Role of topical and systemic immunosuppression in aqueous-deficient dry eye disease

Abstract

Immunosuppression in aqueous-deficient dry eye disease (ADDE) is required not only to improve the symptoms and signs but also to prevent further progression of the disease and its sight-threatening sequelae. This immunomodulation can be achieved through topical and/or systemic medications, and the choice of one drug over the other is determined by the underlying systemic disease. These immunosuppressive agents require a minimum of 6–8 weeks to achieve their beneficial effect, and during this time, the patient is usually placed on topical corticosteroids. Antimetabolites such as methotrexate, azathioprine, and mycophenolate mofetil, along with calcineurin inhibitors, are commonly used as first-line medications. The latter have a pivotal role in immunomodulation since T cells contribute significantly to the pathogenesis of ocular surface inflammation in dry eye disease. Alkylating agents are largely limited to controlling acute exacerbations with pulse doses of cyclophosphamide. Biologic agents, such as rituximab, are particularly useful in patients with refractory disease. Each group of drugs has its own side-effect profiles and requires a stringent monitoring schedule that must be followed to prevent systemic morbidity. A customized combination of topical and systemic medications is usually required to achieve adequate control, and this review aims to help the clinician choose the most appropriate modality and monitoring regimen for a given case of ADDE.

Dry eye disease (DED) can be classified as aqueous-deficient DED (ADDE) and evaporative DED.[1] Management of ADDE in the past was directed toward the mere replacement of the decreased tear production. However, the identification of different inflammatory pathways in the pathogenesis of ADDE has resulted in a drastic shift in the therapeutic protocols of ADDE.[2,3] The adoption of anti-inflammatory and immunosuppressive therapy as the primary line of therapy for ADDE has opened up several potential avenues of therapeutic modalities for ADDE eyes as a wide range of systemic and topical medications are available for the same.

The choice of treatment can be challenging, and these medications are associated with significant side effects that require rigorous monitoring.[4] Furthermore, these drugs are not in the conventional armamentarium of an anterior segment ophthalmologist, and thus these factors may cause the clinician to refrain from prescribing them even when indicated. This review aims to provide an overview of the various groups of immunosuppressive medications available, their side-effect profiles, and indications in the context of the different etiologies of ADDE.

Causes of ADDE

The causes of ADDE can be classified as Sjogren’s syndrome (SS) (primary and secondary) and non-Sjogren’s ADDE.[2] Secondary SS is associated with other autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).[2,5] SS is associated with lymphocytic infiltration of the lacrimal and oral salivary glands resulting in the apoptosis of acinar and ductal epithelial cells, which progresses to glandular tissue fibrosis.[5] Non-Sjogren’s ADDE can be due to primary lacrimal gland deficiencies, obstruction of the lacrimal gland ducts, and reflex hyposecretion.[2] Primary lacrimal gland disorders are congenital and include alacrimia and congenital anhidrotic ectodermal dysplasia.[2] Diseases like sarcoidosis can have a combined pathology which includes lacrimal gland involvement along with an impaired reflex arc.[6] Obstruction of the glandular ducts is seen with cicatrizing conjunctivitis (Stevens–Johnson syndrome (SJS), mucous membrane pemphigoid, drug-induced pemphigoid, and graft-versus-host disease (GvHD)).[2,7] These entities have recently been classified as an ocular surface inflammatory disease in order to differentiate them from traditional age-related DED.[8] They can induce dry eye by affecting the goblet cells as well.[9,10]

Immunopathogenesis of DED

The underlying disease pathogenesis is variable with a diverse set of triggers and mediators involved. However, most of these processes converge and bring about their effects through common final pathways. There occurs an increase in inflammatory cells such as lymphocytes and mediators such as interleukin (IL) 1, IL 6, and tumor necrosis factor.[11,12] Recent studies have elaborated on the role of dysfunctional regulatory T cells, which fail to dampen self-activating T cells. Of these, Th 17 cells are more susceptible to this loss of T cell-mediated regulation.[13] As a result, it incites the activation of several inflammatory mediators which includes but is not limited to IL17.[13] This is also associated with a decrease in anti-inflammatory mediators such as lactoferrin.[11-13] This, in combination with increased osmolarity, can aggravate the inflammation within the ocular milieu.[14-16] An increased expression of cell surface adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) ensues on the surface of both the corneal and conjunctival epithelial cells.[17-19] This binds to the lymphocyte function-associated antigen 1 (LFA-1), resulting in the recruitment of lymphocytes and activation of several cascades of the inflammatory pathway.[17-19] A culmination of these factors results in goblet cell apoptosis, and direct damage to the lacrimal gland and to the tissue surrounding it.[20,21]

Immunosuppressive agents

Several groups of immunosuppressive agents are available, and this review will focus on the ones used most for DED. These medications are chosen based on their property to target the immune mediators discussed in the previous section to ensure an effective outcome with minimal collateral damage to healthy cells.

