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Clinical RheumatologyJournal of the InternationalLeague of Associations forRheumatology ISSN 0770-3198 Clin RheumatolDOI 10.1007/s10067-011-1809-z

Comparable efficacy of standardizedAyurveda formulation andhydroxychloroquine sulfate (HCQS) in thetreatment of rheumatoid arthritis (RA): arandomized investigator-blind controlledstudyArvind Chopra, Manjit Saluja, GirishTillu, Anuradha Venugopalan, GumdalNarsimulu, Rohini Handa, Lata Bichile,Ashwinikumar Raut, et al.

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ORIGINAL ARTICLE

Comparable efficacy of standardized Ayurveda formulationand hydroxychloroquine sulfate (HCQS) in the treatmentof rheumatoid arthritis (RA): a randomized investigator-blindcontrolled study

Arvind Chopra & Manjit Saluja & Girish Tillu & Anuradha Venugopalan &

Gumdal Narsimulu & Rohini Handa & Lata Bichile & Ashwinikumar Raut &Sanjeev Sarmukaddam & Bhushan Patwardhan

Received: 31 March 2011 /Revised: 17 June 2011 /Accepted: 4 July 2011# Clinical Rheumatology 2011

Abstract Hydroxychloroquine sulfate (HCQS) is a populardisease-modifying antirheumatic drug (DMARD) despitemodest efficacy and toxicity. Ayurveda (ancient Indiamedicinal system) physicians treat rheumatoid arthritis (RA)with allegedly safer herbal formulations. We report a head-to-head comparison in an exploratory drug trial. The objective isto compare standardized Ayurvedic formulations and HCQSin the treatment of RA. One hundred twenty-one patients withactive moderately severe RA (ACR 1988 classified) wererandomized into a 24-week investigator-blind, parallelefficacy, three-arm (two Ayurvedic and HCQS) multicenterdrug trial study; polyherb (Tinospora cordifolia and Zingiber

officinale based) and monoherb (Semecarpus anacardium).Study measures included joint counts (pain/tenderness andswelling), pain visual analogue scale, global disease assess-ments, and health assessment questionnaire. Oral meloxicam(fixed-dosage schedule) was prescribed to all patients duringthe initial 16 weeks. Patients on prednisolone could continuea fixed stable dose (<7.5 mg daily). Rescue oral use ofparacetamol was permitted and monitored. All groupsmatched well at baseline. An intent-to-treat analysis(ANOVA, significance P<0.05) did not show significantdifferences by treatment groups. In the polyherb, monoherb,and HCQS arms, 44%, 36%, and 51%, respectively, showed

Trial registration: ICMR CTRI registry, TEMP UTRN 115644567-050320101825344

Key messages (1) Since ancient times, the Indian (Asian) Ayurvedicmedicinal system advocates a holistic approach including herbalformulations to treat RA.(2) A standardized Ayurvedic drug is demonstrated to be a goodalternative DMARD to hydroxychloroquine in treating RA.

A. Chopra (*) :M. Saluja :A. Venugopalan : S. SarmukaddamCentre for Rheumatic Diseases (CRD),1988 Convent Street, Hermes Elegance, Camp,Pune 411001, Indiae-mail: crdp@vsnl.netURL: www.rheumatologyindia.org

G. Tillu : B. PatwardhanInterdisciplinary School of Health Sciences (SHS),University of Pune,Pune 411007, India

G. NarsimuluRheumatology Department,Nizam Institute of Medical Sciences (NIMS),Panjagutta, Hyderabad 500082, India

R. HandaRheumatology Department,All India Institute of Medical Sciences (AIIMS),Ansari Nagar, New Delhi 110029, India

L. Bichile :A. RautRheumatology Department,KEM Hospital and GS Medical College and SPARC,Parel, Mumbai 400012, India

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ACR 20 index improvement. Several efficacy measuresimproved significantly in the HCQS and polyherb groupswith no difference between the groups (corrected P).However, the latter was individually superior to monoherb.Only mild adverse events (gut and skin, and none withdrew)were reported with no differences between the groups.Forty-two patients dropped out. This preliminary drug trialcontrolled for HCQS demonstrated a standardized Ayurvedicpolyherb drug to be effective and safe in controlling activeRA. A better-designed study with a longer evaluation periodis recommended.

Keywords Ayurveda . Botanical medicinal product .

Clinical trial . Complementary and alternative medicine .

Rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) is an extremely painful chronicpolyarticular autoimmune inflammatory disease, whichoften causes joint deformity, disability, and prematuremortality. Despite tremendous progress in modern-daytherapeutics, RA continues to be a difficult-to-treat disorder.Complementary and alternative medicines (CAM) arepopularly used to treat several ailments including arthritis.In 2007, the CAM therapies most commonly used by USadults [1] were nonvitamin–nonmineral natural products(17.7%), deep breathing exercises (12.7%), meditation(9.4%), chiropractic or osteopathic manipulation (8.6%),massage (8.3%), and yoga (6.1%).

