Vitamin D and Curcumin Piperine Attenuates Disease Activity and Cytokine Levels in Systemic Lupus Erythematosus Patients

Systemic Lupus Erythematosus Clinical Trial

Official title:

The Combination of Vitamin D and Curcumin Piperine Attenuates the Disease Activity and Pro-Inflammatory Cytokines Levels in Systemic Lupus Erythematosus Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05430087
• Other study ID #: 38/SK/UN10.F08.06/KS/2019
• Status: Completed
• Phase: Phase 2
• Start date: March 1, 2020
• Est. completion date: January 31, 2022

Study information

• Verified date: June 2022
• Source: Saiful Anwar Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with a relatively high mortality and morbidity rate, especially in developing countries such as Indonesia. In Indonesia, a previous study demonstrated that almost 71% of SLE patients experience hypovitaminosis D, with serum vitamin D 25 levels less than 30 ng/ml. Several factors contribute to the low vitamin D levels among SLE patients. Less exposure to sunlight or insufficient vitamin D intake contributes to SLE patients low vitamin D levels. Some other studies also revealed that vitamin D metabolism gene polymorphisms are also associated with patients with SLE. Vitamin D is essential for bone health and has an essential role in immune system modulation and controlling autoimmune diseases, including SLE. Another study demonstrates that curcumin supplementation in premenopausal women and dysmenorrhea improves vitamin D levels. Despite the promising properties of curcumin in improving vitamin D biological actions, our previous study reveals that the addition of curcumin in vitamin D administration do not significantly improve the disease activity or cytokine imbalance in SLE patients. The synergistic property of curcumin with vitamin D in regulating immune cells is an open opportunity for researchers to increase the response to vitamin D3 therapy. Several studies have reported the efficacy of vitamin D or curcumin for SLE treatment. However, none mentioned the combination of curcumin added with piperine and vitamin D3. We hypothesized that adding curcumin piperine with vitamin D3 as a complementary treatment in SLE patients would improve the clinical symptoms or cytokine balance among SLE patients. Therefore, this study aims to observe the effects of adding curcumin-piperine with vitamin D3 in clinical outcomes and cytokines levels in SLE patients with hypovitaminosis D.

Description:

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease with a relatively high mortality and morbidity rate, especially in developing countries such as Indonesia. In Indonesia, a previous study demonstrated that almost 71% of SLE patients experience hypovitaminosis D, with serum vitamin D (25(OH)D3) levels less than 30 ng/ml. Several factors contribute to the low vitamin D levels among SLE patients. Less exposure to sunlight or insufficient vitamin D intake contributes to SLE patients' low vitamin D levels. Some other studies also revealed that vitamin D metabolism gene polymorphisms are also associated with patients with SLE. Vitamin D is essential for bone health and has an essential role in immune system modulation and controlling autoimmune diseases, including SLE. An increase in the pro-inflammatory cytokine, such as interleukin-6 (IL-6), is found in SLE patients with hypovitaminosis D. SLE patients with hypovitaminosis D have a more severe clinical condition and disease activity. However, previous meta-analysis shows that vitamin D supplementation is effective in increasing the serum 25(OH)D levels, may improve fatigue, and is well-tolerated in patients with SLE. However, it does not seem to have significant effects in decreasing the positivity of anti-dsDNA and disease activity. Thus, another approach to enhance the effect of vitamin D to suppress the pro-inflammatory condition in SLE should be considered. Curcumin is a phenolic compound widely found in ginger, turmeric, and curcuma plants and has the potential as an immunomodulator for the complementary treatment of SLE. Curcumin acts as an activator or inhibitor of several transcription factors that play a role in activating and differentiating Th1, Th2, Th17, and Tregs. In a previous report, curcumin synergistically interacts with vitamin D because it is also a natural ligand for the vitamin D receptor (VDR). Previous studies reveal that administering a combination of curcumin and vitamin D3 resulted in a better recovery of neuronal cells from Alzheimer's disease. Another study demonstrates that curcumin supplementation in premenopausal women and dysmenorrhea improves vitamin D levels. Despite the promising properties of curcumin in improving vitamin D biological actions, our previous study reveals that the addition of curcumin in vitamin D administration do not significantly improve the disease activity or cytokine imbalance in SLE patients. Because of the pharmacokinetics of curcumin, this substance is poorly absorbed in the gut and has low bioavailability when administered by the oral route. Therefore, special treatment is needed to improve the bioavailability of curcumin. One of the potential strategies is adding the piperine when administering curcumin orally. Piperine can be found in plants of the Piperaceae family, including 2-7.4% of black pepper and white pepper (Piper nigrum L.). Piperine also has antioxidant, immunomodulatory, and anti-inflammatory activities. Piperine can increase the in vivo bioavailability of curcumin by inhibiting its metabolism and reducing the required dose of curcumin in the clinical setting. Piperine can also increase cell membrane permeability, thereby increasing drug absorption. Piperine binds to several areas of the enzyme to form a hydrogen bond complex with curcumin that can increase its bioavailability up to twenty times. The synergistic property of curcumin with vitamin D in regulating immune cells is an open opportunity for researchers to increase the response to vitamin D3 therapy. Several studies have reported the efficacy of vitamin D or curcumin for SLE treatment. However, none mentioned the combination of curcumin added with piperine and vitamin D3. We hypothesized that adding curcumin piperine with vitamin D3 as a complementary treatment in SLE patients would improve the clinical symptoms or cytokine balance among SLE patients. Therefore, this study aims to observe the effects of adding curcumin-piperine with vitamin D3 in clinical outcomes and cytokines levels in SLE patients with hypovitaminosis D.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: January 31, 2022
• Est. primary completion date: January 31, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• SLE patients referred to the Rheumatology outpatient clinic Saiful Anwar General Hospital, Malang, Indonesia
• Had an active disease, characterized by the Mexican SLE Disease Activity Index (Mex-SLEDAI) score >3
• Had low vitamin D levels (serum vitamin D3 levels <30 ng/ml)

