DJO Jan- Mar -2022 Volume 32 No (3)

DJO Vol. 32, No. 3, January-March 2022

SUMMARY orangell and methyl violet. Int J Retina Vitreous. 2015 Apr 15;1:1.
12. Rickmann A, Al-Nawaiseh S, Della Volpe M, et al. Assessment
Substance Dose Molecular Dilution Affinity Preventing
Weight vitreous Retinal of Macular Function Following Internal Limiting Membrane
Triamcinolone 40mg/ ILM Toxicity Peeling With ILM Blue®. Cureus. 2020;12(12):e11873.
434 Dalton no 13. Maia M, Furlani BA, Souza-Lima AA, Martins DS, Navarro RM,
ILM Using Belfort R Jr. Lutein: a new dye for chromovitrectomy. Retina.
acetonide ml (4%) preservative- 2014 Feb;34(2):262-72.
free solution Cite This Article as: Shreyangshi Dipta, Shruti Bhattacharya,
Indocyanine 5mg 775 Dalton (0.05%) Khushboo Chawla. Vital Stains in Retina and Vitreous. Delhi Journal
green (0.5%) 3-5% dissolve Add 1ml of Ophthalmology.2022; Vol 32, No (3): 97- 99.
25mg iodine in small water to 1 Acknowledgments: Nil
(2.5%) amount, vial of 5 mg, Conflict of interest: None declared
50mg use take 0.1ml Source of Funding: None
(5%) BSS for of it and mix Date of Submission: 26 Mar 2022
dilution with 0.9ml Date of Acceptance: 01 April 2022
BSS
Infracyanine 5mg 775 Dalton (0.05%) Address for correspondence
green (0.5%) Same dissolve Add 1-2ml Shruti Bhattacharya
25mg as ICG, in 5% of 5%
(2.5%) but no glucose glucose to 1 MBBS, MS, DNB
sodium, vial of 5mg
iodine Department of Ophthalmology,
Retina Clinic, Guru Nanak Eye
Trypan blue 1.2mg/ 960 Dalton no ERM Mix 0.3ml Centre, New Delhi, India
ml with 0.1ml of Email : [email protected]
(0.15%) 5% glucose
Quick Response Code
Brilliant blue 0.25mg/ 854 Dalton no ILM Use with
ml dilution
(0.025%)

Patent blue 2.5mg/ 582 Dalton no ERM Mix 0.3ml
ml with 0.1ml of
(0.25%) 5% glucose

References

1. Hernández F, Alpizar-Alvarez N, Wu L. Chromovitrectomy: an
update. J Ophthalmic Vis Res. 2014 Apr;9(2):251-9.

2. Al-Halafi AM. Chromovitrectomy: update. Saudi J Ophthalmol.
2013;27(4):271-276. doi:10.1016/j.sjopt.2013.10.004

3. Rodrigues EB, Penha FM, de Paula Fiod Costa E, Maia M,
Dib E, et al. Ability of new vital dyes to stain intraocular
membranes and tissues in ocular surgery. Am J Ophthalmol.
2010 Feb;149(2):26577.

4. Stanescu-Segall D, Jackson TL. Vital staining with indocyanine
green: a review of the clinical and experimental studies relating
to safety. Eye (Lond). 2009 Mar;23(3):504-18.

5. Feldman A, Zerbib J, Glacet-Bernard A, Haymann P, Soubrane
G. Clinical evaluation of the use of infracyanine green staining
for internal limiting membrane peeling in epimacular membrane
surgery. Eur J Ophthalmol. 2008 Nov-Dec;18(6):972-9.

6. Imai H, Tetsumoto A, Inoue S, Takano F, Yamada H, Hayashida
M, et al. Intraoperative Three-Dimensional Fluorescein
Angiography-Guided Pars Plana Vitrectomy for the Treatment
of Proliferative Diabetic Retinopathy: The Maximized Utility of
the Digital Assisted Vitrectomy. Retina. 2020 Apr 17

7. Steeples LR, Anand N, Moraji J, Jones NP. Clinical Outcomes
of Intravitreal Preservative-Free Triamcinolone Preparation
(Triesence®) for Cystoid Macular Oedema and Inflammation in
Patients with Uveitis. Ocul Immunol Inflamm. 2018;26(7):997-
1004

8. Caiado RR, Moraes-Filho MN, Maia A, Rodrigues EB, Farah ME,
Maia M. State of the art in chromovitrectomy. Rev Bras Oftalmol.
2014;73(6):363-76.

9. Mennel S, Meyer CH, Tietjen A, Rodrigues EB, Schmidt JC. Patent
blue: a novel vital dye in vitreoretinal surgery. Ophthalmologica.
2006;220(3):190-3

10. Chuang LH, Wu AL, Wang NK, Chen KJ, Liu L, Hwang YS,
Yeung L, Wu WC, Lai CC. The intraocular staining potential
of anthocyanins and their retinal biocompatibility: a preclinical
study. Cutan Ocul Toxicol. 2018 Dec;37(4):359-366.

11. Badaro E, Souza-Lima RA, Novais EA, Maia M, Hirai F, Meyer
CH, Farah ME, Rodrigues EB. Investigation of new dyes for
chromovitrectomy: preclinical biocompatibility of trisodium,

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DJO Vol. 32, No. 3, January-March 2022

Abstract Theme Article

Biologics in Oculoplasty

Priyanka Golhait, Gaurav Singh

Department of Ophthalmology, Guru Nanak Eye Centre, New Delhi, India.

Recent advancements in oncology and immunology have led to the development of biologics, which are newer drugs that
target specific molecules involved in tumorigenesis and inflammatory pathways. The current use of targeted therapy has
transformed the therapeutic approach for many orbital cancers and inflammatory disorders that were previously treated
with conventional treatment modalities. The purpose of this article is to highlight the therapeutic potential of targeted
therapy for common orbital cancers and inflammatory conditions.

