International Ophthalmology

, Volume 35, Issue 6, pp 903–912 | Cite as

Biologic therapy for refractory scleritis: a new treatment perspective

  • Tania Sales de Alencar de Fidelix
  • Luis Antonio Vieira
  • Denise de Freitas
  • Virginia Fernandes Moça Trevisani


Scleritis is an umbrella term for a heterogeneous group of ocular diseases that can be associated with autoimmune or systemic disorders. The purpose of this article was to review the literature regarding the use of biologic drugs to treat refractory scleritis. A search of the MEDLINE, Embase, and LILACS electronic databases was conducted, and the reference lists of published articles were hand-searched. No language filters were used. This search strategy yielded no randomized trials of the use of biologic therapies to treat scleritis; only case reports and retrospective studies were retrieved. These studies suggest that monoclonal antibodies (infliximab and adalimumab) are superior to the soluble TNF receptor fusion protein etanercept for the treatment of scleritis in patients that do not respond to corticosteroids and/or to immunosuppressive treatment. Rituximab seems to be the best option for scleritis associated with vasculitis.


Adalimumab Certolizumab Etanercept Infliximab Rituximab 


Author contributions

Tania Sales de Alencar de Fidelix: Substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; Drafting the article and revising it critically for important intellectual content; Final approval of the version to be published. Luis Antonio Vieira: Contributions to conception and drafting of the article; Final approval of the version to be published. Denise de Freitas: Contributions to conception and drafting of the article; Final approval of the version to be published. Virginia Fernandes Moça Trevisani: Contributions to conception and drafting of the article; Final approval of the version to be published.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Financial disclosure

The authors have no financial relationships relevant to this article to disclose.