Ayurveda has been popularly taught and practiced in theIndian subcontinent since time immemorial [2–4]. Theclassic text contains vivid descriptions of arthritis and itsmanagement and further acknowledges the failure in treatingcertain complex forms of arthritis [3]. In an attempt tomodernize Ayurveda, several antiarthritic formulations havebeen evaluated in controlled trials [5–9]. However, thoughexcellent safety has been repeatedly endorsed, the efficacyin the latter has been modest and often not superior toplacebo. There have been several limitations especially withrespect to trial design and using actual Ayurvedic therapy(clinical practice). Standardization, validation, and determi-nation of active biomarkers and mechanism of action forAyurvedic drugs have been a major challenge [10].

The concept of a “golden triangle” wherein “modernscience, modern medicine, and traditional medicine” can beconjointly developed [11] was recently mooted by theCouncil of Scientific and Industrial Research, Governmentof India, and the “New Millennium Indian TechnologyLeadership Initiative” (NMITLI) was launched [12] whichincluded validation of Ayurvedic drugs for global use. Werecently published [9] an overview of the NMITLI arthritis

project and the results of the first exploratory drug evaluationin patients suffering from symptomatic osteoarthritis knees.

In this report, we present results of another NMITLI-based exploratory evaluation of two oral Ayurvedic herbalformulations (polyherb and monoherb) and a head-to-headcomparison with oral hydroxychloroquine sulfate (HCQS)in the treatment of active RA. HCQS is in popular disease-modifying antirheumatic drug (DMARD) use since severaldecades despite modest efficacy and toxicity and limitedclinical drug trial data. It is recommended [13] to be used innot so aggressive RA with bad prognostic features.However, HCQS is often combined with other DMARD(especially methotrexate and sulfasalazine) to treat acutesevere RA [13].

The polyherb formulation, called B formulation, containedpurified extracts of four known Ayurvedic medicinalplants—Zingiber officinale (shunthi), Tinospora cordifolia(guduchi), Withania somnifera (ashwagandha), and Tribu-lus terrestris (gokshur). The monoherb formulation, calledBhallataka Parpati (BPRT), contained an extract ofSemecarpus anacardium (Bhallataka); popular Ayurvedicusage nomenclature shown in parenthesis in italics. Wehypothesized that both B formulation and BPRT haveDMARD properties in the long-term management of RA.

Patient and methods

The trial was conducted at the Centre for RheumaticDiseases (CRD, Pune), Nizam Institute of Medical Sciences(NIMS, Hyderabad), All India Institute of Medical Sciences(AIIMS, NewDelhi), and KEMHospital andMedical College(Mumbai) and Swami Prakashananda Ayurveda ResearchCentre (SPARC, Mumbai). The protocol was approved by theinstitutional ethics committee of each trial site.

Design

This was a randomized, single-blind (investigator-blind),parallel efficacy, active comparator-controlled multicenterdrug trial of 24 weeks duration in patients with active RA.The trial was essentially exploratory in nature and notstatistically designed for sample size nor powered (for alow type II error). Ayurvedic-derived formulations wereused as investigational drugs in two arms, while HCQS wasused as a comparator arm.

Ayurveda formulations

The formulations were prepared as per Ayurvedic principlesand guidelines, classical methods [14, 15], and prior artknowledge. Based on classic and teaching medical litera-ture, experiential database, and consensus within the group

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(in particular Ayurvedic experts), medicinal plants wereselected to create a standardized polyherbal B formulation(Z. officinale, T. cordifolia, W. somnifera, and T. terrestris).BPRT, a single-plant (Bhallataka) formulation, was chosenbecause of its popular traditional use by local Ayurvedicphysicians to treat RA.

B formulation

The raw materials were provided by authentic sourcesalong with passport data. The raw materials were subjectedto pharmacognosy, chemical quality (using spectroscopicand chromatographic methods) testing, molecular standard-ization (using plant DNA fingerprinting methods), andAyurvedic pharmacopoeia standards [15]. Aqueous extractof the plant material was used. The trial material wasmanufactured centrally in a pharmaceutics facility in theform of capsules (approximately 500 mg each) as per goodmanufacturing practice guidelines for botanical drugs. Theproduct master file was created and maintained as perregulatory requirements.

BPRT formulation

This was prepared under direct supervision of a seniorlocal Ayurvedic physician (Dr. Yashwant Govind Joshi,unpublished) who is a renowned expert in the traditionalprocess (not published) used for making BPRT in clinicalpractice. In brief, the oil extract of Bhallataka wasextracted and treated with a resin of a medicinal plantcalled Shorea robusta in a systematic process to yield a drypowder (called Parpati in Ayurveda). Bhallataka is knownfor its potential toxicity (see below) and the latter processis allegedly thought to reduce it significantly whileretaining the therapeutic potential.