Delhi J Ophthalmol 2022; 32; 100-103; Doi http://dx.doi.org/10.7869/djo.757

Keywords: Biologics Targeted Therapy Monoclonal Antibodies Small Molecule Inhibitors Hedgehog Pathway

Introduction a humanized mouse monoclonal antibody (-zumab) acting
against VEGF-A of circulatory system (-ci).3 Antibodies
Recent advances in our understanding of the biological derived entirely or in part from non-human DNA are more
pathways involved in cancers and orbital inflammatory likely to cause hypersensitivity reactions and to induce the
disorders have resulted in the development of agents formation of neutralizing antibodies.
that act at a specific molecular level, thereby blocking
the pathogenesis. Biologics are proteins that have been Small molecule inhibitors inhibit a specific metabolic step in
specifically designed by recombinant DNA technology the target cell, halting cell growth.2 The name of the agent
or monoclonal antibody technology and are used to treat indicates the specific enzymatic step blocked. The ending in
diseases as per the molecular etiopathogenesis.1 These -tinib is for tyrosine kinase, -zomib for proteasome, -ciclib
"molecularly targeted agents"2 have resulted in a paradigm for cyclin-dependent kinase, -parib for poly-ADP-ribose
shift in the management of advanced ocular and periocular polymerase inhibitor.3 For example, imatinib inhibits the
malignancies, from "life-sparing" to "eye-sparing" to "vision- Bcr-Abl fusion protein tyrosine kinase, an abnormal protein
sparing" strategies. produced by chronic myeloid leukaemia cells, inhibiting
Traditional chemotherapeutics and anti-inflammatory proliferation, and inducing apoptosis.
drugs have been widely used to reduce ocular morbidity
and slow disease progression. However, their action is non- Biologics In Oculoplasty- Oncologic Conditions
specific, affecting all cells with high mitotic activity and
causing significant side effects in other tissues with a high Periocular malignancies pose a management challenge for
turnover rate. Their long-term use is thus constrained by both functional and cosmetic reasons. Surgery remains the
their potential toxicity and suboptimal outcomes. Targeted mainstay of treatment for locally aggressive eyelid tumors,
treatment interferes with specific molecules implicated with the goal of achieving tumor free margins. Invasion of
in inflammatory or carcinogenic pathways, rather than the orbital septum is considered as orbital extension of the
working against all cells with mitotic turn-over. As a result, tumor.4 Orbital invasion of periocular malignancies is one of
systemic adverse effects can be significantly decreased while the most common indications of orbital exenteration.5 Though
still delivering precise and effective targeting. a definitive therapeutic treatment, orbital exenteration is a
radical, destructive, and cosmetically disfiguring procedure
Nomenclature Of Biologics that causes significant psychological trauma to the patient.

Monoclonal antibodies and small molecule inhibitors are the Basal cell carcinoma (BCC) is the most common type of
two types of chemicals used in targeted therapy.3 The name malignant eyelid tumor. It is locally aggressive, with a lower
of a monoclonal antibody agent ends in -mab, whereas that of predilection to metastasize, and the majority of cases are
small molecule inhibitors ends in -ib.2 Monoclonal antibodies amenable to wide local excision with tumor-free margins.
are developed against specific cell surface antigens and can Advanced inoperable periocular tumors, on the other hand,
either block or bind to the cell surface receptor. Blocking the would result in significantly higher morbidity with surgery.6
receptor will disable the signaling pathway that would have Our recent understanding of the role of abnormalites
occurred as a result of natural ligand binding to the receptor. in Hedgehog signaling pathway in the pathogenesis of
Attachment to the cell surface receptor triggers an antigen- BCC and chemotherapeutic resistance has resulted in the
antibody immune response, which leads to cell death. development of targeted therapy.7 The Hedgehog pathway
includes the PTCH1 receptor gene, a tumour suppressor
The name of the monoclonal antibody describes its origin and gene that has been found to be inhibited in 90% of BCC
its specific target molecule. The antecedent mu (-mumab) cases.4 This deactivating mutation causes overactivation
indicates fully human antibody, zu (-zumab) humanized of the Hedgehog signaling via SMO receptor, resulting
mouse antibody, xi (-ximab) indicates chimeric or mixed in cell proliferation and tumorigenesis.8,9 Vismodegib
human-animal antibody. The target is indicated by adding and sonidegib are anti-SMO therapies that inhibit the
-ci(r) for circulatory system, -li(m) for immune system, -t(u) downstream activation of Hedgehog signaling pathway.4
for tumor. For instance, Bevacizumab, an anti-VEGF-A, is Targeting the Hedgehog pathway could aid in the avoidance

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DJO Vol. 32, No. 3, January-March 2022