Corticosteroids

Mechanism of action

Corticosteroids have a dose-dependent mechanism of action with lower doses acting via intracellular receptors and higher doses mediating their actions through the transcellular receptors.[22-24] The former causes inactivation of the nuclear factor- kB, which in turn prevents transcription of proinflammatory cytokines like IL 1, IL 2, tumor necrosis factor, etc., while stimulating the production of anti-inflammatory mediators such as IL10 and lipocortin-1 [Fig. 1].[22-24] At higher doses, the corticosteroids induce a rapid effect and inhibit phospholipase A2 and cyclooxygenase enzymes. As a result, they prevent vasodilatation, migration, and activation of inflammatory cells. In conjunction with the anti-inflammatory activity, the corticosteroids mediate immunosuppression by decreasing B-cell humoral immunity and reduce the T-cell activation by inhibition of IL2.[25,26]

Figure 1.

Immunopathogenesis of aqueous-deficient dry eye disease with the mechanism of action of the commonly used anti-inflammatory agents. The color codes represent the specific factors which are inhibited by the respective drugs. Gray boxes indicate mediators which are not specifically inhibited by these agents. CXR: chemokine receptors, TNF-α: tumor necrosis factor alpha; IL: interleukin; JNK: c-Jun N-terminal kinase; ERK: extracellular signal-related kinase; APC: Antigen-presenting cells; MMP: matrix metalloproteinase; ICAM-1: intercellular adhesion molecule 1; IFN-γ: interferon gamma, MAP-Ks, mitogen-activated protein kinase

Available medications and dosage

Systemic corticosteroids: Several formulations are available which can be classified based on the duration of action into short acting (<12 h; hydrocortisone, cortisol), intermediate (12–36 h; prednisone, prednisolone, methylprednisolone, triamcinolone), and long acting (>36 h; dexamethasone, betamethasone).[27,28] The potency is also proportional with shorter-acting formulations being the least potent. Oral prednisolone is started at a 1–1.5 mg/kg/day dose and given in a tapering fashion. The duration of the tapered dose depends upon the severity of the disease being managed. Patients requiring a maintenance dose are usually placed on 5–7.5 mg/day of prednisolone/prednisone. Steroids can also be given as a pulse dose (e.g. methylprednisolone 500–1000 mg) either just before any surgical intervention or to subdue any acute exacerbations.

Topical corticosteroids: Prednisolone acetate 1% is the most used medication within this category. Being a suspension, it has good penetration through the cornea.[29,30] Prednisolone sodium phosphate is a solution and does not have good diffusion into the aqueous.[29,30] Both topical dexamethasone and betamethasone are long-acting potent medications with moderate to poor permeation into the aqueous. Fluorometholone (0.1%, 0.25%) has a safer side effect profile and is preferred in eyes requiring long-term topical steroids.[28] Its acetate derivative is more potent than the fluorometholone alcohol.[28] Loteprednol etabonate (0.2%, 0.5%) is the only ester-based topical molecule and is converted to inactive products within the cornea due to this property.[22,28] Its intraocular penetration is low leading to lesser adverse effects. Other topical corticosteroids that are available are clobetasone butyrate 0.1% and difluprednate 0.05%.[28]

Adverse effects

The most common side effects of topical corticosteroids are ocular hypertension and secondary glaucoma.[22,28] The incidence of these findings is dose dependent and is higher with more potent, nonester molecules and in eyes with chronic exposure to steroids.[22] While the ocular hypertension is transient and resolves with the discontinuation of the steroids, the optic nerve damage is irreversible. Reactivation of corneal herpetic infections can also occur with the use of topical steroids.[28] Posterior subcapsular cataracts are a frequent complication of both topical and systemic corticosteroids.[4,28] Central serous chorioretinopathy is also associated with systemic steroid use.[28] Other side effects of systemic corticosteroids include gastritis, impaired wound healing, purpura, osteoporosis, dyslipidemia, diabetes mellitus, and myopathy.[22]

Monitoring

Screening for risk factors for secondary glaucoma such as diabetes mellitus, high myopia, and family history of glaucoma is recommended. Subsequently, they should undergo regular intraocular pressure checks and optic disc assessment.[28] Prior to instituting systemic steroids, a baseline body weight, blood pressure (BP) measurement, lipid, and glycemic profile should be obtained [Table 1].[22] If a maintenance dose of steroids is anticipated, then a baseline bone mineral density scan is required. This scan is repeated after 1 year of steroids—if a decrease is noted, then the scan is repeated annually. If the scan is normal, then it is carried out every 2–3 years.[22] Ruling out systemic infections such as tuberculosis, syphilis, and obtaining a viral serology is recommended prior to starting oral steroids. Other parameters that require monitoring have been detailed in Table 1. Patients are also placed on oral calcium (500 mg/day) and vitamin D (500–1000 IU/day) to reduce the risk of osteoporosis.

Table 1.