Experimental toxicity studies

Acute and subacute animal toxicity studies for bothAyurvedic formulations were carried out at AgharkarResearch Institute, Pune, as per Organisation for EconomicCo-operation and Development Guidelines Serial No. 423[16]. Even at a maximum possible dose, the animals did notshow any known toxic effects.

Patient selection

Patients suffering from RA were screened in rheumatol-ogy outpatient services and free-of-cost arthritis camps[6]. Eligible patients (as per protocol) who signedinformed consent were enrolled as per a predeterminedrandomization schedule and the sample size allotted toeach trial site.

Inclusion criteria

Patients of either gender belonging to 17 to 70 years of ageand with clinically active (six painful/tender joints, fourswollen joints, and early morning stiffness >30 min) RA[17] were selected. Patients were required to be ambulant(allowed self-support), using analgesic and/or nonsteroidalanti-inflammatory drug (NSAID) for pain relief, notsatisfied with the ongoing antiarthritis treatment, andseeking treatment change.

Exclusion criteria

Women who were pregnant or lactating and those havingchild-bearing potential but not following adequate contra-ceptive measures; patients with known contraindication toany of the investigational products and medicinal plants;those with other inflammatory arthritis (such as lupus),severe degenerative joint diseases, or other joint diseaseswhich would interfere with the evaluation of RA; patientson any kind of DMARD (including biologic) unless thesame had been discontinued at least 2 months prior to thestudy; those with severe disabling arthritis and/ or incapac-itated and bedridden; patients with history of intra-articularknee injection (in particular corticosteroids and hyaluronanequivalents) within the month preceding the study; thosewho were on treatment with anticoagulants, hydantoin,lithium, higher-dose steroids (7.5 mg or more dailyprednisolone), colchicine; those with history of activepeptic ulcer anytime in the preceding 6 months or bleedingulcer anytime in the past; patients with evidence of severeunstable renal, hepatic, hemopoietic, and cardiac disorderas revealed by history and/or investigations; those havinghistory of any investigational drug received in the preced-ing 1 month; those who were unwilling to come for regularfollow-up for the entire duration of the study; those withnoncooperative attitude; and those who did not justify theinclusion in the opinion of the investigator were excluded.

Washout period

All eligible patients were entered into a supervised washoutperiod based on current NSAID use or a maximum of 5 days.All pain-relieving medications were discontinued but patientscould be considered for early enrolment if they experiencedintolerable pain. In case of intolerable pain, patients werepermitted to use oral paracetamol (500mg tablet taken three tofour times in a day) as rescue medication.

Randomization

Eligible patients were enrolled on first come first servebasis and assigned a treatment arm based on a standard

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computer software-generated randomization schedulecreated under the supervision of a senior investigator (BP)who was not actively associated with the clinical trials.Patients were randomized in a 1:1 ratio into any of the threetreatment groups. Each center was assigned blocks inmultiples of three according to the predetermined enrolmenttarget. Post screening and baseline, predetermined evalua-tion visits were made at the second and fourth weeks, andevery 4 weeks thereafter till study completion at the 24-week end point.

Treatment

The Ayurvedic drug was administered as two capsules twicea day (750 mg daily), while HCQS was administered as onetablet of 200 mg twice a day. The latter was to be takenwith water after lunch and dinner. Patients were notprovided with any dietary restrictions.

Concomitant medication

Following randomization, all patients were prescribed oralmeloxicam (NSAID), as a single morning (post breakfast)dose, 15 mg daily during the initial 8 weeks, followed by7.5 mg daily for the subsequent 8 weeks. Paracetamol(tablet strength 500 mg and provided to the patient at everyvisit as per protocol schedule) was permitted as a rescueanalgesic and consumption was monitored. No otheranalgesic, NSAID, or DMARD were allowed. Patients ona fixed daily dose of prednisolone (<7.5 mg daily), whichwas stable for at least 1 month prior to the study, wascontinued and no change was permitted during the study.

Other concurrent long-term stable-dose medication forchronic diseases (such as diabetes, hypertension) werepermitted. Patients were allowed to continue exercise and/orphysiotherapy program, but discouraged from beginning anyspecific program during the trial duration. Patients were notallowed to seek therapy from any other alternative medicinalsystem (e.g., homeopathy, acupuncture, acupressure, etc).