of invasive, cosmetically disfiguring procedures as well as therapy in SGC of eyelid has not yet been reported, but a
the treatment of inoperable tumors and multifocal BCC like recent study has reported the upregulation of Hedgehog
Gorlin syndrome. pathway.22 Anti-SMO molecules as in BCC can come into
play as targeted therapy. Studies have also reported the
Squamous cell carcinoma (SCC) accounts for 5-10% of involvement of the HER2 and Pi3K signalling pathways in
malignant eyelid tumors.10 Most cases are managed by wide SGC and are potential targets for further clinical studies.23,24
local excision with or without adjuvant radiation therapy.
Studies have reported overexpression of EGFR (epithelial Biologics In Oculoplasty- Orbital Inflammatory
growth factor receptor) receptor in both cutaneous and Conditions
conjunctival SCC.11 Erlotinib, a tyrosine kinase inhibitor, is
an EGFR inhibitor recently developed for treatment of SCC Commonly encountered orbital inflammatory conditions
and has been reported to show efficacy in advanced SCC include thyroid eye disease (TED), dacryoadenitis,
and candidates ineligible for surgery.12 It has been proved myositis, cellulitis. They present with a variety of clinical
as a reasonable option for palliative treatment of orbital and manifestations, the most common of which are periorbital
cutaneous SCC and significantly improved the quality of swelling and pain. The standard treatment regimen includes
life.13 systemic corticosteroids, as well as immunosuppressants
such as alkylating agents, antimetabolites, cytotoxic drugs,
The advancement of targeted therapies has resulted in a calcineurin inhibitors, lymphocyte inhibitors, and tumor
significant improvement in the prognosis of melanomas. necrosis factor-α inhibitors. However, suboptimal response
Conjunctival melanomas share characteristics with and toxicity with prolonged use of immunosuppressants has
cutaneous melanomas, such as clinical features, lymphatic prompted the development of alternate treatment options
metastasis, and a high load of genetic mutations. Surgical targeting the abnormal biochemical pathways.
excision is followed by a high recurrence rate of 30 to
60%, resulting in lethal metastasis.14 BRAF, KRAS, NRAF, Thyroid eye disease is one of the most common causes of
and NF1 mutations are frequently found in conjunctival orbital inflammation, and several monoclonal antibodies
and cutaneous melanomas.15,16,17 Targeted therapy with have been developed to treat it. Rituximab (RTX), a well-
anti-BRAF and anti-MEK biologics has shown promising known lymphoma treatment, is an anti-CD20 monoclonal
results in patients with locally advanced and metastatic antibody that targets CD20 on B-cells, the cells that produce
melanomas.18,19 In fact, determining BRAF mutation status antibodies. It works in TED by decreasing TSH-receptor
is a standard part of the treatment protocol for conjunctival antibodies, which reduces inflammation and TED activity.
and cutaneous melanomas.20 In metastatic melanomas Its role in compressive optic neuropathy is debatable due
that are not amenable to surgery, targeted therapy with to the possibility of edema and orbit volume expansion
checkpoint inhibitors such as pembrolizumab or nivolumab caused by massive B-cell lysis.25 TNF-α inhibitors, which
has been found to be beneficial. Checkpoint inhibitors are were originally used to treat cancer, are now being used
currently approved against the molecules CTLA4, PD-1, and as pleiotropic cytokines in immune and inflammatory
PDL-1, and they work by blocking the interaction of their responses by regulating apoptosis and cell survival.26 They
target with T-cells, allowing the T-cells to attack the tumor work by inducing cellular toxicity in TNF-α overexpressing
immunologically.17 cells via antibody-dependent and complement-dependent
mechanisms.27 These drugs, which include infliximab,
Uveal melanoma is the most common primary intraocular adalimumab, etanercept, golimumab, and certolizumab,
tumor in adults, accounting for about 5% of all malignant have been shown to be effective in reducing soft tissue signs
melanomas.21 Standard treatment options include surgical and compressive optic neuropathy.
resection, radiation therapy and enucleation. Uveal
melanomas differ significantly from cutaneous and Tocilizumab is an interleukin-6 (IL-6) receptor antagonist that
conjunctival melanomas in terms of clinical features and has recently been discovered to be an effective biologic in the
course, risk factors, metastasis pattern, genetic mutations, treatment of orbital inflammatory disorders. IL-6 is a pro-
and response to chemotherapy, and thus treatment options inflammatory cytokine that activates T-cells and promotes
for cutaneous melanomas cannot be extrapolated to those immunoglobulin production, and it is found in high
for uveal melanomas. In comparison to cutaneous and concentrations in thyroid eye disease.28 Tocilizumab works
conjunctival melanomas, uveal melanomas have a lower by blocking IL-6 receptors and has been shown to improve
number of genetic mutations and a worse prognosis, with life clinical activity scores in refractory cases. Teprotumumab
expectancy significantly reduced in the event of metastasis.17 is the most promising drug for thyroid eye disease, and it
There is currently no approved targeted therapy for uveal has been recently approved by the FDA. It is an antibody
melanomas, but clinical trials with the tyrosine kinase that binds to IGF-1 (insulin-like growth factor-1) receptors
inhibitor sunitinib (c-KIT, CD117) and anti-receptor tyrosine and prevents thyroid stimulating hormone from activating
kinase crizotinib (crizotinib) are ongoing (ROS-1, ALK).17 proinflammatory cytokines.2 It is the only medication that
Sebaceous gland carcinoma (SGC) of eyelid is a rare has been shown to improve clinical activity and proptosis
periocular malignancy, managed by surgical wide local while also providing a consistent response.29 Its main
excision with tumor free margins. The use of targeted advantage over other biologics is a significant improvement
in proptosis. Though there is insufficient data on clinical

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DJO Vol. 32, No. 3, January-March 2022

