Systemic drugs and their ocular symptoms can complicate treatment

Drugs that treat systemic diseases can be lifesaving, but when these drugs lead to poor ocular health or vision, the treatment paradigms can be difficult to balance. When a systemic disease and its treatment are negatively affecting vision, hard choices need to be made.

Physician specialists tend to forget how systemic medications affect other parts of the body, and they can miss reactionary symptoms stemming from those medications, OSN Retina/Vitreous Board Member Pravin U. Dugel, MD, said.

“We’ve become so involved in our own specialties that we learn less and less about the broad field of medicine,” Dugel said.

Source: Andrew G. Lee, MD

As more treatments become available for systemic conditions, the ophthalmologist must be disciplined to stay abreast of the negative ocular impact these drugs can have and be able to recognize treatment-related symptoms, Dugel said.

“We need to take ourselves outside of our own silos,” he said, by communicating with other physicians when a patient exhibits warning signs of something more serious.

A three-step process should be performed during every ocular examination, according to Dugel. First, be aware of all the patient’s therapies and all the patient’s symptoms. Second, communicate potential concerns with the patient. Third, communicate these concerns also with the treating physician.

The process starts with asking questions.

“We were all taught this process at medical school, but the more specialized we become, the more we forget this process,” he said.

Weighing treatments and symptoms

Successfully identifying which medication is causing the ocular symptom is the first step toward creating a treatment plan, which could be as simple as switching to another drug or lowering a drug dose.

However, when a lifesaving therapy such as chemotherapy causes ocular symptoms, the treatment plan becomes more complicated.

According to a study in the Journal of Cancer Therapeutics and Research, ophthalmic complications induced by cytotoxic chemotherapy are often underestimated and underreported. An ophthalmic baseline examination before treatment can help distinguish complications from preexisting conditions.

With patients living longer due to these therapies, treating the associated ocular symptoms becomes more of a necessity.

“One of the side effects of having better drugs in the modern era is that people live longer and therefore live longer to experience the side effects of the chemotherapeutic agents,” OSN Neurosciences Section Editor Andrew G. Lee, MD, said.

New therapies mean new side effects

In addition to traditional chemotherapeutic and radiation therapies, physicians now can treat cancer with immune therapies, which can lead to a whole new host of side effects, Lee said.

These immune therapies include monoclonal antibodies and small synthetic molecule inhibitors to produce immune regulatory changes to enhance the body’s ability to kill cancer. However, when the body’s ability to attack cancer is enhanced, it is also inherently enhancing the body’s ability to attack itself, he said.

According to the American Cancer Society, researchers can design monoclonal antibodies to target certain antigens, such as ones found on cancer cells.

“These antibodies can attack cancer, they can attack inflammatory cells, they can bind to antigens, and they can stimulate immune responses. It’s a very powerful therapy,” Lee said.

Small synthetic molecules targeting immune checkpoint receptors also have success as anticancer therapies, according to a study published in Oncotarget.

These can include PD-1 inhibitors such as Opdivo (nivolumab, Bristol-Myers Squibb), CTLA-4 inhibitors such as Yervoy (ipilimumab, Bristol-Myers Squibb) and PD-L1 inhibitors such as Tecentriq (atezolizumab, Genentech). These small synthetic molecules inhibit processes that normally control inflammation. These medications can turn off the “regulatory checkpoints” that normally control the cells’ ability to attack, Lee said.

“Tumors have evolved mechanisms to inhibit the immune system’s attack on them. They have a shield. The tumors have a shield, and in order to break that shield, we use a checkpoint inhibitor. But in the process of breaking the tumor’s shield, we are unleashing immune disease,” he said.

Immune-related adverse events

Immune therapies can induce immune-related adverse events, which can lead to ocular manifestations such as uveitis, posterior uveitis, panuveitis, conjunctivitis and other forms of inflammation in all parts of the eye, Lee said.

A retrospective study in Ophthalmology showed 1% of 1,474 patients treated with nivolumab, with or without ipilimumab, developed an ophthalmic immune-related adverse event. The events were observed in the anterior and posterior segments and included corneal erosions and perforations, uveitis, hypotony, maculopathy and cystoid macular edema.