Clinical evaluation [18]

Standard case record was used to capture the primaryefficacy variables [19] (1) joint count for pain/tenderness ona 68-joint examination, (2) joint count for swelling on a 66-joint (hips excluded) examination, (3) global assessment ofdisease activity by a physician and a patient on a five-gradescale (asymptomatic, mild, moderate, severe, and verysevere; scored 0–4), (4) a validated Indian modified version[6, 20] of the modified Stanford Health AssessmentQuestionnaire (HAQ); the HAQ score ranged from 0 to24, (5) pain visual analogue scale (VAS, maximum painexperienced during the previous 24 h and recorded on a 0-

to 100-mm horizontal scale, anchored at 0 for nil pain), and(6) a predetermined checklist of common drug-relatedtoxicity for reference by the patients.

Laboratory investigations

Routine laboratory workup was done at baseline and oncompletion of the study and included (1) hematology:hemogram, total and differential white blood cell count,platelet count, erythrocyte sedimentation rate (Westergren),(2) biochemistry: blood sugar (fasting), blood urea, serumcreatinine, serum calcium, serum uric acid, serum bilirubin,total serum proteins/albumin/globulin, serum aminotrans-ferases, and alkaline phosphatase, (3) rheumatoid factor(RF) assay by nephlometry (cutoff=40 IU/ml), (4) C-reactive protein (CRP) assay by nephlometry (cutoff=5 mg/dl), (5) urinalysis, (6) others: serum cytokine (interleukin/IL-1β, IL-6, and tumor necrosis factor/TNF-α) andhyaluronic acid assays were carried out at baseline andcompletion using standard ELISA technique in CRD, Pune(largest sample size allotment, i.e., 72 patients).

Radiology and other investigations including X-rays ofhands and wrists were taken to confirm diagnosis. RoutineEKGs were taken for all patients at entry.

Adverse events

Patients were specifically questioned regarding commonsymptoms (anorexia, nausea, vomiting, diarrhea, constipa-tion, dysuria, skin rash, giddiness, oral mucous ulcers,dyspepsia, and abdominal discomfort and pain) at everyvisit and further encouraged to volunteer information thatthey considered as adverse events (AE) or a side effect (SE).Severe and life-threatening AE were to be investigated,treated, and notified as per standard trial practices. Theinvestigator recorded opinion on the causality/relevance ofAE/SE in each case.

Withdrawals

Patients could withdraw voluntarily or at the discretion ofthe investigator. Patients were not replaced and the nextpatient enrolled was allotted the next consecutive random-ization number. An effort was made in each case to identifythe reason for a failed follow-up visit and/or withdrawal.

Statistical analysis

Thirty patients were required to complete the trial in eacharm and the sample size was not based on any statisticalmethod or assumptions regarding “effect size.” Anintention-to-treat analysis was carried out with “lastobservation carried forward” for dropouts. An ACR 20%

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and 50% index improvement response [21] was calculatedfor each patient on completion of the study. A two-tailedP<0.05 was considered to be statistically significant.Ninety-five percent confidence intervals were calculatedfor all means (of variables) and mean change over time.ANOVA was used to compare mean values. Within-groupefficacy was evaluated by one-sample Student’s t test.Bonferroni’s correction was applied for multiple compar-isons between treatment arms. Chi-square testing was usedfor all categorical outcomes including the SE/AE. Standardstatistical software program SPSS version 12.5 was used foranalysis.

Observations and results

At baseline, the treatment arms were well matched. Onehundred twenty-one patients (Table 1) were randomized tothree intervention arms (Fig. 1). Of the patients, 78% and67% were seropositive for RF and showed radiologicalerosions, respectively.

The current arthritis status/flare at baseline (Table 1) wasof at least 6 weeks duration and had been treated withNSAID and/or steroids by a family physician. At the timeof enrolment (Table 2), the patients had moderately severepain (>60 mm on pain VAS) with high joint counts for pain/tenderness and swelling and an elevated ESR (>55 mm fall,Westergren) that suggested moderately severe diseaseactivity (Table 2); mean HAQ limitation score >8 out of atotal score of 24 in each of the groups. The majority ofpatients (∼60%) could not recall in detail past medicaltreatment history or carry sufficient medical records. Ourestimates on past medication in Table 1 are approximationsbased on oral descriptions, past medicine prescriptions, orused medicine package material. However, none of thepatients were treated with a standard of care DMARDregimen during the 6-month period prior to enrolment.Ayurvedic polyherb B formulation and HCQS were compa-rable and better than BPRT for several efficacy measures.Significant improvement was seen for several efficacyvariables in polyherb “B” and HCQS treatment arms(Table 2). Except for physician global assessment, therewas no significant difference between the intervention arms(Table 2) including analgesic consumption (data notshown). However, HCQS was numerically superior(Table 2) to polyherb “B” for all efficacy measures exceptpatient global assessment and ESR. Interestingly, theproportion of patients showing 50% or more improvement(Fig. 2) was higher or equal to HCQS for the number ofswollen joints, number of tender joints, patient andphysician global assessment, and ESR. The ACR 20 indeximprovement response was 44%, 36%, and 51% in thepolyherb “B,” BPRT, and HCQS, respectively. The ACR 50

index improvement response was 12%, 3%, and 10% in thepolyherb “B,” BPRT, and HCQS, respectively.

