Approach to Eye-irAE diagnosis and general guidance statements

Eye-irAEs were broadly classified anatomically into ocular surface disorders, uveitis, orbital disorders and neuro-ophthalmic diseases. Note that the neuro-ophthalmic irAEs discussed in this paper primarily affect the optic nerve and other cranial nerves (CNs). In contrast, the neurologic irAEs discussed in the irAE-N guidelines primarily affect the peripheral nervous system (PNS) and central nervous system (CNS), but may have some overlapping neuro-ophthalmic implications (eg, immune-related neuromuscular junction disorders).14

Each Eye-irAE guidance statement describes: possible symptoms and signs, supportive examination findings, recommended tests, diagnostic criteria, and treatment recommendations. These descriptions are intended to be dynamic: as the diagnostic workup evolves and the patient undergoes appropriate evaluation by the appropriate specialist, the diagnosis may be updated. For instance, an Eye-irAE may first be described as uveitis, and then the subtype of uveitis may be delineated.

Several features increase the likelihood that visual symptoms or signs starting after ICI administration represent an Eye-irAE. The diagnosis requires that other potential etiologies have been reasonably excluded through appropriate workup. Most Eye-irAEs occur early in treatment, usually within 6 months of starting ICIs, although they could occur anytime while on treatment or after completion.17 However, generally to be considered an Eye-irAE, symptoms should begin within 12 months of the last ICI dose. If a new condition occurs 6–12 months or later after the last ICI dose, diagnosis of an Eye-irAE may require a higher burden of proof than those outlined in these guidance statements.

While improvement in symptoms and signs with holding ICI therapy and/or initiation of corticosteroids or other immunomodulators is not specific, this occurrence increases diagnostic certainty of an Eye-irAE. However, some Eye-irAEs may be treatment resistant, result in chronic disease, and/or have irreversible deficits. Therefore, lack of improvement with appropriate treatment may prompt an expansion of the differential diagnosis but does not exclude the possibility of an Eye-irAE. Some visual symptoms such as blurred vision without objective ocular abnormalities may be too non-specific to assign a particular Eye-irAE syndrome or could be related to other irAEs, for example, CNS disease, or to non-irAE complications of cancer therapy (eg, radiation optic neuropathy).

Eye-irAE consensus definitions

For each section, possible symptoms were proposed followed by supportive examination findings. Ancillary tests including laboratory tests and imaging, were divided into required tests, recommended tests and other suggested workup. Based on the symptoms, physical examination, and required ancillary tests, the definite definition was proposed. Probable and possible disease definitions based on all findings including recommended and suggested tests are provided. The treatment indications and recommendations about holding ICIs are also provided.

Diagnostic and management features for Panel A and B diseases are summarized in tables 1 and 2. The online supplemental tables 2 – 22 provide the complete Delphi process findings and should be the primary source of reference for investigators and clinicians.

Table 1

Panel A: optic nerve and orbital disorders

Table 2

Panel B: uveitis and ocular surface disease

Panel B: uveitis and ocular surface diseaseImmune-related anterior uveitis, immune-related intermediate uveitis, immune-related posterior uveitis, immune-related panuveitis

We have grouped the consensus results for the four anatomic locations of uveitis (anterior, intermediate, posterior and panuveitis) together here as there is significant overlap between them. We have also highlighted differences between them, particularly with regard to treatment (online supplemental tables 13–16).

Common: Patients who develop uveitis (immune-related anterior uveitis (irAU), immune-related intermediate uveitis (irIU), immune-related posterior uveitis (irPosU), immune-related panuveitis (irPanU)) typically present with bilateral findings and symptoms, although cases can be asymmetric. As with other irAEs, onset is typically within the first 6 months after initiation of ICI therapy, although late presentations can occur. Symptom onset is generally acute. For irAU, the most common symptoms are eye redness, eye pain, headache, photophobia and blurry vision. For irIU and irPosU, floaters and photopsias are more frequently noted than in irAU, but they can also have irAU symptoms. Because the entire eye is inflamed in irPanU, any of the above symptoms can be noted. Diagnostic findings include inflammatory cells in the eye compartment indicated by the disease. For irAU, there is anterior chamber cell and/or flare on slit lamp examination. For irIU, vitreous cells or haze are present as well as pars plana vitreous exudates. For irPosU, inflammatory chorioretinal lesions and/or retinal perivascular exudates are present. Vitreous cells or haze are also often present. For irPanU, supportive examination findings include the presence of anterior chamber cell or flare in addition to inflammation in the vitreous, retina, and/or choroid. Anatomic complications of uveitis may be present on examination. Cystoid macular edema (CME) can occur with any anatomic location of uveitis. Choroidal neovascular membrane (CNVM) typically is only found with irPosU and irPanU.

