The Use of Curcumin in the Comprehensive Treatment of HLA-B27-Associated Uveitis

Abstract. Relevance. Curcumin is a potential candidate for the treatment of uveitis due to its anti-inflammatory effect and minimal side effects, as it is a natural plant-based product. Study objective: to improve the efficacy of treatment for anterior HLA-B27-associated uveitis by adding a curcumin-containing preparation to the complex therapy. Materials and methods: 27 patients (47 eyes) with anterior HLA-B27-associated uveitis. The follow-up period was 24 months. All included patients received systemic therapy with methylprednisolone and methotrexate. Patients in the main group took a complex preparation containing curcumin throughout the entire follow-up period. Patients in the control group received complex preparations with a similar composition but without curcumin. Results. We found no difference between the groups in the number of relapses. We found a significant difference between the groups in the intensity of inflammation, as determined by laser photometry during relapses. Most episodes of uveitis recurrence in patients in the main group had photometry readings ranging from 20 to 50, while in the control group, they ranged from 50 to 100. In patients in the main group, photometry readings were below 20 in 6 episodes of uveitis. In contrast, photometry values below 20 were not observed at all in patients in the control group. Photometry values above 100 were recorded in only two episodes in the main group, and in five episodes in the control group. We observed a difference between the groups in visual acuity at the onset of recurrence: in the main group, visual acuity was 0.52 (SD 0.24) versus 0.32 (SD 0.21), p = 0.0003. A strong correlation was established between photometry readings and visual acuity during a uveitis relapse. The duration of the relapse in the main group was 9.62 (SD 1.98) days, and in the control group—10.14 (SD 2.24), with a statistically insignificant difference. Conclusions. Adding a curcumin-containing preparation to complex therapy improves the efficacy of treatment for anterior HLA-B27-associated uveitis. With its continuous use, the severity of uveitis recurrence is significantly reduced and visual impairment is less pronounced; however, curcumin use does not affect the frequency of recurrences.
Keywords: uveitis; therapy; curcumin

Introduction
Uveitis is a T-cell-mediated abnormal immune response to antigens in the eye, leading to acute or chronic dysregulation of the normal immune response of the eyes [5]. The predominant form of uveitis in most studied populations is anterior uveitis, accounting for approximately 50–60% of all uveitis cases observed in tertiary care centers. HLA-B27-associated uveitis is the most common form of anterior uveitis, accounting for 18–32% of all cases of anterior uveitis worldwide [21]. Treatment typically involves the use of topical (instillations and injections) and systemic corticosteroids, disease-modifying antirheumatic drugs such as methotrexate and sulfasalazine, as well as TNF-α inhibitors [3]. However, all these drugs have quite severe side effects with long-term use [6, 12, 18, 19]. Therefore, the search for new drugs and more effective treatment regimens for uveitis while minimizing side effects is ongoing.
Curcumin caught our attention as a potential candidate for the treatment of uveitis due to its anti-inflammatory effect with minimal side effects, as it is a natural plant-based product [7, 10, 14, 16].
The aim of this study was to improve the efficacy of treatment for anterior HLA-B27-associated uveitis by adding a curcumin-containing drug to the complex therapy.