Pairwise comparisons (corrected significant P<0.02) didnot show significant differences between the B formulationand HCQS (Table 3). However, both HCQS and Bformulation were individually superior to BPRT for severalefficacy variables.

Data on RF and proinflammatory cytokines suggested animproved biological response. However, the interventionarms did not differ significantly with respect to serumhyaluronic acid, serum RF, and serum cytokines (proin-flammatory) on completion of the study (Table 4). Bformulation and HCQS showed a modest reduction in theRF titer. Though not statistically significant, impressivereductions were seen in serum IL-6 with the B formulationand serum hyaluronic acid with HCQS. All the threeinterventions showed an impressive fall in serum IL-1β.

Forty-two patients (Fig. 1 and Table 1) withdrew butnone due to any AE or drug-related toxicity; there were nodifferences between the withdrawers and completers andbetween the patients who withdrew in each of the treatmentgroups (Table 1 and 2, Fig. 1).Table 5 shows the number ofpatients reporting AE in each of the treatment groups. AllAE were predominantly mild in nature and treatedsymptomatically. Few patients (less than three) in each ofthe treatment groups reported moderately severe AE whichwere vomiting, epigastric burning, and brief intense skinitching (infrequently anal region). None of the patientsvolunteered any eye-related complaint and we did not carryout any expert systematic eye examination (includingscreening by Amsler grid). None of the patients in thestudy recorded a serious AE. None of the AE required anyinvasive investigation or any therapeutic interventionrequiring hospitalization. There were no statistically signif-icant differences between the groups (chi-square testing).However, the incidence of several gut-related AE washigher in the Ayurvedic arms than HCQS. More patients inthe HCQS group suffered from burning in the epigastricregion, episodic generalized itching, and nonspecificgeneralized skin rash (usually slightly hyperpigmentedmacules).

No significant change was observed in the routinelaboratory parameters of hepatic, renal, and metabolicfunction to monitor safety (data not shown). A significantfavorable change in the lipid profile (Table 4) was observedin each of the three intervention arms which did not differbetween the groups.

Discussion

The efficacy of standardized Ayurvedic herbal formulationB was comparable to HCQS in the treatment of moderately

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severe active RA in this multicenter controlled drug trialevaluation of 24 weeks (Tables 2, 3, and 4). Both the latterinterventions were superior to the third intervention(BPRT). Though not statistically powered to reduce typeII error (false-negative outcome), this study lends credenceto the purported antiarthritis effects of a standardizedAyurvedic formulation in the treatment of active RA. This

study is limited by a relatively small sample size and a highdropout rate (Fig. 1). However, we have used intention-to-treat analysis in the current exploratory study to base ourconclusions.

We have carried out several controlled (often placebo)drug trials to evaluate the efficacy and safety of standard-ized Ayurvedic medicines in patients suffering from arthritis

Fig. 1 Flow of participants in athree-arm (HCQS, Ayurvedicformulations “B” and “BPRT”)drug trial of patients with activeRA

Features B (N=41) BPRT (N=39) HCQS (N=41) Total (N=121)

Females, N (%) 34 (82.9) 36 (92.3) 38 (92.7) 108 (89.2)

Age (years), mean±SD 43.6±12.4 46.1±10.8 44.9±11.5 44.8±11.5

Disease duration (years), mean±SD 6.9±7.4 4.7±5.2 5.5±4.6 5.7±5.9

Seropositive RF (%) 80.5 76.9 75.6 77.7

Erosions in X-ray (%) 78.5 57.1 65.5 67.1

Current steroid use (%) 15 15 10 13

Past steroid use (%) 34 36 20 23

Past MTX use (%) 12 10 17 13

Past CQN use (%) 12 18 17 16

Withdrawals, N 16 13 13 42

Age 42.4±14.3 43.4±9.8 44.5±12 43.4±11.9

Female, N (%) 12 (80.0%) 11 (78.6%) 12 (92.3%) 35 (83.3%)

Disease duration (years), mean±SD 5.1±7.3 2.9±3.8 5.4±4.2 4.5±5.4

Seropositive RF (%) 86% 71% 77% 79%

Table 1 Demographic andbaseline variables of patients(N=121) by treatment groups:Ayurvedic arms (polyherb “B”and monoherb “BPRT”) andhydroxychloroquine (HCQS)

N number, B polyherb, BPRTmonoherb, HCQS hydroxy-chloroquine, RF rheumatoidfactor, SD standard deviation,MTX methotrexate, CQNchloroquine

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[6–9, 22]. The current trial is probably the first attempt inmodern medicine to compare head to head an Ayurvedicmedicine with a modern medicine DMARD, and the resultswere presented at an international rheumatology meeting[23]. The latter was made possible by a combined concertedmodern rheumatology Ayurvedic team approach.