  1. 1.
    Wakefield D, Di Girolamo N, Thurau S, Wildner G, McCluskey P (2013) Scleritis: immunopathogenesis and molecular basis for therapy. Prog Retin Eye Res 35:44–62. doi: 10.1016/j.preteyeres.2013.02.004 CrossRefPubMedGoogle Scholar
  2. 2.
    Foster CS (2013) Ocular manifestations of the potentially lethal rheumatologic and vasculitic disorders. J Fr Ophtalmol 36:526–532. doi: 10.1016/j.jfo.2012.12.004 CrossRefPubMedGoogle Scholar
  3. 3.
    Watson PG, Hayreh SS (1976) Scleritis and episcleritis. Br J Ophthalmol 60:163–191PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Kraus CL, Culican SM (2012) Use of biologic agents in ocular manifestations of rheumatic disease. Int J Rheumatol 203819Google Scholar
  5. 5.
    Okada AA (2005) Immunomodulatory therapy for ocular inflammatory disease: a basic manual and review of the literature. Ocul Immunol Inflamm 13:335–351CrossRefPubMedGoogle Scholar
  6. 6.
    Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117:244–279CrossRefPubMedGoogle Scholar
  7. 7.
    Rachitskaya A, Mandelcorn ED, Albini TA (2010) An update on the cause and treatment of scleritis. Curr Opin Ophthalmol 21:463–467. doi: 10.1097/ICU.0b013e32833f1060 CrossRefPubMedGoogle Scholar
  8. 8.
    Herrera-Esparza R, Avalos-Diaz E (2009) Infliximab treatment in a case of rheumatoid scleromalacia perforans. Reumatismo 61:212–215PubMedGoogle Scholar
  9. 9.
    Sen HN, Sangave A, Hammel K, Levy-Clarke G, Nussenblat RB (2009) Infliximab for the treatment of severe scleritis. Can J Ophthalmol 44:e9–e12PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Doctor P, Sultan A, Syed S, Christen W, Bhat P, Foster CS (2010) Infliximab for the treatment of refractory scleritis. Br J Ophthalmol 94:579–583. doi: 10.1136/bjo.2008.150961 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Oh JY, Kim MK, Wee WR (2011) Infliximab for progressive peripheral keratitis in a patient with juvenile rheumatoid arthritis. Jpn J Ophthalmol 55:70–71. doi: 10.1007/s10384-010-0889-7 CrossRefPubMedGoogle Scholar
  12. 12.
    Jabbarvand M, Fard MA (2010) Infliximab in a patient with refractory necrotizing scleritis associated with relapsing polychondritis. Ocul Immunol Inflamm 18:216–217. doi: 10.3109/09273941003624914 CrossRefPubMedGoogle Scholar
  13. 13.
    Ashok D, Ayliffe WH, Kiely PD (2005) Necrotizing scleritis associated with rheumatoid arthritis: long-term remission with high-dose infliximab therapy. Rheumatology (Oxford) 44:950–951. doi: 10.1093/rheumatology/keh635 CrossRefGoogle Scholar
  14. 14.
    Cazabon S, Over K, Butcher J (2005) The successful use of infliximab in resistant relapsing polychondritis and associated scleritis. Eye (Lond) 19:222–224CrossRefGoogle Scholar
  15. 15.
    Murphy C, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D (2004) Tumor necrosis factor blockade with infliximab for refractory uveitis and scleritis. Ophthalmology 111:352–356CrossRefPubMedGoogle Scholar
  16. 16.
    El-Shabrawi Y, Hermann J (2005) Anti-TNF alpha therapy in chronic necrotizing scleritis resistant to standard immunomodulatory therapy in a patient with Wegener’s granulomatosis. Eye (Lond) 19:1017–1018. doi: 10.1038/sj.eye.6701712 CrossRefGoogle Scholar
  17. 17.
    Atchia II, Kidd CE, Bell RW (2006) Rheumatoid arthritis-associated necrotizing scleritis and peripheral ulcerative keratitis treated successfully with infliximab. J Clin Rheumatol 12:291–293. doi: 10.1097/01.rhu.0000249766.24780.95 CrossRefPubMedGoogle Scholar
  18. 18.
    Sobrin L, Kim EC, Christen W, Papadaki T, Letko E, Foster CS (2007) Infliximab therapy for the treatment of refractory ocular inflammatory disease. Arch Ophthalmol 125:895–900. doi: 10.1001/archopht.125.7.895 CrossRefPubMedGoogle Scholar
  19. 19.
    Weiss K, Rieger R, Keitzer R, Pleyer U (2007) Successful infliximab treatment of posterior scleritis in a 13-year-old child refractory to other immunosuppressive. Graefes Arch Clin Exp Ophthalmol 245:1735–1737CrossRefPubMedGoogle Scholar