Doses, adverse effects, and monitoring protocols of different groups of immunosuppressive agents

Drug	Dose		Adverse effects	Monitoring
	Loading	Maintenance		Baseline	Follow up
Corticosteroids Prednisolone	1-1.5mg/kg/day Pulse dose: 500mg stat (intravenous)	5-7.5mg/day	Ocular hypertension , glaucoma osteoporosis, dyslipidemia, diabetes mellitus	Screening for risk factors for glaucoma Body weight, blood pressure measurement, lipid and glycemic profile Rule out tuberculosis, syphilis and other systemic infections	Regular intraocular pressure and optic disc assessment Bone mineral density repeated after 1 year: if decreased is noted-repeat annually. If normal: repeat every 2-3 years Adults >65 years : Lateral spine X rays Blood glucose profile: every 3–6 months for the first year; Annually after that check. Lipid profile: every 6-12 months
T cell inhibitors  Cyclosporine  Tacrolimus	2.5-5 mg/kg/day in two divided doses 0.05-0.1mg/kg/day	Gradually decreased to 0.5mg/kg/day.	Common to both drugs: Renal dysfunction, hypertension, hyperlipidemia, hyperglycemia, infection, hyperuricemia and gout Cyclosporine: hirsutism and gum hyperplasia Tacrolimus: alopecia, gastric intolerance and hyperglycemia	Blood pressure Renal and liver function tests Glycemic profile Serum electrolytes Uric acid Rule out tuberculosis, syphilis and other systemic infections	Same tests as baseline repeated every 2-3 months Tacrolimus: therapeutic drug monitoring
Antimetabolites  Methotrexate  Azathioprine  Mycophenolate mofetil	7.5-10mg/once a week. increased by 2.5mg + Folic acid 1mg x5 days or 5mg x1 day 2-3 mg/kg/day given in two divided doses, increased by 0.5 mg/kg/day 2g/day (2 divided doses) for 6 months	Decreased by 2.5-5mg/week until maintenance dose Reduced by 0.5 mg/kg every month 0.5-3 g/day.	Hepatotoxicity, gastrointestinal intolerance, increased infection risk, aplastic anemia and photosensitivity. Gastrointestinal intolerance, Myelosuppression, hypersensitivity, hepatotoxicity, infections. Gastric intolerance and myelosuppression.	Common to all drugs: Complete blood count (CBC), Renal function test (RFT), Liver function test (LFT) Viral serology (hepatitis B and C) Rule out tuberculosis and syphilis, and pregnancy. Thiopurine methyltransferase levels before starting azathioprine	Weekly CBC, LFT and RFT x1 month. Repeated every 2-3 months CBC, LFT: repeated every 1-2 weeks until the maintenance dose is achieved Thereafter: every three monthly CBC: every week x1 month, two weekly x 2 months, monthly check. Regular RFT and LFT check
Alkylating agents Cyclophosphamide	Pulse dose 10-15 mg/kg (500-750mg) (intravenous) 1-3 mg/kg/day (intake of fluids is encouraged)	1-3 mg/kg/day	Hemorrhagic cystitis, myelosuppression, sterility, nausea, vomiting, secondary malignancies, and alopecia	Complete blood count with differential and urine analysis Fertility counselling Rule out systemic infections	Repeat CBC and urine analysis every month

T-cell inhibitors (cyclosporine and tacrolimus)

Mechanism of action

Calcineurin inhibitors prevent the self-activation of T cells via IL 2 [Fig. 1].[4,31] These drugs bind to immunophilins within the T-cell cytoplasm. Cyclosporine binds to cyclophilin, while tacrolimus binds to FK binding protein.[32] These complexes then competitively inhibit calcineurin activity, and as a result, transcription of several cytokines genes is prevented. One of these is the IL2 gene which is required for T-cell activation and proliferation. This effect is exerted on the T-helper, T suppressor, and T cytotoxic cells. Thus, these medications mediate immunosuppression by blocking T cell activity.

Available medications and dosage

Cyclosporine and tacrolimus are the most frequently used topical and systemic drugs within this group. Other formulations that are available include pimecrolimus and voclosporin. Oral cyclosporine is given in two divided doses with an initial dose of 2.5–5 mg/kg/day. Once the inflammation is under control, the dose can be gradually decreased to 0.5 mg/kg/day. Topical cyclosporine is available as 0.05% and 0.1% eye drop preparations and is administered twice a day.[4] Higher concentrations of cyclosporine can be prepared from the injectable medication (1% cyclosporine) and the oral one (2%), by compounding with artificial tears or sterile oil.[33] The primary concern with topical cyclosporine is its hydrophobic nature, which prevents adequate penetration through the precorneal tear film. Both a cationic and an anionic formulation are available as an emulsion and have low ocular bioavailability.[34,35] To circumvent these issues an aqueous nanomicellar preparation (0.09%) has been devised with the cyclosporine molecules encapsulated within a hydrophobic core. This is surrounded by a hydrophilic capsule which delivers a higher concentration of this drug both in the cornea and conjunctiva.[36-38]

Oral tacrolimus is available as an immediate-release and an extended-release formulation. It is given as a 0.05–0.1 mg/kg/day dose in two divided doses, which are 12 h apart[4] Topical tacrolimus is available as 0.02–0.03% ointment and 0.005-0.1% solutions/suspension, which is given as a twice a day or a once nighttime dose.[39] Similar to cyclosporine the hydrophobic nature of the drug prevents its deeper penetration. The use of nano-formulations and liposomes has been explored to circumvent this issue.[40,41]

Monitoring

Patients who are on calcineurin inhibitors (CI) require monitoring of BP, renal, and hepatic functions along with serum electrolytes and glucose [Table 1].[42] Ruling out systemic infections is essential before starting these medications. Tacrolimus has a narrow therapeutic range and requires therapeutic drug monitoring.

