The role of Interleukins and their inhibitors in the development of autoimmune uveitis

Nadiya B. Kuryltsiv, Kateryna M. Halei

Danylo Halytsky Lviv national medical university, ophthalmology department, Lviv, Ukraine


Introduction: Autoimmune uveitis (AU) is an inflammation of the uvea due to an autoimmune reaction to self-antigens. There are no standardized treatment protocols for AU. A new class of drugs called biologics, that target the various mediators of the inflammation cascade, may potentially provide more effective and less toxic corticosteroids treatment of AU.

The aim: The aim of this review was to make the evaluatation of the interleukins influence on intraocular inflammation in available literature and summarize the expediency of using anti-interleukins agent in case of AU.

Material and methods: This article is a review and summary of the up-to-date results of pivotal experimental and clinical trials targeting the Interleukins (IL), including IL-6, IL-10, IL-17, IL-22, IL-23, and tumor necrosis factor alpha (TNF-α). Also reviews focus on the potential use of anti-interleukin therapy for the treatment of autoimmune diseases (AD).

Conclusions: AU is an inflammation of the uvea due to an autoimmune reaction to self-antigens. The most important IL in the pathogenesis of AU are IL-6, IL-10, IL-17, IL-22, IL-23 and TNF-α. Anti-interleukin therapy is partially described. Future randomized controlled trials are urgently needed to be conduct.

KEY WORDS: autoimmune uveitis, Interleukins, anti-interleukin therapy, tumor necrosis factor alpha

Wiad Lek 2019, 72, 4, 716-722


Uveitis is a general term for inflammatory disorders of the uveal tract, the vascular membrane of the eye, and encompasses a wide range of underlying etiologies. In fact, untreated uvea inflammation leads to 5–10% of visual impairment worldwide and it is one of the main cause of blindness [1-4]. The prevalence and phenotypic expression of various uveitis types depend on age, sex, race, geographic distribution, environmental influence, genetic factors, and social habits [5, 6]. Since uveitis typically affects the working age group (20–60 years of age), not only may quality of life be severely impacted but there may also be profound socioeconomic consequences for affected patients. [7-10].

Uveitis may be idiopathic, associated with systemic diseases or result from a variety of infectious agents. Until recently, although uveitis was proposed to be frequently an autoimmune disease, repeated attempts to induce experimental uveitis with uveal antigens met with failure [11]. In the latter form, a uveal component, whether tissue damage or a microbial trigger, stimulates the generation of antigen-specific T cells and/or autoantibodies that are believed to play a pathogenetic role, hence the term autoimmune uveitis (AU) [12]. AU can present as an isolated entity or associated with a systemic autoimmune disorders. Diseases such as rheumatoid arthritis (RA) [13, 14], systemic lupus erythematous (SLE) [13], Vogt Koyanagi Harada Syndrome (VKHS) [15] are commonly associated with posterior type of uveitis. On the other hand, anterior uveitis typically appears as the initial manifestation in autoinflammatory diseases such as psoriatic arthritis (PA) [16, 17 ], Behcet’s disease (BD) [18, 19, 20], Juvenile idiopathic arthritis (JIA) [ 13, 21, 22], Crohn’s disease (CD) [23], ankylosing spondilitis (AS) [23, 24]There is a clear association described with the HLA-B27 positivity and a higher risk of presenting recurrent anterior uveitis in AS [25].

There are no standardized treatment protocols for AU.Topical corticosteroids are the typical first-line agent, although systemic corticosteroids are used in intermediate, posterior intraocular inflamation, and panuveitis. Corticosteroids are not considered to be long-term therapy due to potential ocular and systemic side effects [26-28]. This impact has stimulated the development of more effective treatment strategies for uveitis.

Etiological treatments for autoimmune diseases affecting millions of patients worldwide are still lacking and current available therapies do not control satisfactorily the disease evolution [29]. Current therapeutic strategies for all autoimmune diseases rely on immunosuppressive and/or symptomatic therapies that preserve only partially the patients’ quality of life. Thus, new technological approaches to these disorders should be developed [30].

The aim

The aim of this review was to make the evaluatation of the interleukins influence on intraocular inflammation in available literature and summarize the expediency of using anti-interleukins agent in case of autoimmune uveitis.

