Dr. Jeremy Chung Bo Chiang is a postdoctoral research associate at the School of Optometry in Aston University. His expertise is in ocular surface imaging and dry eye disease.
Inflammation is one of the hallmarks of dry eye disease (DED) pathophysiology. The global community of eye care practitioners has recognized the importance of dampening harmful inflammation in this condition since the advent of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshops.1,2 While the immune system is highly complex and often daunting to most clinicians, this timely manuscript by Periman and colleagues details the relevant inflammatory processes that are associated with DED pathogenesis and treatment. We will first look at how the authors effectively summarize these processes in a stepwise fashion and cap it off with three clinical takeaways applicable to our everyday management of DED.
Immunopathogenesis
As clinicians, we should understand the underlying pathophysiological mechanisms of a disease in order to manage it effectively. The vicious circle of inflammation contributes to the chronic nature of DED and is succinctly demonstrated through four stages in Figures 1 and 3: initiation through proinflammatory cytokine release, amplification with T cell differentiation and proliferation, recruitment of T cells, and the disruption of proper resolution or immunoregulation. Without successful resolution and return to homeostasis, the perpetuation of ocular surface damage continues. As the cycle repeats, the processes occur in concert exacerbating the chronicity of DED. (Figures 1 and 3 in the paper are available here. Free access, available online and as a pdf.)
Figure 2 aids clinicians in visualizing the host of immune cells and signalling molecules involved in immunopathogenesis. In the initiation stage, cytokines and chemokines (groups of small proteins secreted for cellular signalling) are released from specific pathways such as those of the mitogen-activated protein kinases (MAP-K). This follows initial injury or loss of homeostasis on the ocular surface, which could be observed clinically as epithelial damage or tear film abnormalities. Antigen-presenting cells are also subsequently activated, most notably dendritic cells. These immune cells, which usually reside at the ocular surface, then migrate to the lymph nodes to facilitate the differentiation of naïve T cells into different types, each with important roles in heightening the immune response (effector T cells such as TH1 and TH17) or modulating/dampening inflammation (regulatory T cells or Tregs). As an analogy, one could think of the antigen-presenting cells as scouts or messengers, while the T cells are soldiers with different jobs in this inflammatory battle. Following the differentiation and proliferation of effector T cells, they are recruited to the ocular surface to further direct the inflammatory response. Imbalance and dysregulation of these T cells cause epithelial apoptosis, goblet cell damage and tear film dysfunction if left unchecked. Disruption of normal immunoregulatory processes which help resolve the inflammatory response creates a positive feedback loop that reinitiates and perpetuates this vicious circle. (Figure 2 in the paper is available here. Free access, available online and as a pdf.)
Interactions and Topical Treatments
Periman and colleagues also present the three main types of clinically available drugs that target inflammation. Topical corticosteroid eyedrops have been a mainstay medication for quelling ocular inflammation due to their potency in inhibiting the key drivers of pro-inflammatory processes, including the inhibition of phospholipase A2 synthesis required for the production of inflammatory molecules, and reducing immune cell infiltration. Most clinicians are cognizant of the side effects that can arise from prolonged use of these immunosuppressive agents, including increased intraocular pressures and cataracts. However, ongoing research and innovation have sought to minimise these issues by developing corticosteroid eyedrops with less potency or penetration, and modified delivery systems which optimize the efficacy of their use in DED.
Another class of DED treatment relates to the various immunomodulatory agents. Cyclosporine is the most widely adopted from this class of drugs for the purpose of treating DED. Its main mechanism of action is as an inhibitor of calcineurin. Since calcineurin is required for the production of proinflammatory cytokines, inhibiting it reduces effector T cell activation and function. As summarized in the article, several studies have demonstrated the positive impact of topical cyclosporine treatment on alleviating DED signs, including corneal staining and tear production with Schirmer’s test at 3 to 6 months of treatment, and symptoms including subjective improvements in vision after 4 weeks of treatment. These encouraging findings are supported by biopsy studies showing the increase in goblet cell density and decreased epithelial apoptosis with cyclosporine treatment.
