Recalcitrant dry eye disease (DED) can often be secondary to myriad etiologies that are autoimmune in nature. Expedient and accurate diagnosis of the underlying processes driving these DED cases is essential to help clinicians better tailor their treatment approaches. Common causes of autoimmune disease-related DED include Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Grave’s disease or ocular graft versus host disease. When patients initially present with severe DED to the clinic, it is important to:

1. Identify any systemic conditions contributing to their ocular surface disease
2. Implement ancillary tests to help diagnose DED.

After those two steps, the clinician is equipped to outline a detailed, step-wise approach for treatment.¹ Here is my guide to the process.

FIRST, THE DETECTIVE WORK

History

Begin by performing a cogent review of systems (ie, ask about a family history of autoimmune disease, respiratory difficulties, dry mouth symptoms) and a quick body exam. Look for signs of systemic autoimmune disease such as:

• Abnormal joints (rheumatoid arthritis)
• Swollen parotid glands (Sjögren’s syndrome)
• Exophthalmos (Grave’s disease)
• Rashes (systemic lupus erythematosus)

These signs can clue the clinician into a concomitant disease process that is driving their patient’s ocular surface dysfunction. Evaluate their medication list to see if any agents they are taking suggest an autoimmune condition or can contribute to DED. The ophthalmologist can initiate testing to verify autoimmune disease. If any abnormalities are noted, results are sent either to the patient’s PCP or rheumatology.

Diagnostic tools

Then, assess the ocular surface. The clinician should start with fluorescein or lissamine green staining to evaluate the pattern of tear film distribution (Figure 1) and conjunctival staining, as well as measure the tear-break up time. Schirmer’s testing can assess the degree of tear production. Particularly in cases of atypical DED, point-of-care testing such as elevated tear osmolarity measurements and positive matrix metalloproteinase-9 (MMP-9) testing can help clinicians determine states of increased ocular inflammation. Abnormal eyelid anatomy such as eyelid laxity, entropion, ectropion, conjunctival cicatrization or lid margin thickening and keratinization should be noted as potential contributors to an abnormal tear film.

Meibography (Figure 2) can be used to image the meibomian glands and identify abnormal meibomian gland architecture (ie, gland atrophy, dropout and tortuosity) that is contributing to an unstable tear film and is linked to the patient’s underlying systemic disorder.²

Collaboration required

Treatment of DED cases occurring in the context of autoimmune disease often requires a multidisciplinary approach. This means collaboration of clinicians in internal medicine, rheumatology and ophthalmology. First and foremost, comprehensive treatment of the systemic disorder that is driving the patient’s DED is necessary, not only to reduce the burden of disease but also to mitigate recurrent flares. Comanagement and constant communication with the patient’s internist or rheumatologist are critical to ensure that a thorough plan of action is in place.

FOR THE MILD TO MODERATE DED PATIENT

OTC therapies and lifestyle changes

First-line therapies for mild to moderate DED in patients with atypical DED can include over-the-counter, preservative-free artificial tears; lubricating ointments; night-time tape tarsorrhaphies and moisture goggles. Environmental modifications, such as using a humidifier, avoiding sitting near fans or heating systems and reducing allergens, can also reduce DED symptoms. However, patients who have systemic conditions often require prescription therapies as well to stimulate tear production and quell ocular surface inflammation.

The in-office and prescription route

If patients have positive point-of-care testing for increased tear osmolarity or MMP-9, clinicians can start topical cyclosporine 0.05% (Restasis, Allergan), cyclosporine 0.09% (Cequa, Sun Pharmaceuticals) or lifitegrast (Xiidra, Novartis); these agents can be overlapped with a short pulse of topical steroid therapy for 2 to 3 weeks for added anti-inflammatory effect. Punctal occlusion can be considered to increase the longevity of tears on the surface of the eye. Dissolvable plugs can be trialed initially then transitioned to permanent silicone plugs in both the upper and lower eyelid puncta if successful.

FOR THE SEVERE DED PATIENT

When to move on

If the conservative therapies employed for mild to moderate DED detailed above do not show sufficient effect after a 3- to 6-month trial, the case is categorized as more severe. For severe DED cases in this cohort of patients, additional therapies can be employed in a sequential fashion. These additional therapies can be tried either one at a time or in conjunction with one another, depending on the patient’s tolerance to symptoms and severity of disease.

The therapies

Now for a discussion on the therapies we use to help this cohort of patients, in no specific order. We select options based on what we think the individual patient needs, and may try them individually or in combination.

Amniotic membranes can be placed on the ocular surface for 1 to 2 weeks to serve as protective corneal bandages and decrease ocular surface inflammation. Prokera (Biotissue) is one such amniotic membrane that comes in various sizes (classic, slim, plus and clear) and the appropriate size and design can be chosen based on the patient’s forniceal anatomy and visual needs. The Prokera membrane sits on a ring that can at times be uncomfortable for the patient. I prefer using the Prokera Slim for dry eye, as its dimensions and ComfortRING technology allow it to better contour on the patient’s ocular surface. A tape tarsorrhaphy can be placed over the lid crease to narrow the eye opening and help keep the Prokera centered on the cornea and prevent excessive movement. Fluorescein can be used to check epithelial healing with the membrane in place, and pressure can also be checked with a Tono-Pen (Reichert).