Materials and methods

This article is a review and summary of the up-to-date results of pivotal experimental and clinical trials targeting the Interleukins (IL), including IL-6, IL-10, IL-17, IL-22, IL-23, and tumor necrosis factor alpha (TNF-α). Also reviews focus on the potential use of anti-interleukin therapy for the treatment of autoimmune diseases (AD). An extensive literature research was performed in the Medline database (PubMed) for articles, also some additional references were taken from books written on the subject. Additionally, attention was given to articles referenced in the selected articles.

Review and discussion

Immune-mediated inflammation can be tolerated in many organs, however in the eye it has devastating consequences, as many of the tissues in the visual axis have limited or no capacity for regeneration. Multiple mechanisms and anatomical adaptations limit the expression of immune-mediated inflammation in the eye. Among these is the generation of regulatory T cells (Tregs), which act to prevent the induction and expression of T cell inflammation [31]. Tregs formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. [32]. T cells expressing the surface marker cluster of differentiation 4 (CD4) are known as T helper (Th) cells play important roles in the pathogenesis of autoimmune diseases including uveitis. Th cells can be classified into different functional categories: defined by the transcription factor T-bet and secretion of interferon gamma, were the dominant cell type ‘helping’ cellular immunity, and Th2 cells, defined by the transcription factor GATA binding protein 3 and secretion of IL -4 and IL-5, were responsible for helping humoral immunity [33].

Cytokines are made by many cell populations, but the predominant producers are Th and macrophages. Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and IL (cytokines made by one leukocyte and acting on other leukocytes). There are both pro-inflammatory cytokines and anti-inflammatory cytokines [34].

As a result of the analysis of many literary sources, it is known that the most important IL in the pathogenesis of uveitis are IL-6, IL-10, IL-17, IL-22, IL-23 and TNF-α.

IL-6 stimulates the inflammatory and auto-immune processes in many diseases. There is evidence for the important role of IL-6 hyperproduction not only in RA, but also in other immune inflammatory BD, systemic lupus erythematosus, scleroderma systematica, idiopathic inflammatory myopathies, giant cell arteritis, etc.), also in diabetes, atherosclerosis, Alzheimer’s disease, multiple myeloma and prostate cancer [35-43]. It is important mediator of AD including AU [44]. The binding of IL-6 to its receptor results in the activation of the mitogen-activated protein kinase pathways, ultimately leading to the expression of inflammatory cytokines, vascular endothelial growth factor and differentiation of naive CD4+ T cells into Th17 cells [45].

Some studies in mice with EAU found that inflammation is significantly attenuated in IL-6 deficient animals and intravitreal anti-IL-6 reduces inflammation [46, 47]. Also, in human’s studies, elevated levels of IL-6 have been detected in the aqueous humour of BD, VKHS, sarcoid, idiopathic uveitis, acute retinal necrosis and HLA-B27 mediated uveitis when compared with controls [48-50]. Futhermore, IL-6 also plays a role in uveitis complications such as neovascularization and macular oedema [51-53].

IL-10, also known as human cytokine synthesis inhibitory factor, and it continues to be one of the more important immunoregulatory cytokines, controlling and moderating inflammatory responses [54]. It is secreted by activated T cells, macrophages, dendritic cells, natural killer (NK) cells and B-cells [55]. In patients and animals with uveitis, elevated intraocular IL-10 levels have been identified and it has protective roles. [56-58]. Moreover, in animal model with endotoxininduced uveitis protective role of local IL-10 was confirmed [59, 60]. Сorrelation between level of IL-10 to level of IL-6 allows to determine the diagnosis (uveitis or intraocular tumor) [61, 62].

One of the main subunit of IL-10 is IL-22, that is produced by T cells, Th1 and Th17 cells, NK cells and innate lymphoid cells. IL-22 initiates innate immune responses against bacterial pathogens especially in epithelial cells such as respiratory and gut epithelial cells. Generally, IL-22 may primarily have immune regulatory rather than inflammatory functions in the eye [63]. In experimental model IL-22 developes worse inflammation and led to a reduced severity of uveitis. In humans elevated levels of serum IL-22 have been identified in patients with uveitis in case of BD and scleritis [64-67]. Some athours review, that IL-22 can contribute to immune disease through the stimulation of inflammatory responses, S100s and defensins. IL-22 also promotes hepatocyte survival in the liver and epithelial cells in the lung and gut similar to IL-10. In some contexts, the pro-inflammatory versus tissue-protective functions of IL-22 are regulated by the often co-expressed cytokine IL-17A [68, 69].

