This study, based on the FAERS database established in January 2004, conducted a comprehensive and systematic analysis of drug-induced MGD adverse reactions. To our knowledge, this is the first study to explore drug-induced MGD based on the FAERS database, providing validation through real-world data. There is a lack of sufficient foundational research exploring the mechanisms of drug-induced MGD. Our findings offer data support and a theoretical basis for reducing drug-induced MGD and guiding rational clinical medication use.
MGD is a common eyelid margin disease involving dysfunction of the meibomian glands (tiny oil glands located inside the eyelids). These glands primarily secrete lipids that form the outer layer of the tear film, helping to reduce tear evaporation and maintain eye lubrication and health. Dysfunction of these glands can lead to reduced or poor-quality lipid secretion, affecting tear film stability and resulting in dry eye symptoms and other ocular discomforts[20]. A cross-sectional study indicated that compared to younger individuals, older adults have a higher frequency of eyelid margin abnormalities (such as vascular patency, and keratinization)[21]. Other studies supporting this observation have shown that age-related changes in metabolic quality affect both polar and neutral lipid spectra[22, 23]. These findings seem to align with documented increases in the incidence and prevalence of dry eye disease with age [24]. In our study, the age distribution of subjects was primarily 51.69 ± 18.34 years, with women comprising 65.44% (125 cases). Research has observed that postmenopausal women have a higher prevalence of MGD compared to premenopausal women [25]. Our findings align with prior epidemiological research on MGD. Additionally, the weight distribution of subjects was mainly 73.67 ± 19.04Kg. Increasing observational clinical studies suggest that dyslipidemia (elevated cholesterol, triglycerides, or lipoprotein levels) can trigger the development of MGD [26]. A strong correlation exists between obesity and dyslipidemia, suggesting obesity might also be a contributing factor to MGD, though conclusive evidence is still lacking.
In our current study, a variety of drugs were identified as causing drug-induced MGD. Based on the statistical indicators of the ROR method, including a > 3 and the lower limit of the 95% CI lower > 1, and PRR signals with a ≥ 3 and 95% CI lower > 1, nine drugs with positive signals were screened. Among ophthalmic drugs, ranibizumab is a significant cause of drug-induced MGD. Ranibizumab, a humanized recombinant monoclonal antibody fragment, targets vascular endothelial growth factor A (VEGF-A) and effectively inhibits choroidal neovascularization[27]. Ranibizumab was first approved by the FDA in 2006 for the treatment of neovascular age-related macular degeneration (NVAMD)[28]. The mode of action of Ranibizumab involves blocking the interaction between VEGF-A and its endothelial cell receptors, thereby hindering endothelial cell proliferation, vascular permeability, and neovascularization[29]. Notable adverse effects of ranibizumab encompass conjunctival hemorrhage, ocular discomfort, and vitreous floaters, along with both acute and chronic increases in intraocular pressure[30–32]. While the likelihood of systemic adverse reactions with ranibizumab is generally minimal, this risk escalates in older patients[33, 34]. A study based on the FAERS database indicated a strong positive signal for dry eye disease as an adverse reaction induced by ranibizumab[35], but no study has yet shown a correlation between ranibizumab and MGD, nor is its mechanism of action and development clear. Therefore, in clinical ophthalmic practice, physicians need to assess not only the therapeutic purpose of the drug but also consider its potential risk of inducing drug-induced MGD in patients, further optimizing the use of clinical ophthalmic drugs.
In the dermatological drug category, isotretinoin, primarily used for treating facial acne, has a positive signal. Typical ocular adverse reactions during long-term use of isotretinoin include changes in eyelids and corneal surface, tear gland abnormalities, refractive changes, retinal function abnormalities, and optic nerve head edema[36]. Our analysis indicates that the mechanism of drug-induced MGD by isotretinoin may involve abnormal meibomian gland secretion, gland atrophy, decreased tear break-up time (TBUT), increased tear film osmolarity, and symptoms of evaporative dry eye[37–39]. Therefore, when diagnosing and treating MGD patients, it is necessary to consider their history of recent dermatological drug use. Similarly, dermatologists should assess patients' ocular conditions and provide safe, personalized treatment plans.