trials of biologics in thyroid eye disease, these drugs appear study in France over the 2006–2017 period. Ophthalmic
to be a promising tool for improving the quality of life in Epidemiol 2020;28,1–6.
these patients. 6. Yin VT, Pfeiffer ML, Esmaeli B. Targeted therapy for orbital and
periocular basal cell carcinoma and squamous cell carcinoma.
Rituximab is being used successfully as an adjunct to steroids Ophthal Plast Reconstr Surg 2013;29(2):87-92.
and radiation therapy as well as a steroid-sparing agent in 7. Gailani MR, Stahle-Backdahl M, Leffell DJ, et al. The role of the
other orbital inflammations such as IgG4 disease, idiopathic human homologue of Drosophila patched in sporadic basal cell
orbital inflammation, granulomatosis polyangiitis, and carcinomas. Nat Genet 1996;14:78–81.
mucous membrane pemphigoid. TNF-α inhibitors, 8. Ozgur OK, Yin V, Chou E, Ball S, Kies M, William WN, et al.
particularly infliximab, are being reserved for recalcitrant Hedgehog pathway inhibition for locally advanced periocular
and recurrent cases of idiopathic orbital inflammation, as basal cell carcinoma and basal cell nevus syndrome. American
well as IgG4 disease.30-32 Journal of Ophthalmology 2015;4:40.
9. Macha MA, Batra SK, Ganti AK. Profile of vismodegib and its
Commonly Encountered Side Effects With Biologics potential in the treatment of advanced basal cell carcinoma.
Cancer Management and Research 2013;5:197–203.
A number of side effects have been reported with the use 10. Wang JK, Liao SL, Jou JR, Lai PC, Kao SCS, Hou PK, et al.
of biologics in the orbit, eyelid and lacrimal system. When Malignant eyelid tumours in taiwan. Eye 2003;17:216-20.
used for metastatic melanomas, BRAF inhibitors such as 11. Allen, RC. Molecularly targeted agents in oculoplastic surgery.
vemurafenib and sorafenib have been linked to cutaneous Curr Opin Ophthalmol 2017;28:485-92.
squamous cell carcinomas and keratoacanthomas.33 The 12. Yin VT, Pfeiffer ML, Esmaeli B. Targeted therapy for orbital and
EGFR receptor is involved in the normal development and periocular basal cell carcinoma and squamous cell carcinoma.
differentiation of hair follicles, and its inhibition can result Ophthalmic Plast Reconstr Surg 2013;29(2):87-92.
in abnormal hair growth. EGFR inhibitors, which are used 13. El-Sawy T, Sabichi A L, Myers JN, Kies MS, William WN, Glisson
to treat squamous cell carcinomas, can cause blepharitis, BS, Esmaeli B. Epidermal Growth Factor Receptor Inhibitors for
Meibomian gland dysfunction, dry eye, hypertrichosis and Treatment of Orbital Squamous Cell Carcinoma. Archives of
poliosis.34 Imatinib, a tyrosine kinase inhibitor has been Ophthalmology 2012;130(12):1608.
reported to cause periorbital edema, chemosis, blockage of 14. Shields CL, Shields JA, Gunduz K, et al. Conjunctival melanoma:
lacrimal drainage.35 EGFR and VEGF inhibitors have been risk factors for recurrence, exenteration, metastasis, and death in
shown to slow wound healing, and ibrutinib has been shown 150 consecutive patients. Arch Ophthalmol 2000;118:1497-507.
to interfere with coagulation.2 Checkpoint inhibitors can 15. Scholz SL, Cosgarea I, Süßkind D, Murali R, Möller I, Reis H,
increase post-operative inflammation and are more likely et al. NF1 Mutations in Conjunctival melanoma. Br J Cancer
to cause post-operative infection.2 Thus, prior to planning 2018;118:1243-7.
surgery for patients who are already receiving targeted 16. Weber JL, Smalley KS, Sondak VK, Gibney GT. Conjunctival
therapy, a thorough discussion with the oncologist should Melanomas Harbor BRAF and NRAS Mutations-Letter. Clin
be held. Cancer Res 2013;15;19(22):6329-30.
17. Jonas RA, Rokohl AC, Heindl LM. Targeted therapy for
Conclusion malignant ocular melanomas. Ann Eye Sci 2021;6:7.
18. Kim JM, Weiss S, Sinard JH, Pointdujour-Lim, R. Dabrafenib
The use of biologics has resulted in a paradigm shift in and trametinib for BRAF-mutated conjunctival melanoma. Ocul
the treatment of orbital, lacrimal, and eyelid oncology and Oncol Pathol 2020;6:35–8.
immunology. The widespread use and innovation of these 19. Dagi Glass LR, Lawrence DP, Jakobiec FA, Freitag SK.
agents emphasises the importance of understanding the Conjunctival melanoma responsive to combined systemic BRAF/
molecular basis of etiopathogenesis of the disorders in order MEK inhibitors. Ophthalmic Plast Reconstr Surg 2017;33:114–6.
to develop targeted rational therapeutic approaches. There 20. Zeng Y, Hu C, Shu L, Pan Y, Zhao L, Pu X, et al. Clinical treatment
is still a lack of data on prospective, randomised studies on options for early-stage and advanced conjunctival melanoma.
targeted agents, which should be the next goal in the near Surv Ophthalmol 2020;66:461–70.
future. This can aid in understanding the validity of their 21. Triozzi PL, Eng C, Singh AD. Targeted therapy for uveal
long-term efficacy, outcomes and adverse effects. melanoma. Cancer Treat Rev 2008;34:247-58.
  22. Bladen JC, Moosajee M, Tracey-White D, Beaconsfield M,
O’Toole EA, Philpott MP. Analysis of hedgehog signaling
References in periocular sebaceous carcinoma. Graefes Arch Clin Exp
Ophthalmol 2018;256:853–60.
1. Pasadhika S, Suhler EB. Biologic therapies for ocular 23. Kwon MJ, Shin HS, Nam ES, Cho SJ, Lee MJ, Lee S, et al.
inflammatory diseases. Current Insight AAO. 2008; May 21. Comparison of HER2 gene amplification and KRAS alteration
in eyelid sebaceous carcinomas with that in other eyelid tumors.
2. Allen RC. Molecularly targeted agents in oculoplastic surgery. Pathol Res Pr 2015;211:349–55.
Curr Opin Ophthalmol 2017;28:000–000. 24. Tetzlaff MT, Singh RR, Seviour EG, Curry JL, Hudgens CW, Bell
D, et al. Next-generation sequencing identifies high frequency of
3. Gerber DE. Targeted therapies: a new generation of cancer mutations in potentially clinically actionable genes in sebaceous
treatments. Am Fam Physician 2008;77:311–9. carcinoma. J Pathol 2016;240:84–95.
25. Stan MN, Garrity JA, Carranza Leon BG, et al. Randomized
4. Martel A, Lassalle S, Picard-Gauci A, Gastaud L, Montaudie H, controlled trial of rituximab in patients with Graves’ orbitopathy.
Bertolotto C et al. New Targeted Therapies and Immunotherapies J Clin Endocrinol Metab 2015;100:2:432-41.
for Locally Advanced Periocular Malignant Tumours: Towards a 26. Ahmad S, Azid NA, Boer JC, et al. The Key Role of TNF-TNFR2
New ‘Eye-Sparing’ Paradigm? Cancers 2021;13:2822. Interactions in the Modulation of Allergic Inflammation: A
Review. Front Immunol. 2018;9:2572.
5. Martel A, Nahon-Esteve S, Gastaud L, Bertolotto C, Lassalle S, 27. Ping L, Ying Z, Xin C. Drugs for Autoimmune Inflammatory
Baillif S, et al. Incidence of orbital exenteration: A nationwide Diseases: From Small Molecule Compounds to Anti-TNF
Biologics. Frontiers in Pharmacology 2017;8:460.
28. Slowik M, Urbaniak-Kujda D, Bohdanowicz-Pawlak A, et

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DJO Vol. 32, No. 3, January-March 2022

al. CD8þCD28-lymphocytes in peripheral blood and serum Cite This Article as: Priyanka Golhait. Biologics In
concentrations of soluble interleukin 6 receptor are increased Oculoplasty. Delhi Journal of Ophthalmology.2022; Vol 32, No
in patients with Graves’ orbitopathy and correlate with disease (3): 100- 103.
activity. Endocr Res 2012;37:89-95. Acknowledgments: Nil
29. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid- Conflict of interest: None declared
associated ophthalmopathy. N Engl J Med 2017;376:18:1748-61. Source of Funding: None
30. Garrity JA, Coleman AW, Matteson EL, et al. Treatment of Date of Submission: 10 Mar 2022
recalcitrant idiopathic orbital inflammation (chronic orbital Date of Acceptance: 05 April 2022
myositis) with infliximab. Am J Ophthalmol 2004;138:925-30.
31. Wilson MW, Shergy WJ, Haik BG. Infliximab in the treatment Address for correspondence
of recalcitrant idiopathic orbital inflammation. Ophthal Plast Priyanka Golhait, MBBS, MS, DNB
Reconstr Surg 2004;20:381–3.
32. Karim F, Paridaens D, Westenberg LE, et al. Infliximab for Department of Ophthalmology,
IgG4-related orbital disease. Ophthal Plast Reconstr Surg 2017; Guru Nanak Eye Centre,
33:162–5. New Delhi, India
33. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous Email : [email protected]
squamous-cell carcinomas in patients treated with BRAF
inhibitors. N Engl J Med 2012; 366:207–15.
34. Saint-Jean A, Sainz de la Maza M, Morral M, et al. Ocular adverse
events of systemic inhibitors of the epidermal growth factor
receptor: report of 5 cases. Ophthalmology 2012; 119:1798–802.
35. Esmaeli B, Prieto VG, Butler CE, et al. Severe periorbital edema
secondary to STI571 (Gleevec). Cancer 2002;95:881–7.