Uveitis is also a common side effect of cancer treatments. A study in the American Journal of Ophthalmology found 22% of 568 patients treated with vemurafenib, a treatment for metastatic cutaneous melanoma, developed an adverse ocular effect. The most common ocular diagnosis was uveitis, accounting for 4% of the total adverse ocular effects, Lee said.

Oral or intravenous steroids can be used to control these types of inflammation if located in the back of the eye. Anterior uveitis can usually be treated with drops, but if not, then the systemic medication will have to be continued without treatment of the ocular symptoms, he said.

“The prescribing doctor is the one in the position to determine the risks and benefits of stopping medicine vs. continuing medicine. ... I would not advise ophthalmologists to stop the treatment without talking to the prescribing physician first because the drug may be lifesaving,” Lee said.

Treatment can be difficult

Even if symptoms from systemic medications are recognized, treatment can be difficult. Plaquenil (hydroxychloroquine, Sanofi-Aventis), a therapy commonly used to treat rheumatoid arthritis or lupus, had been dosed at high levels for years before a 2016 recommendation by the American Academy of Ophthalmology to reduce dosing levels, Dugel said.

The high dosing levels led to an increased risk for retinal toxicity. Previously, physicians used a weight-based dose of 6.5 mg/kg with a maximum dosage of 400 mg per day for hydroxychloroquine. A retrospective review of 2,361 Kaiser Permanente patients found retinal toxicity rates increased with prolonged exposure. Researchers reported retinal toxicity in 20% of patients who had used the drug for 20 or more years.

In 2016, the AAO recommended a maximum daily hydroxychloroquine dose of less than 5 mg/kg of real weight, Dugel said.

Early identification of retinal toxicity from hydroxychloroquine is “extremely important,” and ophthalmologists should look for changes in OCT examinations, notably pigmentary changes of the eye, to identify the complication, Dugel said.

Toxicity can lead to a characteristic bull’s eye maculopathy in the retina, and catching it before it reaches this stage should be the goal, he said.

“The main problem with Plaquenil toxicity is even when you recognize it, when you stop the medication, the drug can remain in the retinal epithelium and still cause toxicity,” Dugel said.

A balancing act

When a systemic medication is lifesaving or lifechanging, modifying the treatment regimen can be a tricky balancing act. In these cases, ophthalmologists should recognize their role as a member of a “total health care team” and understand the importance of collaboration with other physicians, OSN Cornea/External Disease Board Member Marjan Farid, MD, said.

Hormone replacement therapies, as well as many cancer treatments, can affect lacrimal and meibomian glands, causing significant dry eye symptoms that are difficult to treat, she said.

“I don’t alter these medications and try to treat the ocular dryness with an aggressive multifaceted approach including meibomian gland disorder treatments, anti-inflammatories and regenerative topical treatments such as autologous serum or amniotic membrane. Collaboration with the patient’s gynecologist, endocrinologist or oncologist can often help in managing the systemic medication or changing dosing to help with ocular symptoms,” Farid said.

Antihypertensives, antidepressants and antihistamines all may cause significant ocular surface disease. Some may cause benign changes or deposits at the subepithelial layer that diminish once the patient comes off the medication, she said.

However, antihypertensives, diuretics, antidepressants and antipsychotics may cause significant tear film dysfunction. This can lead to significant burning, irritation and ocular fatigue, Farid said.

Treating the symptoms, rather than altering the systemic medications, is a sound strategy, Farid said.

“I don’t usually alter the systemic medication but rather treat the tear film separately with topical anti-inflammatories, artificial tears, punctal plugs and/or meibomian gland disease management. If the symptoms are severe, it is reasonable to consult with the patient’s primary doctor to see if a change in type or dose of medication may improve the ocular side effects,” she said.

Dry eye is common

Antihistamines and nasal decongestants can cause drying of the eyes. The Tear Film and Ocular Surface Society Dry Eye Workshop II report recommended reviewing and identifying the systemic medications causing symptoms and considering switching to local treatment for allergies, Farid said.

