Checkpoint Inhibitors and Ocular Side Effects
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Checkpoint Inhibitors and Ocular Side Effects

  • Overview of Checkpoint Inhibitors:
    • Checkpoint inhibitors are humanized monoclonal antibodies that activate T-cells to target tumor cell antigens, first FDA-approved in 2011.
    • Common agents: pembrolizumab, ipilimumab, nivolumab (recognizable by “-mab” suffix).
    • Treat a wide range of cancers, including cutaneous melanoma, lung cancer, and gastrointestinal/genitourinary cancers, with objective response rates up to 60–70%.
    • Revolutionized oncology by leveraging the immune system, particularly for cancers with previously limited treatment options.
  • Ocular Side Effects Prevalence:
    • Ocular adverse events occur in 1–3% of patients in clinical trials, but a retrospective MD Anderson study reported up to 10% prevalence when pooling data across all checkpoint inhibitors over 10 years.
    • Ophthalmologists must be vigilant due to the increasing use of these agents and their cumulative ocular effects.
  • Mechanisms of Ocular Toxicity:
    • Checkpoint inhibitors disrupt immune privilege, particularly by targeting PD-L1 on retinal pigment epithelium (RPE), which normally suppresses aberrant T-cells in the eye.
    • In melanoma patients, lysis of melanoma cells releases melanin-associated proteins, triggering a Vogt-Koyanagi-Harada (VKH)-like uveitis due to cross-reactivity with melanosome-rich tissues (e.g., uvea).
    • Ocular side effects mimic autoimmune diseases, affecting any part of the eye (orbit to retina).
  • Common Ocular Side Effects:
    • Anterior Segment:
      • Dry eye disease: Common, under-reported, and exacerbated in cancer patients; may mimic Sjogren’s-like ocular surface disease.
      • Anterior uveitis/iritis: Often linked to PD-L1 inhibition, presenting with cells, flare, or conjunctival inflammation.
      • Keratitis: Beyond dry eye, may involve corneal inflammation.
      • Episcleritis/scleritis: Inflammatory changes mimicking autoimmune conditions.
    • Posterior Segment:
      • Posterior uveitis/panuveitis: May present with vitreous cell, resembling VKH (e.g., serous retinal detachments).
      • VKH-like syndrome: Characterized by vitiligo, uveitis, and serous detachments, especially in melanoma patients.
    • Other:
      • Orbital inflammatory disease.
      • Vitreous infiltration mimicking inflammation but potentially due to cancer cells (non-responsive to checkpoint inhibitors in the immune-privileged eye).
  • Diagnostic Challenges:
    • No characteristic presentation; ocular side effects mimic autoimmune or infectious etiologies, requiring a broad differential.
    • Rule out common causes first: HLA-B27-associated uveitis, syphilis, sarcoidosis, Lyme disease, and viral infections (e.g., HSV, due to immunosuppression).
    • Clues to checkpoint inhibitor-related etiology:
      • Temporal correlation with dosing (symptoms 2–7 days post-dose, resolving before the next dose).
      • Concurrent systemic inflammatory events (e.g., GI inflammation).
    • Vitreous infiltration may represent cancer cells, not inflammation, necessitating biopsy in unclear cases (e.g., diagnostic vitrectomy or anterior chamber tap).
    • Baseline ophthalmic exams are ideal but not always feasible; community ophthalmologists should be proactive in evaluating referred patients.
  • Management Strategies:
    • Goal: Minimize systemic immunosuppression to preserve the anti-cancer effect of checkpoint inhibitors.
    • Anterior Segment:
      • Topical corticosteroids (e.g., prednisolone acetate) for dry eye, keratitis, episcleritis, or mild uveitis; often sufficient without dose adjustment.
      • Cycloplegics for anterior uveitis to prevent synechiae.
    • Posterior Segment:
      • Intravitreal corticosteroids (e.g., Ozurdex, Yutiq) preferred over periocular injections for posterior uveitis or macular edema, based on clinical trial data (e.g., POINT trial).
      • Short bursts of low-dose oral prednisone (≤10 mg/day) if local therapy is insufficient, tapered quickly to avoid dampening anti-cancer effects.
    • Systemic Immunomodulatory Therapy (IMT):
      • Rarely used (e.g., methotrexate for inflammatory arthritis); avoided unless multi-organ involvement requires it, due to immune suppression risks.
    • Coordination with Oncologists:
      • Essential to balance ocular and oncologic outcomes; involves discussing dose delays, reductions, or pre-treatment with steroids.
      • Stopping checkpoint inhibitors is rare for ocular side effects alone unless severe, as patients prioritize cancer control.
  • When to Stop Checkpoint Inhibitors:
    • Discontinuation is uncommon unless multi-organ toxicity or intolerable systemic side effects occur.
    • If ocular inflammation is severe but isolated, local therapy and dose adjustments (e.g., reducing dose or extending intervals) are preferred.
    • Patients may refuse discontinuation if the drug is life-sustaining, necessitating aggressive local management.
  • Treatment Duration and Switching Agents:
    • No defined stopping point; typical course is ~1 year, but patients with partial response may continue indefinitely.
    • Switching checkpoint inhibitors is rare after severe toxicity; protocols often exclude patients with prior toxicity from new trials.
    • Dual-agent therapy (e.g., CTLA-4 + PD-1 inhibitors) may be de-escalated to a single agent to reduce toxicity while maintaining efficacy.
    • Newer agents targeting different immune pathways may offer flexibility in the future.
  • Practical Recommendations:
    • Baseline ophthalmic exams are valuable for establishing a reference, especially in academic centers or clinical trials.
    • Community ophthalmologists should promptly evaluate patients referred for ocular symptoms, advising oncologists to continue therapy until assessment.
    • Work closely with oncologists to tailor treatment, avoiding unnecessary discontinuation of life-saving therapy.
    • Resource: National Comprehensive Cancer Network (NCCN) algorithm for managing immune-related adverse events, updated annually (link in podcast description).
  • Board-Relevant Takeaways:
    • Recognize checkpoint inhibitors by their “-mab” suffix and associate them with a 1–10% risk of ocular side effects.
    • VKH-like uveitis is a hallmark in melanoma patients due to melanin-associated protein release.
    • Differential diagnosis must include infectious and autoimmune etiologies, with syphilis, HSV, and cancer infiltration as key considerations.
    • Local therapy (topical/intravitreal steroids) is first-line to minimize systemic immunosuppression; systemic steroids are limited to ≤10 mg/day.
    • Never assume vitreous cell is inflammatory; biopsy may be needed to rule out cancer infiltration.

Citation of the Podcast

Young, B., Berkenstock, M., Dalvin, L., & Kim, S. (Host). (2025). Checkpoint inhibitors and their ocular side effects. Experts InSight [Podcast]. American Academy of Ophthalmology. Available at: aao.org/podcasts. Additional resource: National Comprehensive Cancer Network (NCCN) Immune-related Adverse Events Panel algorithm (link provided in podcast description).