IL-17 is part of the IL-17 family of cytokines. IL-17 is secreted by Th17 cells as well as NK cells, gamma delta T cells and a subset of CD8+ T cells called Tc17 cells in response to their stimulation with IL-23 [70].

In experiments on mouse, both Th17 cells and IL-17 appear to have an important role in driving inflammation. In the adoptive transfer model of experimental AU, interphotoreceptor retinoid binding protein specific Th17 cells are sufficient to induce uveitis, and treatment with anti-IL-17 antibody is sufficient to block development of disease [71]. In humans, elevated levels of IL-17 were identified in the eyes of patients with immune-mediated uveitis, VKHS, birdshot chorioretinopathy, as well as in HLA-B27 and Behcet’s uveitis [72-75]

IL-23 is a heterodimeric cytokine composed of an IL12B and the IL23A. Prior to the discovery of IL-23, IL-12 had been proposed to represent a key mediator of inflammation in mouse models of inflammation. However, many studies aimed at assessing the role of IL-12 had blocked the activity of IL-12p40, and were therefore not as specific as thought. Studies which blocked the function of IL-12p35 did not produce the same results as those targeting IL-12p40 as would have been expected if both subunits formed part of IL-12 only [76, 77]. Inflammatory cells that express the IL-23R include CD4+ and CD8+ T cells, group 3 innate lymphoid cells and invariant NK cell [78]. The results from different studies are varied. One study identified increased IL-23 in vitreous samples from patients with posterior uveitis [79]. Howewer, a results of analysing aqueous sample did not detect elevated IL-23 in patients with VKHS, Behcet’s, idiopathic, HLA-B27 or sarcoid uveitis [80]. Single nucleotide polymorphisms in the IL-23R gene have also been associated with an increased risk of inflammatory disease, including ankylosing spondylitis associated uveitis, BD, VKHS, and sarcoid uveitis [81-83].

From literary sources it is known that TNFα is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons. A local increase in concentration of TNFα will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, pain and loss of function. Whereas high concentrations of TNFα induce shock-like symptoms, the prolonged exposure to low concentrations of TNFα can result in cachexia, a wasting syndrome. This can be found, for example, in cancer patients. TNFα has both a membrane bound form and a soluble form. TNF Receptor 1 is the main receptor for either form and it is ubiquitously expressed on all cells. Receptor 2 is only expressed on immune cells and only responds to membrane bound TNFα [84-86]. It is interesting fact, that in the experimental autoimmune uveitis model, neutralization of TNFα suppresses disease and mice deficient in TNF Receptor 1 are resistant to the development of uveitis [87, 88]. Chen et al. showed that in patients with anterior uveitis (HLA-B27, idiopathic uveitis, VKHS and Behcet’s uveitis) in aqueous humor elevated TNFα levels has identified [89]. In contrast, in one patients with intermediate uveitis aqueous levels of TNFα were similar to controls; however, serum TNFα was elevated [90].

Over the last two decades, advances in the understanding of the pathogenesis of inflammatory diseases, as well as improved biotechnology, have enabled selective targeting of the chemical mediators of diseases. Recently, a new class of drugs called biologics, that target the various mediators of the inflammation cascade, may potentially provide more effective and less toxic treatment [91]. There are a wide variety of new and emerging biological agents currently being used in the treatment of uveitis which has expanded the therapeutic horizons far beyond previous limitations [92].

A large number of scientific research gives us the opportunity to make quality conclusions about the possibility of using anti-interleukin therapies in some diseases, as evidenced by experimental and clinical studies (table I) The most studied agents among the anti-interleukins in case of autoimmune deseases are Tocilizumab, Sirukumab, Secukinumab, Ixekizumab, Brodalimumab, Ustekinumab, Risankizumab and Fezakinumab. Golimumab, Intliximab, Adalimumab, Ustekinumab, Secukinumab were studied in noninfection uveitis. Etanercept, although paradoxically responsible in very rare cases of the onset of uveitis in patients with inflammatory rheumatic conditions, is still an effective drug for the treatment of inflammatory ocular diseases [93-107].