Lifitegrast is a novel drug under the class of lymphocyte function-associated antigen 1 (LFA-1) antagonists, which has begun to enter the global market of DED treatment. It blocks the binding between LFA-1 (a cell-surface glycoprotein on T cells) and intercellular adhesion molecule 1 (ICAM-1, a glycoprotein expressed on epithelial and vascular endothelial cell surfaces). This LFA-1:ICAM-1 interaction facilitates the immunopathogenesis of DED by promoting the activation, differentiation and recruitment of T cells both from the lymph nodes and at the ocular surface. By preventing the binding of the natural ligand ICAM-1 to LFA-1, studies have shown a reduction in effector T cells, such as TH17 cells in the conjunctiva and proinflammatory cytokine levels in experimental models. Similar to cyclosporine, lifitegrast treatment has improved goblet cell density and epithelial integrity in animal models, with human studies demonstrating an alleviation of signs and symptoms of DED. The side effect profile differs slightly between these two drugs, with the most common side effect of cyclosporine being ocular burning sensation, while lifitegrast may produce altered taste sensation.
Three Clinical Takeaways
- In clinical practice, eye care practitioners would be familiar with potential acute flare-ups in patients with DED if additional insults exacerbate the vicious cycle of inflammation. These include ocular surface conditions such as meibomian gland dysfunction3 and Demodex blepharitis.4 Lifestyle factors may also contribute to suboptimal ocular surface health, as covered by the recently published series of TFOS Lifestyle Reports including nutrition, cosmetics and environmental conditions.5-7 Remember to consider both internal and external factors when managing inflammation in DED.
- In contrast to corticosteroids, which can act on acute phases of inflammation, effective treatment with immunomodulatory agents including cyclosporine can take some time. As described by Periman and colleagues, activated T cells can present for extended periods of time up to 164 days. Hence, remember to counsel patients that it could take 3 to 6 months for cyclosporine medications to produce clinical improvement, to minimize the potential for drop-out or dissatisfaction due to the apparent lack of potential efficacy. Studies have shown that lifitegrast seems to act within weeks rather than months, potentially due to the different mechanisms of action.
- Patients with DED have diverse profiles, hence therapies that successfully control and treat this condition in one patient may not work as effectively in others. New potential therapies are constantly being developed in the pipeline, such as RGN-259 mentioned in the manuscript, which is a thymosin beta 4 (Tβ4)-based eyedrop that promotes anti-inflammation and wound repair. Another recent development relevant to targeting inflammation not listed in this manuscript is reproxalap,8 a small molecule modulator of reactive aldehyde species elevated with inflammation. Some clinical improvements and success have been observed with these drugs in initial trials,8,9 however these therapies are still under investigation.
Conclusion
These three clinical takeaways stemming from this well-written manuscript highlight the complex nature of DED pathophysiology and the treatment decisions of this condition which has fast become a global health issue. Any clinician who encounters patients with DED will find that Periman and colleagues’ review provides succinct yet adequately detailed information on the immune system and inflammatory processes highly relevant to the management of this prevalent condition.
REFERENCES:
- Jones L, Downie L, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
- No authors listed. Management and therapy of dry eye disease: Report of the management and therapy subcommittee of the international Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):163-78.
- Baudouin C, Messmer EM, Aragona P, et al. Revisiting the vicious circle of dry eye disease: A focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100(3):300-6.
- Rynerson JM, Perry HD. DEBS – a unification theory for dry eye and blepharitis. Clin Ophthalmol. 2016;10:2455-67.
- Markoulli M, Ahmad S, Arcot J, et al. TFOS lifestyle: Impact of nutrition on the ocular surface. Ocul Surf. 2023;29:226-71.
- Sullivan DA, da Costa AX, Del Duca E, et al. TFOS lifestyle: Impact of cosmetics on the ocular surface. Ocul Surf. 2023;29:77-130.
- Alves M, Asbell P, Dogru M, et al. TFOS lifestyle report: Impact of environmental conditions on the ocular surface. Ocul Surf. 2023;29:1-52.
- Clark D, Sheppard J, Brady TC. A randomized double-masked Phase 2a trial to evaluate activity and safety of topical ocular reproxalap, a novel RASP inhibitor, in dry eye disease. J Ocul Pharmacol Ther. 2021;37(4):193-9.
- Clark D, Tauber J, Sheppard J, Brady TC. Early onset and broad activity of reproxalap in a randomized, double-masked, vehicle-controlled Phase 2b trial in dry eye disease. Am J Ophthalmol. 2021;226:22-31.
