Recent Advances in the Treatment of Ocular Complications of Rheumatoid Arthritis: A review of current literature
DOI:
https://doi.org/10.12775/JEHS.2024.59.007Keywords
rheumatoid arthritis, scleritis, episcleritis, ocular inflammation, dry eye syndrome, keratoconjunctivitis sicca, treatmentAbstract
Introduction: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that often causes ocular complications, of which keratoconjunctivitis sicca (KCS), scleritis and episcleritis are the most common entities. When left untreated, they can adversely affect eye health and cause vision loss in severe cases. Therefore, early and effective treatment of ophthalmic complications may significantly improve visual outcomes in patients with rheumatoid arthritis.
Aim of the study: The aim of the study was to compile and analyze the current literature on the treatment of the most prevalent ocular manifestation associated with RA. Special emphasis was placed on recently approved drugs and those in late-stage clinical trials.
Methods and materials: Publication research was conducted using the PubMed database and Google Scholar with a primary focus on literature from the past 10 years. Firstly, common ocular complications of rheumatoid arthritis were identified and relevant treatment modalities were extracted for further analysis. Finally, the names of relevant drugs or drug classes were used along with the names of the aforementioned disease entities to discover clinical trials regarding their efficacy and safety. Additionally, references from selected manuscripts were included.
Summary: The landscape of treatment for ocular complications associated with RA offers a promising future for patients and clinicians. Three new therapeutic modalities for dry eye disease have been approved in 2023, and three additional drugs are in late-stage clinical trials. Furthermore, recent advances in biologic therapy have shown considerable promise in treating scleritis, especially in patients refractory to conventional treatment or with severe symptoms of the disease.
References
Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA. 2018;320(13):1360-1372. https://doi.org/10.1001/jama.2018.13103
Rossini M, Rossi E, Bernardi D, et al. Prevalence and incidence of rheumatoid arthritis in Italy. Rheumatol Int. 2014;34(5):659-664. https://doi.org/10.1007/s00296-014-2974-6
Turk MA, Hayworth JL, Nevskaya T, Pope JE. Ocular Manifestations in Rheumatoid Arthritis, Connective Tissue Disease, and Vasculitis: A Systematic Review and Metaanalysis. J Rheumatol. 2021;48(1):25-34. https://doi.org/10.3899/jrheum.190768
Bhamra MS, Gondal I, Amarnani A, et al. Ocular Manifestations of Rheumatoid Arthritis: Implications of Recent Clinical Trials. Int J Clin Res Trials. 2019;2019. https://doi.org/10.15344/2456-8007/2019/139
Kemeny-Beke A, Szodoray P. Ocular manifestations of rheumatic diseases. Int Ophthalmol. 2020;40(2):503-510. https://doi.org/10.1007/s10792-019-01183-9
Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017;15(3):276-283. https://doi.org/10.1016/j.jtos.2017.05.008
Bron AJ, De Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510. https://doi.org/10.1016/j.jtos.2017.05.011
Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;27 Suppl 1(Suppl 1):3-47. https://doi.org/10.1097/01.icu.0000512373.81749.b7
Zeev MSB, Miller DD, Latkany R. Diagnosis of dry eye disease and emerging technologies. Clin Ophthalmol Auckl NZ. 2014;8:581-590. https://doi.org/10.2147/OPTH.S45444
Schargus M, Geerling G. [The “wet” dry eye]. Ophthalmol Z Dtsch Ophthalmol Ges. 2009;106(3):235-238, 240-241. https://doi.org/10.1007/s00347-008-1908-7
Mertzanis P, Abetz L, Rajagopalan K, et al. The relative burden of dry eye in patients’ lives: comparisons to a U.S. normative sample. Invest Ophthalmol Vis Sci. 2005;46(1):46-50. https://doi.org/10.1167/iovs.03-0915
Guo OD LW, Akpek E. The negative effects of dry eye disease on quality of life and visual function. Turk J Med Sci. 2020;50(SI-2):1611-1615. https://doi.org/10.3906/sag-2002-143
Uchino M, Schaumberg DA. Dry Eye Disease: Impact on Quality of Life and Vision. Curr Ophthalmol Rep. 2013;1(2):51-57. https://doi.org/10.1007/s40135-013-0009-1
Pucker AD, Ng SM, Nichols JJ. Over the counter (OTC) artificial tear drops for dry eye syndrome. Cochrane Database Syst Rev. 2016;(2). https://doi.org/10.1002/14651858.CD009729.pub2
Akpek EK, Amescua G, Farid M, et al. Dry Eye Syndrome Preferred Practice Pattern®. Ophthalmology. 2019;126(1):P286-P334. https://doi.org/10.1016/j.ophtha.2018.10.023
Ambroziak AM, Szaflik J, Szaflik JP, Ambroziak M, Witkiewicz J, Skopiński P. Immunomodulation on the ocular surface: a review. Cent-Eur J Immunol. 2016;41(2):195-208. https://doi.org/10.5114/ceji.2016.60995
Periman LM, Mah FS, Karpecki PM. Mechanism of Action of Cyclosporine A: The Role of Cyclosporine A in Dry Eye Disease and Recent Formulation Developments. Clin Ophthalmol. 2020;14:4187-4200. https://doi.org/10.2147/OPTH.S279051
Hunter PA, Wilhelmus KR, Rice NS, Jones BR. Cyclosporin A applied topically to the recipient eye inhibits corneal graft rejection. Clin Exp Immunol. 1981;45(1):173-177.