It is extreamly important to understand the mechanisms underlying the pathogenesis of uveitis for create set-up innovative treatments aimed to reduce inflammation and prevent severe ocular complications, such as glaucoma, keratic precipitates, retinal (macular) oedema and neovascularization. Futhermore prospective randomized controlled trials for biologics are urgently needed to ascertain their actual role in the therapy of uveitis.


1. AU is an inflammatory process of the uveal components due to an autoimmune reaction to self-antigens. It can present as an isolated entity or associated with a systemic autoimmune disease. AU may lead to significant visual limitation or total blindness.

2. The most important interleukins in the pathogenesis of AU are IL-6, IL-10, IL-17, IL-22, IL-23 and TNF-α.

3. Anti-interleukin therapy is partially described. Golimumab, Intliximab, Adalimumab, Ustekinumab, Secukinumab were studied in noninfection uveitis Just few agents (Golimumab, Intliximab, Adalimumab, Ustekinumab, Secukinumab) are showed positive therapeutic effect on uveitis. Future randomized controlled trials are urgently needed to be conduct to define both benefits and risks of these agents in the treatment of the autoimmune uveitis.


1. Gritz D.C, Wong I.G. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology.2004; 111:491–500.

2. Suttorp-Schulten M.S, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol.1996; 80(9):844–8.

3. Miserocchi E, Fogliato G, Modorati G, et al. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol.2013; 23:705–17.

4. Thorne J.E, Suhler E, Skup M, et al. Prevalence of noninfectious uveitis in the United States: a claims-based analysis. JAMA ophthalmology.2016; 134(11):1237-45.

5. De Smet M.D, Taylor S.R, Bodaghi B, et al. Understanding uveitis: the impact of research on visual outcomes. Prog Retin Eye Res.2011; 30:452–70.

6. Tsirouki T, Dastiridou A, Symeonidis C, et al. Focus on the Epidemiology of Uveitis. Ocular Immunology and Inflammation.2016;1-15.

7. Durrani O.M, Tehrani N.N, Marr J.E, et al. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol.2004; 88(9):1159–62.

8. Chams H.R, Mohammadi S.F, Ohno S. Epidemiology and prevalence of uveitis: review of literature. Iranian J Ophthalmol.2009; 21:4–16.

9. Hassan A. Al Dhibi, Hanan N. Al Shamsi, Ammar M. Al-Mahmood, et al. Patterns of Uveitis in a Tertiary Care Referral Institute in Saudi Arabia. Ocular Immunology and Inflammation. 2016; 5: 1-8.

10. Miserocchi E, Fogliato G, Modorati G, Bandello F. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol.2013; 23(5):705-17.

11. Niederkorn J. Y, Kaplan H. J. Immune response and the eye. Karger; Basel. 2007:336 p.

12. Gritz D.C, Wong I.G: Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology.2004; 111:491–500.

13. Nussenblatt R, Whitcup S. Uveitis: fundamentals and clinical practice. Elsevier; Canada. 2010:263 p.

14. Munoz-Fernandez S, Martin-Mola E. Uveitis. Best Pract Res Clin Rheumatol. 2006; 20: 487–505.

15. Fang W, Yang P. Vogt-koyanagi-harada syndrome. Curr Eye Res.2008; 33:517–23.

16. Durrani K, Foster C.S. Psoriatic uveitis: a distinct clinical entity? Am J Ophthalmol.2005; 139:106–11.

17. Mercy K, Kwasny M, Cordoro KM, et al. Clinical manifestations of pediatric psoriasis: results of a multicenter study in the United States. Pediatr Dermatol.2013; 30:424–8.

18. Davatchi F, Assaad-Khalil S, Calamia KT, et al. The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol.2014; 28(3):338-47.

19. Demiroglu H, Dundar S. Effects of age, sex, and initial presentation on the clinical course of Behçet’s syndrome. South Med J.1997; 90:567.

