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Randomized double blind trial of an Ayurvedic plant derived formulation for treatment of rheumatoid arthritis
Abstract
To evaluate RA-1, a standardized plant extract formulation, traditionally considered a safe, effective antiarthritic in the Asian-Indian Ayurvedic medicinal system.
One hundred eighty-two patients with active-on-chronic rheumatoid arthritis (RA) participated in a 16 week randomized, double blind, placebo controlled, parallel efficacy clinical drug trial in Pune, India. Tenderness, pain, swelling, and several other efficacy measures were assessed by (1) ACR core set 20% and 50% improvement; (2) ACR 20% improvement response. An intent-to-treat analysis was performed; p<0.05 considered significant.
Seventeen patients withdrew (active = 9; placebo = 8); none withdrew due to drug toxicity. An unprecedented placebo response (often p<0.001 in within-group change) was observed. The active RA-1 group remained numerically superior at all evaluation timepoints. RA-1 demonstrated few significant differences: (1) increased proportion with 50% reduction in swollen joint count (95% CI approximately 1.52, 29.90) and swollen joint score (95% CI approximately 0.91, 28.73); (2) reduced rheumatoid factor (95% CI approximately -303.7, -2.72); 39% in the RA-1 group versus 30% placebo showed ACR 20% improvement (95% CI approximately -5.48, 24.59). Only minor side effects were seen, with no significant differences by treatment group.
In a trial with sufficient power, RA-1 revealed efficacy that was not significantly superior to the strong placebo response, except for improvement in joint swelling. Further, the effect on RF and good safety profile led to an open label phase.
... However, the contribution of most of them to anti-arthritic activities should be further uncovered; 60 percent of those who suffer from rheumatoid arthritis look for herbal remedies [39]. According to Chopra et al., when it comes to establishing the legitimacy of traditional herbal medicines on a global scale, more rigorous studies are necessary to determine their efficacy and safety [40]. The main goal of our study was to find new molecules from NAT that showed promise and could be used to treat arthritis with few side effects. ...
Rheumatoid arthritis (RA) is an autoimmune disease characterized by bone and joint degeneration. Existing anti-inflammatory chemotherapy drugs offer temporary relief but come with undesirable side effects. Herbal medications have shown positive effects on RA symptoms with minimal adverse reactions. In this study, we investigated the potential of Nyctanthes arbor-tristis (NAT) through in vitro and in silico research. Hydroethanolic extracts of harsingar were prepared using the reflux method, containing alkaloids, phenol, saponin, steroids, proteins, tannins, terpenoids, carbohydrates, glycosides, and flavonoids, which exhibited TPC (98.56 ± 0.46 mg GAE/g) and TFC (34.51 ± 0.45 mg CE/g). LC–MS/MS analyzes the active compounds in the extract. NAT exhibited the best scavenging capabilities at 1 mg/mL in anti-oxidant and anti-arthritic activity. Maximum splenocyte proliferation occurred at 250 µg/mL. In vitro cell splenocyte studies revealed the downregulation of TNF-α and the upregulation of IL-10. Additionally, an in silico study demonstrated that bioactive constituents and targets bind with favorable binding affinity. These findings demonstrate the potential of Nyctanthes arbor-tristis in exerting anti-arthritic effects, as supported by in vitro and in silico studies. Further mechanistic research is necessary to validate the therapeutic potential of all phytoconstituents in RA treatment.
... The secondary outcome of the study consisted of a change in the WOMAC subscale of pain (WOMAC-P; scale of 0-4; averaged response of 5 questions), stiffness (WOMAC-S; scale of 0-4; averaged response for 2 questions), and physical function (WOMAC-PF; scale of 0-4; averaged response for 17 questions) at the end of week 4, 8, and 12 from baseline [20]. Other measures performed included health-related quality of life as evaluated by a validated EQ-5D-5L questionnaire consisting of 5 domains -mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression using 5 response levels -no problems, slight problems, moderate problems, severe problems, and extreme problems [21]. ...
Purpose:
Knee osteoarthritis (OA) is the most common form of clinical arthritis in middle-aged and older individuals. Undenatured or native type II (TII) collagen derived from the chicken sternum has a good therapeutic effect on relieving severe pain of OA. Hence, the present study aimed to investigate the efficacy and safety of TII collagen (Native CT-II®) in individuals with knee OA.
