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Research Experience (Major Projects)

Title: A study of ‘polyarthritides’ with special reference to rheumatoid arthritis (RA).
        The study was conducted in Armed Forces Medical College and Command Hospital, Pune & Military Hospital, Belgaum during 1981-87. Begun as a cross-sectional clinical case study, a cohort of patients with atypical early seronegative polyarthritis were followed up.

        Clinical, immunologic, radiologic and epidemiologic aspects, relevant to Indian scenario, of over 200 patients, mostly servicemen, were analysed in detail.

        A clinical syndrome of RA-seronegative spondarthritis (SSA) overlap in young servicemen was defined.
Subsequently, HLA A and B profiles, using microlyphocytotoxicity technique on Terasaki plates, were defined in patients with SSA and healthy controls.

        The findings of the initial 50 patients were described in a dissertation submitted to the University of Pune for the award of MD (general medicine).

Further data and results were presented in various national meetings and published.

Dr. Berry Memorial Award for the best research paper at the national meeting of the Association of Physicians of India, Madurai, 1987.
E. Merck Award for the best research paper at the national meeting of the Association of Physicians of India, Pune, 1988
Title: A study of neurological complications of hemorrhagic viral conjunctivitis
        The study was begun during an epidemic of conjunctivitis in Armed Forces Medical College and Command Hospital, Pune in 1981.The cause was later identified as Enterovirus-70. Number of patients developed polyradiculoneuropathy with dysautonomias akin to Guillain-Barre syndrome; detail clinical and serological, including CSF, studies were undertaken. A cohort of patients was followed up.

A new neurological profile as a complication of Enterovirus-70 was defined.

        The results were published (J of Tropical & Geographical Medicine 1986, V 38: 197-202), and received wide spread attention from numerous medical centers in the world.
Title: A study of arthritis and rheumatism in the community through medical camps
        Free of cost diagnostic evaluation and therapy guidance to over 6000 patients has been provided in medical camps conducted in the Pune metropolis and neighboring rural areas and towns from 1992 to 1996.Detail clinical records were maintained.

        An indigenously-designed-software-based patient database was created; probably for the first time in India. The clinical results, including the design of the arthritis soft-ware program, were presented in numerous national and international meetings.

        A public health education campaign, as part and parcel of the arthritis camps, was also organized in conjunction with the School of Health Sciences, University of Pune, in the Pune metropolis, in 1992.

the IRA gold medal and the BOOTS best research paper award at the national conference of the Indian Rheumatism Association , Hyderabad 1990.
APLAR travel fellowship to present the some of the data from medical camps in the APLAR (Asia-Pacific League of Associations for Rheumatology) Congress, Bali, Indonesia, 1992.
Title: A community oriented program for control of rheumatic diseases (COPCORD) under the auspices of WHO-ILAR-APLAR
        The maiden COPCORD in India was launched in village Bhigwan (Pune District) in Feb 1996.The COPCORD epidemiological model envisages measurement of the rheumatic musculoskeletal (RMSD) burden, and not necessarily well-defined rheumatic syndromes, in the community. In the first stage (3 phases)-house to house survey, identification of rheumatic patients and rheumatologic evaluation is completed. Stages 2 and 3 include health education, identification of risk factors and control strategies.

        The Bhigwan COPCORD model has successfully taken cognizance of the Indian traditions and life styles and created an extensive community oriented data base. The latter includes details on pain, disability, concepts, beliefs and perceptions of the Bhigwan people.

        The initial Bhigwan survey interviewed about 7000 village residents by validated questionnaires served by trained village volunteers; 774 patients were identified. Besides clinical evaluation, diagnostic laboratory and radiological work up was also set up.
A sera bank from the village patients was created in Center for Rheumatic Diseases (CRD), Pune.

Till date, patients have been followed up every 3-4 weeks in a planned schedule.

In 1999, a resurvey of the village adult population was undertaken.

        Prevalence and incidence data from this rural study has been presented in numerous national and international meetings, and published. An unusually high prevalence of inflammatory arthritis, RA in particular, has been found. The study has also established the predominant nature of RMSD in the community. Ill defined soft tissue aches and pains and soft tissue rheumatism are the dominant problems of the community.

The COPCORD Bhigwan is the first prospective study of its kind in the World, and is now extended till 2008.

        The WHO while launching the Bone and Joint Decade in Jan 2000, has listed the COPCORD Bhigwan study in its Global data inventory and has used its data to represent the South East Asian scenario in its publication, a Technical Research Series, on the global burden of musculoskeletal diseases in the new millennium. .

         Under this program, HLA DRB1 analysis of the patients with inflammatory arthritis has been undertaken in collaboration with Univ of Manchester, UK. The results are in total variance with what is generally believed to the case e.g. there is no association of RA from this rural community with HLA DRB1*0404.

