Anti-inflammatory Therapy for MGD

Topical anti-inflammatory medications such as corticosteroids present a see-saw of benefits and risks for different clinical situations. The efficacy of these agents is incontrovertible in the treatment of many pathological processes across a spectrum of disease states that vary considerably in the role of inflammation as the primary or secondary pathophysiologic process.

Few ophthalmologists would question topical anti-inflammatories as first-line therapy in treating uveitis, whether autoimmune, posttraumatic, postsurgical or even idiopathic. In the treatment of allergic disease, efficacy must be balanced against potential side effects, especially in a chronic disease likely to present recurrent flare-ups over a lifetime. Treatment of inflammation associated with infectious conditions is even more controversial, raising concern of microbial growth or increased risk of secondary superinfection. Many clinicians find that the decision to add corticosteroid therapy becomes harder as the location of the infectious process moves inward from conjunctiva to cornea to intraocular tissues such as vitreous and retina.

The role of topical corticosteroids in the treatment of external diseases with components of both microbial infection and inflammation is controversial,^1,2,3 with well-informed advocates on both sides and few studies to support strongly voiced opinions. Awareness has increased of the importance of eyelid margin disease in many ophthalmic conditions, including increased risks associated with ocular surgery in the setting of uncontrolled inflammatory lid disease. Topical anti-inflammatories can effectively manage destructive processes that can lead to vision-limiting complications; however, these agents must be respected to avoid complications, dependency and misuse.

Astute clinicians make treatment decisions mindful of the disease process involved, the specific ocular tissues affected and the available alternatives. These issues will be briefly reviewed in relation to the use of anti-inflammatory medications in the treatment of eyelid disease.

Disease Process

Medications should be prescribed to treat the primary pathophysiologic process, related inflammation, symptoms and dysfunction caused by a disease. Studies about the pathophysiologic abnormalities that underlie eyelid margin disease are limited. Reports of the International Workshop of Meibomian Gland Dysfunction (IWMGD) represent the best compilation of knowledge about these diseases.⁴

Meibomian gland dysfunction (MGD), the precursor to blepharitis and meibomitis, can be understood as a disease of abnormal regulation of keratin metabolism within the meibomian gland (Figure 1).⁴ Over time, abnormal keratin occludes the lumen and orifices of the glands, leading to acinar dilation and atrophy, inflammation and infection (Figure 2). Whether microbial presence precedes or causes altered keratin metabolism is unknown, leaving unanswered whether the use of antibiotics treats MGD itself or its complications. Also uncertain is whether an inflammatory process is the initial abnormality in MGD or a consequence of stagnated secretions.

Figure 1

Representation of keratin granules within the lumen of meibomian glands.
Source: Image provided courtesy of Alcon Laboratories for educational purposes only

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Figure 2

Representation of occluded orifices of meibomian glands.
Source: Image provided courtesy of Alcon Laboratories for educational purposes only

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Affected Tissues

The ideal treatment for MGD would normalize meibomian gland secretions, but the changes in these secretions that lead to obstruction of the gland orifice, irritative symptoms and evaporative dry eye disease are not known. Clinicians rely primarily on oral tetracyclines,^5,6 oral omega-3 supplements⁷ and, recently, topical azithromycin⁸ to change the character of meibomian secretions in patients with symptomatic lid margin disease. Studies that support these clinical decisions have been well reviewed in the Management and Treatment Report of the IWMGD.⁹ Few large, randomized, controlled studies have examined treatment of MGD.

When normalizing meibomian secretions is not possible, use of artificial lubricants to simulate the function of the lipid component of the tear film may be effective. Unfortunately, ranking lubricants in their ability to mimic healthy tear film is difficult. Commercially available lubricants differ significantly by polymer and viscosity, but these properties may not directly translate into efficacy. Several newer lubricants are specifically marketed as mimicking the functions of the tear lipid component and restoring balance to the disturbed tear film in MGD.

Recent studies have raised doubts about whether excessive tear-film evaporation could have enough impact on tear-film volume to be responsible for generating symptoms of ocular irritation.¹⁰ These and other studies¹¹ suggest that increased tear-film osmolarity may need to reach levels higher than 600 mOsm to generate symptoms of dryness or irritation. Thus, aspects of tear film other than tear evaporation or osmolarity may be responsible for symptomatic complaints in MGD. These studies hint at a potentially primary role for inflammation in MGD symptomatology.

Treatment Options

Topical anti-inflammatories (generally corticosteroids alone or in combination with antibiotics) are often prescribed to treat lid margin disease. Even without clinical trials to guide practice, clinicians prescribe these medications in several different situations. Often, an acute flare-up of lid-related irritative symptoms cannot be brought under control without a course of topical corticosteroids lasting from 1week to several months. At the same time, most practitioners have encountered a patient dependent on chronic corticosteroid therapy, sometimes on a once-daily dosing schedule or every few days. Certain ocular diseases that are likely precipitated by MGD or meibomitis are difficult to manage without a course of topical corticosteroids.

In each of these scenarios, clinicians are well advised to prescribe corticosteroids, but must diligently monitor potential side effects, including elevated intraocular pressure, bacterial superinfection, and recurrence of herpetic keratitis or dermatitis. Because of the diversity of situations in which corticosteroid therapy is appropriately prescribed, the challenge is to precisely define the role of anti-inflammatory medications in the treatment of lid margin disease. This challenge is even greater when one considers the nature of the inflammatory process in greater depth.

“Inflammation” is a term widely used in ocular surface disease, but one that can encompass very different processes. Celsus (30 BC to 45 AD) first described inflammation as rubor (redness), calor (warmth), tumor (swelling) and dolor (pain), and his words are still taught in every medical school today. Skin, lid and conjunctival redness and swelling are common in lid margin disease, whether anterior (blepharitis) or posterior (meibomitis). This inflammation is different from “tissue inflammation,” which describes a cellular or molecular process that may be pathogenic either before or in the absence of clinical signs of inflammation.

If the primary abnormality in MGD remains obscure, even less is known about the roles of different pathways of inflammation. Most clinicians understand that important differences exist in the pathogenesis and treatment strategies for allergic, cell-mediated and cytokine-mediated inflammation. Fewer clinicians are knowledgeable about the nuances of inflammation mediated by helper T cell subsets TH1, TH2 and TH17 or the family of mitogen-activated protein (MAP) kinase pathways.^12-14 Peroxisome-proliferator–activated receptors (PPAR family) have been recently reported to play an important role in lipid metabolism, apoptosis and inflammation.^15,16

Available anti-inflammatories for ocular disease include mast cell–stabilizing agents, nonsteroidal anti-inflammatory agents, immunomodulators (cyclosporine, tacrolimus) and corticosteroids. With all of these choices, specifically suppressing isolated pathways of inflammation is still not possible. The most powerful anti-inflammatory agents available (corticosteroids) are nonspecific and produce side effects presumably related to their actions on multiple receptors in multiple cell types. Future pharmaceutical refinements will surely provide selective anti-inflammatory medications that target receptors to limit the actions of the drug to more specific therapeutic pathways. Studies of selective anti-inflammatory agents have begun to appear.¹⁷

Anti-inflammatory drugs have an important place in the treatment of MGD, and as our understanding of relevant pathways increases and the specificity of anti-inflammatory medications increases, this role will become even greater. Complete avoidance of corticosteroids in treating MGD is inappropriately dogmatic and will result in persistent symptoms in moderate-severity MGD and vision loss in severe MGD.

References

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