Materials and Methods
The study was conducted at the V.P. Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine. The study included 27 patients aged 18 to 40 years (47 eyes) with anterior HLA-B27-associated uveitis. In 20 patients, uveitis was bilateral; in the remaining 7, it was unilateral. Ophthalmological examination of the patients included assessment of patient complaints, visual acuity testing, biomicroscopy, ophthalmoscopy, tonometry, and laser photometry (Kowa FM-600). The follow-up period was 24 months. The study included only patients receiving systemic therapy with methylprednisolone (dose ranging from 2 to 8 mg daily, continuous administration) and methotrexate (dose ranging from 7.5 to 17.5 mg weekly, continuous administration). Patients who did not receive these medications or who received other therapies (e.g., adalimumab, sulfasalazine, azathioprine, mycophenolate mofetil, etc.) were excluded from the study to avoid introducing potential bias in the assessment of the efficacy of adjunctive curcumin therapy. Patients were enrolled in the study during remission of uveitis and were already receiving systemic therapy that was controlling their condition. That is, at the start of the study, patients had a history of at least one episode of uveitis.
Treatment of uveitis was conducted in an inpatient setting and included the use of topical corticosteroids in the form of parabulbar/subconjunctival injections, systemic nonsteroidal anti-inflammatory drugs, and, in some cases, an increase in the doses of methylprednisolone and/or methotrexate. Additionally, in the presence of complications such as ocular hypertension/secondary glaucoma, cystoid macular edema, and optic nerve edema, necessary medications were prescribed, namely antihypertensive eye drops, diuretics, and neuroprotectants.
Patients were divided into 2 groups: patients in the main group (a total of 14 patients, 10 patients with bilateral uveitis, 4 patients with unilateral uveitis) received the complex preparation Optix Premium, which contains 50 mg of curcumin, in addition to the main systemic therapy on a continuous basis throughout the entire observation period. In addition to curcumin, the complex preparation contains omega-3 fatty acid ethyl esters, vitamin C, vitamin E, lutein, coenzyme Q10, zinc, astaxanthin, zeaxanthin, copper, and vitamin D. Patients in the control group (a total of 13 patients, 10 with bilateral uveitis and 3 with unilateral uveitis) received complex preparations with a similar composition but without curcumin in addition to their primary systemic therapy.
The criteria for assessing treatment efficacy included the annual recurrence rate, laser photometry data during exacerbations, visual acuity at the onset of recurrence and during remission (one month after recurrence), and the duration of recurrence.
For the convenience of assessing the intensity of inflammation based on laser photometry data, we defined categories according to the photometry data (unit of measurement—number of photons/ms). Up to 20—first category, 20 to 50—second category, 50 to 100—third category, over 100—fourth category.
Statistical analysis was performed using Statistica 9 software, and the mean, SD, and correlation coefficient were calculated.
The study was conducted in accordance with the rules and principles of bioethics. Patients were informed about the content of diagnostic and therapeutic procedures and signed an informed consent form as study participants.

Results
Of the 27 patients included in the study, 21 had uveitis associated with a systemic disease from the group of seronegative spondyloarthropathies, while 6 patients had isolated uveitis without any systemic involvement. Of these patients with an established systemic diagnosis from the group of seronegative spondyloarthropathies, 18 had ankylosing spondylitis, 1 had reactive arthritis, and 2 had psoriasis. All of these patients, in addition to being monitored by an ophthalmologist, were under the care of a rheumatologist.
The average number of uveitis relapse episodes in the main group was 1.54 (SD 1.14), ranging from a minimum of 0 to a maximum of 4 episodes over 2 years. The total number of uveitis relapse episodes in this group was 37 cases over 2 years.
The number of uveitis recurrence episodes in patients in the control group averaged 1.48 (SD 1.08), with the same minimum of 0 and maximum of 4 episodes over 2 years. The total number of uveitis recurrence episodes in this group was 34 cases over 2 years.
No statistically significant difference was found between the number of uveitis flare-up episodes among patients in the main and control groups, p = 0.85.
In contrast to the number of uveitis recurrence episodes, we found a difference between the groups regarding the intensity of inflammation, as determined by laser photometry during recurrences. The difference between the groups is statistically significant, p = 0.0002.
Importantly, in patients in the main group, the intensity of inflammation during 6 episodes of uveitis was in the first category, i.e., photometry readings were below 20. In contrast, photometry readings below 20 were not observed at all in patients in the control group. Inflammation intensity of the second category (i.e., within the laser photometer range of 20 to 50) was observed in 19 recurrence episodes in patients in the main group versus 9 episodes among patients in the control group. There were 10 cases with third-category laser photometry readings (50–100) in the main group versus 20 cases in the control group. Furthermore, photometer readings above 100 were observed in only two episodes of uveitis in the main group, whereas in the control group, they were observed in five episodes. Thus, in the main group, photometry readings ranged from 20 to 50 in most patients, while in the control group, they ranged from 50 to 100 in most patients.
Thus, we observed significantly lower uveitis activity during recurrence in patients in the main group compared to patients in the control group.
We also observed a difference between the groups in visual acuity at the onset of the relapse. Specifically, in the main group, visual acuity was 0.52 (SD 0.24) versus 0.32 (SD 0.21), p = 0.0003. With a minimum of 0.1 and a maximum of 1.0 for the main group and a minimum of 0.05 and a maximum of 0.8 in the control group.
However, we found no difference in visual acuity during remission (measured one month after each relapse). In the main group, visual acuity was 0.92 (SD 0.12), and in the control group, 0.88 (SD 0.16); the difference was not statistically significant, p = 0.07.
We found a strong correlation between photometric parameters and visual acuity during a uveitis relapse. For the main group, the correlation coefficient was 0.9, and for the control group, 0.92.
The duration of the relapse in the main group was 9.62 (SD 1.98) days, and in the control group—10.14 (SD 2.24). However, the difference is not statistically significant, p = 0.3.