Adverse effects

Both cyclosporine and tacrolimus can cause renal dysfunction, which can resolve by decreasing the dose of the medication. However, irreversible damage to the renal cells can also occur with chronic use of the medications.[43,44] Hypertension, hyperlipidemia, hyperuricemia, and gout can ensue with long-term use of these medications.[43,45,46] While chronic use of cyclosporine can result in hirsutism and gum hyperplasia, tacrolimus use is associated with alopecia, gastric intolerance, and hyperglycemia.[47-49] Tacrolimus has a diabetogenic potential as a result of direct toxicity to the β-cells and via inhibition of the transcription of the insulin gene.[50] This can result in hyperglycemia, insulin resistance, and paraesthesia. Other rare complications also include neurotoxicity, lymphoproliferative disorders, squamous cell cancers, and systemic infections.[32,51] Topical side effects include ocular discomfort and blurring of vision.[39,52]

Alkylating agents

Mechanism of action

Several drugs such as chlorambucil, ifosfamide, melphalan, and procarbazine are included in the category. Since cyclophosphamide is used frequently in the context of DED, this drug will be discussed in this section. This nitrogen mustard inhibits protein synthesis by preventing RNA transcription from DNA by alkylating the DNA molecules.[53,54] In addition to this antimitotic action, the agent also has immunomodulatory effect which is T-cell specific. Since the medication is not cell cycle specific, it exerts its effect on resting and dividing cells.[4] As a result, the toxicity associated with cyclophosphamide is significant, limiting its use in ocular surface diseases to pulse doses.

Dosage

Intravenous cyclophosphamide is infused as a pulse dose of 10–15 mg/kg, which can be repeated 2–3 times, depending upon the disease severity.[53] The oral form of cyclophosphamide is given in the morning (1–3 mg/kg/day) and patients are advised to consume adequate fluids in order to prevent urinary bladder toxicity.

Adverse effects and Monitoring

The two most common side effects of cyclophosphamide include hemorrhagic cystitis and myelosuppression.[55,56] The former is also associated with other features of urinary tract toxicity such as frequency and urgency. This occurs because of acrolein, which is one of the metabolites of cyclophosphamide. Intake of adequate fluids to decrease the contact time of acrolein with the urinary system has been recommended.[55] Other side effects include amenorrhea, sterility, nausea, vomiting, and alopecia.[55,56] A complete blood count (CBC) and urine analysis is recommended prior to starting the medication and requires monthly repetition when on therapy. Since cyclophosphamide can affect male fertility, young patients receiving this medication should be counseled appropriately and referred to sperm banks, cryopreservation centers, and fertility specialists to explore these preserving options before commencing therapy.[57] These patients are also at an increased risk of developing secondary malignancies, such as bladder cancer, acute leukemias, lymphomas, and thyroid cancer, and a thorough age-appropriate screening is recommended.

Antimetabolites

Mechanism of action

These medications act by inhibiting the replication of DNA and RNA, which ultimately interferes with cellular metabolism [Fig. 1].[58] There are four groups of drugs under this category, and each group has a unique mechanism of action. These include folate antagonists, cytidine analogues, purine analogues, and pyrimidine analogues. Of these, folate antagonists, purine, and pyrimidine analogues are the most used in ophthalmology.

• Purine analogues get converted into active metabolites which then get integrated with DNA strands and stop further synthesis.[59] Azathioprine is one such example that gets converted to 6-mercaptopurine within the liver.

• Folate antagonists (methotrexate) mediate their action by preventing the formation of tetrahydrofolate and the subsequent DNA and RNA synthesis.[60] This effect is facilitated by the inhibition of dihydrofolate reductase. An additional effect is its anti-inflammatory action which occurs due to the accumulation of adenosine.[61] This results in a decreased activation and proliferation of both cellular and humoral immunity mediators.[61]

• Mycophenolate mofetil (MMF) was designed to specially target lymphocytes and their cytokines.[62] This drug impedes the action of inosine-5′-monophosphate dehydrogenase. Its specificity is facilitated by the fact that its inhibition of the type II isoform is more potent than that of the type I isoform.[62] The former is present in T and B cells, while the latter is more ubiquitously present and, thus the cytotoxic effect is exerted only on the lymphocytic cells.

Available medications and dosage

• Azathioprine is given as a once daily dose of 2–3 mg/kg/day.[63] It can be started as 1 mg/kg/day in two divided doses which is slowly increased by 0.5 mg/kg/day every 6–8 weeks until the inflammation is under control. A reversal of the process is followed by reducing the dose by 0.5 mg/kg every month until the maintenance dose has been attained. This is defined as the lowest dose at which the quiescence is maintained.