The Ayurvedic medicinal plants used in the current studywere known to possess anti-inflammatory properties and

“Rasayana” attributes [24–32]. Rasayana [2–4] is anAyurvedic unifying concept to enhance immunity, reduceinflammation, promote tissue repair and healing, andpromote health. In the current perspective, “Rasayana” alsomeans immunomodulation. The rationale of polyherb Bformulation in the current study was based on Ayurvedicprinciples of synergism between plant extracts shunthi (Z.officinale) and guduchi (T. cordifolia) and augmentation of

Table 2 Comparing mean change (95% confidence interval) in theprimary efficacy measures by treatment groups in a controlled oraldrug trial study of Ayurvedic formulations (polyherb “B” and

monoherb “BPRT”) and hydroxychloroquine (HCQS) in the treatmentof RA: baseline data of withdrawals is also shown for comparison

Efficacy parameters B (N=41) BPRT (N=39) HCQS (N=41) P (ANOVA) P (KW)

Baseline Mean change Baseline Mean change Baseline Mean change

Joint count pain tenderness/JCPT (0–68) 18.9 5.2 (1.3, 9.0)* 19.9 1.7 (−2.0, 5.3) 20.9 6.7 (3, 10.3)* 0.16 0.17

Joint count swelling/JCSW (0–66) 9.5 3.1 (0.5, 5.6) 8.6 1.8 (−1, 4.7) 9.2 4.5 (3, 6.5)* 0.14 0.26

Pain visual analogue scale/VAS (0–100 mm) 70.3 12.5 (3.8, 21.2)* 65.8 4.7 (−0.8, 11.2) 65.5 17.2 (8.3, 26)* 0.11 0.14

Patient global assessment (grade 1–5) 3.8 −1.4 (−5.1, 2.3) 3.7 0.19 (−0.09,0.5) 3.9 −0.12 (−1.9, 1.6) 0.07 0.08

Physician global assessment (grade 1–5) 3.6 0.7 (0.3, 1.0)* 3.5 0.4 (0.07, 0.7) 3.5 0.8 (0.5, 1.1)* 0.04* 0.05*

HAQ (0–24) 12.5 2.2 (0.3, 4.1)* 11.3 −0.16 (−1.9, 1.6) 12.4 3.3 (1.3, 5.4)* 0.18 0.18

ESR (mm, end of first hour) 60.7 −2.1 (−15.6, 1.5) 56.7 5.5 (−2.6, 13.6) 60.3 5 (−2.5,12.6) 0.35 0.31

Withdrawals (N=42; B=16, BPRT=13, HCQS=13)

JCPT (SD) 19.7 (9.4) 21(7.01) 21.8 (6.2) NS

JCSW (SD) 9.5 (7.6) 9.9 (5.3) 7.6 (6.2) NS

Pain VAS (SD) 67.7 (16.4) 69.2 (14.9) 68.8 (13.4) NS

N number of patients, ESR erythrocyte sedimentation rate, SD standard deviation, KW Kruskal–Wallis, NS not significant

*P<0.5, significant

Fig. 2 Proportion of patientsshowing 50% reduction

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efficacy by ashwagandha (W. somnifera) and gokshur (T.terrestris). Bhallataka, the single-plant extract in BPRT inthe current study, is a highly potent anti-inflammatoryRasayana drug and used to treat several rheumatic andneuromuscular disorders. In an earlier study [9], the currentpolyherb B formulation (earlier coded as “B” formulationalso) was shown to be superior to placebo, albeit notstatistical, in providing pain relief.

The role of the gut in the etiology of arthritis is afundamental concept in Ayurveda [33]. According toAyurveda, an imbalance in biological humoral forces (calleddoshas in Ayurveda) and disturbed digestion causes anaccumulation of a toxic slimy substance (called “Aam” inAyurveda and not characterized by modern science so far).This latter substance spreads to the joints and causes a type

of arthritis that has been found to be similar in descriptionto RA [33]. Invariably, Ayurvedic treatment modalitiestarget the gut. Both the Ayurvedic formulations (B andBPRT) in the current study are considered to improvedigestion and metabolism and thereby reduce the toxicsubstance mentioned above.

