What is Tyrosine Kinase Inhibitor Keratitis?

Tyrosine kinases (TKs) are special proteins found only in the cells of many-celled animals. They act as mediators or messengers in the cell, helping to control cell growth and death. Tyrosine kinases can be split into two groups: receptor protein tyrosine kinase (RTK) and non-receptor protein tyrosine kinase (NRTK). The RTK group includes important cell receptors like the platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR). NRTKs are located inside the cell and regulate vital cell functions like cell death and cell differentiation.

The RTKs are enzymes that sit on the surface of the cell as transmembrane receptors. They have an outside part that works to bind or attach to certain ligands (protein chains that relay signals). A ligand binding to the outside part of the receptor changes the protein’s shape, allowing the inside part of the receptor to add phosphate groups to itself in a process called auto-phosphorylation.

The energy molecule ATP provides the phosphate. Once the protein removes phosphate from ATP and auto-phosphorylates, the phosphate sites serve as docking points for other proteins involved in relaying signals further inside the cell. This process helps control cell differentiation, cell growth, and cell death. Because tyrosine kinases have such a critical role in cell division, cancer specialists target them to try to reduce unchecked cell division.

Cancer medicines are known for causing many side effects, from skin symptoms to heart-related side effects. Doctors often have to deal with unplanned complications when giving cancer therapy. More and more, they are turning to targeted treatments, like tyrosine kinase inhibitors, because they are more effective and less harmful to healthy tissue. Tyrosine kinase inhibitor keratitis is a condition where the cornea (the clear front surface of your eye) becomes inflamed because of disruption to the normal wound healing and hydration processes.

Anti-cancer medicines known to cause this eye inflammation are called EGFR-tyrosine kinase inhibitors. However, tyrosine kinase inhibitors affecting other pathways may also lead to this problem. The EGFR pathway controls not just cell growth but also eye tissue differentiation (the process of becoming specialized). When you inhibit this, you can decrease the growth of cancer cells but also potentially lead to eye damage. Eye doctors should thus be aware of such complications in patients undergoing targeted cancer therapy and should be equipped to treat them quickly. Though research on TKI keratitis is limited, most case studies suggest that most patients do well, with only a few being resistant to the maximum treatment.

This article will discuss the cause, the frequency, the pathophysiology (how the condition develops), symptoms, and management of TKI keratitis and its complications.

What Causes Tyrosine Kinase Inhibitor Keratitis?

The medications that most frequently cause a condition known as “tyrosine kinase inhibitor keratitis” are drugs that affect a specific cellular pathway, called EGFR. These drugs include cetuximab, afatinib, erlotinib, and gefitinib. However, other types of drugs in this class, like imatinib, vemurafenib, ruxolitinib, osimertinib, vandetanib, and ponatinib, can also cause this condition.

Cetuximab is a drug that specifically targets a part of the EGFR pathway and is mainly used for patients diagnosed with advanced colorectal cancer. Most reported side effects include a rash similar to acne, feeling sick, electrolyte imbalance, weakness, and general discomfort. The reported eye-related side effects have been limited and mainly include unusually long eyelashes, inflammation of the eye surface or eyelids, and some isolated reports of keratitis, which is inflammation of the cornea, the clear layer at the front of the eye.

Afatinib is typically used as an initial treatment for a type of lung cancer called non-small cell lung cancer (NSCLC) in patients with certain genetic mutations. Common side effects of afatinib include dry eyes, ulcerated corneas (keratitis), blurred vision, sensitivity to light, and inflammation of the eye surface. The rate of keratitis in patients using this medication is about 0.8%.

Erlotinib is a newer drug used for advanced NSCLC and as part of a combination therapy in advanced pancreatic cancer. It often causes unusually long eyelashes and a rash around the eyes. Inflammation of the eyelids, dry eyes, and keratitis are less common side effects.

Gefitinib is an oral medication used first-line to treat NSCLC in patients with certain genetic mutations. The drug specifically inhibits a part of the EGFR pathway. Its most common side effects include dry skin, diarrhea, and rashes, which are generally mild and reversible. In some cases, patients have experienced keratitis and unusually long eyelashes.