Exclusion Criteria:

• Pregnant or breast-feeding patients
• Took supplementations containing vitamin D or curcumin in the last three months
• Had severe liver disorders (AST or ALT levels >2.5 times of upper normal limit)
• Had impaired renal function (GFR < 25 ml/min or oliguria with urine output < 400 ml/day)
• Had other autoimmune diseases or severe infections such as tuberculosis, pneumonia, or HIV, history of renal stones, hypercalciuria, intestinal malabsorption
• Refusal to participate in the study

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus

Intervention

Drug:
• Observe the clinical outcome and inflammatory cytokines levels in patients with systemic lupus erythematosus (SLE) after being supplemented with Cholecalciferol (Vitamin D3) and Curcumin-Piperine.
All patients and physicians were blinded to group assignment and treatment allocation. All subjects received the tablets for three months. All subjects were still required to consume their routine medications during the supplementation according to the disease activity. Patients were evaluated at baseline and after the end of supplementation for clinical and laboratory parameters. Adherence to therapy was assessed by monthly pill counts of returned tablets and biweekly phone calls to the patients.

Locations

Country	Name	City	State
Indonesia	Saiful Anwar General Hospital	Malang	East Java

Sponsors (1)

Lead Sponsor	Collaborator
Saiful Anwar Hospital

Country where clinical trial is conducted

Indonesia, 

References & Publications (30)

Alamro AA, Alsulami EA, Almutlaq M, Alghamedi A, Alokail M, Haq SH. Therapeutic Potential of Vitamin D and Curcumin in an In Vitro Model of Alzheimer Disease. J Cent Nerv Syst Dis. 2020 May 27;12:1179573520924311. doi: 10.1177/1179573520924311. eCollectio — View Citation

Arabnezhad L, Mohammadifard M, Rahmani L, Majidi Z, Ferns GA, Bahrami A. Effects of curcumin supplementation on vitamin D levels in women with premenstrual syndrome and dysmenorrhea: a randomized controlled study. BMC Complement Med Ther. 2022 Jan 22;22(1 — View Citation

Aranow C, Kamen DL, Dall'Era M, Massarotti EM, Mackay MC, Koumpouras F, Coca A, Chatham WW, Clowse ME, Criscione-Schreiber LG, Callahan S, Goldmuntz EA, Keyes-Elstein L, Oswald M, Gregersen PK, Diamond B. Randomized, Double-Blind, Placebo-Controlled Trial — View Citation

Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, Smolen JS, Wofsy D, Boumpas DT, Kamen DL, Jayne D, Cervera R, Costedoat-Chalumeau N, Diamond B, Gladman DD, Hahn B, Hiepe F, Jacobsen S, Khanna D, Lerstrøm K, Massarotti E, McCune J, — View Citation

Bartik L, Whitfield GK, Kaczmarska M, Lowmiller CL, Moffet EW, Furmick JK, Hernandez Z, Haussler CA, Haussler MR, Jurutka PW. Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. J Nu — View Citation