        Based on the concepts, beliefs and lack of scientific information in the community, the WHO has sponsored a publication of a health education booklet for free circulation in the region. The book, in the regional language, contains information on arthritis in a question-answer format and is illustrated with cartoons.
Title: Detection of anti-nuclear antibodies (ANA) from serum and filter paper blood clots (FPBC) using indirect immunoenzyme (IIE)
        Indirect immunofluorescence (IIF) has been the gold standard for detection of ANA from patients with systemic connective tissue diseases (CTD) but is a technically cumbersome and expensive test besides being sparsely available in India. IIE is a simpler method using color enzymes that can demonstrate ANA under light microscope but has not found popular use anywhere in the World. FPBC, obtained through finger/ heel pricking, have been used in epidemiological studies, mostly in pediatric diseases (e.g. poliomyelitis) to collect blood samples for serodiagnosis.

        A project was begun in 1992 to standardize the technique of ANA detection by IIE using serum and FPBC from patients with CTD.A protocol was designed to randomly and blindly compare the results of IIE with those of the IIF. More than 270 paired samples were collected both from patients and healthy controls. A pilot study was undertaken in the Dept of Rheumatology, The St George Hospital, Sydney, Australia as part of the APLAR study grant award 1992, to standardize the extraction of serum equivalent elute from FPBC, and then detect ANA using IIE. The results were comparable with those of IIF on FPBC elutes.

        The results demonstrated that IIE is a viable option to IIF for detection of ANA. The use of FPBC to collect samples and then apply IIE for detecting ANA will enhance the feasibility of population surveys on uncommon diseases like CTD in countries like India.
Title: Development of validated quality of life (QOL) instruments to evaluate the functional outcome in diseases like RA and OA.
        The popular Stanford modified HAQ (health assessment questionnaire) was chosen for modification as per the Indian style of living and customs. The basic structure covering the 8 activities was preserved, but the questions were changed to address the Indian issues of dressing, traveling, working and activities of daily living including toilet use. A consensus approach was used, and after pilot testing in a cohort of patients and healthy people the Indian HAQ was validated systematically in cross-sectional evaluation of patients of RA, and in a long term drug trial study using DMARDs. The Indian HAQ was further applied to patients with varying types of rheumatic disorders from a rural population (see COPCORD Bhigwan study above).This is the first Indian HAQ which has now been used in numerous drug trials in India, notably randomized controlled studies of meloxicam and celecoxib. This HAQ is also being used routinely in the referral practice at the CRD, Pune, since 1995; over 5000 patients of RA have been evaluated with HAQ.

        The WOMAC (Western Ontario McMaster University, Canada) instrument for OA of the hips and knees was selected for modification and later validation. While the pain and stiffness component of the parent index was unchanged, the ‘physical difficulty’ component was changed to suit the Indian life style, especially of squatting and sitting cross legged. The Indian WOMAC has been successfully used in numerous drug trials using Ayurvedic medication, and selective COX-2 inhibitors.
Title: Controlled drug studies of an Ayurvedic formulation in patients with RA and OA.
        A literature search to study the role of Ayurveda in diagnosis and management of arthritis was undertaken, and modern experimental evidence on medicinal plants was evaluated. The need to validate ancient medicines which are still in popular use in the modern context was recognized. A concept of modern medicine-Ayurveda interface was developed and presented in a meeting of Ayurvedic scholars in the Pune Univ in 1994.

        RA-1, an Ayurvedic anti-arthritis formulation derived from well known Ayurvedic medicinal plants’ extracts (ashwagandha, gugulla, ginger, turmeric), had been identified by Prof B Patwardhan, School of Health Sciences, Pune University and meticulously standardized by modern pharma techniques. RA1 was also proven to be extremely safe in both acute and chronic animal toxicity models.

        Under an Indo-US collaboration, an international standard protocol driven randomized double blind (RDB) drug trials comparing RA-1(an Ayurvedic formulation) with identical placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were conducted in CRD, Pune during the period 1994-1999. The drug trial protocols were co-designed with Prof Polisson, Arthritis Unit, Massachusetts General Hospital and Howard Medical School, USA. The entire project was sponsored by Ayurcore Inc., USA.

        182 eligible patients with active RA were randomized to receive RA 1 or placebo in a RDB drug trial of 16 weeks duration; later the patients were followed up in an open label phase for over 3 years.RA-1 showed impressive efficacy and excellent safety. The trial results were selected to be poster presented in the annual congress of the American College of Rheumatology (ACR) 1996, and published in peer reviewed journal (J Rheum 2000). The research module used and the subject of Ayurveda and arthritis was also published in the Rheum Clinics of N America 2000.