• Methotrexate is given as a weekly dose and is usually started at 7.5–10 mg.[64] This can be increased by 2.5 mg until the desired effect is seen, and subsequently, in a manner similar to that of azathioprine, the dose is decreased to a maintenance level. The maximum therapeutic dose is 25 mg/week.[65] Concurrent daily administration of folic acid is also required to protect normal cells from the effects of methotrexate.[66] This is administered as a 1 mg/day dose on all days other than the day when methotrexate is given or a single 5 mg dose.[67] Methotrexate can be given by a subcutaneous or intramuscular route and this has a higher bioavailability along with decreased gastric and hepatic adverse effects.[68-70]

• Mycophenolic acid is available in two formulations which include MMF and enteric-coated mycophenolate sodium. Oral MMF is given as 2 g/day dose for 6 months and then replaced with a maintenance dose of 0.5–3 g/day.[71,72] The maximum dose that can be administered per day is 3 g.[73] The enteric-coated tablet has a lower dose.

Monitoring

Prior to starting antimetabolites, a baseline CBC, renal function test (RFT), and liver function test (LFT) are procured. Obtaining a viral serology (hepatitis B and C) and ruling out tuberculosis and syphilis are also recommended. In women, it is essential to rule out pregnancy.[4,43] A comprehensive diagnostic metabolic panel is also recommended.

• For azathioprine, the CBC is repeated every 1–2 weeks until the maintenance dose is achieved, after which it is repeated every 3 months.[74] LFT is also repeated at the same interval. Thiopurine methyltransferase is an enzyme that converts azathioprine to inactive metabolites. Its reduced activity results in an increased concentration of 6-mercaptopurine and its associated side effects.[75] Thus, checking its levels is also advocated prior to starting azathioprine.

• Once methotrexate has been initiated, weekly CBC, LFT, and RFT are required for the initial month. Subsequently, these tests are repeated every 2–3 months.

• CBC is obtained every week for a month when starting MMF and is then done every two weeks for 2 months, followed by a monthly check.[76] Regular assessment of RFT and LFT is also recommended.

Adverse effects

• The most common side effect associated with use of azathioprine is myelosuppression. Others include gastric intolerance, hypersensitivity, hepatotoxicity, and an increased risk of infections. It can rarely cause macrocytic anemia, myalgia, lymphoma, skin cancer, and alopecia.[77] The concurrent use of allopurinol has to be avoided as it can increase the risk of myelosuppression.[78]

• Methotrexate use is associated with hepatotoxicity and gastrointestinal intolerance.[79] Other side effects include alopecia, increased infection risk, leucopenia, aplastic anemia, and cutaneous photosensitivity.

• MMF is associated with hypertriglyceridemia, hyperglycemia, and myelosuppression.[80,81] Gastric intolerance is common and the risk of the same is reduced by using enteric-coated tablets.[80,81]

Other agents

Lifitegrast

This molecule blocks the binding of the lymphocyte function-associated antigen-1 (LFA-1) antagonist to ICAM-1.[82] As a result, it prevents the migration of antigen-presenting cells to the nearby lymph nodes, which in turn prevents the activation of T cells residing within it.[82] Additionally, it also blocks the migration of the activated T cells and, thus, halts the ensuing ocular surface damage that these cells could have caused.[82,83] It can also directly decrease the production of interferon-γ, IL 1, and IL 10.[84] The use of this drug is associated with mild ocular discomfort, stinging, and dysgeusia.[19] Several studies have shown that lifitegrast can reduce corneal staining and improve subjective scores in eyes with ADDE.[85-87] In contrast to CI, the onset of action is faster with effects seen as early as 14 days.[88]

Repository corticotropin injection (RCI)

RCI (Acthar® Gel; Mallinckrodt Pharmaceuticals, Hampton, NJ, USA) is a combination of pituitary peptides and adrenocorticotropic hormone (ACTH), which is injected subcutaneously (twice weekly).[89,90] This induces endogenous cortisol production which dampens the inflammatory activity.[89] It also has nonsteroidogenic mechanisms of action, which are exerted by directly inhibiting the activity of inflammatory mediators such as T cells, B cells, and immunoglobulins.[89-91] This novel agent has shown the reduction of ocular surface staining and improvement in patient symptomatology scores, which typically occurred after three months of use of the agent.[89,92] This improvement was also noted in eyes that did not respond to traditional immunosuppressive therapy.[92] Future studies that compare this therapy with conventional immunomodulators will help understand its potential in treating DED.