Antihistamines can also cause dystrophy of the corneal epithelium, Dugel said, which can be associated with a high degree of discomfort.

Patients with significant dry eye symptoms and signs due to systemic antihistamines should decrease their use and switch instead to inhalants, nasal sprays, or other topical or local treatments for the specific type of allergy, Farid said.

While steroids can control inflammation from systemic disease, steroid exposure can also increase the risk for cataract formation, OSN Cornea/External Disease Board Member Preeya K. Gupta, MD, said.

“Patients who are using a chronic nasal steroid spray for seasonal allergies are coming in with a higher incidence of cataracts. Patients who use oral steroids for autoimmune disease or asthma patients who take inhaled steroids can all increase their systemic exposure to steroids in the process of treating their systemic disease, and that can lead to cataracts,” she said.

Researchers used the Blue Mountains Eye Study, a population-based cohort analysis that included 3,654 Australians 49 years or older between 1992 and 1994, to examine the link between inhaled and oral corticosteroids and cataract formation. At baseline, 103 subjects were identified as current inhaled steroid users and 120 were former users.

Adjusted for age and gender, the researchers found current steroid users had a higher risk for developing posterior subcapsular and nuclear cataracts, but not cortical cataracts, compared with those who did not use inhaled or oral corticosteroids.

Long-term steroid use has also been connected with a higher risk for glaucoma, especially in developing countries, through overprescribing and unmonitored self-use, according to a study in the Journal of Current Glaucoma Practice.

While the exact mechanism is unknown, researchers in a study in Eye said corticosteroids are believed to decrease outflow by inhibiting degradation of extracellular matrix material in the trabecular meshwork. This can lead to aggregation of material within the outflow channels and increase in outflow resistance.

The researchers said IOP elevation has been observed in both topical and systemic administration of cortico­steroids.

Higher exposure to steroids leads to more risk for developing steroid-induced glaucoma, OSN Glaucoma Board Member Douglas J. Rhee, MD, said.

“Injectables, sustained implants — they’ll all carry a pretty high risk. Topical drops will have a high risk. Topical creams, if they’re applied around the face, are relatively high risk, not higher than the others, but still high,” Rhee said.

Other systemic medications have also led to an increase in glaucoma risk. Topamax (topiramate, Janssen), a sulfamate-substituted monosaccharide to prevent and control seizures and also to treat migraines, has been shown to have a link to bilateral acute closed-angle glaucoma, Rhee said.

Almost all cases of topiramate-induced glaucoma are bilateral acute closed-angle glaucoma, which usually occurs within the first 2 weeks after starting the medication or a change in dose. Acute myopia may occur in a matter of hours after starting the drug and take several weeks to resolve once topiramate is discontinued, according to a 2011 study in Eye.

“It’s helpful to remember that it’s not topiramate itself, but it’s the sulfamate component of the drug. Any sulfamate-containing drug has the potential to do this,” Rhee said.

Commonly used drugs can be threats

Other commonly used drugs can pose threats to the eye and the ocular surface. Phosphodiesterase-5 inhibitors such as Viagra (sildenafil, Pfizer) or Cialis (tadalafil, Eli Lilly), used for erectile dysfunction, can cause ischemic optic neuropathy and may also cause changes in photoreceptors, Dugel said.

Blurry vision, light sensitivity, difficulty telling colors apart, a blue-green tinge to vision and decreased color vision are all possible side effects from these therapies, according to the AAO.

More seriously, these inhibitors can also lead to non-arteritic anterior ischemic optic neuropathy, causing sudden vision loss in one eye. Taking the therapies can lower blood pressure and put men at a higher risk for the complication.

Phosphodiesterase-5 inhibitors may also increase the risk for developing retinitis pigmentosa. The therapies can inhibit PDE6, an enzyme important for vision, and lead to decreased vision.

Treating symptoms caused by systemic medications is a team effort. Ophthalmologists should embrace their role as a total health care team member for patients faced with these challenges. Collaboration with other physicians is important when determining the correct course of treatment, Farid said.