20. Germain B.F, Moroney J.D, Guggino G.S, et al. Anterior uveitis in Kawasaki disease. J Pediatr.1980; 97:780–1.

21. Berntson L, Nordal E, Aalto K, et al. HLA-B27 predicts a more chronic disease course in an 8-year followup cohort of patients with juvenile idiopathic arthritis.2013; 40:725–31.

22. Amador-Patarroyo M.J, Rodriguez-Rodriguez A, Montoya-Ortiz G. How does age at onset influence the outcome of autoimmune diseases? Autoimmune Dis.2012; 2012:251-73.

23. Andrade F.A, Foeldvari I, Levy R.A. Diagnostic Criteria in Autoimmune Diseases. NJ: Humana Press.2008;461–5.

24. Sampaio-Barros P.D, Conde R.A, Bonfiglioli R, et al. Characterization and outcome of uveitis in 350 patients with spondyloarthropathies. Rheumatol Int.2006; 26:1143–6.

25. Chang J.H, McCluskey P.J, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol.2005; 50:364–88.

26 Kara C. LaMattina, Debra A. Goldstein Adalimumab for the Treatment of Uveitis. Expert Review of Clinical Immunology.2017; 1:1-23.

27. LeHoang P. The gold standard of noninfectious uveitis: corticosteroids. Dev Ophthalmol.2012; 51:7–28.

28. Gregory 2nd A.C, Kempen J.H, Daniel E, et al. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis: The Systemic Immunosuppressive Therapy for Eye Diseases Study. Ophthalmology.2013; 120(1):186–92.

29. Adorini L. Cytokine-based immunointervention in the treatment of autoimmune diseases. Clin Exp Immunol.2003; 132:185-92.

30. Prud’homme G.J. Gene Therapy of Autoimmune Disease. Plenum Publishers and Kluwer Academic; USA.2005:140 p.

31. Greiner K, Amer R. The role of cytokines for the diagnosis of uveitis. Klin Monbl Augenheilkd.2008; 225:564–569.

32. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature.2006; 441(7090):235-8.

33. Mosmann T.R, Coffman R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol.1989; 7:145–73.

34. Jun-Ming Zhang, Jianxiong An. Cytokines, Inflammation and Pain. Int Anesthesiol Clin.2007; 45(2):27–37.

35. Nasonov YEL. Farmakoterapiya revmatoidnogo artrita–vzglyad v 21 vek. Klinicheskaya meditsina.[Pharmacotherapy for rheumatoid arthritis — a look into the 21st century] 2005;6:8-12. 

36. Kristiansen O.P, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes.2005; 114–24.

37. Dubinski A, Zdrojewicz Z. The role of interleukin-6 in development and progression of atherosclerosis. Polski Merkuriusz Lekarski (in Polish).2007; 22(130):291–4.

38. Dowlati Y, Herrmann N, Swardfager W, et al. «A meta-analysis of cytokines in major depression». Biological Psychiatry.2010; 67(5):446–57.

39. Swardfager W, Lanctot K, Rothenburg L, et al. A meta-analysis of cytokines in Alzheimer’s disease. Biological Psychiatry.2010; 68(10):930–41.

40. Tackey E, Lipsky P.E, Illei G.G (2004). Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus.2004; 13(5):339–43.

41. Gado K, Domjan G, Hegyesi H, Falus A. Role of Interleukin-6 in the pathogenesis of multiple myeloma. Cell Biology International.2000; 24(4):195–209.

42. Smith P.C, Hobisch A, Lin D.L, et al. Interleukin-6 and prostate cancer progression. Cytokine & Growth Factor Reviews.2001; 12(1):33–40.

43. Hirohata S, Kikuchi H. Changes in biomarkers focused on differences in disease course or treatment in patients with neuro-Behçet’s disease. Internal Medicine.2012; 51(24):3359–65.

44. Lin P. Targeting interleukin-6 for noninfectious uveitis. Clin Ophthalmol.2015; 9:1697–702.

45. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol.2014; 6:286-95.

46. Yoshimura T, Sonoda K.H, Ohguro N, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology.2009; 48:347–54.

47. Tode J, Richert E, Koinzer S, et al. Intravitreal injection of anti-interleukin (IL)-6 antibody attenuates experimental autoimmune uveitis in mice. Cytokine.2017; 96:8–15.