Wirta DL, Torkildsen GL, Moreira HR, et al. A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease. Ophthalmology. 2019;126(6):792-800. https://doi.org/10.1016/j.ophtha.2019.01.024
Akpek EK, Wirta DL, Downing JE, et al. Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease. JAMA Ophthalmol. 2023;141(5):459-466. https://doi.org/10.1001/jamaophthalmol.2023.0709
Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL. NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: The Randomized Phase 3 MOJAVE Study. Am J Ophthalmol. 2023;252:265-274. https://doi.org/10.1016/j.ajo.2023.03.008
Tauber J, Berdy GJ, Wirta DL, et al. NOV03 for Dry Eye Disease Associated with Meibomian Gland Dysfunction: Results of the Randomized Phase 3 GOBI Study. Ophthalmology. 2023;130(5):516-524. https://doi.org/10.1016/j.ophtha.2022.12.021
Protzko EE, Segal BA, Korenfeld MS, Krösser S, Vittitow JL. Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study. Cornea. Published online November 3, 2023. https://doi.org/10.1097/ICO.0000000000003418
Tian L, Gao Z, Zhu L, et al. Perfluorohexyloctane Eye Drops for Dry Eye Disease Associated With Meibomian Gland Dysfunction in Chinese Patients: A Randomized Clinical Trial. JAMA Ophthalmol. 2023;141(4):385-392. https://doi.org/10.1001/jamaophthalmol.2023.0270
Ballesteros-Sánchez A, De-Hita-Cantalejo C, Sánchez-González MC, et al. Perfluorohexyloctane in dry eye disease: A systematic review of its efficacy and safety as a novel therapeutic agent. Ocul Surf. 2023;30:254-262. https://doi.org/10.1016/j.jtos.2023.10.001
Syed YY. Lotilaner Ophthalmic Solution 0.25%: First Approval. Drugs. 2023;83(16):1537-1541. https://doi.org/10.1007/s40265-023-01947-9
Gaddie IB, Donnenfeld ED, Karpecki P, et al. Lotilaner Ophthalmic Solution 0.25% for Demodex Blepharitis: Randomized, Vehicle-Controlled, Multicenter, Phase 3 Trial (Saturn-2). Ophthalmology. 2023;130(10):1015-1023. https://doi.org/10.1016/j.ophtha.2023.05.030
Clark D, Tauber J, Sheppard J, Brady TC. Early Onset and Broad Activity of Reproxalap in a Randomized, Double-Masked, Vehicle-Controlled Phase 2b Trial in Dry Eye Disease. Am J Ophthalmol. 2021;226:22-31. https://doi.org/10.1016/j.ajo.2021.01.011
Starr CE, Nichols KK, Lang JR, Brady TC. The Phase 3 INVIGORATE Trial of Reproxalap in Patients with Seasonal Allergic Conjunctivitis. Clin Ophthalmol Auckl NZ. 2023;17:3867-3875. https://doi.org/10.2147/OPTH.S441009
J MI, Mc SH, I D, A L. The Importance of Preventing and Managing Tear Dysfunction Syndrome in Allergic Conjunctivitis and How to Tackle This Problem. J Investig Allergol Clin Immunol. 2023;33(6). https://doi.org/10.18176/jiaci.0960
Petrov A, Perekhvatova N, Skulachev M, Stein L, Ousler G. SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model. Adv Ther. 2016;33(1):96-115. https://doi.org/10.1007/s12325-015-0274-5
Watson SL, Jones LW, Stapleton F, et al. Efficacy and safety of AZR-MD-001 selenium sulfide ophthalmic ointment in adults with meibomian gland dysfunction: A vehicle-controlled, randomized clinical trial. Ocul Surf. 2023;29:537-546. https://doi.org/10.1016/j.jtos.2023.07.002