Among antineoplastic drugs, four drugs have positive signals for causing MGD: paclitaxel, bortezomib, docetaxel, and trastuzumab. Paclitaxel, with the highest ROR value (87.16) among the nine drugs, poses a significantly high risk of inducing MGD. Paclitaxel is a microtubule stabilizer, a class of chemotherapeutic agents used to treat various malignancies, such as breast and lung cancer[40]. One rare side effect of this drug includes cystoid macular edema (CME), which often resolves or diminishes upon discontinuation of the drug[41]. A cross-sectional analysis indicates that cancer patients undergoing paclitaxel therapy, a type of neurotoxic chemotherapy, exhibit an increased likelihood of experiencing ocular surface discomfort linked to DES, particularly when peripheral neuropathy is present[41]. Regrettably, dedicated research into the mechanisms underlying paclitaxel-induced dry eye and MGD remains absent. Nonetheless, studies have demonstrated that paclitaxel therapy significantly diminishes epidermal nerve fibers that express the neuropeptide substance P, which correlates with neuropathic symptoms in rats[42]. Considering a substantial portion of the sensory nerve fibers that serve the ocular surface, especially the cornea, also express substance P[43], this could signify a potential connection between the neurotoxic effects of paclitaxel and ocular surface discomfort in affected patients, forming a focal point for future research endeavors. The proteasome inhibitor bortezomib is a novel anticancer drug showing promise in treating refractory multiple myeloma; docetaxel is a standard chemotherapy agent for breast cancer; trastuzumab is a monoclonal antibody targeting the HER2 receptor, widely used in treating HER2-positive breast cancer. The mechanisms of these various cancer treatment drugs in inducing dry eye are mainly related to their target sites, which also play important roles in normal cells. The treatment process may adversely affect normal tissues, including changes in tear secretion and the structure and function of corneal epithelial cells, leading to drug-induced dry eye. However, the mechanisms underlying the development of MGD remain unclear. Clinical physicians should be aware of the potential long-term toxicity of chemotherapy on the ocular surface and the potential pathophysiological mechanisms, assessing ocular surface conditions in cancer patients and making targeted medication choices.
In the immunomodulating drug category, gilenya significantly induces drug-induced MGD. Gilenya stands as the inaugural oral treatment for relapsing-remitting multiple sclerosis. Fingolimod-associated macular Edema (FAME) is a notable adverse effect linked to Gilenya. The role of Sphingosine-1-phosphate (S1P) receptors in the regulation of vascular permeability and the fortification of endothelial barrier integrity is well-established. Gilenya can disrupt this barrier functionality as a structural analog of S1P, resulting in heightened vascular permeability[44]. This disruption may underlie the pathophysiological processes associated with FAME. To date, no researchers have studied the potential association between gilenya and drug-induced MGD. Detailed information on the potential mechanism of drug-induced MGD induced by Gilenya is still unclear, and further research in this area is warranted. Dupilumab, the first monoclonal antibody approved for treating moderate to severe atopic dermatitis (AD) and severe asthma in adults and children over six years of age with AD[45], has been reported in clinical trials and confirmed in real data to commonly cause ocular surface abnormalities, observed only in AD patients. Clinical manifestations are predominantly eyelid conjunctivitis; however, cicatricial ectropion, keratitis, eye pruritus, and dry eye syndrome have also been observed[45]. We have yet to find studies on the association between Dupilumab and MGD. We speculate that the mechanism of drug-induced MGD by Dupilumab could involve its ability to block the interleukin-4 receptor subunit, thereby inhibiting interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling. IL-4 and IL-13, secreted by CD4 + Th2 lymphocytes, drive various inflammatory processes, including the immunoglobulin class switch from IgM to IgE antibodies, leading to mast cell activation, which may cause damage to the meibomian glands[46]. Overall, there is currently a lack of research on immunomodulatory drugs causing MGD adverse reactions, and additional empirical evidence is needed to enhance our understanding. Thus, in this process, we can recognize that immune balance plays a significant role in the pathologic mechanism of MGD.
In the category of urogenital system drugs, allopurinol has been identified as a significant cause of drug-induced MGD. Allopurinol is an effective xanthine oxidase inhibitor primarily used to treat hyperuricemia and gout[47]. Studies have found that severe cutaneous adverse reactions induced by allopurinol are closely related to the HLA-B58:01 allele, with 94.57% of affected patients carrying this allele[48, 49]. HLA-B58:01 is a biomarker for allopurinol-induced scarring. There is currently no specific research on allopurinol's ocular adverse reactions. We speculate that allopurinol may cause an immune response in the eyes, leading to impaired meibomian gland function and consequently MGD. Therefore, urologists should assess patients' ocular conditions and exercise caution when treating hyperuricemia and gout.
In practical applications, pharmacovigilance serves as an effective tool for the identification and corroboration of potential ocular toxicities associated with medications. We have noted a change in the primary causative drugs of MGD in recent years, with antineoplastic drugs becoming a significant category causing MGD. Capturing these changes will help find drugs with an original fundamental focus, and our study provides opportunities and strategies for capturing these changes.
However, this study is subject to certain unavoidable limitations. Initially, the voluntary basis of FAERS reporting and the non-peer-reviewed nature of some submissions may induce biases in our findings. Additionally, the absence of data on the total patient population using these medications precludes accurate determination of the true prevalence of drug-induced MGD. Furthermore, the detection of signals merely suggests a statistical correlation, necessitating further scrutiny to confirm a definitive causal link. Also, the potential influence of concurrent medications and/or existing health conditions on the development of MGD cannot be disregarded, which might impact the outcomes of our signal detection. Finally, comprehensive external validation is imperative for research concerning specific pharmaceuticals.