48. Abu El-Asrar A.M, Berghmans N, Al-Obeidan S.A, et al. The cytokine interleukin-6 and the chemokines CCL20 and CXCL13 are novel biomarkers of specific endogenous uveitic entities. Invest Ophthalmol Vis Sci.2016; 57:4606–13.

49. Chen W, Zhao B, Jiang R, et al. Cytokine expression profile in aqueous humor and sera of patients with acute anterior uveitis. Curr Mol Med.2015; 15:543–9.

50. De Visser L, H de Boer J, T Rijkers G, et al. Cytokines and chemokines involved in acute retinal necrosis. Invest Ophthalmol Vis Sci.2017; 58:2139–51.

51. Mansour A.M, Arevalo J.F, Ziemssen F, et al. Long-term visual outcomes of intravitreal bevacizumab in inflammatory ocular neovascularization. Am J Ophthalmol. 2009; 148:310–16.

52. Weiss K, Steinbrugger I, Weger M, et al. Intravitreal VEGF levels in uveitis patients and treatment of uveitic macular oedema with intravitreal bevacizumab. Eye.2009; 23:1812–8.

53. Valentincic N.V, de Groot-Mijnes J.D, Kraut A, et al. Intraocular and serum cytokine profiles in patients with intermediate uveitis. Mol Vis.2011; 17:2003–10.

54. Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nature Reviews. Immunology.2010; 10(3):170–81.

55. Verma R, Balakrishnan L, Sharma K, et al. A network map of Interleukin-10 signaling pathway. J Cell Commun Signal 2016; 10:61–7.

56. Foxman E.F, Zhang M, Hurst SD, et al. Inflammatory mediators in uveitis: differential induction of cytokines and chemokines in Th1- versus Th2-mediated ocular inflammation. J Immunol.2002; 168:2483–92.

57. Sauer A, Villard O, Creuzot-Garcher C, et al. Intraocular levels of interleukin 17A (IL-17A) and IL-10 as respective determinant markers of toxoplasmosis and viral uveitis. Clin Vaccine Immunol.2015; 22:72–8.

58. Beebe A.M, Cua D.J, de Waal Malefyt R. The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS).Cytokine & Growth Factor Reviews. 2003;13(4–5):403–12.

59. Broderick C.A, Smith A.J, Balaggan K.S, et al. Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis. Mol Ther. 2005; 12:369–73.

60. Agarwal R.K, Horai R, Viley A.M, et al. Abrogation of antiretinal autoimmunity in IL-10 transgenic mice due to reduced T cell priming and inhibition of disease effector mechanisms. J Immunol. 2008; 180:5423–9.

61. Pochat-Cotilloux C, Bienvenu J, Nguyen A.M, et al. Use of a threshold of interleukin-10 and IL-10/IL-6 ratio in ocular samples for the screening of vitreoretinal lymphoma. Retina. 2018, 38(4):773-81.

62. Kuo D.E, Wei M.M, Armbrust K.R, et al. Gradient boosted decision tree classification of endophthalmitis versus uveitis and lymphoma from aqueous and vitreous IL-6 and IL-10 levels. J Ocul Pharmacol Ther.2017; 33:319–24.

63. Nikoopour E, Bellemore SM, Singh B. IL-22, cell regeneration and autoimmunity. Cytokine.2015; 74(1):35–42.

64. Caspi R.R, Mattapallil M.J, Rigden R, et al. Neuroprotective effects of IL-22 during CNS inflammation (CCR4P.203). J Immunol.2015; 175(2):268–84.

65. Sugita S, Kawazoe Y, Imai A, et al. Role of IL-22- and TNF-alpha-producing Th22 cells in uveitis patients with Behcet’s disease. J Immunol.2013; 190:5799–808.

66. Kim Y, Kim T.W, Park Y.S, et al. The role of interleukin-22 and its receptor in the development and pathogenesis of experimental autoimmune uveitis. PLoS One. 2016; 11:154-64.

67. Sainz-de-la-Maza M, Molins B, Mesquida M, et al. Interleukin-22 serum levels are elevated in active scleritis. Acta Ophthalmol.2016; 94:395–99.