  20. 20.
    Ahn SJ, Oh JY, Kim MK, Wee WR (2009) Treating refractory scleritis with infliximab. Jpn J Ophthalmol 53:286–287. doi: 10.1007/s10384-008-0652-5 CrossRefPubMedGoogle Scholar
  21. 21.
    Sassa Y, Kawano Y, Yamana T, Mashima T, Ishibashi T (2012) A change in treatment from etanercept to infliximab was effective to control scleritis in a patient with rheumatoid arthritis. Acta Ophthalmol 90:e161–162. doi: 10.1111/j.1755-3768.2010.02090.x CrossRefPubMedGoogle Scholar
  22. 22.
    Huynh N, Cervantes-Castaneda RA, Bhat P, Gallagher MJ, Foster CS (2008) Biologic response modifier therapy for psoriatic ocular inflammatory disease. Ocul Immunol Inflamm 16:89–93. doi: 10.1080/09273940802023786 CrossRefPubMedGoogle Scholar
  23. 23.
    Medina GMA, Domínguez JG, Villaverde GR, Alvarez ER (2010) Infliximab para el tratamento de la escleritis anterior necrosante associada a artritis reumatoide seropositiva. Med Clin (Barc) 134:234–236CrossRefGoogle Scholar
  24. 24.
    Smith JR, Levinson RD, Holland GN, Jabs DA, Robinson MR, Whitcup SM, Rosenbaum JT (2001) Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 45:252–257. doi: 10.1002/1529-0131(200106)45:3<252:AID-ART257>3.0.CO;2-5 CrossRefPubMedGoogle Scholar
  25. 25.
    Díaz-Valle D, Sánchez RM, Espartero MCF, Allen DP (2009) Tratamiento de la escleritis anterior difusa refractaria con infliximab. Arch Soc Esp Oftalmol 79:405–408Google Scholar
  26. 26.
    Restrepo JP, Molina MP (2010) Successful treatment of severe nodular scleritis with adalimumab. Clin Rheumatol 29:559–561. doi: 10.1007/s10067-009-1368-8 CrossRefPubMedGoogle Scholar
  27. 27.
    Pasut G (2014) Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol. BioDrugs 28(Suppl 1):15–23. doi: 10.1007/s40259-013-0064-z CrossRefGoogle Scholar
  28. 28.
    Tlucek PS, Stone DU (2012) Certolizumab pegol therapy for rheumatoid arthritis-associated scleritis. Cornea 31:90–91. doi: 10.1097/ICO.0b013e318211400a CrossRefPubMedGoogle Scholar
  29. 29.
    Le Garrec J, Marcelli C, Mouriaux F (2009) Can tumor necrosis factor inhibitors induce sclero-uveitis? J Fr Ophthalmol 32:511CrossRefGoogle Scholar
  30. 30.
    Gaujoux-Viala C, Giampietro C, Gaujoux T, Ea HK, Prati C, Orcel P, Wendling D, Liote F (2012) Scleritis: a paradoxical effect of etanercept? Etanercept-associated inflammatory eye disease. J Rheumatol 39:233–239. doi: 10.3899/jrheum.110865 CrossRefPubMedGoogle Scholar
  31. 31.
    Benucci M, Manfredi M, Puttini PS, Atzeni F (2010) Predictive factors of response to rituximab therapy in rheumatoid arthritis: what do we know today? Autoimmun Rev 9:801–803. doi: 10.1016/j.autrev.2010.07.006 CrossRefPubMedGoogle Scholar
  32. 32.
    De Vita S, Quartuccio L (2006) Treatment of rheumatoid arthritis with rituximab: an update and possible indications. Autoimmun Rev 5:443–448. doi: 10.1016/j.autrev.2006.02.007 CrossRefPubMedGoogle Scholar
  33. 33.
    Dörner T, Isenberg D, Jayne D, Wiendl H, Zillikens D, Burmester G (2009) Current status on B cell depletion therapy in autoimmune diseases other than rheumatoid arthritis. Autoimmun Rev 9:82–89CrossRefPubMedGoogle Scholar
  34. 34.
    Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM (2006) The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54:1390–1400. doi: 10.1002/art.21778 CrossRefPubMedGoogle Scholar
  35. 35.
    Smolen JS, Keystone EC, Emery P, Breedveld FC, Betteridge N, Burmester GR, Dougados M, Ferraccioli G, Jaeger U, Klareskog L, Kvien TK, Martin-Mola E, Pavelka K (2007) Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 66:143–150PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Visentini M, Ludovisi S, Petrarca A, Pulvirenti F, Zaramella M, Monti M, Conti V, Ranieri J, Colantuono S, Fognani E, Piluso A, Tinelli C, Zignego AL, Mondelli MU, Fiorilli M, Casato M (2011) A phase II, single-arm multicenter study of low-dose rituximab for refractory mixed cryoglobulinemia secondary to hepatitis C virus infection. Autoimmun Rev 10:714–719. doi: 10.1016/j.autrev.2011.04.033 CrossRefPubMedGoogle Scholar