Bernauer W, Pleisch B, Brunner M. Five-year outcome in immune-mediated scleritis. Graefes Arch Clin Exp Ophthalmol. 2014;252(9):1477-1481. https://doi.org/10.1007/s00417-014-2696-1
Lin P, Bhullar SS, Tessler HH, Goldstein DA. Immunologic Markers as Potential Predictors of Systemic Autoimmune Disease in Patients with Idiopathic Scleritis. Am J Ophthalmol. 2008;145(3):463-471.e1. https://doi.org/10.1016/j.ajo.2007.09.024
Yoshida A, Watanabe M, Okubo A, Kawashima H. Clinical characteristics of scleritis patients with emphasized comparison of associated systemic diseases (anti-neutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis). Jpn J Ophthalmol. 2019;63(5):417-424. https://doi.org/10.1007/s10384-019-00674-7
Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol. 1976;60(3):163-191. https://doi.org/10.1136/bjo.60.3.163
Caimmi C, Crowson CS, Smith WM, Matteson EL, Makol A. Clinical Correlates, Outcomes, and Predictors of Inflammatory Ocular Disease Associated with Rheumatoid Arthritis in the Biologic Era. J Rheumatol. 2018;45(5):595-603. https://doi.org/10.3899/jrheum.170437
Abdel-Aty A, Gupta A, Del Priore L, Kombo N. Management of noninfectious scleritis. Ther Adv Ophthalmol. 2022;14:25158414211070879. https://doi.org/10.1177/25158414211070879
Tappeiner C, Walscheid K, Heiligenhaus A. Diagnose und Therapie der Episkleritis und Skleritis. Ophthalmol. 2016;113(9):797-810. https://doi.org/10.1007/s00347-016-0344-3
Foster CS, Kothari S, Anesi SD, et al. The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management. Surv Ophthalmol. 2016;61(1):1-17. https://doi.org/10.1016/j.survophthal.2015.07.001
Sainz de la Maza M, Molina N, Gonzalez-Gonzalez LA, Doctor PP, Tauber J, Foster CS. Scleritis Therapy. Ophthalmology. 2012;119(1):51-58. https://doi.org/10.1016/j.ophtha.2011.07.043
Dutta Majumder P, Agrawal R, McCluskey P, Biswas J. Current Approach for the Diagnosis and Management of Noninfective Scleritis. Asia-Pac J Ophthalmol. 2021;10(2):212. https://doi.org/10.1097/APO.0000000000000341
Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000;130(4):469-476. https://doi.org/10.1016/s0002-9394(00)00710-8
Nevares A, Raut R, Libman B, Hajj-Ali R. Noninfectious Autoimmune Scleritis: Recognition, Systemic Associations, and Therapy. Curr Rheumatol Rep. 2020;22(4):11. https://doi.org/10.1007/s11926-020-0885-y
McCluskey P, Wakefield D. Intravenous Pulse Methylprednisolone in Scleritis. Arch Ophthalmol. 1987;105(6):793-797. https://doi.org/10.1001/archopht.1987.01060060079037
Sohn EH, Wang R, Read R, et al. Long-Term, Multicenter Evaluation of Subconjunctival Injection of Triamcinolone for Non-Necrotizing, Noninfectious Anterior Scleritis. Ophthalmology. 2011;118(10):1932-1937. https://doi.org/10.1016/j.ophtha.2011.02.043
Albini TA, Zamir E, Read RW, Smith RE, See RF, Rao NA. Evaluation of Subconjunctival Triamcinolone for Nonnecrotizing Anterior Scleritis. Ophthalmology. 2005;112(10):1814-1820. https://doi.org/10.1016/j.ophtha.2005.05.008
Promelle V, Goeb V, Gueudry J. Rheumatoid Arthritis Associated Episcleritis and Scleritis: An Update on Treatment Perspectives. J Clin Med. 2021;10(10):2118. https://doi.org/10.3390/jcm10102118
Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for Ocular Inflammatory Diseases. Ophthalmology. 2009;116(11):2188-2198.e1. https://doi.org/10.1016/j.ophtha.2009.04.020
Hiyama T, Harada Y, Kiuchi Y. Clinical characteristics and efficacy of methotrexate in Japanese patients with noninfectious scleritis. Jpn J Ophthalmol. 2021;65(1):97-106. https://doi.org/10.1007/s10384-020-00778-5
Thorne JE, Jabs DA, Qazi FA, Nguyen QD, Kempen JH, Dunn JP. Mycophenolate Mofetil Therapy for Inflammatory Eye Disease. Ophthalmology. 2005;112(8):1472-1477. https://doi.org/10.1016/j.ophtha.2005.02.020
Daniel E, Thorne JE, Newcomb CW, et al. Mycophenolate Mofetil for Ocular Inflammation. Am J Ophthalmol. 2010;149(3):423-432.e2. https://doi.org/10.1016/j.ajo.2009.09.026
Karam M, Alsaif A, Al-Naseem A, et al. Mycophenolate versus Methotrexate in Non-infectious Ocular Inflammatory Disease: A Systematic Review and Meta-Analysis. Ocul Immunol Inflamm. 2023;31(3):613-620. https://doi.org/10.1080/09273948.2022.2034166
Pujari SS, Kempen JH, Newcomb CW, et al. Cyclophosphamide for Ocular Inflammatory Diseases. Ophthalmology. 2010;117(2):356-365. https://doi.org/10.1016/j.ophtha.2009.06.060
Lawuyi LE, Gurbaxani A. Refractory necrotizing scleritis successfully treated with adalimumab. J Ophthalmic Inflamm Infect. 2016;6:37. https://doi.org/10.1186/s12348-016-0107-y
Fabiani C, Sota J, Sainz-de-la-Maza M, et al. Effectiveness of TNF-α blockade in the treatment of refractory non-infectious scleritis: a multicentre study. Clin Exp Rheumatol. 2020;38(6):1138-1144.
Sassa Y, Kawano Y ichi, Yamana T, Mashima T, Ishibashi T. A change in treatment from etanercept to infliximab was effective to control scleritis in a patient with rheumatoid arthritis. Acta Ophthalmol (Copenh). 2012;90(2):e161-e162. https://doi.org/10.1111/j.1755-3768.2010.02090.x
Iaccheri B, Androudi S, Bocci EB, Gerli R, Cagini C, Fiore T. Rituximab Treatment for Persistent Scleritis Associated with Rheumatoid Arthritis. Ocul Immunol Inflamm. 2010;18(3):223-225. https://doi.org/10.3109/09273941003739928
Tlucek PS, Stone DU. Certolizumab Pegol Therapy for Rheumatoid Arthritis–Associated Scleritis. Cornea. 2012;31(1):90. https://doi.org/10.1097/ICO.0b013e318211400a
Nicolela Susanna F, Pavesio C. A review of ocular adverse events of biological anti-TNF drugs. J Ophthalmic Inflamm Infect. 2020;10:11. https://doi.org/10.1186/s12348-020-00202-6
Suhler EB, Lim LL, Beardsley RM, et al. Rituximab Therapy for Refractory Scleritis: Results of a Phase I/II Dose-Ranging, Randomized, Clinical Trial. Ophthalmology. 2014;121(10):1885-1891. https://doi.org/10.1016/j.ophtha.2014.04.044
Ng CC, Sy A, Cunningham ET. Rituximab for non-infectious Uveitis and Scleritis. J Ophthalmic Inflamm Infect. 2021;11(1):23. https://doi.org/10.1186/s12348-021-00252-4
Silpa-archa S, Oray M, Preble JM, Foster CS. Outcome of tocilizumab treatment in refractory ocular inflammatory diseases. Acta Ophthalmol (Copenh). 2016;94(6):e400-e406. https://doi.org/10.1111/aos.13015
Poelman HJ, Van Daele PLA, Rothova A. Successful Tocilizumab Treatment for Scleritis. Ocul Immunol Inflamm. 2020;28(2):285-287. https://doi.org/10.1080/09273948.2019.1617885