Trehalose

Trehalose is a disaccharide that acts primarily by preventing protein denaturation in the absence of water.[93] Its anti-inflammatory property is secondary to its ability to activate transcription factor EB.[94-96] This induces autophagosome activity which causes the breakdown of the inflammatory cells.[94-96] Furthermore, it decreases levels of cytokines, especially TNF-α, IL 1, and IL 6.[93] Clinically, these effects translate to a thicker tear film and decreased staining of the ocular surface.[95] Improvement of goblet cell density has also been reported with the topical use of trehalose.[97]

Hydroxychloroquine

Hydroxychloroquine exerts its anti-inflammatory effect by blocking the toll-like receptors.[98,99] Its use has been described primarily for SS. Although a few reports have described a decrease in the serum levels of inflammatory mediators with the betterment of the objective symptomatic and surface staining scores, randomized controlled trials have failed to demonstrate an improvement in corneal or conjunctival scores.[98-102] The efficacy of this medication is perhaps limited to a specific subset of cases, and further studies which can identify biomarkers which are predictive of the same can help employ hydroxychloroquine in DED management.[103]

Biologic agents

These medications include TNF-α inhibitors, lymphocyte inhibitors, and specific receptor inhibitors.[4,104] TNF-α inhibitors act by blocking the binding of TNF-α and preventing the release of a proinflammatory cascade.[105] Lymphocyte inhibitors target T cells (abatacept) and B cells (rituximab and belimumab).[106] Of these, rituximab is used most commonly in ADDE and is a chimeric antibody. It acts directly by binding to the CD 20 positive cells and inducing cell death.[107] Indirect mechanisms have also been described and can occur via complement and antibody-mediated cytotoxicity.[107] It is administered as a 1 g dose which is repeated after 2 weeks. Since its infusion is associated with reactions, administration of prior antihistamines and nonsteroidal anti-inflammatory drugs is recommended.

Omega fatty acids

These typically are the omega-3 fatty acids, and when they are metabolized, they give rise to resolvins, lipoxins, and protectins.[108-110] These metabolites help decrease cytokine levels and protect corneal cells as well. Both topical and oral supplementation has been described to counter ADDE inflammation. Although the evidence in literature is variable regarding their efficacy, a large majority have supported the claim that these essential fatty acids improve the health of the ocular surface while decreasing the staining of the cornea and conjunctiva.[108-110] Furthermore, these medications are extremely safe and, hence, have been incorporated into standardized treatment regimens.[108,111]

Immunoglobulins

Intravenous immunoglobulins (IVIg) are reconstituted from the pooled plasma of several thousands of donors.[112] The anti-inflammatory effect of IVIg is achieved at a higher dose than that used for immune deficiencies.[112] This effect is mediated by inhibiting migration of inflammatory cells, complement inactivation, T and B cell blockade, and is typically given at a dose of 2–3 g/kg/month over 3 days.[112,113] IVIg has a relatively safe profile and is associated with headaches following infusion along with allergic cutaneous reactions.[112] They can very rarely cause acute renal failure, anaphylactic shock, and thromboembolic events.[112]

Approach to immunosuppression in DED

A stepwise guide to choosing the most appropriate modality of immunosuppression has been provided below based on the type of ADDE present in the patient [Table 2].

Table 2.

Approach to immunosuppression in different etiologies of aqueous-deficient dry eye disease

	Drug	Topical therapy			Systemic therapy
		Indication	Course of therapy	Drug of choice
Sjogren- associated ADDE	Primary Sjogren’s Syndrome	Surface inflammation	Tapering course of topical steroids followed by calcineurin inhibitors	Loteprednol/fluorometholone Tacrolimus Cyclosporine	Not indicated for ocular involvement in isolation
		Significant corneal and conjunctival staining	Calcineurin inhibitors
	Secondary Sjogren’s syndrome	Surface inflammation	Tapering course of topical steroids followed by calcineurin inhibitors	Loteprednol/fluorometholone Tacrolimus Cyclosporine	Choice of therapy is dictated by the underlying autoimmune disorder
		Significant corneal and conjunctival staining	Calcineurin inhibitors
Non-Sjogren ADDE	Stevens-Johnson Syndrome	Persistent conjunctival inflammation not corrected by addressing local pathologies	Tapering course of topical steroids followed by calcineurin inhibitors	Loteprednol/fluorometholone Tacrolimus Cyclosporine	Methotrexate/azathioprine/and mycophenolate mofetil
	Mucous membrane pemphigoid	Acute exacerbation	Tapering course of topical steroids	Prednisolone acetate	Step-ladder approach Mild disease: Dapsone Moderate disease: Tapering dose of oral corticosteroids along with oral methotrexate/azathioprine/mycophenolate mofetil Severe/acute exacerbation: IV methyl prednisolone±cyclophosphamide pulse dose along with systemic therapy as per moderate disease Refractory disease: biologics (rituximab) ±intravenous immunoglobulins
	Graft-versus-Host disease	Significant corneal and conjunctival staining or hyperemia	Tapering course of topical steroids followed by calcineurin inhibitors (tacrolimus and cyclosporine)	Loteprednol/fluorometholone Tacrolimus Cyclosporine	Given in conjunction with the hematologist/oncologist Oral corticosteroids combined with calcineurin inhibitors, mycophenolate mofetil, or biological agents

Sjogren’s syndrome

Primary Sjogren’s syndrome

In eyes with active surface inflammation, the first choice of therapy is with topical corticosteroids [Figs. 1 and 2].[4] Depending upon the severity, either loteprednol or prednisolone acetate can be given in a tapering fashion.[4] Since these cases also require maintenance therapy, topical immunomodulators such as cyclosporine and tacrolimus are also indicated. Cyclosporine can help improve symptoms and ocular staining scores, the tear film break-up time, and the Schirmer values [Fig. 2].[52,114] These effects of cyclosporine may require several months to manifest, and faster results have been obtained with the use of the nano-micellar preparations where the results are seen within 1 month of usage.[36,114,115] Cyclosporine can also address the neurotrophic component by improving the corneal sensations which are typically reduced in ADDE.[116] An increase in tear production has also been reported, which is greater with the 0.09% formulation.[36,37]

Figure 2.