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Delhi Journal of Ophthalmology

DJO Vol. 32, No. 3, January-March 2022

Theme Article

An Overview of Topical Immunomodulators used in
Ophthalmology

Abstract Pranita Sahay1, Devesh Kumawat2

1Department of Ophthalmology, Centre for Sight Eye Hospital, New Delhi, India.
2Department of Ophthalmology, Lady Hardinge Medical College, New Delhi, India.

Immunomodulators (IMT) are a novel class of drug that suppress the host immune response and inhibit the inflammatory
cascade. They have several advantage over steroids when used for clinical conditions requiring long-term inflammation
control. In the field of ophthalmology, IMT have been put to use for various indications like uveitis, dry eye disease, allergic
eye disease, ocular surface tumours and other ocular surface disorders. It is also used intra-operatively in glaucoma
surgeries, pterygium excision and photo-refractive keratectomy to increase the surgical success. The topical use of these
drugs is relatively safe when compared to systemic use; hence, majority of the above conditions are treated with topical
IMT. Cyclosporine A, Tacrolimus, Mitomycin C, 5-Fluorouracil and Interferon-alpha are some of the commonly used
topical IMT in ophthalmic practice. Topical Lifitegrast is a recently approved drug with immunomodulatory mechanism
of action that is used in management of refractory dry eye disease. In this review, we aim to provide the readers an
overview of the pharmacology, clinical uses and adverse effects of these commonly used topical IMT.

Delhi J Ophthalmol 2022; 32; 104-110; Doi http://dx.doi.org/10.7869/djo.758

Keywords: Immunomodulator; Topical Immunomodulators; Topical Immunosuppressants; Topical Tacrolimus; Topical Cyclosporine; Topical Lifitegrast;
Topical 5-Fluorouracil; Topical Mitomycin C.

Introduction Anti-metabolite (5-Fluorouracil) and Biologic response
modifiers (Interferon-α2b, Lifitegrast, Anakinra, Isunakinra).
Immunomodulator drugs have been in use ever since 1959. (Refer Table 1)
(1) In the past six decades, various immunomodulator
drugs with different mechanism of action (MOA) have been Calcineurin inhibitors
described. These drugs were initially described for systemic
use predominantly to reduce the risk of graft rejection; 3.1. Cyclosporine A
however, with time their indications for use has increased Cycosporine A (CsA) was discovered in 1970 and was initially
by leaps and bounds.1 used for management of graft rejection following organ
transplant.(11) Its ophthalmic use in the form of topical CsA
Ocular surface disease (Dry eye disease (DED), allergic 0.05% emulsion (Restasis; Allergan, Inc., Irvine, CA) and
conjunctivitis, cicatrizing conjunctivitis), scleritis and non- CsA 0.09% (Cequa, Sun Pharma, Cranbury, NJ, USA) is US-
infectious uveitis are few of the common clinical conditions FDA approved for management of Dry eye disease (DED).
in ophthalmology that run a chronic inflammatory course.2–6 (12) CsA is produced by fungi Tolypocladium inflatum and
In the past, steroids were the only available drug to control Beauveria nevus.11
the acute inflammatory cascade in these conditions.
However, their prolonged/recurrent use was fraught with 3.1.1. Mechanism of action
risk of blinding complications like steroid induced cataract, CsA acts by inhibiting the T- cell activation.11,13 It binds with
glaucoma and increased risk of ocular infections.7–9 The cytoplasmic protein cyclophilin A that inhibits the activity
introduction of immunomodulator drugs in the field of of calcineurin. This in turn blocks the de-phosphorylation of
ophthalmology led to a paradigm shift in the management nuclear factor for T-cell activation (NF-AT) in the cytoplasm
of non-infectious inflammatory conditions.2,10 They are now which prevents its transport to the nucleus. This inhibits
used as a steroid sparing agent to achieve sustained control increased transcription of IL-2 gene and other genes involved
of inflammation which is core to the management of these in activation of T-cells. 11,13
clinical conditions. The use of both topical and systemic
formulations of immunomodulator drugs have been In addition, CsA binds with the cytoplasmic protein
described for these conditions. cyclophilin D and inhibits apoptosis or programmed cell
death.11,13 The CsA-cyclophilin D complex binds with the
In this review, we aim to provide a comprehensive mitochondrial permeability pore and inhibits its opening.
overview of the topical immunomodulator drugs used This in turn reduces the release of mitochondrial enzymes
in the field of ophthalmology. (Table 1) The mechanism that are responsible for apoptosis.
of action, pharmacokinetics, pharmacodynamics, clinical
outcome and adverse effect of the commonly used topical 3.1.2. Pharmacokinetics & Pharmacodynamics
immunomodulator drugs will be discussed in addition to Topical CsA is available in solution, emulsion, suspension
their indications for use. and gel formulations.11,13 The large molecular weight and
hydrophobic nature of CsA are responsible for the poor
Classification ocular penetration. Hence, oil in water emulsions (Restasis)
and micelle based solutions are used to increase its
Based on mechanism of action, the topical immunomodulator bioavailability. Use of oil vehicles results in burning, itching,
drugs can be classified into Inhibitors of T-cell Signalling redness and epithelial keratitis. Glycerine, polysorbate 80
(Calcineurin inhibitor), Alkylating agent (Mitomycin C),

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DJO Vol. 32, No. 3, January-March 2022

Table 1: An Overview Of Topical Immunomodulator Drugs Use In Ophthalmic Practice

S.No. Group Drug Mechanism of action Dose Major Indications Adverse Effect

1 Inhibitors Cyclosporine A Calcineurin 0.05%-2% BD •DED • Burning of eyes
•VKC & AKC (Most common)
of T-cell inhibitor •Phlyctenular Keratoconjunctivitis
•Acute posterior blepharitis, • Stinging
Signalling •Cicatrizing conjunctivitis, • Discharge
•Others- Sjogren syndrome, Graft • FB sensation
• Hyperaemia
rejection, Ocular rosacea, GVHD,
Sterile CU, Thygeson’s superficial
punctuate keratitis, Ligneous
conjunctivitis, SLKC, HSV stromal
keratitis, and Neurotrophic CU

Tacrolimus/ Calcineurin 0.005% to • VKC, AKC • Transient ocular
FK-506 inhibitor 0.1% BD • Others - Refractory uveitis, irritation
(0.03% is
commonly Scleritis, GVHD associated DED • corneal infection
used) or Cicatrizing conjunctivitis, (rare)
SLKC, Sub-epithelial infiltrates in
adenoviral keratoconjunctivitis