Discussion
The most promising effects of curcumin are its anti-inflammatory and antioxidant properties. Curcumin disrupts the regulation of TNF-α and pro-inflammatory interleukins (IL-1, IL-2, IL-6, IL-8, and IL-12) due to its ability to inhibit Janus kinase and influence transcription [8, 11, 13]. It is known that in autoimmune uveitis, TNF-α production plays a very important role, and this cytokine is the target of the most modern treatment for this condition (TNF-α inhibitors). TNF-α is a pro-inflammatory cytokine that plays a key role in the development of the inflammatory response. Furthermore, in addition to the normal inflammatory response, TNF-α also triggers pathological immune reactions, such as excessive inflammation and tissue damage. Macrophages and lymphocytes, as well as a number of non-immune cells, are responsible for the production of this cytokine [2, 17, 20].
We believe that in our study, long-term curcumin administration, due to its ability to inhibit the synthesis of pro-inflammatory cytokines, specifically TNF-α, contributed to a reduction in uveitis activity during relapse. Of course, the fact that visual acuity in patients who took curcumin was higher than in patients in the control group is explained by the fact that they had a milder course of uveitis. That is, the number and concentration of so-called inflammatory cells in the anterior chamber were higher in patients in the control group, which, in turn, led to greater formation of fibrinous membranes in the pupil and, consequently, a more severe decline in vision. In addition, curcumin possesses neuroprotective properties [1, 9]. There have also been studies demonstrating that curcumin protects retinal cells from oxidative stress [4]. Therefore, we hypothesize that it could have a positive effect on the condition of the retina in cases of cystoid macular edema, a complication frequently associated with HLA-B27-associated uveitis. However, the effect of curcumin on uveitis complications, particularly those involving the posterior pole of the eye—which we did not evaluate in this study—requires more detailed further investigation.
There is an interesting study on the use of curcumin specifically for chronic uveitis, the data from which correlate to some extent with our results [15]. Of course, the study design differed significantly. First, most of the patients studied had a tuberculous etiology of uveitis, and there were no patients with a positive HLA-B27 antigen at all. Second, the patients were divided such that both the control and the main group received curcumin. The difference between the groups was that patients in the main group took only curcumin, while those in the control group received anti-tuberculosis therapy along with curcumin. Patients with a stronger PPD (purified protein derivative) reaction were selected for the control group. That is, in our study, curcumin was added to the treatment regimen, whereas in the study by V. Lal and colleagues, curcumin was the primary treatment for uveitis. Furthermore, patients in both groups did not take any systemic or topical corticosteroids at all. The authors, like us, assessed uveitis recurrences. During the follow-up period (3 years), 55% of patients in the treatment group and 36% in the control group developed a recurrence. A significant number of patients in the study experienced vision loss due to complications: 22% in the treatment group and 21% in the control group. And although there was no significant difference between the groups in the study—even regarding recurrences, with patients in the control group showing better results—it should be noted that curcumin monotherapy was administered (without the addition of corticosteroids or antituberculosis drugs). Thus, curcumin demonstrated very good results in the treatment of chronic uveitis. The authors explain the effectiveness of curcumin therapy by its action, similar to that of corticosteroids. This is consistent with our study results, in which curcumin (as an adjunctive therapy) demonstrated efficacy in reducing inflammatory activity in autoimmune uveitis.

Conclusions
Adding a curcumin-containing preparation (Optix Premium) to complex therapy allows for increased treatment efficacy in anterior HLA-B27-associated uveitis. With its regular use, the severity of uveitis recurrence is significantly reduced and vision is less impaired, but curcumin use does not affect the frequency of recurrences.

Conflict of interest. The authors declare no conflict of interest in the preparation of this article.

Funding information. The study was conducted using public funds from a state source.

Information on each author’s contribution. Zborovska O.V. — concept, study design, analysis of data; Dorokhova O.E. — data collection and processing, drafting the text.