Response to systemic immunosuppression in aqueous-deficient dry eye disease. A case of undiagnosed primary Sjogren’s syndrome with corneal epithelial defect (A1) responded to systemic hydroxychloroquine and azathioprine (A2). Two cases of mucous membrane pemphigoid presented with severe dry eye (B1, C1), underwent conjunctival biopsy for the confirmation of the diagnosis and responded remarkably to oral mycophenolate mofetil with the resolution of the corneal epitheliopathy (B2, C2)

Topical tacrolimus has also been used for the control of ocular inflammation in primary SS.[117,118] Tacrolimus use can bring about changes in the ocular surface staining within 1 month of use, while parameters such as Schirmer’s and tear film break up time can take up to 3 months to stabilize.[117-119] Furthermore, both CI can also improve the goblet cell density and have a protective effect on lacrimal glandular cells, which provides an added benefit over topical corticosteroids.[117,120,121] Both CI are employed for moderate to severe dry eye and have shown good tolerance rates for up to 12 months of use, even in eyes with severe ADDE.[34,117,122,123] Although no period of therapy has been defined for the use of CI, persistent decreases in ocular staining scores have been reported with long-term usage, which persevered despite discontinuation of medications.[124] These effects were particularly seen in eyes, which had received these medications for at least 1 year.

Systemic immunosuppressants for ADDE in isolation are typically not required and are indicated in the presence of extra-glandular involvement such as arthritis or dermatological manifestations. This requires a referral to the rheumatologist for the initiation of immunosuppression. Several recent studies have shown mixed results of biologic agents such as rituximab in patients with primary SS.[106,125] Similarly, TNF-α inhibitors are not preferred in primary SS because of the higher risk of lymphoproliferative disorders following their use.[106,126]

Secondary Sjogren’s syndrome

Here, the dose and modality of immunosuppression are determined by the autoimmune disorder causing the ADDE. The approach to immunosuppression in patients with RA is complex and depends upon the duration of the disease (greater than or less than 6 months) and the severity at presentation. The patients are usually started on a monotherapy of methotrexate, which is then escalated to a combination therapy with either another disease-modifying antirheumatic drug (leflunomide/hydroxychloroquine) or with a biologic agent (rituximab).[65,127] Usually, these medications require 6–12 weeks for their effects to peak and oral corticosteroids are given during this period.[4] A similar graded approach is used for the management of SLE with low-dose steroids for mild disease which is not life or organ threatening. Immunomodulators such as MMF, CI, and biologic agents are administered when the disease is severe.[128] The therapy in such cases is typically handled by the immunologist or a rheumatologist with an active input from the ophthalmologist to tailor the degree of immunosuppression.

Topical immunosuppression in secondary Sjogren’s is carried out in a similar manner to primary Sjogren’s disease with CI being the mainstay of therapy [Fig. 3]. The patients can also have ocular exacerbations, which require immediate immunosuppression. These can manifest as corneal thinning or perforation, and a detailed ocular exam is warranted to ascribe them to an immune-mediated or a dry-eye-mediated process. In case of a peripheral ulcerative keratitis like presentation, an underlying inflammatory process is more likely, whereas cases with a central melt with surrounding unhealthy epithelium are more likely to be secondary to an aqueous-deficient activity. Similarly, in the presence of associated scleritis, an autoimmune pathology is considered. These conditions warrant an immediate increase in systemic immunomodulators and can often also require pulse doses of systemic immunosuppressants. The presence of systemic vasculitic activity such as acute renal failure or pneumonitis should be looked out for if an autoimmune disorder is suspected. A complete autoimmune panel with antineutrophil cytoplasmic antibodies and appropriate histopathological workup can help cinch the diagnosis of the underlying condition. Additionally, cases with DED are predisposed to develop cataract and require a good pre and perioperative control of the underlying inflammation for the same.[129]

Figure 3.

Response to systemic immunosuppression in a case of aqueous-deficient dry eye recalcitrant to topical medications. A 13-year-old child with juvenile systemic lupus erythematosus (SLE) and secondary Sjogren’s syndrome presented with severe bilateral dry eyes (A1,B1) with upper forniceal scarring and keratinization (C1 and D1) in the left eye. The child was on half-hourly lubricants and cyclosporine, and improved dramatically with the reduction of the corneal staining (A2, B2) and conjunctival keratinization (C2,D2) after using systemic hydroxychloroquine and steroids

Non-Sjogren’s ADDE

Of the several causes of non-Sjogren’s ADDE, a select few require immunosuppression to arrest the inflammation and prevent sequelae such as cicatrizing conjunctivitis and limbal stem cell deficiency. Its role in ADDE is to halt the peri-ductal and glandular fibrosis, which can worsen the dry eye component.