68. Moore K.W, de Waal Malefyt R, Coffman R.L, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annual Review of Immunology. 2001; 19:683–765.

69. Sonnenberg G.F, Nair M.G, Kirn T.J, et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. The Journal of Experimental Medicine.2010; 207(6): 1293–305.

70. Song X, Qian Y. The activation and regulation of IL-17 receptor mediated signaling. Cytokine. 2013; 62:175–82.

71. Zhang R, Qian J, Guo J, et al. Suppression of experimental autoimmune uveoretinitis by anti-IL-17 antibody. Curr Eye Res.2009; 34:297–303.

72. Kuiper J.J, Mutis T, de Jager W, et al. Intraocular interleukin-17 and proinflammatory cytokines in HLA-A29-associated birdshot chorioretinopathy. Am J Ophthalmol.2011; 152:177–82.

73. El-Asrar AM, Struyf S, Kangave D, et al. Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis. Clin Immunol.2011; 139:177–84.

74. Jawad S, Liu B, Agron E, et al. Elevated serum levels of interleukin-17A in uveitis patients. Ocul Immunol Inflamm.2013; 21:434–9.

75. Na S.Y, Park M.J, Park S, Lee E.S. Up-regulation of Th17 and related cytokines in Behcet’s disease corresponding to disease activity. Clin Exp Rheumatol.2013; 31:32–40.

76. Leonard J.P, Waldburger K.E, Goldman S.J. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. Journal of Experimental Medicine.1995; 181(1):381–6.

77. Becher B, Durell B.G, Noelle R.J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. Journal of Clinical Investigation.2002;110(4):493–7.

78. Kastelein R.A, Hunter C.A, Cua D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol.2007; 25:221–42.

79. Velez G, Roybal C.N, Colgan D, et al. Precision medicine: personalized proteomics for the diagnosis and treatment of idiopathic inflammatory disease. JAMA Ophthalmol.2016; 134:444–8

80. Abu El-Asrar A.M, Berghmans N, Al-Obeidan S.A, et al. The cytokine interleukin-6 and the chemokines CCL20 and CXCL13 are novel biomarkers of specific endogenous uveitic entities. Invest Ophthalmol Vis Sci.2016; 57:4606–13.

81. Dong H, Li Q, Zhang Y, et al. IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population. PLoS One.2013; 8:55-67.

82. Hou S, Kijlstra A, Yang P. Molecular genetic advances in uveitis. Prog Mol Biol Transl Sci.2015; 134:283–98.

83. Kim S.W, Kim E.S, Moon C.M, et al. Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowe disease. Gut.2011; 60:1527–36.

84. Locksley R.M, Killeen N, Lenardo M.J. The TNF and TNF receptor superfamilies: integrating mammalian biolog. Cell.2001; 104(4):487–501.

85. Horiuchi T, Mitoma H, Harashima S, et al. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology.2010; 49:1215–28.

86. Dowlati Y, Herrmann N, Swardfager W. A meta-analysis of cytokines in major depression». Biol Psychiatry.2010; 67 (5): 446–57.

87. Dick A.D, Duncan L, Hale G, et al. Neutralizing TNF-alpha activity modulates T-cell phenotype and function in experimental autoimmune uveoretinitis. J Autoimmun.1998; 11:255–264.

88. Raveney B.J, Copland D.A, Dick A.D, Nicholson L.B. TNFR1-dependent regulation of myeloid cell function in experimental autoimmune uveoretinitis. J Immunol.2009; 183:2321–9.

89. Chen W, Zhao B, Jiang R, et al. Cytokine expression profile in aqueous humor and sera of patients with acute anterior uveitis. Curr Mol Med.2015; 15:543–9.

90. Valentincic N.V, de Groot-Mijnes J.D, Kraut A, et al. Intraocular and serum cytokine profiles in patients with intermediate uveitis. Mol Vis.2011; 17:2003–10.

91. Servat J.J, Mears K.A, Black E.H, Huang J.J. Biological agents for the treatment of uveitis. Expert Opin Biol Ther.2012; 12(3):311-28.