For all uveitis anatomic locations, testing is recommended to rule out other etiologies of uveitis, particularly infectious etiologies. This includes serum testing and imaging as outlined in online supplemental tables 13–16. For all uveitis anatomic locations, testing to rule out syphilis, tuberculosis, Lyme disease (in endemic areas) and sarcoidosis should be done. For irAU, human leukocyte antigen B27 (HLA-B27) should additionally be checked. For irIU, an MRI brain to evaluate for demyelinating disease should additionally be checked if the patient has neurologic symptoms. For irPosU and irPanU, if retinal vasculitis is also present, testing for lupus, ANCA vasculitis and IgG4 disease should additionally be checked.

For irAU, a topical ophthalmic corticosteroid is recommended with follow-up every 1–2 weeks until symptoms and signs resolve. The corticosteroid regimen should be clinically adjusted to the lowest possible dose that maintains quiet disease. If posterior synechiae develop, the addition of a topical cycloplegic agent is needed. Consensus was reached that the ICI should not be discontinued and that irAU can generally be successfully controlled with topical therapy.

For irIU, we recommended initiating a topical ophthalmic corticosteroid with follow-up every 1–2 weeks. If findings persist on follow-up, then periocular or intraocular corticosteroid injections may be considered.

For irPosU, if the disease is mild, it could be observed with close follow-up. If findings persist or worsen on follow-up, then intraocular steroids may be considered. If the disease progresses despite this, consider holding the ICI and/or initiating oral corticosteroids.

For irPanU, the recommended treatment would be to initiate a topical ophthalmic corticosteroid to treat the anterior segment inflammation with follow-up every 1–2 weeks. If findings persist or worsen on follow-up, then intraocular steroids may be considered. If disease progresses despite this, consider holding the ICI and/or initiating oral corticosteroids.

Possible

If the diagnosis of irAU is uncertain (eg, inflammation may not be isolated to the anterior chamber), then additional ancillary testing can be considered including FAF, FFA, and macula OCT. This would help rule out other immune-related uveitic diseases. For treatment, if the patient is unresponsive to topical corticosteroids, periocular or intraocular injectable corticosteroids may be considered.

If the diagnosis of irIU is uncertain, then additional ancillary testing can be considered including FFA and macula OCT. As with irAU, this would help rule out other immune-related uveitic diseases. For treatment, if CME is detected on ancillary testing, topical non-steroidal anti-inflammatory drugs (NSAIDs) may be added with further escalation to intraocular steroids as necessary. If vascular leakage is detected on FFA, escalation to intraocular steroids may be necessary.

If the diagnoses of irPosU or irPanU are uncertain, then additional ancillary testing can be considered including FAF, FFA, indocyanine green angiography (ICGA), macula OCT, and OCT angiography. As with irAU and irIU, this would help rule out other immune-related uveitic diseases. These tests could also detect the presence of focal chorioretinitis, CME, CNVM, and retinal vasculitis. As with irIU, if CME is detected on ancillary testing, topical NSAIDs may be added with further escalation to intraocular steroids as necessary. If vascular leakage is detected on FFA, escalation to intraocular steroids may be necessary. If CNVM is detected on FFA or OCT angiography, intravitreal anti-vascular endothelial growth factor injections may be necessary.

Uncommon: If any of the uveitis anatomic locations cannot be adequately controlled with localized corticosteroid therapy, then a scheduled break in ICI may be discussed with the oncology team. In addition, short-term systemic corticosteroid therapy and long-term immunomodulatory therapy may be discussed with the oncology team.