Breslin LC, Magee PJ, Wallace JM, McSorley EM. An evaluation of vitamin D status in individuals with systemic lupus erythematosus. Proc Nutr Soc. 2011 Nov;70(4):399-407. doi: 10.1017/S0029665111001613. Epub 2011 Aug 24. Review. — View Citation

Correa-Rodríguez M, Pocovi-Gerardino G, Callejas-Rubio JL, Ríos-Fernández R, Martín-Amada M, Cruz-Caparrós MG, DelOlmo-Romero S, Ortego-Centeno N, Rueda-Medina B. Vitamin D Levels are Associated with Disease Activity and Damage Accrual in Systemic Lupus E — View Citation

de Souza VA, Bastos MG, Fernandes NM, Mansur HN, Raposo NR, de Souza DM, de Andrade LC. Association of hypovitaminosis D with Systemic Lupus Erythematosus and inflammation. J Bras Nefrol. 2014 Oct-Dec;36(4):430-6. doi: 10.5935/0101-2800.20140062. English, — View Citation

Guimaraes-Stabili MR, de Aquino SG, de Almeida Curylofo F, Tasso CO, Rocha FRG, de Medeiros MC, de Pizzol JP Jr, Cerri PS, Romito GA, Rossa C Jr. Systemic administration of curcumin or piperine enhances the periodontal repair: a preliminary study in rats. — View Citation

Hamijoyo L, Candrianita S, Rahmadi AR, Dewi S, Darmawan G, Suryajaya BS, Rainy NR, Hidayat II, Moenardi VN, Wachjudi RG. The clinical characteristics of systemic lupus erythematosus patients in Indonesia: a cohort registry from an Indonesia-based tertiary — View Citation

Hamza RT, Awwad KS, Ali MK, Hamed AI. Reduced serum concentrations of 25-hydroxy vitamin D in Egyptian patients with systemic lupus erythematosus: relation to disease activity. Med Sci Monit. 2011 Dec;17(12):CR711-8. — View Citation

Handono K, Pratama MZ, Endharti AT, Kalim H. Treatment of low doses curcumin could modulate Th17/Treg balance specifically on CD4+ T cell cultures of systemic lupus erythematosus patients. Cent Eur J Immunol. 2015;40(4):461-9. doi: 10.5114/ceji.2015.56970 — View Citation

Haq IU, Imran M, Nadeem M, Tufail T, Gondal TA, Mubarak MS. Piperine: A review of its biological effects. Phytother Res. 2021 Feb;35(2):680-700. doi: 10.1002/ptr.6855. Epub 2020 Sep 14. Review. — View Citation

Islam MA, Khandker SS, Alam SS, Kotyla P, Hassan R. Vitamin D status in patients with systemic lupus erythematosus (SLE): A systematic review and meta-analysis. Autoimmun Rev. 2019 Nov;18(11):102392. doi: 10.1016/j.autrev.2019.102392. Epub 2019 Sep 11. — View Citation

Karimzadeh H, Shirzadi M, Karimifar M. The effect of Vitamin D supplementation in disease activity of systemic lupus erythematosus patients with Vitamin D deficiency: A randomized clinical trial. J Res Med Sci. 2017 Jan 27;22:4. doi: 10.4103/1735-1995.199 — View Citation

Lima GL, Paupitz J, Aikawa NE, Takayama L, Bonfa E, Pereira RM. Vitamin D Supplementation in Adolescents and Young Adults With Juvenile Systemic Lupus Erythematosus for Improvement in Disease Activity and Fatigue Scores: A Randomized, Double-Blind, Placeb — View Citation

Liu W, Zhai Y, Heng X, Che FY, Chen W, Sun D, Zhai G. Oral bioavailability of curcumin: problems and advancements. J Drug Target. 2016 Sep;24(8):694-702. doi: 10.3109/1061186X.2016.1157883. Epub 2016 Mar 17. Review. — View Citation

Magro R, Saliba C, Camilleri L, Scerri C, Borg AA. Vitamin D supplementation in systemic lupus erythematosus: relationship to disease activity, fatigue and the interferon signature gene expression. BMC Rheumatol. 2021 Dec 3;5(1):53. doi: 10.1186/s41927-02 — View Citation

Marinho A, Carvalho C, Boleixa D, Bettencourt A, Leal B, Guimarães J, Neves E, Oliveira JC, Almeida I, Farinha F, Costa PP, Vasconcelos C, Silva BM. Vitamin D supplementation effects on FoxP3 expression in T cells and FoxP3(+)/IL-17A ratio and clinical co — View Citation

Mok CC, Birmingham DJ, Leung HW, Hebert LA, Song H, Rovin BH. Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis. Rheumatology (Oxford). 2012 Apr;51(4):644- — View Citation