Mucous membrane pemphigoid

A stepwise approach has been described for the management of this cicatricial disorder.[4] Dapsone is the first line of management in these cases, and in eyes where the inflammation is not sufficiently controlled with the same, either methotrexate, azathioprine, or MMF is added [Fig. 2].[4,130] In eyes which present with severe disease or have acute manifestations such as corneal perforations and melt require immediate immunosuppression with intravenous methylprednisolone which can be combined with intravenous cyclophosphamide.[4,131] In eyes with refractory disease, a trial of biological agents such as rituximab, etanercept, and infliximab can be given.[132,133] The efficacy of rituximab has been described in isolation and in combination with IVIg. It is effective not only in refractory disease but can also induce remission in advanced cases as well.[132,134,135] Although the expense can be inhibitory, the overall side effect profile is very favorable, especially when compared to cyclophosphamide, and thus this medication has become a frontrunner in the management of this challenging ocular disorder.

Stevens–Johnson syndrome

Ophthalmologists are mostly involved in the management of the chronic ocular sequelae of SJS. Ocular inflammation in the chronic phase is usually secondary to local causes such as distichiatic lashes or lid margin keratinization.[136] However, this inflammation can also occur in isolation and requires control to prevent damage to the residual stem cells and the lacrimal gland.[137,138] Additionally, an inflamed ocular surface can persist despite adequate management of the lid margin keratinization and ADDE. In such cases, topical and/or systemic immunosuppression is warranted. The most commonly used medications include methotrexate, azathioprine, and MMF for systemic immunosuppression, while topical immunosuppression is usually managed with steroids and CI.[137,139,140] Unlike Sjogren’s disease where an active autoimmune disorder is present, the immune dysregulation of SJS is a one-time event. Thus, isolated immune-mediated melts are extremely rare, and if present, a complete systemic workup is indicated to rule out an underlying connective tissue disorder.

Graft-Versus-Host Disease

Ocular GvHD occurs as the inflammatory cascade activated by the donor T cells, which results in dry eye secondary to glandular fibrosis and decreased goblet cell density.[141] The use of topical CI such as tacrolimus has been shown to improve the patient comfort, surface staining scores, and objective parameters such as Schirmer’s test and the tear film break-up time.[35,142-145] Other medications that have been used for chronic ocular GvHD include topical anakinra and tranilast, both of which improve dry-eye-related ocular surface disease.[141] Janus kinase inhibitors have also been used both topically and systemically in chronic GvHD and can be considered as alternatives to corticosteroids for the control of inflammation.[146-148] In the presence of systemic features of chronic GvHD, the patients are placed on systemic immunosuppression with CI, MMF, and biological agents such as rituximab.[149-151] If chronic ocular GvHD is present in isolation, systemic immunosuppression is warranted and can be instituted in conjunction with hematologist and oncologist.[152]

Future Perspectives

The search for newer molecules that can effectively address inflammation in ADDE is ceaseless and the number of novel therapeutic agents being devised for the same is endless. An ideal molecule would target and mitigate specific inflammatory mediators without affecting normal healthy cells. These molecules would be specific to a particular disease, have minimal side effects, and an easy dosing schedule. Certain avenues that are currently being explored include topical biological agents such as tanafaercept (TNF – a inhibitor), topical anakinra (IL-1 antagonist).[153,154] These medications have been shown to decrease ocular surface staining and improve patient comfort. The role of proteoglycan-4 (lubricin) in maintaining ocular surface integrity and the health of the corneal epithelial cells is being investigated. Recombinant proteoglycan-4 has been studied in animal models and has been shown to objectively decrease the level and activity of inflammatory cytokines.[155,156] Thus, this molecule can not only better the surface lubrication but also exert anti-inflammatory properties. Other options that can offer therapeutic targets include costimulatory molecules such as CD40 as their levels are increased in SS.[106] Antibodies that block the effects of these ligands, such as iscalimab, can prevent the ensuing inflammatory mediator release.[106] Inhibition of the B-cell activating factor receptor by ianalumab has a similar mechanism, and preliminary studies with these molecules have shown promising results.[106] Newer formulations of existing drugs that improve upon the penetration and the side effect profile are also being explored.[3,157]

Conclusion

Although immunosuppression is indicated in eyes with DED, the exact indications and treatment protocols are not well elucidated and current management is usually carried out based on experience with other ocular inflammatory diseases. Future studies that look at these newer drugs in the context of the different etiologies and existing treatment modalities of ADDE will provide a better perspective of their safety and efficacy in these patients.

Financial support and sponsorship

This work was funded by the Hyderabad Eye Research Foundation Hyderabad, India. The sponsoring organization had no role in the design or conduct of this research.

Conflicts of interest

There are no conflicts of interest.