Imatinib often used as a treatment for various cancer types. It has been noted to cause ulcerative keratitis in some patients, especially when used in combination with another drug, perifosine, for a specific type of tumor. However, it’s not clear if Imatinib was the main cause of the keratitis.

Vemurafenib, mainly used for treating melanoma, was found to cause keratitis in a very small number of patients. Similarly, Ruxolitinib, used for a type of bone marrow disorder, was also found to make patients more vulnerable to a specific type of fungal keratitis although the number of occurrences was quite small.

Osimertinib, a first-line treatment for certain types of NSCLC, can cause keratitis in a relatively small percentage of patients. Vandetanib and Ponatinib, used for treating thyroid cancer and a type of leukemia respectively, are believed to make patients more susceptible to keratitis, although detailed studies are lacking.

In conclusion, several types of drugs used for various cancers may cause keratitis, with the incidence varying based on the specific drug and patient’s individual circumstances.

Risk Factors and Frequency for Tyrosine Kinase Inhibitor Keratitis

Tyrosine kinase inhibitors, which are typically prescribed for cancer patients, are most commonly used in cases where age cannot be changed as a risk factor. A lot of patients who use these are diagnosed with cancers like NSCLC at an older age. For patients diagnosed with a condition known as tyrosine kinase inhibitor keratitis, they are typically over 60 years old. This stands true for all genders and ethnicities. However, because it’s a rare condition, more research is needed to pin down exactly when symptoms first show up and when the diagnosis is typically made.

Signs and Symptoms of Tyrosine Kinase Inhibitor Keratitis

Tyrosine kinase inhibitor keratitis is an eye condition that might cause a person to experience light sensitivity, eye pain, a feeling of something in the eye, decreased sharpness of vision, or noticeable redness.

When a doctor examines the eye with a tool called a slit lamp, they might notice characteristics related to this condition. These characteristics can vary and typically appear mild. There may be thread-like lesions attached to the cornea, which is a condition known as filamentary keratitis. In diffuse punctate keratitis, the cornea has small, scattered marks. In superficial punctate keratitis, the surface of the cornea has tiny bumps.

Testing for Tyrosine Kinase Inhibitor Keratitis

Lissamine green dye and fluorescein 2% dye are commonly used to spot any changes on the surface of the eye’s cornea, as well as any defects in the skin layer of the eye known as the epithelium due to a condition called keratitis. These dyes will color any tiny defects or scratches, making them easier to see when examined by your doctor with an instrument known as a slit-lamp.

If you have keratitis, your doctor will carry out lab tests to figure out what may be causing it. This is usually necessary if the doctor discovers a corneal ulcer or infiltrate (an area of inflammation) during a physical examination. There are many things that can cause keratitis, including bacteria, fungi, or viruses. To identify these potential causes when there’s a break in the epithelium, your doctor may use several tests, including Giemsa stain (a type of dye used in microbiology), gram stain (another staining method to detect bacteria), and PCR (a method that enables them to make millions of copies of a specific DNA sample).

Treatment Options for Tyrosine Kinase Inhibitor Keratitis

Tyrosine kinase inhibitor keratitis is a condition that affects the eyes. For its treatment, the main goal is to hydrate the damaged part of the eye, known as the cornea. The most common method to do this is by using artificial tears or lubricants. Another form of treatment can include topical corticosteroids, which are medicines that help with inflammation and can provide fast relief from discomfort. However, these corticosteroids can increase the pressure inside the eye and can cause a condition called glaucoma in some people. That’s why they are generally used for a short period. In severe cases, where the clear outer layer of the eye (the epithelium) gets damaged, bandage contact lenses may be used. These lenses help protect the cornea from further injury.

In one study, a patient with lung cancer developed recurring keratitis due to a persistent damage to the epithelium, even though they were treated with lubricating eye drops, anti-inflammatory therapy, and a bandage contact lens. Unfortunately, their condition didn’t improve until the medication causing keratitis, called erlotinib, was stopped. After two weeks, the epithelial damage healed. In some situations, stopping the medication that may be causing eye complications could help in recovery, if the patient can tolerate it.