Farhat R, Clavel G, Villeneuve D, et al. Sustained Remission with Tocilizumab in Refractory Relapsing Polychondritis with Ocular Involvement: A Case Series. Ocul Immunol Inflamm. 2021;29(1):9-13. https://doi.org/10.1080/09273948.2020.1763405
Fabiani C, Sota J, Tosi GM, et al. The emerging role of interleukin (IL)-1 in the pathogenesis and treatment of inflammatory and degenerative eye diseases. Clin Rheumatol. 2017;36(10):2307-2318. https://doi.org/10.1007/s10067-016-3527-z
Bottin C, Fel A, Butel N, et al. Anakinra in the Treatment of Patients with Refractory Scleritis: A Pilot Study. Ocul Immunol Inflamm. 2018;26(6):915-920. https://doi.org/10.1080/09273948.2017.1299869
Knickelbein JE, Tucker WR, Bhatt N, et al. Gevokizumab in the treatment of autoimmune, non-necrotizing, anterior scleritis: Results of a phase I/II clinical trial. Am J Ophthalmol. 2016;172:104-110. https://doi.org/10.1016/j.ajo.2016.09.017
Fleischmann R, Kremer J, Cush J, et al. Placebo-Controlled Trial of Tofacitinib Monotherapy in Rheumatoid Arthritis. N Engl J Med. 2012;367(6):495-507. https://doi.org/10.1056/NEJMoa1109071
van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or Adalimumab versus Placebo in Rheumatoid Arthritis. N Engl J Med. 2012;367(6):508-519. https://doi.org/10.1056/NEJMoa1112072
Mease P, Hall S, FitzGerald O, et al. Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis. N Engl J Med. 2017;377(16):1537-1550. https://doi.org/10.1056/NEJMoa1615975
Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017;376(18):1723-1736. https://doi.org/10.1056/NEJMoa1606910
Paley MA, Karacal H, Rao PK, Margolis TP, Miner JJ. Tofacitinib for refractory uveitis and scleritis. Am J Ophthalmol Case Rep. 2019;13:53-55. https://doi.org/10.1016/j.ajoc.2018.12.001
Fabiani C, Sota J, Sainz-de-la-Maza M, et al. New Potential Weapons for Refractory Scleritis in the Era of Targeted Therapy. Mediators Inflamm. 2020;2020:8294560. https://doi.org/10.1155/2020/8294560
Pyare R, Kaushik V, Dutta Majumder P, Biswas J. Tofacitinib in recalcitrant scleritis: First case report from India. Indian J Ophthalmol. 2020;68(9):1988-1990. https://doi.org/10.4103/ijo.IJO_534_20
Sota J, Girolamo MM, Frediani B, Tosi GM, Cantarini L, Fabiani C. Biologic Therapies and Small Molecules for the Management of Non-Infectious Scleritis: A Narrative Review. Ophthalmol Ther. 2021;10(4):777-813. https://doi.org/10.1007/s40123-021-00393-8
Dammacco R, Guerriero S, Alessio G, Dammacco F. Natural and iatrogenic ocular manifestations of rheumatoid arthritis: a systematic review. Int Ophthalmol. 2022;42(2):689-711. https://doi.org/10.1007/s10792-021-02058-8
Zlatanović G, Veselinović D, Cekić S, Živković M, Đorđević-Jocić J, Zlatanović M. Ocular manifestation of rheumatoid arthritis-different forms and frequency. Bosn J Basic Med Sci. 2010;10(4):323-327.
Paul Pandian V, Srinivasan R. Ocular manifestations of rheumatoid arthritis and their correlation with anti-cyclic citrullinated peptide antibodies. Clin Ophthalmol. Published online February 2015:393. https://doi.org/10.2147/OPTH.S77210
Alghamdi AH. Treatment of Steroid-Resistant Nodular Episcleritis With Tacrolimus: A Case Report. Cureus. 15(10):e47057. https://doi.org/10.7759/cureus.47057
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