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

Study Overview
=================
Brief 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.

Detailed 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.

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

Conditions
-----------------
Systemic Lupus Erythematosus

Intervention / Treatment
-----------------
* 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.


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients who fulfilled the inclusion and exclusion criteria were randomized into three parallel groups: Vitamin D + placebo (group I), Curcumin-Piperine + placebo (group II), and vitamin D + Curcumin-Piperine (group III). All patients and physicians were blinded to group assignment and treatment allocation
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D + Placebo<br>The first group received 400 IU cholecalciferol (Nature Plus) t.i.d (three times a day) and placebo (Saccharum lactis) t.i.d. | 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.<br>* 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.<br>|
| Experimental: Curcumin-Piperine + Placebo<br>The second group received a tablet containing curcumin (632 mg) - piperine (15,800 mg) (Bioglan) one time daily and a placebo (Saccharum lactis) t.i.d. | 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.<br>* 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.<br>|
| Experimental: Vitamin D + Curcumin-Piperine<br>The third group received 400 IU cholecalciferol (Nature Plus) t.i.d and curcumin (600 mg) - piperine (15,800 mg) (Bioglan) one time daily | 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.<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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-β (TGF-β), 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
systemic lupus erythematosus, vitamin D, curcumin, piperine, disease activity