A new treatment for this type of keratitis includes using drops that contain human epidermal growth factor (EGF). In a report, a patient with filamentous keratitis, which is a specific type of eye inflammation, didn’t have any relief of symptoms despite standard treatment for a month. After the usage of EGF drops, however, the patient’s symptoms gradually subsided, and the keratitis fully healed within three weeks. Importantly, the patient didn’t have to stop their other medication, cetuximab.

When trying to diagnose tyrosine kinase inhibitor keratitis, a type of eye inflammation, doctors need to rule out other possible causes. They use a variety of tests including the Gram stain and Giemsa stain tests, which can confirm whether a patient has a bacterial or fungal infection. Viral keratitis, another type of eye inflammation, is typically diagnosed based on symptoms, but a special test called PCR can be used to confirm it. The usual symptoms of all forms of keratitis include blurred vision, eye redness, pain, tearfulness, and sensitivity to light.

Bacterial keratitis is often discovered in people who wear contact lenses and is a common cause of infectious eye infection. Symptoms can include stromal melting, ground glass appearance infiltrates with well-defined borders and hypopyon, a type of pus. Patients with bacterial keratitis often have ulcers that progress quickly compared to those caused by fungal or viral keratitis. Almost 70% cases can be diagnosed clinically, with gram staining tests used to confirm the diagnosis.

Fungal keratitis is more common in tropical areas and makes up over half of all infectious keratitis cases there. However, in temperate climates, it’s rare. Like bacterial keratitis, wearing contact lenses can put a person at risk. Symptoms can include a raised surface on the eye, satellite lesions, feathery margins, and infiltrates. Doctors usually use an infectious disease workup to confirm their suspicions. A correct diagnosis based on symptoms alone is only achieved in about 62% of cases.

Herpetic keratitis is the most common type of viral keratitis. It may recur and turn chronic, affecting about half a million people in the U.S. and 1.5 million people worldwide. Other less common causes of viral keratitis include varicella-zoster virus and cytomegalovirus. The presence of dendritic ulcer and stromal keratitis on an eye exam can be a clear sign of herpetic keratitis. In atypical cases, a PCR test is available to confirm the diagnosis.

What to expect with Tyrosine Kinase Inhibitor Keratitis

Patients that develop keratitis, which is an inflammation of the eye’s cornea, while taking a type of medication called tyrosine kinase inhibitors, often find that their condition improves when treated with the standard method used to rehydrate the cornea. However, in some instances, other treatments might be needed. These alternative treatments can include stopping the use of the tyrosine kinase inhibitors, using a bandage contact lens, or using EGF eyedrops. For most patients, these alternative treatments successfully resolve the symptoms of keratitis when the standard method does not work.

Possible Complications When Diagnosed with Tyrosine Kinase Inhibitor Keratitis

Despite limited research on keratitis caused by tyrosine kinase inhibitors (TKI keratitis), certain case studies report patients facing severe problems after diagnosis. These issues include corneal perforation, infections, and ulcerative keratitis. A case study by McKelvie and colleagues reports a patient using afatinib who developed ulcerative keratitis in both eyes. Their tests didn’t point to any microbial causes. Considering the patient’s severe keratitis and high risk of perforation and secondary infection, doctors immediately recommended stopping afatinib. They also began treatment involving a bandage contact lens, steroids, and antibiotics. Thanks to this aggressive treatment and drug cessation, the patient eventually recovered from the bilateral epithelial defects.

In a much more severe case by Sobol and colleagues, a patient receiving erlotinib treatment was diagnosed with streptococcus dysgalactiae (a type of bacteria) infectious keratitis. This eventually led to a corneal perforation. This patient not only became highly prone to keratitis but also developed epithelial defects. Despite rigorous medical attention, the patient’s condition escalated to endophthalmitis (an eye infection) and orbital cellulitis (an infection of the eye tissues). The patient’s visual acuity (sharpness of vision) declined progressively and, ultimately, the eye had to be eviscerated (removed).