References
1. Askarizadeh A., Barreto G.E., Henney N.C., Majeed M., Sahebkar A. Neuroprotection by curcumin: A review on brain delivery strategies. Int. J. Pharm. 2020 Jul 30. 585. 119476. doi: 10.1016/j.ijpharm.2020.119476. Epub 2020 May 27. PMID: 32473377.
2. Balevic S.J., Rabinovich C.E. Profile of adalimumab and its potential in the treatment of uveitis. Drug Des. Devel. Ther. 2016. 10. 2997-3003. doi: 10.2147/DDDT.S94188.
3. Bouzid N. et al. Impact of systemic treatments on the course of HLA-B27-associated uveitis: A retrospective study of 101 patients. PLoS One. 2020. 15(3). e0230560. doi: 10.1371/journal.pone.0230560.
4. Bucolo C., Drago F., Maisto R., Romano G.L., D’Agata V., Maugeri G., Giunta S. Curcumin prevents high glucose damage in retinal pigment epithelial cells through ERK1/2-mediated activation of the Nrf2/HO-1 pathway. J. Cell. Physiol. 2019. 234. 17295-17304.
5. Becker M.D., Adamus G., Davey M.P., Rosenbaum J.T. The role of T cells in autoimmune uveitis. Ocul. Immunol. Inflamm. 2000. 8. 93-100. PMID: 10980681.
6. Castiblanco C., Foster C.S. Review of Systemic Immunosuppression for Autoimmune Uveitis. Ophthalmol. Ther. 2014. 3(1–2). 17–36.
7. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). The Journal of Alternative & Complementary Medicine. 2003. 9(1). 161-168. DOI: 10.1089/107555303321223035.
8. Cho J.W., Lee K.S., Kim C.W. Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int. J. Mol. Med. 2007 Mar. 19(3). 469-74. PMID: 17273796.
9. Cole G.M., Teter B., Frautschy S.A. Neuroprotective effects of curcumin. Adv. Exp. Med. Biol. 2007. 595. 197-212. doi: 10.1007/978-0-387-46401-5_8. PMID: 17569212; PMCID: PMC2527619.
10. Fadus M.C. et al. Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. Journal of Traditional and Complementary Medicine. 2017. 7(3). 339-346. doi: 10.1016/j.jtcme.2016.08.002.
11. Franzone F., Nebbioso M., Pergolizzi T., Attanasio G., Musacchio A., Greco A. et al. Anti-inflammatory role of curcumin in retinal disorders (Review). Experimental and Therapeutic Medicine. May 21, 2021. 790. https://doi.org/10.3892/etm.2021.10222.
12. García-Lagunar M.H. et al. Reasons for discontinuation and adverse effects of TNFα inhibitors in a cohort of patients with rheumatoid arthritis and ankylosing spondylitis. Annals of Pharmacotherapy. 2017. 51(5). 388-393.
13. Jain S.K., Rains J., Croad J., Larson B., Jones K. Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-alpha, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid. Redox Signal. 2009 Feb. 11(2). 241-9. doi: 10.1089/ars.2008.2140. PMID: 18976114; PMCID: PMC2933148.
14. Jurenka J.S. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern. Med. Rev. 2009 Sep. 14(3). 277. PMID: 19594223.
15. Lal B., Kapoor A.K., Asthana O.P., Agrawal P.K., Prasad R., Kumar P., Srimal R.C. Efficacy of curcumin in the management of chronic anterior uveitis. Phytother. Res. 1999 Jun. 13(4). 318-22. doi: 10.1002/(SICI)1099-1573(199906)13:4<318::AID-PTR445>3.0. CO;2-7. PMID: 10404539.
16. Menon V.P., Sudheer A.R. Antioxidant and anti-inflammatory properties of curcumin. Adv. Exp. Med. Biol. 2007. 595. 105-125. doi: 10.1007/978-0-387-46401-5_3.
17. Pérez-Guijo V. et al. Tumor necrosis factor-alpha levels in aqueous humor and serum from patients with uveitis: the involvement of HLA-B27. Curr. Red. Res. Opin. 2004. 20(2). 155-157.
18. Sampaio-Barros P.D., van der Horst-Bruinsma I.E. Adverse effects of TNF inhibitors in SpA: are they different from RA? Best Practice & Research Clinical Rheumatology. Oct. 2014. 28(5). 747-763. doi: 10.1016/j.berh.2014.10.001. Epub 2014 Oct 31.
19. Taylor S.R., Isa H., Joshi L. et al. New developments in corticosteroid therapy for uveitis. Ophthalmologica. 2010. 224 Suppl. 1. 46-53. doi: 10.1159/000318021.
20. Tracey D., Klareskog L., Sasso E.H. et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther. 2008 Feb. 117(2). 244-279. doi: 10.1016/j.pharmthera.2007.10.001.
21. Wakefield D., Chang H.J., Amjadi S., Maconochie Z., el-Asrar A.A., McCluskey P. What is new in HLA-B27-associated acute anterior uveitis? Ocul. Immunol. Inflamm. 2011 Apr. 19(2). 139-44. doi: 10.3109/09273948.2010.542269.