92. Simon R Taylor. Biologic Therapy in Uveitis. European Ophthalmic Review.2016; 10(1):17–8.

93. Calabrese L.H, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol.2014; 10(12): 720-7.

94. Sheppard M, Laskou F, Stapleton P.P, Hadavi S. Tocilizumab (Actemra). Hum Vaccin Immunother.2017; 13(9):1972–88.

95. Dalen C.I, Duny Y, Barnetche T, et al. Effect of TNF inhibitors on lipid profile in rheumatoid arthritis: a systematic review with meta-analysis. Ann Rheum Dis.2012; 71:862-8.

96. Paroli M.P, Abbouda A, Abicca I, Sapia A. Biological agents in the treatment of uveitis. Advances in Bioscience and Biotechnology.2013; 4: 64-72.

97. Aikawa E, de Carvalho N, Silva A.A, Bonfa C. Immunogenicity of Anti-TNF- alpha agents in autoimmune diseases. Clinical Reviews in Allergy & Immunology.2010; 38:82-9.

98. Aaltonen, K.J., Virkki, L.M., Malmivaara, A., et al. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One.2012; 7(1):194-56.

99. Evereklioglu C. Ocular Behcet disease: current therapeutic approaches. Current Opinion in Ophthalmol.2011; 22:508-16.

100. Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: Results of a prospective open-label study. Annals of the Rheumatic Diseases.2009; 68:696-701.

101. Schmeling H, Horneff G. Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology.2005; 44:1008-11.

102. Tappeiner C, Heinz C, Ganser G, Heiligenhaus A. Is tocilizumab an effective option for treatment of refractory uveitis associated with juvenile idiopathic ar- thritis? The Journal of Rheumatology.2012; 39:1294-5.

103. William M, Faez S, Papaliodis G.N, Lobo A.M. Golimumab for the treatment of refractory juve- nile idiopathic arthritis-associated uveitis. Journal of Ophthalmic Inflammation and Infection.2012; 2:231-3.

104. Langley R.G, Elewski B.E, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med.2014; 371:326.

105. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med.2015; 373:1318–28.

106. Papp K.A, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med.2017; 376:1551–60.

107. Blauvelt A, Papp K.A, Griffiths C.E, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol.2017; 76:405–417.

Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.


Nadiya B. Kuryltsiv

69 Pekarska str, Lviv, Ukraine


Received: 15.02.2019

Accepted: 01.04.2019

Table I. Spectrum of specific anti-interleukin drugs

Generic Name/

Brand Name



Disease area

Tocilizumab /Actemra, RoActemra

La Rochе

IL – 6

Registration with RA,
Juvenile Rheumatoid Arthritis



IL – 6


Sarilumab/ Kevzara

Regeneron and Sanofi

IL – 6

RA, Spondylitis



IL – 6

RA, Spondylitis,



IL – 6


Secukinumab/ Consentyx


IL – 17

phase IІI trials for Psoriasis, PA, RA, AS,

a phase II trial for chronic noninfecton uveitis

Ixekizumab/ Taltz

Eli Lilly

IL – 17

a phase II trial for psoriasis, a phase II trial for PA, a phase I trial for RA

Brodalimumab/ Siliq


IL – 17

a phase II trial for psoriasis, (PA), RA, asthma



IL – 17



Roche’s Genentech

IL – 17




IL – 17


Ustekinumab/ Stelara

Centocor, Janssen

IL – 23

Psoriasis, PA, a phase II trial for AS, a phase III trial for Crohn’s disease, sarcoidosis, cirrhosis, phase II trials for uveitis

Tildrakizumab/ Ilymya

Sun Pharmaceuticals



Guselkumab/ Tremfya



Psoriasis, PA, RA




Crohn’s disease




Psoriasis, Crohn’s disease, psoriatic arthritis

CNTO 1959


IL – 23

a phase II trial for Psoriasis



IL – 23

a phase II trial for Psoriasis



IL – 23

Psoriasis, a phase II trial for Crohn’s disease

Adalimumab/ Humira



RA, noninfectious uveitis

Infliximab/ Remicade



noninfectious uveitis

Golimumab/ Simponi



PA, RA, AS, ulcerative colitis, noninfectious uveitis




a phase I trial for psoriasis, a phase II trial for RA,

a phase II trial for atopic dermatitis

Etanercept/ ENBREL



RA, AS, JIA, PA, chronic uveitis