Bioavailable Curcumin for Rheumatoid Arthritis

Relation

Amalraj A, Varma K, Jacob J, et al. A novel curcumin formulation with high bioavailability improves symptoms and diagnostic indicators in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled, two-dose, three-arm, parallel-group study.J Med Food. 2017;20(10):1022-1030.

Objective

To determine the efficacy and safety of oral administration of 2 different doses of a novel curcumin formulation in patients with active rheumatoid arthritis (RA).

Draft

pilot study; randomized, double-blind, placebo-controlled three-arm study.

Participant

Thirty-six individuals aged 22 to 55 years, 15 women and 22 men, with RA according to the 2010 revised American College of Rheumatology (ACR) criteria.

According to ACR criteria, all participants were functional class II and had a disease activity score greater than 5.1, with the sum of their tender joints and swollen joints greater than 8 at screening and baseline. They had either a C-reactive protein (CRP) greater than 0.6 mg/dL or an erythrocyte sedimentation rate (ESR) greater than 28 mm/h. The presence of Sjögren's syndrome or limited cutaneous vasculitis was admitted.

Unfortunately, we have to weigh the long-term benefits and costs of the different forms of curcumin available on the market.

Patients were excluded if they had RA that required disease-modifying anti-inflammatory drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), significant secondary involvement of a systemic organ, inflammatory joint diseases other than RA, other systemic autoimmune diseases, or requiring surgical treatment within 12 weeks of baseline or surgery within 24 Weeks after randomization into the study is planned. Also excluded were patients who were taking anti-inflammatory, antirheumatoid, analgesic, steroids or other drugs that, in the opinion of the investigators, would interfere with the study 4 weeks before the study, in the case of parenteral or intra-articular drugs, and 2 weeks before, in the case of oral drugs, before enrollment and during the study.

intervention

Patients were randomized to receive either 250 mg curcumin extract twice daily, 500 mg curcumin extract twice daily, or 500 mg food-grade starch twice daily as placebo for 90 days. The turmeric product consisted of main components of the turmeric root. The dietary supplement used (turmeric matrix) was recreated by recombining extracted curcuminoids (50%), turmeric essential oil (3.0%), protein (2.0%), total carbohydrate (40.0%) and fiber (5.0%). The curcuminoids were extracted with ethanol, the essential oil was extracted by steam distillation, and the carbohydrates, fiber and proteins were extracted with water.

The study was conducted at Dhanwantri Ayurvedic College Hospital and Research Centre, Siddapur, Karnataka, India. Three of the authors are employees of Aurea BioLabs Ltd, the manufacturer of the nutritional supplements and a research subsidiary of Plant Lipids Ltd. The other authors report no conflicts.

Study parameters assessed

Total cholesterol, random serum glucose, creatine, sodium, potassium, urea, total bilirubin, total protein, albumin, alkaline phosphatase, CRP, ESR, rheumatoid factor (RF), disease activity score 28 (DAS28), visual analogue scale (VAS), American College of Rheumatology 20 (ACR20), totally swollen joints and totally tender joints.

Key insights

There were no significant changes between baseline and end of visit or between the 3 treatment groups in the following measures: height, weight, BMI, total cholesterol, random glucose, creatine, sodium, potassium, urea, total bilirubin, total protein, albumin, and alkaline phosphatase.

Statistically significant changes in scores compared to baseline include:

• VAS verbesserte sich in jeder Gruppe: niedrig dosiert, 62,5 %; hochdosiert 72,3 %; Placebo, 3,5 %
• DAS-28 verbesserte sich in den Gruppen mit niedriger (52,6 %) und hoher Dosis (66 %), blieb aber in der Placebogruppe unverändert
• ESR fiel in jeder Gruppe: niedrig dosiert, 88,1 %; hochdosiert, 88,6 %; Placebo, 29,6 %
• CRP fiel in jeder Gruppe: niedrig dosiert, 29,9 %; hochdosiert 51,2 %; Placebo, 11,3 %
• RF fiel in jeder Gruppe: niedrig dosiert, 80,2 %; hochdosiert 84,2 %; Placebo, 13,1 %
• Die ACR20-Scores fielen in der Niedrigdosis- (70,3 %) und Hochdosis- (75,7 %) Gruppe, blieben aber in der Placebogruppe unverändert
• Insgesamt geschwollene Gelenke fielen in jeder Gruppe: niedrig dosiert, 80,4 %; hochdosiert, 84,8 %; Placebo, 3,7 %
• Gesamtschmerzhafte Gelenke fielen in jeder Gruppe: niedrig dosiert, 78,1 %; hochdosiert, 88,0 %; Placebo, 4,4 %

All improvements in assessment and reduction of inflammatory markers were statistically significant compared to placebo in both the high-dose and low-dose treatment groups (P≤ 0.001 for all but the low dose for overall tender joints [P≤0.01]). Although the high-dose group had larger changes compared to the low-dose group, they were not significantly larger.