Momtazi-Borojeni AA, Haftcheshmeh SM, Esmaeili SA, Johnston TP, Abdollahi E, Sahebkar A. Curcumin: A natural modulator of immune cells in systemic lupus erythematosus. Autoimmun Rev. 2018 Feb;17(2):125-135. doi: 10.1016/j.autrev.2017.11.016. Epub 2017 Nov — View Citation

Peng Y, Ao M, Dong B, Jiang Y, Yu L, Chen Z, Hu C, Xu R. Anti-Inflammatory Effects of Curcumin in the Inflammatory Diseases: Status, Limitations and Countermeasures. Drug Des Devel Ther. 2021 Nov 2;15:4503-4525. doi: 10.2147/DDDT.S327378. eCollection 2021 — View Citation

Ruiz-Ballesteros AI, Meza-Meza MR, Vizmanos-Lamotte B, Parra-Rojas I, de la Cruz-Mosso U. Association of Vitamin D Metabolism Gene Polymorphisms with Autoimmunity: Evidence in Population Genetic Studies. Int J Mol Sci. 2020 Dec 17;21(24). pii: E9626. doi: — View Citation

Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998 May;64(4):353-6. — View Citation

Singgih Wahono C, Diah Setyorini C, Kalim H, Nurdiana N, Handono K. Effect of Curcuma xanthorrhiza Supplementation on Systemic Lupus Erythematosus Patients with Hypovitamin D Which Were Given Vitamin D(3) towards Disease Activity (SLEDAI), IL-6, and TGF-ß — View Citation

Stockton KA, Kandiah DA, Paratz JD, Bennell KL. Fatigue, muscle strength and vitamin D status in women with systemic lupus erythematosus compared with healthy controls. Lupus. 2012 Mar;21(3):271-8. doi: 10.1177/0961203311425530. Epub 2011 Oct 17. — View Citation

Terrier B, Derian N, Schoindre Y, Chaara W, Geri G, Zahr N, Mariampillai K, Rosenzwajg M, Carpentier W, Musset L, Piette JC, Six A, Klatzmann D, Saadoun D, Patrice C, Costedoat-Chalumeau N. Restoration of regulatory and effector T cell balance and B cell — View Citation

Uribe AG, Vilá LM, McGwin G Jr, Sanchez ML, Reveille JD, Alarcón GS. The Systemic Lupus Activity Measure-revised, the Mexican Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and a modified SLEDAI-2K are adequate instruments to measure diseas — View Citation

Wöbke TK, Sorg BL, Steinhilber D. Vitamin D in inflammatory diseases. Front Physiol. 2014 Jul 2;5:244. doi: 10.3389/fphys.2014.00244. eCollection 2014. Review. — View Citation

Zheng R, Gonzalez A, Yue J, Wu X, Qiu M, Gui L, Zhu S, Huang L. Efficacy and Safety of Vitamin D Supplementation in Patients With Systemic Lupus Erythematosus: A Meta-analysis of Randomized Controlled Trials. Am J Med Sci. 2019 Aug;358(2):104-114. doi: 10 — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Activity from the SLE patients after the Treatments	Disease activity was assessed using the Mexican SLE Disease Activity Index (Mex-SLEDAI) score, consisting of 10 simple clinical and laboratory components obtained during the examination, which the results are grouped into remission (score of 0-1), mild (score of 2-5), moderate (score of 6-9), severe (score of 10-13), and very severe (score of > 14).	three months
Primary	Fatigue Assessment from the SLE patients after the Treatments	Fatigue assessment was done using a specific questionnaire called the Fatigue Severity Scale (FSS) score. The FSS score used in this study was a validated Indonesian version consisting of nine questions to assess fatigue, including physical functioning, vitality, emotional, social, and mental health. The items are scored on a seven point scale with 1 refers to strongly disagree and 7 refers to strongly agree. The minimum FSS score is 9 and the maximum score possible is 63, with the higher the score the greater the fatigue severity	three months
Primary	Comparison of Cytokines Levels before and After the Treatments	We also monitor the pro-inflammatory and anti-inflammatory cytokines from the sera of SLE patients three months after the therapies; Serum cytokine levels, including interleukin-6 (IL-6) and transforming growth factor-ß (TGF-ß), were measured at the baseline and three months after therapy using enzyme-linked immunosorbent assay (ELISA) by the commercially kits (Elabscience, cat number E-EL-H0102 and E-EL-0162, respectively). Both results were shown in pg/ml.	three months