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

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.

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.

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