2 Alkylating Mitomycin C Inhibits DNA 0.02% - 0.04% • Pterygium surgery • Scleral melt

agent synthesis during QID 1 week • Glaucoma surgeries • Thin walled blebs

late G1 & S phase of on 2-3 week (trabeculectomy and glaucoma • Bleb leak

cell cycle by off OR drainage device) • Mild

• free radical 2 week on 2 • Refractive surgery -PRK keratoconjunctivitis

release, week off • DCR

• DNA alkylation, • OSSN

• cross-links

between

complimentary

DNA strands

3 Anti- 5-Fluorouracil Pyrimidine 2.5% - 5% • Glaucoma surgeries • Punctate

metabolite analogue that (5% is (trabeculectomy, glaucoma keratopathy

inhibits DNA commonly drainage device) • Keratoconjunctivitis

synthesis by used) • Post Trabeculectomy • Filamentary

inhibits thymidylate subconjunctival injections along keratopathy

synthetase enzyme with needling in failing bleb • Whorl like

(cell-cycle specific) • OSSN keratopathy

• Pterygium surgery • Thin walled bleb

• Bleb leak

4 B i o l o g i c Interferon-α2b • Enhances the 1 million IU/ • Ocular surface tumours- OSSN, • Moderate follicular

response phagocytic and ml QID conjunctival papilloma, primary conjunctivitis,

modifiers cytotoxic activity (stored in acquired melanosis with atypia, • Superficial punctate

• Inhibits refrigerator at conjunctival melanoma, Mucosa- keratopathy

biosynthetic 2-8 οC) associated lymphoid tissue • Corneal epithelial

enzymes lymphoma microcyst formation

• Decreases • Recalcitrant VKC • Reactive lymphoid

blood vessel • Acyclovir resistant HSV keratitis hyperplasia

proliferation • Others - Limbal stem cell deficiency,

• Induces Mooren’s ulcer, prevention

apoptosis post-PRK corneal haze, DME,

• Inactivates viral Pseudophakic CME, Uveitic ME

RNA

Lifitegrast Lymphocyte 5% BD Refractory DED Eye irritation (Most
common)
function associated Dysgeusia
Reduced visual acuity
antigen-1 antagonist

Anakinra Interleukin 1 2.5% TDS Refractory DED

receptor antagonist

Isunakinra Blocks IL-1 receptor 5 mg/ml and Moderate and severe DED
1 (IL-1β and IL-1Ra) 20 mg/ml TDS

Footnotes
DED- Dry eye disease; VKC- Vernal Kerato-conjunctivitis; AKC – Atopic Kerato-conjunctivitis; GVHD- Graft versus host disease; CU- Corneal Ulcer;
SLKC- Superior limbic keratoconjunctivitis; HSV- Herpes simplex virus; PRK- Photo-refractive keratectomy; DNA- Deoxyribonucleic acid; DCR-
Dacryocystorhinostomy; OSSN- Ocular surface squamous neoplasia; RNA;- Ribonucleic acid; DME- Diabetic macular oedema; CME- Cystoid macular
oedema; ME- Macular oedema.

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DJO Vol. 32, No. 3, January-March 2022

and sodium hydroxide can be added to these emulsions to and inhibits the calcineurin activity.10,20 This inhibits the
improve patient comfort. Restasis (0.05%) is a preservative dephosphorylation of NF-AT which in turn decreases the
free anionic oil in water nano-emulsion that contains CsA release of inflammatory cytokines and stimulation of other
dissolved in castor oil with polysorbate 80 as emulsifying inflammatory cells.
agent and Carbomer as stabilizing agent.11,13 Topical CsA
is available in varying concentrations – 0.05%, 0.1%, 0.5%, 3.2.2. Pharmacokinetics & Pharmacodynamics
1% and 2%. The higher concentration formulations are not Topical tacrolimus is available in solution, emulsion, cream
commonly available in market and are often produced in and gel formulation.20 It has a high molecular weight and
hospital compounding pharmacies. The usual dosing is is hydrophobic in nature. Hence, it has a poor corneal
twice daily; however, even QID dosing has been reported penetration, limiting the use of topical tacrolimus for
in few cases.14 management of ocular surface inflammatory conditions. A
nanoscale based drug delivery system such as nanoparticle
Animal studies suggest that topical application of CsA have been reported to increase the drug penetration. Topical
achieves sufficient concentration for immunomodulation on preparation with concentrations varying from 0.005% to
the conjunctiva and cornea but very low levels (<1ng/ml) in 0.1% is in clinical use. Majority of clinical research is based
aqueous, vitreous and plasma. on suspension/ointment formulation of tacrolimus with
concentration of 0.03% and 0.1% formulation of this drug,
3.1.3. Indication of use suggesting that even low dose topical tacrolimus has good
The common ophthalmic uses of topical CsA include DED, immunosuppressive effect.20
vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis
(AKC), phlyctenular keratoconjunctivitis (PKC), acute, 3.2.3. Indication of use
posterior blepharitis, and cicatrizing conjunctivitis.11–13,15 Its Allergic eye diseases (VKC, AKC) are the most common
use has also been reported in Sjogren syndrome, corneal clinical condition for which topical Tacrolimus has been
graft rejection, ocular rosacea, conjunctival graft versus host used.10,21 Other indications include refractory uveitis, scleritis,
disease (GVHD) sterile corneal ulcer, Thygeson’s superficial GVHD associated dry eye or cicatrizing conjunctivitis, SLKC,
punctuate keratitis, ligneous conjunctivitis, superior limbic sub-epithelial infiltrates in adenoviral keratoconjunctivitis
keratoconjunctivitis (SLKC), herpes simplex stromal and post-keratoplasty to reduce risk of graft rejection.20
keratitis, and neurotrophic ulcer with variable success.11,13
Topical tacrolimus (0.1% and 0.03%) has been reported to
Literature review suggests that topical CsA is effective be effective in management of both severe and refractory
in management of DED and also improves the goblet cell allergic conjunctivitis not responding to steroids and CsA.22
density.12,16 However, few studies have shown variable It has shown to improve both the patients’ symptoms as
results suggesting need for well planned, longer follow-up well as clinical signs. The ability of tacrolimus to decrease
studies to evaluate its role in DED. giant papillae gives it an edge over CsA when dealing with
such cases.23 Few studies suggest that topical tacrolimus is
Role of topical CsA in management of VKC is well established. more effective and more tolerable when compared to topical
It is especially useful in management of moderate to severe CsA.24,25
cases of VKC as well as shield ulcers.17 A recent metanalysis
study on efficacy of medical treatment for VKC showed 3.2.4. Adverse effect
similar results for CsA and tacrolimus.18 Favourable results Topical tacrolimus is usually a well-tolerated drug and
have also been reported with combined use of topical CsA has a good safety profile.24 Transient ocular irritation upon
and tacrolimus in management of severe steroid intolerant instillation of the drug and burning sensation are the common
VKC.19 adverse effects noted.20 However, they do not necessitate
discontinuation of this drug. Risk of corneal infection with
3.1.4. Adverse effect prolonged use of topical preparation of tacrolimus is rare but
Burning of eyes is the most common adverse effect with has been reported in literature.21 There is a theoretical risk of
topical CsA followed by, stinging, discharge, foreign body T-cell lymphoma with use of topical calcineurin inhibitors
sensation and hyperaemia.11,12 and hence a “black box” warning has been issued by USFDA
against this drug.26
3.2. Tacrolimus
Tacrolimus, also known as FK506, is a macrolide antibiotic Anti-metabolite agents
that has immunosuppressant effect. It is produced by
fermentation of the bacteria Streptomyces tsukubaensis. 4.1. Mitomycin C
Tacrolimus has been in use for management of organ Mitomycin C (MMC) is an antibiotic isolated from the
transplant rejection for over three decades. Its dermatological bacteria Streptomyces caespitosus.27 It was primarily used
preparation is USFDA approved for management of atopic as a chemo-therapeutic agent. It is used In the field of
dermatitis; however, its ophthalmic use is still off-label. ophthalmology, it was first used in 1963 for management of
pterygium cases.27 Ever since, the wound healing modulation
3.2.1. Mechanism of action properties of MMC has been put to use in various other
Tacrolimus acts by inhibiting the T-cell activation. It clinical conditions in ophthalmology.
binds with the FK-506 binding protein within the T cells