  37. 37.
    Kong JS, Teuber SS, Gershwin ME (2006) Potential adverse events with biologic response modifiers. Autoimmun Rev 5:471–485. doi: 10.1016/j.autrev.2006.02.014 CrossRefPubMedGoogle Scholar
  38. 38.
    Garcia-Carrasco M, Jimenez-Hernandez M, Escarcega RO, Mendoza-Pinto C, Galarza-Maldonado C, Sandoval-Cruz M, Zamudio-Huerta L, López-Colombo A, Cervera R (2009) Use of rituximab in systemic lupus erythematosus: an update. Autoimmun Rev 8:343–348CrossRefPubMedGoogle Scholar
  39. 39.
    Conti F, Perricone C, Ceccarelli F, Valesini G (2010) Rituximab treatment of systemic lupus erythematosus in controlled trials and in clinical practice: two sides of the same coin. Autoimmun Rev 9:716–720. doi: 10.1016/j.autrev.2010.07.013 CrossRefPubMedGoogle Scholar
  40. 40.
    Stasi R, Stipa E, Del Poeta G, Amadori S, Newland AC, Provan D (2006) Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford) 45:1432–1436. doi: 10.1093/rheumatology/kel098 CrossRefGoogle Scholar
  41. 41.
    Eriksson P (2005) Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab. J Intern Med 257:540–548. doi: 10.1111/j.1365-2796.2005.01494.x CrossRefPubMedGoogle Scholar
  42. 42.
    Tobon GJ, Pers JO, Youinou P, Saraux A (2010) B cell-targeted therapies in Sjogren’s syndrome. Autoimmun Rev 9:224–228. doi: 10.1016/j.autrev.2009.08.001 CrossRefPubMedGoogle Scholar
  43. 43.
    Quartuccio L, Fabris M, Salvin S, Maset M, De Marchi G, De Vita S (2009) Controversies on rituximab therapy in Sjogren syndrome-associated lymphoproliferation. Int J Rheumatol. doi: 10.1155/2009/424935 PubMedCentralPubMedGoogle Scholar
  44. 44.
    Lim L, Suhler EB, Smith JR (2006) Biologic therapies for inflammatory eye disease. Clin Experiment Ophthalmol 34(4):365–374CrossRefPubMedGoogle Scholar
  45. 45.
    Ahmadi-Simab K, Lamprecht P, Nolle B, Ai M, Gross WL (2005) Successful treatment of refractory anterior scleritis in primary Sjogren’s syndrome with rituximab. Ann Rheum Dis 64:1087–1088. doi: 10.1136/ard.2004.027128 PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Cheung CM, Murray PI, Savage CO (2005) Successful treatment of Wegener’s granulomatosis associated scleritis with rituximab. Br J Ophthalmol 89:1542. doi: 10.1136/bjo.2005.075689 PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Kurz PA, Suhler EB, Choi D, Rosenbaum JT (2009) Rituximab for treatment of ocular inflammatory disease: a series of four cases. Br J Ophthalmol 93:546–548. doi: 10.1136/bjo.2007.133173 CrossRefPubMedGoogle Scholar
  48. 48.
    Chauhan S, Kamal A, Thompson RN, Estrach C, Moots RJ (2009) Rituximab for treatment of scleritis associated with rheumatoid arthritis. Br J Ophthalmol 93:984–985CrossRefPubMedGoogle Scholar
  49. 49.
    Onal S, Kazokoglu H, Koc A, Yavuz S (2008) Rituximab for remission induction in a patient with relapsing necrotizing scleritis associated with limited Wegener’s granulomatosis. Ocul Immunol Inflamm 16:230–232. doi: 10.1080/09273940802331643 CrossRefPubMedGoogle Scholar
  50. 50.
    Taylor SR, Salama AD, Joshi L, Pusey CD, Lightman SL (2009) Rituximab is effective in the treatment of refractory ophthalmic Wegener’s granulomatosis. Arthritis Rheum 60:1540–1547CrossRefPubMedGoogle Scholar
  51. 51.
    Iaccheri B, Androudi S, Bocci EB, Gerli R, Cagini C, Fiore T (2010) Rituximab treatment for persistent scleritis associated with rheumatoid arthritis. Ocul Immunol Inflamm 18:223–225. doi: 10.3109/09273941003739928 CrossRefPubMedGoogle Scholar
  52. 52.
    Gómez LMZ, Franco CJV, Foronda JCH, Alzate CFC (2012) Uso de rituximabe en una paciente con escleritis anterior difusa necrotizante asociada a vasculitis con c-ANCA refractaria a immunomoduladores convencionales. Rev Colomb Reumatol 19:183–189Google Scholar
  53. 53.