List of Complications:

  • Corneal perforation
  • Secondary infection
  • Ulcerative keratitis
  • Epithelial defects, or injuries to the eye’s outermost layer
  • Endophthalmitis, an infection within the eye
  • Orbital cellulitis, an infection of the tissues surrounding the eye
  • Decrease in visual acuity
  • Evisceration, or removal, of the eye

Preventing Tyrosine Kinase Inhibitor Keratitis

Keratitis, an inflammation of the eye, caused by a type of medication known as Tyrosine Kinase Inhibitor (TKI), is usually not severe. Most patients only experience a mild form of this condition. However, in rare instances, it can have severe consequences, such as complete loss of vision.

If you are taking TKI medication, be alert for symptoms of possible ocular (eye-related) toxicity. This means you should seek immediate medical help if you feel pain around the eye, become sensitive to light (photophobia), notice a decrease in sharpness of vision, feel as if there’s something in your eye, or notice a distinct redness in your eyes.

The good news is that patients generally have a good outcome if the disease is diagnosed and treated quickly. So, acting swiftly at the first sign of these symptoms can greatly help manage the condition.

Frequently asked questions

Most case studies suggest that most patients with Tyrosine Kinase Inhibitor Keratitis do well, with only a few being resistant to the maximum treatment. The prognosis for this condition is generally good, and patients typically experience improvement in their symptoms with standard treatment methods. In some instances, alternative treatments may be needed, but overall, the prognosis is favorable.

Tyrosine kinase inhibitor keratitis can be caused by certain medications, specifically drugs that affect the EGFR pathway, such as cetuximab, afatinib, erlotinib, gefitinib, imatinib, vemurafenib, ruxolitinib, osimertinib, vandetanib, and ponatinib.

Signs and symptoms of Tyrosine Kinase Inhibitor Keratitis include: - Light sensitivity - Eye pain - Feeling of something in the eye - Decreased sharpness of vision - Noticeable redness When a doctor examines the eye with a slit lamp, they might notice the following characteristics related to this condition: - Thread-like lesions attached to the cornea, known as filamentary keratitis - Small, scattered marks on the cornea, known as diffuse punctate keratitis - Tiny bumps on the surface of the cornea, known as superficial punctate keratitis

To properly diagnose Tyrosine Kinase Inhibitor Keratitis, the following tests may be ordered by a doctor: - Lissamine green dye and fluorescein 2% dye to spot changes on the cornea and defects in the epithelium - Giemsa stain to identify potential causes such as bacteria, fungi, or viruses - Gram stain to detect bacteria - PCR to make copies of a specific DNA sample for further analysis.

A doctor needs to rule out other possible causes when diagnosing Tyrosine Kinase Inhibitor Keratitis. These include bacterial keratitis, fungal keratitis, and viral keratitis.

The side effects when treating Tyrosine Kinase Inhibitor Keratitis can include corneal perforation, secondary infection, ulcerative keratitis, epithelial defects (injuries to the eye's outermost layer), endophthalmitis (an infection within the eye), orbital cellulitis (an infection of the tissues surrounding the eye), decrease in visual acuity, and evisceration (removal) of the eye.

An eye doctor or ophthalmologist should be consulted for Tyrosine Kinase Inhibitor Keratitis.

The incidence of Tyrosine Kinase Inhibitor Keratitis varies based on the specific drug and patient's individual circumstances.

Tyrosine Kinase Inhibitor Keratitis is treated by hydrating the damaged part of the eye, known as the cornea. This can be done using artificial tears or lubricants. Topical corticosteroids may also be used to help with inflammation and provide fast relief from discomfort, but they are generally used for a short period due to the potential side effects of increased eye pressure and glaucoma. In severe cases, bandage contact lenses may be used to protect the cornea from further injury.

Tyrosine Kinase Inhibitor Keratitis is a condition where the cornea becomes inflamed due to disruption to the normal wound healing and hydration processes caused by tyrosine kinase inhibitors, specifically EGFR-tyrosine kinase inhibitors. This inflammation can occur as a side effect of targeted cancer therapy and may lead to eye damage.

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