Immune-related Vogt-Koyanagi-Harada-like syndrome

Common: Immune-related Vogt-Koyanagi-Harada-like syndrome (irVKHLS) is a specific type of irPanU characterized by diffuse choroidal thickening and serous retinal detachments. Patients who are developing irVKHLS typically present with bilateral findings and symptoms weeks to months following initiation of ICI therapy. The most common symptoms are blurred vision, red eye, eye pain, and floaters. Headache, hearing loss, vitiligo, and poliosis are usually less common than in spontaneous VKH but may also be present. Examination findings can include the presence of anterior chamber cell or flare, mutton fat keratic precipitates, and vitreous cells and/or haze. Multiple serous retinal detachments are the finding that is most suggestive of irVKHLS in the presence of other findings consistent with irPanU. Optic nerve hyperemia and/or disc edema may also be present. The same testing to rule out other etiologies of irPanU as in online supplemental table 16 should be done. Treatment with topical, periocular and/or intraocular corticosteroids, as described above for irPanU, are the typical treatment approach (online supplemental table 17).

Possible: If the diagnosis of irVKHLS is uncertain, and if ancillary testing has not been obtained, then it should include: macula OCT, FAF, FFA and ICGA. Findings that would support the diagnosis include large serous retinal detachments with subretinal fluid on OCT macula. FFA may show multiple hyperfluorescent spots with late leakage and pooling as well as optic disc hyperfluorescence. ICGA may show multiple hypofluorescent dark spots.

Uncommon: If the irVKHLS cannot be adequately controlled with localized corticosteroid therapy, then a scheduled break in ICI may be discussed with the oncology team. In addition, short-term systemic corticosteroid therapy and long-term immunomodulatory therapy may be considered.

Immune-related sarcoidosis-like syndrome

Common: Immune-related sarcoidosis-like syndrome (irSLS) can present as any anatomic location of subtype uveitis along with systemic findings to suggest sarcoidosis. Consequently, the signs and symptoms of irSLS depend on the anatomic location of uveitis as delineated above. Concurrent systemic findings may be present including lymphadenopathy, chest pain, shortness of breath, chronic cough, and skin lesions. Suggestive examination findings include the presence of anterior chamber cell or flare, mutton fat keratic precipitates, iris granulomas, and vitreous cells and/or haze. Other supportive findings include choroidal lesions and perivascular exudates. Testing to rule out other causes of uveitis should be done as noted above depending on the uveitis anatomic location. Recommended treatment depends on the uveitis anatomic location as delineated above (online supplemental table 18).

Possible: If the diagnosis of irSLS is uncertain, then additional ancillary testing can be considered including macula OCT, FAF, and FFA. A finding that would be highly suggestive of irSLS is a choroidal granuloma. FFA may show vascular leakage. If possible, the most easily accessible organ should be biopsied to detect the presence of non-caseating giant cell granulomas, which would definitively diagnose sarcoidosis. Diagnostic vitrectomy and tissue biopsy to rule out other causes of panuveitis may rarely be necessary.

Uncommon: If the irSLS cannot be adequately controlled with localized corticosteroid therapy, then a scheduled break in ICI, short-term systemic corticosteroid therapy and long-term immunomodulatory therapy may be discussed with the oncology team.

PD-L1 inhibitor associated acute macular neuroretinopathy

Common: Patients who are developing acute macular neuroretinopathy (AMNR) can present with bilateral or unilateral symptoms. Symptom onset has been most frequently reported within 2 weeks of ICI initiation. Symptoms are usually acute in onset and include blurry vision, scotomas, photopsias, and metamorphopsia. Patients with this condition sometimes develop concurrent systemic findings such as fever, fatigue, malaise, and arthralgia. Supportive examination findings include the presence of petaloid macular lesions and perivascular exudates. No additional testing is needed when classic symptoms are present and the patient is concurrently using programmed death-ligand 1 (PD-L1) inhibitors. Recommended treatment would be observation with follow-up every 1–2 weeks until symptoms resolve. If findings persist on follow-up, then short-term systemic steroids may be considered, particularly if there is a prominent retinal vasculitis (online supplemental table 19).