    Bogdanic-Werner K, Fernandez-Sanz G, Alejandre Alba N, Ferrer Soldevila P, Romero-Bueno FI, Sanchez-Pernaute O (2013) Rituximab therapy for refractory idiopathic scleritis. Ocul Immunol Inflamm 21:329–332. doi: 10.3109/09273948.2013 CrossRefPubMedGoogle Scholar
  54. 54.
    Suhler EB, Lim LL, Beardsley RM, Giles TR, Pasadhika S, Lee ST, Sardos AS, Butler NJ, Smith JR, Rosenbaum JT (2014) Rituximab in the treatment of refractory scleritis and non-infeccious orbitary inflammation: preliminary results from a Phase I/II prospective, randomized, dose-ranging pilot study. JAMA Ophthalmol 132:572–578. doi: 10.1001/jamaophthalmol.2013.8179 PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Turchetti G, Smolen JS, Kavanaugh A, Braun J, Pincus T, Bombardieri S (2012) Treat-to-target in rheumatoid arthritis: clinical and pharmacoeconomic considerations. Introduction. Clin Exp Rheumatol 30:S1PubMedGoogle Scholar
  56. 56.
    McCluskey P, Wakefield D (1991) Prediction of response to treatment in patients with scleritis using a standardised scoring system. Aust N Z J Ophthalmol 19:211–215CrossRefPubMedGoogle Scholar
  57. 57.
    Sen HN, Sangave AA, Golgstein DA, Suhler EB, Cunningham D, Vitale S, Nussenblatt RB (2011) A stardardized grading system for scleritis. Ophthalmology 118:768–771PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, Dougados M, Emery P, Keystone EC, Klareskog L, Mease PJ (2005) Updated consensus statement on biological agents, specifically tumor necrosis factor α (TNF α) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases. Ann Rheum Dis 64 Suppl 4:iv2-14. doi:  10.1136/ard.2005.044941
  59. 59.
    Freidlin J, Wong IG, Acharya N (2007) Rituximab treatment for peripheral ulcerative keratitis associated with Wegener’s granulomatosis. Br J Ophthalmol 91:1414. doi: 10.1136/bjo.2006.113316 PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Foster CS, Chang PY, Ahmed AR (2010) Combination of rituximab and intravenous immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary report. Ophthalmology 117:861–869. doi: 10.1016/j.ophtha.2009.09.049 CrossRefPubMedGoogle Scholar
  61. 61.
    Huerva V, Sanchez MC, Traveset A, Jurjo C, Ruiz A (2010) Rituximab for peripheral ulcerative keratitis with Wegener granulomatosis. Cornea 29:708–710. doi: 10.1097/ICO.0b013e3181c296ed PubMedGoogle Scholar
  62. 62.
    Beardsley RM, Suhler EB, Rosenbaum JT, Lin P (2013) Pharmacotherapy of scleritis: current paradigms and future directions. Expert Opin Pharmacother 14:411–424. doi: 10.1517/14656566.2013.772982 PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Onrust SV, Lamb HM, Balfour JA (1999) Rituximab. Drugs 58:79–88CrossRefPubMedGoogle Scholar
  64. 64.
    Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN (2014) Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 121(785–796):e783. doi: 10.1016/j.ophtha.2013.09.048 Google Scholar
  65. 65.
    Saw VPJ, Cornelius N, Salama AD, Pusey C, Lightman SL (2008) Infliximab therapy for aggressive Mooren ulceration. Arch Ophthalmol 126:734CrossRefPubMedGoogle Scholar
  66. 66.
    Cordero-Coma M, Méndez RS, Blanco AC, Corral AL, Calleja-Antolin S, Morales JMR (2012) Adalimumab for refractory peripheral ulcerative keratitis. J Ophthal Inflamm Infect 2:227–229. doi: 10.1007/s12348-012-0080-z CrossRefGoogle Scholar
  67. 67.
    Fontana L, Parente G, Neri P, Reta M, Tassinari G (2007) Favourable response to infliximab in a case of bilateral refractory Mooren’s ulcer. Clin Experiment Ophthalmol. 35:871–873. doi: 10.1111/j.1442-9071.2007.01609.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Tania Sales de Alencar de Fidelix
    • 1
  • Luis Antonio Vieira
    • 2
  • Denise de Freitas
    • 2
  • Virginia Fernandes Moça Trevisani
    • 1
  1. 1.Evidence-Based Health DepartmentUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
  2. 2.Ophthalmology DepartmentUNIFESPSão PauloBrazil

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