“Often alternate medications with decreased ocular side effects may be available, but if the primary physician is unaware of the ocular side effects, they may not consider those alternate therapies,” she said. – by Robert Linnehan

• References:
• Combined corticosteroid use associated with elevated risk of posterior subcapsular, nuclear cataracts. www.healio.com/ophthalmology/cataract-surgery/news/online/%7B198e6376-23f9-4e6a-9d64-a7f29ee77192%7D/combined-corticosteroid-use-associated-with-elevated-risk-of-posterior-subcapsular-nuclear-cataracts. Published April 16, 2009. Accessed Nov. 25, 2019.
• Craig JP, et al. Ocul Surf. 2017;doi:10.1016/j.jtos.2017.05.008.
• Kersey JP, et al. Eye (Lond). 2006;doi:10.1038/sj.eye.6701895.
• Laday J. Hydroxychloroquine blood levels predict retinopathy in SLE. www.healio.com/rheumatology/lupus/news/online/%7B7583939b-e4a4-49df-9649-0bbeeb08ab45%7D/hydroxychloroquine-blood-levels-predict-retinopathy-in-sle. Published Oct. 17, 2019. Accessed Nov. 25, 2019.
• Lee AG. Ocular toxicities associated with targeted anti-cancer agents: a brave new world for the ophthalmologist. Presented at: American Academy of Ophthalmology annual meeting; Oct. 11-15, 2019; San Francisco.
• Lukasz S, et al. Oncotarget. 2017;doi:10.18632/oncotarget.20050.
• Monoclonal antibodies to treat cancer. www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/monoclonal-antibodies.html. Accessed Nov. 20, 2019.
• Phulke S, et al. J Curr Glaucoma Pract. 2017;doi:10.5005/jp-journals-l0028-1226.
• Porter D. Erectile dysfunction medication and your eyes and vision. www.aao.org/eye-health/drugs/erectile-dysfunction-medication-your-eyes-vision. Published May 30, 2019. Accessed Dec. 2, 2019.
• Razeghinejad MR, et al. Eye (Lond). 2011;doi:10.1038/eye.2011.128.
• Singh P, et al. J Can Res Ther. 2012;doi:10.7243/2049-7962-1-5.
• Wang JJ, et al. Ophthalmology. 2009;doi:10.1016/j.ophtha.2008.12.001.
• Zheng W, et al. Ophthalmology. 2018;doi:10.1016/j.ophtha.2018.01.007.

• For more information:
• Pravin U. Dugel, MD, can be reached at Retinal Consultants of Arizona, 1101 E. Missouri Ave., Phoenix, AZ 85014; email: pdugel@gmail.com.
• Marjan Farid, MD, can be reached at Gavin Herbert Eye Institute at the University of California, Irvine, 850 Health Sciences Road, Irvine, CA 92697; email: mfarid@uci.edu.
• Preeya K. Gupta, MD, can be reached at Duke University, Department of Ophthalmology, Box 3802, Durham, NC 27710; email: preeya.gupta@duke.edu.
• Andrew G. Lee, MD, can be reached at Houston Methodist, 6560 Fannin St., Suite 450, Houston, TX 77030; email: aglee@houstonmethodist.org.
• Douglas J. Rhee, MD, can be reached at Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Euclid Ave., Mail Stop WRN5068, UHI Institute, Cleveland, OH 44106; email: dougrhee@aol.com.

Disclosures: Dugel reports he is a consultant for Boehringer Ingelheim. Farid, Gupta, and Lee report no relevant financial disclosures. Rhee reports he receives research funding from Allergan, Glaukos and Ivantis; is a consultant for Aerie Pharmaceuticals, Allergan, Alcon, Ivantis, Bausch + Lomb and pH Pharma; is on the scientific advisory board for Ocular Therapeutix; and is on the speakers bureau for Bausch + Lomb, Ivantis and Aerie Pharmaceuticals.

Click here to read the Point/Counter to this Cover Story.