Several patients in the current study suffered frommoderate–severe active RA (Table 2) and in clinicalpractice may be suitable candidates for a more aggressiveDMARD regimen rather than HCQS monotherapy [13].Significant improvement (Table 2 and Fig. 2) was demon-strated in joint counts, pain, physician global assessment,and HAQ in both the HCQS and B formulation groups. Thedropout rate (30%) in the current study was high but thewithdrawals did not differ between the intervention groups

Parameter Pair of arms under consideration T (for SV) P value

JCPT B vs BPRT −1.5387 0.1280

B vs HCQS 0.1667 0.8681

BPRT vs HCQS 1.8747 0.0646

JCSW B vs BPRT −1.1987 0.2344

B vs HCQS 0.6742 0.5024

BPRT vs HCQS 1.9695 0.0534

PATG B vs BPRT −1.8792 0.0642

B vs HCQS 0.1998 0.8422

BPRT vs HCQS 2.3223 0.0230

PHYG B vs BPRT −2.0978 0.0393

B vs HCQS 0.0998 0.9207

BPRT vs HCQS 2.4717 0.0157*

Pain VAS B vs BPRT −2.1060 0.0388

B vs HCQS −0.5451 0.5872

BPRT vs HCQS 1.6311 0.1071

HAQ B vs BPRT −1.5478 0.1257

B vs HCQS 0.0949 0.9246

BPRT vs HCQS 1.6631 0.1003

ESR B vs BPRT 0.8918 0.3786

B vs HCQS 1.2768 0.2081

BPRT vs HCQS 0.6542 0.5162

Table 4 Pairwise multiplecomparisons (*P<0.017, signifi-cant; Bonferroni correction formultiple comparisons)

Variable Baseline Completion

B BPRT HCQS B BPRT HCQS

RF (IU/ml) 288±2.8 275±2.4 294±3.3 274±2.4 299±2.9 283±2.9

LDL/HDL ratio 2.2±1.6 2.2±1.4 2.3±1.5 1.7±1.7 1.7±2.1 1.8±2.2

Hb (g/dl) 11.1±1.1 10.8±1.1 11.1±1.2 11.6±1.1 10.8±1.2 11.2±1.1

HA (ng/ml) 91.2±3.6 138.0±1.8 193.6±2.3 95.5±1.8 100.6±2.2 88.7±3.6

IL-1β (pg/ml) 148.8±1.1 156.8±1.4 148.8±1.2 2.6±4.8 1.42±2.7 1.6±2.9

IL-6 (pg/ml) 35.4±3.9 8.33±4.2 17.6±4.8 11.3±6.5 12.0±3.4 24.3±3.8

TNF-α (pg/ml) 7.5±3.6 12.8±2.8 9.3±2.5 11.3±2.7 9.3±2.0 11.9±2.8

Table 3 Geometric means ofselected laboratory variables atbaseline and completion

Normal LDL/HDL ratio=up to 3.6(male) and up to 3.2 (female). Dataare presented as geometric mean±geometric standard deviation

RF rheumatoid factor, Hb hemo-globin, HA hyaluronic acid, IL-1β interleukin 1beta, IL-6 inter-leukin 6, TNF-α tumor necrosisfactor

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or from the baseline demographics and baseline parametersof the study (Tables 1 and 2). Laboratory parameters, ESRin particular, showed disproportionately lesser improvement(Table 3). The reduction in RF and proinflammatory serumcytokines (IL-6 in particular) suggested a biological effect ofthe B formulation. An additional bonus in the current studywas the observation of a favorable change in the lipid profile(Table 3). Hyperlipidemia is an established comorbidity inpatients with RA leading to premature atherosclerotic-related vascular events and mortality [34]. Therefore, theoverall performance of the standardized Ayurvedic Bformulation in the current study was impressive andpromising.

The overriding advantage claimed by Ayurveda is thesuperior safety of its drugs vis-a-vis modern medicine. Andthis is a deep-rooted belief in the community [29]. SeveralAE (Table 5) were reported in the current study, which weregenerally considered to be mild. Rather than volunteeringinformation, patients were asked about AE symptoms asper a priori checklist and this may have led to an increasednumber of respondents. The latter checklist was prepared inclose consultation with Ayurvedic physicians in the trial andwas influenced by the known toxicity profile of AyurvedicAmruta Bhallataka preparation [14]. None of the patients inthe current study withdrew due to drug toxicity .However,the traditional BPRT preparation used in the current studyproved to be relatively safe. Interestingly, the AE of the Bformulation were quite similar to that of HCQS except foran increased incidence of constipation in the former andepigastric burning sensation in the latter. HCQS is known tocause gastrointestinal and skin-related toxicity in about10% and 5% cases, respectively; ocular toxicity is ratherinfrequent [35]. In clinical practice, HCQS is often used forprolonged period (greater than 6 months) to treat RA. Thecurrent sample size and study duration were probablyinsufficient to capture the true extent of any likely differ-ences between the interventional drugs for toxicity andtolerability.