        90 eligible patients with moderately severe symptomatic OA knees were randomized to receive RA 11(an augmented form of RA 1) or placebo in a RDB drug trial of 32 week duration. The results demonstrated a highly significant superior efficacy for RA 11 in reducing pain and improving quality of life functions related to knee joints (see Indian modified WOMAC described above).RA 11 had an excellent safety profile. Urinary cortisol studies proved that RA 11 did not contain any steroid moiety. The trial results were selected to be poster presented in annual congress of ACR 1998.
Title: Controlled drug trial studies of meloxicam, celecoxib and rofecoxib.
        The advent of selective COX 2 inhibitors is considered to be a major step forward in treating painful and inflammatory conditions such as RA and OA with NSAIDs that are effective but with excellent gastro-intestinal tolerability. While meloxicam is a highly preferential COX-2 inhibitor, both celecoxib and rofecoxib are the only NSAIDs to be highly selective COX-2 inhibitors. These new NSAIDs were introduced in India in 1998-2000.

        International standard protocols were designed for conducting the first Indian RDB multicentric drug trials comparing meloxicam, celecoxib and rofecoxib to piroxicam and diclofenac in CRD, Pune, in patients with RA and OA. Numerous individual trials, all of 4 week duration, were held; over 650 patients randomized. Besides Pune, patients were also recruited in premier medical institutes in Delhi and Bombay. After decoding, the entire patient data base was statistically analyzed in CRD, Pune. Meloxicam, celecoxib and rofecoxib were shown to be as effective as piroxicam and diclofenac but much more safer; similar to the World experience. Results were presented in national meetings and submitted to peer reviewed rheumatology journals.
Title: IRA-01, An Ayurvedic (Asian Indian) drug for Rheumatoid Arthritis (RA): Evaluation for Efficacy and Safety, and a probable lipid modyfying effect
        It would be difficult, if not impossible, to validate the entire Ayurvedic system on an ‘evidence based medicine’ platform. But we, like several other groups, believe that the promise and potential of safety and efficacy of Ayurvedic medicines is borne by their ancient use. However, bypassing the conventional early stages of modern medicine model of drug development, Ayurvedic medicines could be directly tested for their clinical usefulness in controlled clinical situations. Since several years, our group has been validating anti-arthritic formulations using standard clinical drug trial protocols and GCP guidelines.

        IRA-01, an Ayurvedic derived standardized antiarthritic formulation, containing extracts of Boswellia serrata (Salai Guggul),Trigonella foenum-graecum (Fenugreek), Linum usitatissimum (Flaxseed), Camellia sinensis (Greentea), Curcuma longa (Turmeric), Tribulus terrestris (Gokharu), and Piper nigrum ( Black pepper) was evaluated in patients with active rheumatoid arthritis (RA) for a period of one year. This was a randomized, double blind, placebo controlled, parallel efficacy study of 3 months followed by an open label phase.

        IRA-01 demonstrated fair clinical efficacy with excellent safety profile, and with significant lipid lowering effect. The results were presented in the EULAR (European league of rheumatology associations) meeting in Berlin, 2004.
10. Title: NMITLI (New Millennium Indian Technology Leadership Initiative) Arthritis Project 2002-2006
        Under the auspices of Ministry of Science and Technology, Government of India, the CSIR (Council Of Scientific & Industrial Research) has launched a scheme entitled NMITLI that seeks to realize the vision of developed India in Science and Technology. The scheme envisages to support innovation centered scientific & technological developments as a vehicle to attain for the country a global leadership position at least in some selected niche areas. Ayurveda is one such niche area that needs to be developed in the modern context of evidence based medicinal system.

        The primary focus in the NMITLI ARTHRITIS project is to develop Ayurvedic herbal-based preparations for treatment of osteoarthritis (OA) knees , with special reference to pain relief, better quality of life and chondroprotection. The project will also explore early leads of these formulations in patients with early rheumatoid arthritis (RA).

        In the ‘NMITLI ARTHRITIS’ project, it is proposed to carry out numerous standard state-of-the-art clinical drug trial driven evaluations for efficacy and safety of pre selected Ayurvedic plant formulations in patients with symptomatic OA knees.

        The research model envisages concurrent pharmacological and clinical development to achieve quality-standardized product, define mechanism of action, identify active principles, document safety and demonstrate clinically significant efficacy. The clinical drug trial evaluations would begin along with animal and other bench studies- a truly reverse pharmacology paradigm fuelled by historical and authoritative Ayurvedic knowledge of medicinal use spanning thousands of years. However, clinical and all other evaluations would be performed as per state-of-the art protocols using modern medicine science and concepts. Well designed and appropriately powered scientific experiments and explorations, and rigorous drug testing and clinical trials will steer the development and progress step-wise to ultimately finalize the final formulation of the herbal medicine within a four year project beginning 2002.

        This study is being carried out in KEM Hospital Mumbai, Swami Prakashnanda Ayurved Research Center –Mumbai, Nizam’s Institute of Medical Sciences- Hyderabad and All India Institute of Medical Sciences- Delhi. CRD, Pune is the Co-ordinating center for this NMILTI project with Dr Chopra being the Principal Investigator & the Clinical Co-ordinator.
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