCOMES AND MEASURES Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). RESULTS Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. CONCLUSION AND RELEVANCEIn this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

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Higher Checkpoint Inhibitor Arthritis Disease Activity may be Associated With Cancer Progression: Results From an Observational Registry

Chan

Tirpack

Vitone

et al. 2020

ACR Open Rheumatology

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Objective. To describe clinical features associated with cancer outcomes of patients with immune checkpoint inhibitor (ICI)-associated arthritis. Methods. Observational study of patients with ICI-arthritis enrolled in a single-center registry. Arthritis phenotype and activity, medications, and cancer status were recorded at every visit. We used descriptive statistic, and Kaplan-Meier curves using two-sided log-rank test and Cox regression analysis were used to identify factors associated with cancer progression-free survival (PFS). Results. Forty-two patients with ICI-arthritis were followed for a median (interquartile range [IQR]) of 7.4 (1.7, 14.7) months. Fifty-seven percent were female, 33% had melanoma, and 69% received anti-programmed death ligand 1 monotherapy. Median time from ICI initiation to arthritis onset was 2.8 (0.8, 11.2) months. Sixty-two percent had a rheumatoid arthritis (RA)-like small-joint presentation; 27% of all patients were rheumatoid factor and/or cyclic citrullinated peptide positive. Median (IQR) Clinical Disease Activity Index (CDAI) on presentation was 15 (8, 24); 62% required systemic glucocorticoids, 55% required disease-modifying antirheumatic drugs (DMARDs), and 69% had ongoing arthritis at 6 months. Arthritis led to ICI discontinuation in five patients. In univariate analysis, baseline CDAI, DMARD use, earlier arthritis onset, and longer duration of follow-up were associated with shorter PFS. In multivariable Cox regression analysis controlling for DMARD use and time to arthritis onset, CDAI was a significant predictor of cancer progression (hazard ratio 1.09, 95% confidence interval [CI] 1.00-1.19, P = 0.05) Conclusion. ICI-arthritis most commonly presents with an RA-like phenotype. High disease activity, as measured by CDAI, may portend cancer progression.

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Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation

Cited by 173 publications

References 31 publications

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-risk Resected Melanoma

Higher Checkpoint Inhibitor Arthritis Disease Activity may be Associated With Cancer Progression: Results From an Observational Registry

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