Punctal cautery can be performed for permanent closure of all four puncta if the patient has punctal scarring that precludes placement of punctal plugs or if abnormal punctal or canalicular anatomy causes plugs to constantly dislodge. Punctal cautery can be performed in the office setting where, after placing transconjunctival anesthesia along the lower and upper eyelid, high temperature thermal cautery is applied to the area of the puncta or canaliculi or both to induce scarring. In some cases, conjunctival or mucosal grafts can also be obtained and used to help more permanently close the punctal openings.

Note that patients with autoimmune conditions such as Sjögrens should have more aggressive punctal occlusion. Sometimes all four tear ducts require blockage.

Autologous serum tears (AST) are tears produced from a patient’s own blood and require the separation of the liquid and cellular components of the blood. These tears contain many of the biological nutrients and growth factors found in natural tears and have been found to be particularly powerful in the treatment of refractory DED by stimulating tear production and stabilizing the ocular surface.³ AST can be manufactured in various concentrations (as low as 20%, commonly 30-40% and as high as 100%) and can be dosed 4 to 6 times daily.⁴ Typically, patients must be screened for infectious diseases; once cleared, they can have blood drawn every 3 to 4 months to replenish their supply.

In addition, platelet rich plasma (PRP) and plasma rich in growth factors (PRGF) are alternative hemoderivative tear formulations that have shown promise as successful treatments for moderate to severe DED. These formulations are thought to contain platelet derivatives along with higher concentrations of growth factors and anti-inflammatory cytokines that can facilitate ocular surface restoration and healing.³ PRP and PRGF can be dosed similarly to AST and can be given for multiple rounds in cases of severe DED.

Prior to obtaining AST, PRP or PRGF, patients should be tested for any infectious diseases (ie, HIV, hepatitis or syphilis) that could preclude them from being good candidates.

Creating an ocular surface milieu that can suppress bouts of recurrent inflammation is critical in treating challenging cases of DED. Employment of scleral lenses or the prosthetic replacement of the ocular surface ecosystem (PROSE, BostonSight) device are two excellent options for patients with recalcitrant DED. Scleral lenses are large-diameter gas permeable contact lenses that are specifically designed to rest on the sclera and vault over the corneal surface, creating a fluid reservoir that can provide comfort for patients with DED.⁵ The PROSE system is an FDA-approved prosthetic device that is created on a patient-by-patient basis with a custom-designed vault. It is an effective treatment option for patients with severe ocular surface disease.⁶ Comanagement with optometrists specialized in the fitting of these lenses is recommended for patients who require this treatment modality.

Scleral lenses and PROSE lenses are both excellent therapies but can impose a significant cost on patients. As such, these are often employed when the above-listed therapies have failed or provided incomplete relief to DED symptoms.

In patients with significant meibomian gland disease as evidenced on clinical exam and meibography, thermal pulsation therapies can be performed to heat and evacuate inspissated meibum. Therapy options include Tear Care (Sight Sciences) and Lipiflow (Johnson & Johnson Vision) as well as iLux (Alcon), which can be performed directly in the office setting. Thermal pulsation can be offered every 6 to 12 months and should be used in conjunction with the therapies listed above for best results.

A BESPOKE PROTOCOL IS ESSENTIAL

A customized treatment protocol should be designed for each patient with recalcitrant DED related to autoimmune disease (Table). The clinician and physician should have a dynamic conversation to determine which treatment modalities are most and least effective for this patient and make appropriate changes. Input from internal medicine and rheumatology for management of systemic disease will be instrumental in preventing recurrent flares and exacerbations of disease. OM

REFERENCES

1. Starr CE, Gupta PK, Farid M, et al. An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. J Cataract Refract Surg. 2019;45:669-684.
2. Zang S, Cui Y, Cui Y, Fei W. Meibomian gland dropout in Sjögren’s syndrome and non-Sjögren’s dry eye patients. Eye (Lond). 2018;32:1681-1687.
3. Valencia Castillo SL, Martín ES, García Frade LJ, García-Miguel FJ. Autologous serum eye drops improve tear production, both lachrymal flow and stability tests and conjunctival impression cytology with transfer in dry eye disease. Blood Transfus. 2021;19:45-53.
4. Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Autologous serum eye drops for dry eye. Cochrane Database Syst Rev. 2017;2:Cd009327.
5. La Porta Weber S, Becco de Souza R, Gomes JÁ P, Hofling-Lima AL. The Use of the Esclera Scleral Contact Lens in the Treatment of Moderate to Severe Dry Eye Disease. Am J Ophthalmol. 2016;163:167-173.
6. Agranat JS, Kitos NR, Jacobs DS. Prosthetic replacement of the ocular surface ecosystem: impact at 5 years. Br J Ophthalmol. 2016;100:1171-1175.

About the Author

Nandini Venkateswaran, MD, is a member of the Cornea and Refractive Surgery Service at the Massachusetts Eye and Ear Infirmary and an instructor of clinical ophthalmology at Harvard Medical School. She has co-authored more than 30 peer-reviewed publications and numerous book chapters. Email her at Nandini_Venkateswaran@MEEI.harvard.edu. Dr. Venkateswaran reports no relevant financial disclosures.