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DJO Vol. 32, No. 3, January-March 2022

4.1.1. Mechanism of action These complications can be avoided by using appropriate
MMC is an alkylating agent and works primarily by concentration of MMC for appropriate duration. Sponges
inhibiting DNA synthesis during the late G1 and S phase soaked in MMC should be used for local application during
of cell cycle.27 However, MMC is not cell cycle specific. It surgery to avoid contact with the surrounding surfaces.
inhibits DNA synthesis by various mechanisms like free Also, the ocular surface should thoroughly irrigated after its
radical release, DNA alkylation and, cross-links between the use to avoid toxicity.
complimentary DNA strands. It also inhibits the RNA and
protein synthesis.27,28 It acts on both proliferating and non- 4.2. 5-Fluorouracil
proliferating cells by inducing apoptosis. It also inhibits the 5-Fluorouracil (5-FU) is a pyrimidine analogue that acts as an
migration of fibroblasts.27,28 anti-metabolite agent and was primarily used in treatment
of gastro-intestinal, head and neck, and breast cancers.34 It
4.1.2. Pharmacokinetics & Pharmacodynamics also has anti-scarring properties that has been put to use in
MMC is available as a lyophilised powder for intravenous the field of ophthalmology for various clinical conditions.
preparation and liquid form (Jelmyto) for pyelocaliceal
use in urothelial cancer. Its ophthalmic use is off-label. 4.2.1. Mechanism of action
MMC is soluble in water; hence topical MMC is prepared 5-FU has various cytotoxic effects. It inhibits DNA synthesis
by reconstituting the drug with distilled sterile water or by releasing an active metabolite, 5-fluorodeoxyuridine
balanced salt solution (BSS) in the concentration of 0.02% - 5′ monophosphate (FdUMP), that inhibits thymidylate
0.04%.27,28 synthetase enzyme which is responsible for incorporation
of thymidine in DNA.34 This action in cell-cycle specific,
4.1.3. Indication of use affecting only those cells in the S-phase of cell-cycle. 5-FU
Topical MMC acts by modifying the wound healing process also inhibits the RNA synthesis and promotes apoptosis of
and reducing the risk of scarring. Hence it is used in pterygium tenon’s capsule fibroblast.34 However, unlike MMC, it does
surgery to reduce risk of recurrence after pterygium excision not affect the vascular endothelial cells.
surgery.27 In glaucoma surgeries (trabeculectomy and
glaucoma drainage device), it is used to reduce the risk of 4.2.2. Pharmacokinetics & Pharmacodynamics
sub-conjunctival scarring and subsequent risk of failure of 5-FU is commercially available as a solution (50 mg/ml) for
surgery.29 It is used in refractive surgery, primarily in surface parenteral use in cancer patients and cream (5%) for topical
ablation procedures to reduce the risk of post-operative application in skin malignancies. Ophthalmic use of 5-FU
corneal haze especially when treating high refractive is off-label. The parenteral formulation is used for topical
errors.28 It is also put to use in dacryocystorhinostomy application in a concentration of 2.5% or 5%. Studies have
(DCR) surgeries at the osteotomy site to reduce the risk shown that the minimum concentration of 5-FU required
of fibrosis/granulation tissue formation that is often the to induce 50% inhibition of conjunctival fibroblasts is 0.2
cause for failure of DCR.30 MMC has been reported as an microgram/ml and topical application itself is sufficient to
effective treatment for ocular surface squamous neoplasia achieve this concentration in the conjunctiva, cornea and
(OSSN) as a primary therapy, adjuvant to surgical excision aqueous humour. Subconjunctival injection of 5-FU has also
and post-operatively (in cases with positive conjunctival/ been described.35
deeper margins).31 The dosing for primary /post-operative
treatment is 4 times a day for 1 week followed by 2–3 weeks 4.2.3. Indication of use
off until the eye is quiet. Alternatively 7 or 14 days cycle can Similar to MMC, 5-FU is used intra-operatively in glaucoma
also be used. A total of 3–4 cycles are required for treatment. surgeries (trabeculectomy and glaucoma drainage device)
Other than its established role as an adjuvant to surgery for to increase the surgical success.(36) Its post-operative use
cases of primary acquired melanosis with atypia, it has also as subconjunctival injections along with needling have also
been tried as a primary treatment for the same.27 Rarely, its been described for managing failing blebs. Various studies
use has been reported in VKC, strabismus surgery, orbital have compared the outcome of intra-operative MMC and
implant surgery, optic nerve sheath fenestration, posterior 5-FU in trabeculectomy. A systematic review of literature of
capsular opacification and proliferative vitreoretinopathy the same suggests low-quality of evidence for MMC being
(PVR).27,32 better than 5-FU.36

