Introduction:
Immunotherapy agents like immune checkpoint inhibitors (ICPIs) help treat many tumors, including metastatic tumors. However, they give rise to specific side effects, such as ocular inflammation. Such ocular-related adverse effects can be detrimental to the eyes. Immune checkpoint inhibitors have shown tremendous improvements in the treatment of cancer patients.
What Are Immune Checkpoints and Immune Checkpoint Inhibitors?
Immune checkpoints are a part of the immune system. They help prevent the immune system from destroying the body's cells. Immune checkpoints come into play when the proteins on the surface of immune cells, known as T cells, bind to the proteins on the surface of other cells, like tumor cells. These proteins are known as immune checkpoint proteins. Once these partner and checkpoint proteins come into contact, they signal the T cells to stop, thus preventing the immune system from destroying cancer cells.
Immune checkpoint inhibitors block these checkpoint proteins from binding to their partner proteins. This, in turn, prevents the stop signal from being sent, thereby allowing the T cells to kill the cancer. Currently, ten immune checkpoint inhibitors are approved by the U.S. Food and Drug Administration (FDA). Each ICPI (immune checkpoint inhibitors) targets one of the four receptors or checkpoints like programmed cell death 1, PD-1, programmed cell death ligand 1, PD-L1, cytotoxic T-lymphocyte-associated protein 4, CTLA-4, and LAG3. They were first used to treat metastatic melanoma in 2011. Since then, they have been used in treating other cancers like non-small cell lung cancer, lymphoma, urothelial cancer, and clear cell renal cell cancer.
What Is Uveitis?
Uveitis is inflammation of the eyes. It occurs when the immune system fights an infection. Uveitis can also occur if the immune system attacks the healthy tissues of the eyes, leading to inflammation. The presence of inflammation of the anterior chamber cells characterizes Uveitis.
The following are signs of inflammatory activity:
- Vitreous Haze or Vitritis - Vitreous haze is an inflammatory disorder of the posterior part. A decrease in this haze tends to improve vision.
- Active Retinitis - Inflammation of the retina causes permanent loss of vision.
- Retinal Vasculitis - Retinal vasculitis is an inflammatory response of the arterial, venous, or capillary vasculature. The inflammation extends toward the non-vascular structures of the eyes.
ICPI-associated uveitis is an adverse effect of immune checkpoint inhibitor therapy. It refers to the inflammation of the uvea - the part of the eyes consisting of the iris, ciliary body, and choroid. ICPI-associated uveitis is characterized by pain, redness, blurry vision, and light sensitivity.
Two types of ICPI-induced uveitis have been found, sarcoidosis-like uveitis and birdshot-like chorioretinopathy. Immune checkpoint inhibitors may also lead to sarcoidosis-like reactions, affecting the lymph nodes, lungs, or skin. However, a sarcoidosis history does not contraindicate ICPIs. The treatment becomes similar to that of sarcoidosis. Immune checkpoint inhibitors discontinuation should be done in cases of severity after a meticulous assessment.
What Are the Clinical Features of ICPI-Associated Uveitis?
The signs and symptoms of immune checkpoint inhibitor (ICPI)-associated uveitis come to light within a few weeks or months of the beginning of the immune therapy.
The symptoms include:
- Pain in the eyes.
- Inflammation of the eyes.
- Sensitivity to light (photophobia).
- Blurred vision.
- Floaters - Floaters are shapes that float across the eyes. They occur in different shapes and sizes, like spots, wavy lines, threads, or small cobwebs.
How Is ICPI-Associated Uveitis Diagnosed?
The presence of inflammation in the uvea, a flare in the anterior vitreous humor, and the specific signs and symptoms help to establish the diagnosis. Prompt diagnosis of ICPI-associated uveitis is essential to curbing the further progression of the condition, thus preserving eyesight. Most ICPI-associated uveitis occurs within the first six months of starting immune checkpoint inhibitors.
Doctors should be made aware of this, and the patient should also be informed. However, some cases of late-onset uveitis have been reported even after immune checkpoint inhibitors have been stopped. Hence, a proper history regarding past immune checkpoint inhibitors intake should be made an important part of the medical history assessment in individuals with a history of cancer and ocular inflammation. Diagnostic modalities like fundoscopy, comprehensive ophthalmic assessment, and orbital and ocular imaging help identify the condition.
How Is ICPI-Associated Uveitis Managed?
A collaborative effort of the ophthalmologist with oncologists and rheumatologists helps chalk out the management strategy of ICPI-associated uveitis. The first line of treatment is usually topical corticosteroids or NSAID (non-steroidal anti-inflammatory) medications, along with discontinuation of the immune checkpoint inhibitors. These drugs help to reduce inflammation and other related symptoms. In severe cases, systemic corticosteroids or immunosuppressive therapy such as Methotrexate, Infliximab, Abatacept, and Alpha interferon are the treatment of choice. Thus, a multidisciplinary approach is essential to treating ocular inflammation and maintaining immune checkpoint inhibitor therapy. Regular eye screening is necessary to monitor the condition and ensure an appropriate treatment plan.
ICPI-associated uveitis is a side-effect of immunotherapy. Several studies and research programs are being carried out to understand its mode of action, thus optimizing the treatment modalities. The risk factors of ICPI-associated uveitis, such as genetic predisposition or specific types of tumor cells that may help prevent and eradicate the condition, should be recognized. Ongoing clinical trials assess various new therapeutic approaches for ICPI-associated uveitis, including targeted immunomodulatory agents and predictive strategies for personalized treatments. Thus, an amalgamation of specialists, such as ophthalmologists, oncologists, and researchers, is essential for improving the outcome.
Conclusion:
Immune checkpoint inhibitors, new immunotherapy drugs used to treat metastatic diseases, and other tumors are associated with immune-related side effects, including ocular manifestations. ICPI-associated uveitis is one such ocular adverse effect. Immune checkpoint inhibitors have proven to be quite effective in treating cancer; however, the possibility of causing other complications, including ocular inflammation, is a grave concern and should be considered.
A prompt identification, diagnosis, and multi speciality treatment strategy between ophthalmologists, oncologists, and researchers are essential for an accurate result. Future research and clinical trials in this field will help understand ICPI-associated uveitis, leading to effective treatment options. This would help in a successful collaboration between immunotherapy and cancer.