In summary, significant improvements in VAS, DAS-28, ESR, CRP, RF, ACR20, total swollen joints and total tender joints were observed with both curcumin treatment doses at the end of 90 days. Any changes found in the placebo group were minimal and not statistically significant. The difference between the changes in the high-dose group compared to the low-dose group was not statistically significant.

No side effects were observed or reported and both dosages were well tolerated.

Practice implications

Curcumin is known to have therapeutic effects in cardiovascular, neurodegenerative, psychiatric (depression), pulmonary, metabolic, autoimmune and neoplastic diseases.^1.2The main problem was absorption and finding a therapeutic dose that was manageable and did not cause nausea and diarrhea.³Study doses were up to 12 g per day. The result has been a proliferation of products claiming to be more bioavailable than their competitors.⁴

A review of 7 forms of curcumin available on the market found that a hydrophilic carrier disperses curcuminoids slightly better than a curcuminoid-cyclodextrin complex with a 45.9 or⁵The product used in the present study was not part of this review and does not claim to be as bioavailable as the hydrophilic and cyclodextrin forms. One of the study products examined made a bioavailable claim 65 times higher, but methodological anomalies make its determination unclear.

In 2015, Gopi (one of the authors of the present study) et al. conducted a single-dose bioequivalence study with 500 mg of the study reformulation, 500 mg of 95% unformulated curcumin, and placebo.⁶Participants were 12 healthy men aged 18 to 45 years with BMIs of 18.5 to 30.0. The reformulated curcumin was 10 times more bioavailable than the unformulated 95% curcumin.

A systematic review and meta-analysis published in 2016 identified 10,293 publications distilled into 8 randomized clinical trials of joint pain due to osteoarthritis and RA treated with curcumin.⁷The authors concluded that curcumin could be used as a dietary supplement to conventional therapy and supported the concept that a larger clinical trial could lead to its acceptance as a standard therapy for many forms of arthritis.

One of the positive features of the present study is not only the 2-dose regimens but also the 90-day trial period. It can take time for pain to go away, especially in RA, a condition that can wax and wane based on a variety of circumstances. It is important to let patients know approximately how long it may take before they experience sustained improvement. Three months is not unreasonable for a chronic disease like RA, especially since the inflammatory markers measured showed significant improvement at the end of this study. If the pain has subsided, would the patient maintain his gain if we prescribed half the starting dose? Only time or a clinical trial will tell.

It is also important to note that the lower dose was statistically just as effective as the higher dose. If a lower dose is effective, the financial outlay for curcumin treatment should be lower. It can be frustrating for doctors and patients to have a treatment that works but costs much more than the raw material because it is high-tech and out of reach of the patient's wallet. Unfortunately, we have to weigh the long-term benefits and costs of the different forms of curcumin available on the market.

Summary

Rheumatoid arthritis is an autoimmune disease that affects approximately 1% of the world's population and more than 1.3 million Americans; RA is the third most common arthritis after osteoarthritis and gout,⁸and research suggests that 1 in 28 women (3.6%) and 1 in 59 men (1.7%) in the United States will develop RA during their lifetime.⁹Patients with RA typically have a shorter lifespan of 10 to 15 years due to widespread inflammation that extends beyond the joints and affects many organ systems.⁸

The curcumin extract used in this 90-day study was statistically significant compared to placebo at both 250 mg twice daily and 500 mg twice daily. Significance was shown for VAS, DAS-28, ESR, CRP, RF, ACR20, total swollen joints and total tender joints. There were no adverse events. While this product is worth considering in your own practice, the bigger questions remain: which onesTurmeric longaExtract or reformulation is most effective? What costs do our patients incur? How long do you have to take it? What dose is optimal for sustained long-term benefit?