4.1.4. Adverse effect 5-FU is effective is management of OSSN both as a primary
MMC has a prolonged cytotoxic effect on fibroblast and therapy as well as an adjuvant to surgical excision. 1%
vascular endothelial cells. Although, it is important for solution of 5-FU is used for topical application 4 times a
surgical success, however can result in sight-threatening day in a cyclical pattern for a week followed by 3 weeks
complication if not used judiciously. In glaucoma drainage off.37 A total of 4 to 6 cycles may be needed based on the
surgeries, it can result in thin walled blebs that can leak observed clinical response. Intra-operative use of 5-FU in
and put the eye at risk of hypotony, shallow anterior pterygium surgery has been described with limited success
chamber, hypotonic maculopathy, choroidal effusion, and as recurrences were observed in 25% cases.34 Isolated reports
endophthalmitis.27,33 It pterygium surgery, the underlying of its use in PVR and DCR exists in literature.34
sclera can develop scleral melt.27,33 MMC is toxic to the
corneal surface and can result in mild keratoconjunctivitis.27,33 4.2.4. Adverse effect
5-FU, being cell cycle specific agent, predominantly affects

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DJO Vol. 32, No. 3, January-March 2022

the replicating cells. Hence, the corneal epithelium is most 5.1.4. Adverse effect
affected with its use resulting in adverse effects like punctate Topical IFN have minimal adverse effects. It can cause
keratopathy, keratoconjunctivitis, filamentary keratopathy moderate follicular conjunctivitis,
and whorl like keratopathy.34 Its use in glaucoma surgery is superficial punctate keratopathy, and corneal epithelial
associated with risk of thin walled bleb, bleb leak, hypotony, microcyst formation.39,40 Reactive lymphoid hyperplasia
shallow anterior chamber, hypotonic maculopathy, has also been reported with its use which masqueraded as
choroidal effusion and endophthalmitis.34 Few studies have orbital extension in OSSN. Subconjunctival injections are
reported that the risk of these complications are less with associated with flu-like symptoms.37
5-FU when compared to MMC.38
5.2. Lifitegrast
Biologic response modifier Topical Lifitegrast is the second drug after topical
cyclosporine to be US-FDA approved (2016) for management
5.1. Interferon-α2b of DED.43 The OPUS trial which was a double blinded
Interferon (IFN) is a glycoprotein that has anti-neoplastic, randomized controlled trial (RCT) comparing lifitegrast 5%
antiviral and immunomodulatory activity It is of three types with placebo in DED led to its FDA approval.43,44 Lifitegrast
– Type 1 (IFNα, IFNβ), Type 2 (IFNγ) and Type 3. Among is available as 0.2 ml single use dropper which is sufficient
the different types of IFN, IFN-α 2a and 2b has been found to for both eyes.
be of clinical use in various ophthalmic conditions.
5.2.1. Mechanism of action
5.1.1. Mechanism of action Lifitegrast is a Lymphocyte function associated antigen-1
IFN works by enhancing the phagocytic and cytotoxic antagonist (LFA-1).43,45 LFA-1 is an integrin present on
activity, inhibiting the biosynthetic enzymes, decreasing the surface of T and B lymphocyte. Binding of lifitegrast
blood vessel proliferation, inducing apoptosis and to LFA-1 prevents interaction of lymphocyte with inter-
inactivating viral RNA.39 All of the above are responsible for cellular adhesion molecule 1 (ICAM-1). This in turn inhibits
its immunomodulatory and anti-neoplastic effect. the adhesion, activation, migration and proliferation of
inflammatory cells and release of cytokine that is responsible
5.1.2. Pharmacokinetics & Pharmacodynamics for the inflammatory cascade.43,45
IFN-α 2b is available as a solution for injectable use. It is
prepared for topical use by adding distilled water to it to 5.2.2. Pharmacokinetics & Pharmacodynamics
achieve a concentration of 1 million IU/ml.37 The drug needs Lifitegrast is soluble in phosphate buffered saline and can be
to be stored in refrigerator at 2-8 οC and is applied 4 times/ used in concentration of upto 10% at 12 hourly interval.43,45
day. Subconjunctival injection of IFN-α 2b (3 million IU/ml) However, the US-FDA approved concentration of topical
has also been described in literature.37 lifitegrast is 5%. Studies have reported decrease in the
inflammatory mediators, increase in the goblet cell density
5.1.3. Indication of use and tear production with its use.
Topical IFN-α 2b is used in various ocular surface disorders
including conjunctival papilloma, OSSN, primary acquired The time to maximum concentration of lifitegrast in plasma
melanosis with atypia, conjunctival melanoma, Mucosa- is 5 mins suggesting a good absorption rate. The half-life in
associated lymphoid tissue (MALT) lymphoma.31,37 It can be conjunctiva and sclera is 2.02 and 1.97 hrs respectively.43,45
used as a primary therapy or adjunct to surgical excision.
Both topical application (1-3 million IU/ml 4 times/ day for 5.2.3. Indication of use
nearly 12 weeks or 2 month after clinical resolution) and Till date, DED not responding to artificial tears remains the
localized sub-conjunctival injection (3 million IU/ml 0.5 ml only indication for use of topical lifitegrast.2 Studies have
once a week till clinical resolution) have been reported to shown improvement in both symptoms and signs of DED
be effective in management of OSSN.37 Comparative studies with its use over 3 months. The drug has been reported to be
for estimating effective topical dosage of INF-α 2b in OSSN safe for use over 12 months; however long-term efficacy and
suggests comparable result between 1million IU/ml and 3 side effects yet remains unexplored.2
million IU/ml.37
5.2.4. Adverse effect
Its use has also been reported in glaucoma filtering surgeries The most common observed adverse effects with its use
to inhibit the tenon capsule’s fibroblast proliferation. It include eye irritation (15%), dysgeusia (16.4%), and reduced
decreases the recurrence rate following pterygium excision visual acuity (11.4%).43–45 Most of these symptoms are mild
surgery. Topical IFN-α 2b has been reported to be useful to moderate in severity. Less common adverse effects (1-
in management of recalcitrant VKC and acyclovir resistant 5%) include blurred vision, conjunctival hyperaemia, eye
HSV keratitis. Few reports suggest its use in management if irritation, headache, increased lacrimation, eye discharge,
limbal stem cell deficiency, mooren’s ulcer and prevention eye discomfort, eye pruritis and sinusitis.43
post-PRK corneal haze.
Others
Its potential efficacy has been demonstrated in recalcitrant
diabetic macular oedema (DME), pseudophakic cystoid 5.3.1. Anakinra
macular oedema (CME) and uveitic macular oedema.39–42 It Anakinra is a recombinant Interleukin 1 receptor antagonist
is proposed that INF-α 2b stabilises the blood retinal barrier (IL-1Ra) that is approved for treatment of rheumatoid
which helps in improvement of macular oedema.

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DJO Vol. 32, No. 3, January-March 2022

arthritis.46,47 Off-label use of topical Anakinra 2.5% has been 3. Abdel-Aty A, Gupta A, Del Priore L, Kombo N. Management
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