Possible: If the diagnosis of PD-L1 inhibitor associated AMNR (PD-L1 AMNR) is uncertain, then additional ancillary testing can be considered including near-infrared fundus photos, macula OCT, and FFA. Findings suggestive of AMNR are wedge-shaped lesions on near-infrared fundus photos and vascular leakage on FFA. Macula OCT will show bilateral hyperreflective band-like lesions in the outer plexiform and outer nuclear layers with disruption of the ellipsoid zone. If there are concurrent CNS symptoms, a brain MRI should also be considered as T2-weighted signal in the caudate heads and anterior lentiform nuclei has been reported in patients with concurrent confusion.25

Uncommon: If the PD-L1 AMNR does not resolve with time, then a scheduled break in ICI therapy may be considered.

Immune-related dry eye disease

Common: Patients who are developing immune-related dry eye disease (irDED) typically present with bilateral symptoms. As with uveitis, onset is usually within the first 6 months of ICI initiation. Symptoms include blurred vision, subjective feelings of dryness, foreign body sensation, tearing, photophobia, pain, and eye redness. Patients may endorse that symptoms improve with blinking and worsen with reading or screen use. Lack of prior documentation of DED and related conditions can be key to indicate that symptoms are new in onset and more likely related to ICI initiation. However, since many patients have symptoms of ocular surface disease at baseline, symptoms of increased severity after ICI initiation are also highly suggestive of irDED. Supportive examination findings include meibomian gland congestion, conjunctival injection, and superficial punctate keratopathy. Additional supportive testing includes tear breakup time less than 10 s, Schirmer’s test without anesthetic less than 10 mm, staining of the ocular surface with diagnostic dyes, and elevated matrix metalloproteinase-9 in the tear film. Recommended treatments could include use of topical lubricating eye drops, punctal occlusion, anti-inflammatory eye drops, serum tears, varenicline nasal spray, hydroxypropyl cellulose insert, scleral lenses, and partial tarsorrhaphy. Most cases of irDED may be followed every 1–2 months until symptoms resolve, although clinical discretion is necessary (online supplemental table 20).

Possible: If the diagnosis of irDED is uncertain, then blood tests may be considered to rule out Sjögren’s syndrome. These include SS-A (Ro), SS-B (La), and antinuclear antibody (ANA). However, most patients with irDED will not have positive serologies.

Uncommon: If the irDED cannot be adequately controlled with local therapies and there is risk of permanent damage to the cornea, then a scheduled break in ICI may be discussed with the oncology team. For most cases, ICI may be continued.

Immune-related scleritis

Common: Patients who are developing immune-related scleritis (irScl) typically present acutely with eye injection, photophobia, and deep pain exacerbated by touch. Supportive examination findings include deep scleral injection and edema, tenderness to palpation over the area of injection, failure of vessel blanching with instillation of phenylephrine, and absence of inflammation inside the eye on slit lamp examination. Areas of scleral thinning may be seen. Recommended treatment includes oral NSAIDs or oral systemic corticosteroids titrated to signs and symptoms (online supplemental table 21).

Possible: If the diagnosis of irScl is uncertain, then blood tests may be considered to rule out other causes of scleritis. These include testing for ANCA, ANA, rheumatoid factor (RF), cyclic citrullinated peptide (CCP), and HLA-B27.

Uncommon: If the irScl cannot be adequately controlled with the aforementioned therapies, then a scheduled break in ICI may be discussed with the oncology team. In addition, long-term immunomodulatory therapy may be discussed with the oncology team.

Immune-related episcleritis

Common: Patients who are developing immune-related episcleritis (irEpi) typically have an acute onset of eye injection, foreign body sensation, and/or blurred vision. Supportive examination findings include superficial episcleral injection, presence of vessel blanching with instillation of phenylephrine, and absence of inflammation inside the eye. Blood work is not required for typical cases. Recommended treatment includes lubricating eye drops, topical corticosteroids, and oral NSAIDs (online supplemental table 22).

Possible: If the diagnosis of irEpi is uncertain, then blood work and imaging may be considered to rule out causes of scleritis including ANCA, ANA, RF, CCP, and HLA-B27.

Uncommon: If irEpi appears atypical with findings of nodularity, recurrence, and resistance to conservative treatment, then the diagnosis may be more consistent with irScl, and diagnosis and treatment of irScl may be considered.