Despite global enthusiasm for the use of CAM to treatarthritis, scientific evidence is difficult to find. A Cochranereview [36] concluded that the current evidence (efficacy)for herbal treatment of RA, albeit from small sample sizestudies, was sparse but good tolerance was demonstrated. Asystematic analysis [37] of 14 controlled drug trial studiesof herbal formulations to treat RA concluded that theevidence (efficacy) was weak but the drug use wasrelatively safe. The biological basis of use of botanicals inarthritis was recently reviewed [38]. From all this and ourown experience, it is becoming obvious that modern run-of-the-mill drug trials do not seem to capture the strengths ofAyurvedic medicines and that better methodology isrequired [39, 40]. Modern medicine drug trial approachmay not be appropriate to validate CAM as evidence basedsystem [41–43]. Ayurveda is a holistic science. Cointerven-tions, other than drugs, are equally important and includelifestyle modification, diet, exercise, and relaxation techni-ques [33]. Ayurvedic physicians diligently evaluate anindividual’s constitution (called prakruti in Ayurveda) toselect the treatment modality (and drugs) and giveprognosis [4]. Pragmatic trials [44] or a comprehensivepackage care approach [45] may be better suited.

Modern drug trials are overwhelmingly focused ondemonstrating efficacy. Safety is often a trade-off. Minorand not so severe AE may escape attention and are notrecorded properly. Safety and tolerability is a crucialadvantage with Ayurvedic medicines that ought to becaptured by the drug trials. In the current trial, we recordeda wide spectrum of AE in the Ayurvedic intervention arms(Table 5) but all were mild and required reassurance,guidance on healthy diet practices (including adequatewater consumption), and sometimes conventional symp-tomatic treatment. We have recently conceptualized a safetyindex based on the severity of AE and the kind ofintervention required to deal with it [46].

Comparative effectiveness, the modern clinical researchmantra, would be well served if the issues of safety andefficacy are suitably addressed during comparisons betweenCAM and modern medicine. It is likely that someAyurvedic formulations can replace modern medicines inthe long-term management of not so aggressive state ofchronic diseases like RA. On the other hand, we may alsoexplore several other treatment paradigms of combiningAyurveda and modern medicine. This would move ustowards an interface or integration [47, 48]. The currentstudy demonstrating the effectiveness of a standardizedAyurvedic formulation to treat RA and compare well withHCQS was a step towards this direction.

Acknowledgements This study was funded by the NMITLI Cell,TNBD Division of the Council of Scientific and Industrial Research,Government of India and we thank Yogeshwar Rao, Meenakshi Singh,

Table 5 Number of patients reporting AE by treatment group; nilsignificant differences by treatment groups (chi-square test by Yatescorrection)

B (N=41) BPRT(N=39) HCQS (N=41)

Epigastric burning 8 (19.5) 7 (17.9) 15 (36)

Anorexia 15 (36.5) 10 (25.6) 15 (36)

Nausea 7 (17) 9 (23) 6 (14.6)

Diarrhea 4 (9.7) 6 (15.3) 3 (7.3)

Constipation 9 (21.9) 7 (17.9) 5 (12.1)

Oral ulcers 4 (9.7) 4 (10.2) 2 (4.8)

Itching/skin rash 9 (21.9) 13 (33.3) 10 (24.3)

Dysuria 6 (14.6) 2 (5.1) 4 (9.7)

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and Vibha Malhotra for the administrative support. We thank seniorAyurveda physician, Vaidya Y.G. Joshi for his generous contribution toprovide information on the BPRT formulation used in this trial andfurther supervising its preparation. We also acknowledge contributionsof the expert staff and NMITLI aesearch associates and fellows,namely, Dr. Jaishree Patil (Ayurvedic physician, CRD), Dr. Sridevi(Ayurvedic physician, NIMS), Dr. Nilambari (Ayurvedic physician,KEM), Dr. S. Garad (statistics), Mr. Ravi Ghorpade (laboratory anddatabase, CRD), and Mr. Deepak S. (programmer, CRD). We alsothank Kalpana Joshi (NMITLI research associate, SHS) and otherNMITLI research fellows from SHS (Dnyaneshwar Warude, ManishGautam, Preeti Chavan, and Yogita Ghodke). Several other colleaguesand staff at the clinical drug trial centers also participated andprovided administrative and logistic support and professional help.Several senior NMITLI experts provided invaluable assistance, inparticular, Dr. G.N. Qazi, Dr. V. Sumantran, Dr. Ulhas Wagh, Dr.Ashok Vaidya, Dr. Rama Vaidya, Dr. A.M. Majumdar, and Dr.Pushpagandhan. The Ayurvedic formulation drugs were principallydeveloped in SHS and further standardized in Natural Remedies,Bangalore. Animal toxicity and mechanism of action studies werecarried out in ARI. The drug trial protocols were principallydeveloped and coordinated by CRD.

Disclosures None.

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