Methods:
We conducted a 12-week randomised, double-blind, placebo-controlled, parallel-group study on 101 participants aged 40-65 years with knee OA. The participants were randomised to receive either TII collagen, glucosamine hydrochloride + chondroitin sulfate (G + C) or a placebo. The primary outcome was an improvement in the joint health of the participants assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) compared to G + C and placebo.
Results:
Compared with the placebo group (n = 27), the TII collagen group (n = 29) and G + C group (n = 29) significantly improved the overall joint health measured by the change in WOMAC total score (week 12: TII collagen = -32.47 ± 19.51 and G + C = -33.74 ± 24.64 vs. placebo = -13.84 ± 17.61; p < 0.05) and relieved knee joint pain (week 12: TII collagen = -5.69 ± 3.66 and G + C = -6.03 ± 4.72 vs. placebo = -2.71 ± 3.95; p < 0.05). The statistically significant effect was observed as early as 4 weeks after the investigational product administration. Additionally, the TII collagen was more effective in improving the quality of life than the G + C.
Conclusion:
TII collagen not only has a significantly better effect and high safety profile for OA but also improves the quality of life of patients.
Level of evidence:
Level 1 - Randomized Controlled Trial.
Trial registration:
ClinicalTrials.gov Identifier: NCT04470336 ; First submitted date: July 08, 2020; First posted date: July 14, 2020.
... Wight & Arn., Boerhaavia diffusa L., Plumbago zeylanica L., Terminalia chebula Retz., Withania somnifera Dunal, Vitex negundo L., Vanda roxburghii R. Br., Solanum nigrum L., Tinospora cordifolia Miers ex Hook f. & Thoms., Piper longum L., Cyperus scariosus R. Br., and Embelia ribes Burm. F. [21][22][23][24][25] . ...
... Wight & Arn., Boerhaavia diffusa L., Plumbago zeylanica L., Terminalia chebula Retz., Withania somnifera Dunal, Vitex negundo L., Vanda roxburghii R. Br., Solanum nigrum L., Tinospora cordifolia Miers ex Hook f. & Thoms., Piper longum L., Cyperus scariosus R. Br., and Embelia ribes Burm. F. [21][22][23][24][25] . ...
... It has also been stated that mushrooms or mushroom-based dietary products mitigated autoimmune disorders and cancer . A standardized formulation made with purified extract of Withania somnifera, Boswellia serrata, and Curcuma longa has been found effective in improving joint-swelling condition and rheumatoid arthritis (Chopra et al. 2000). In addition, potent vaccine adjuvant properties of Withania somnifera and Asparagus racemosus have also been assessed and recommended for their importance in immunobiological preparations. ...
Medicinally important plant-foods offer a balanced immune function, which is essential for protecting the body against antigenic invasion, mainly by microorganisms. immunomodulators play pivotal roles in supporting immune function either suppressing or stimulating the immune system's response to invading pathogens. Among different immunomodulators, plant-based secondary metabolites have emerged as high potential not only for immune defense but also for cellular immunoresponsiveness. These natural immunomodulators can be developed into safer alternatives to the clinically used immunosuppressants and immunostimulant cytotoxic drugs which possess serious side effects. Many plants of different species have been reported to possess strong immunomodulating properties. The immunomodulatory effects of plant extracts and their bioactive metabolites have been suggested due to their diverse mechanisms of modulation of the complex immune system and their multifarious molecular targets. Phytochemicals such as alkaloids, flavonoids, terpenoids, carbohydrates and polyphenols have been reported as responsible for the immunomodulatory effects of several medicinal plants. This review illustrates the potent immunomodulatory effects of 65 plant secondary metabolites, including dietary compounds and their underlying mechanisms of action on cellular and humoral immune functions in in vitro and in vivo studies. The clinical potential of some of the compounds to be used for various immune-related disorders is highlighted.
... The secondary outcome for the study consisted of a change in WOMAC subscales of pain (scale of 0-4; averaged response of 5 questions), stiffness (scale of 0-4; averaged response for 2 questions), and physical function (scale of 0-4; averaged response for 17 questions) [20]. Other measures performed included health-related quality of life as evaluated by a validated EQ-5D-5L ...
Background
Osteoarthritis (OA) of the knee is the most common type of arthritis, increasing with advancing age and external factors such as obesity. Joint health has historically relied on nutritional supplements derived from herbs and other natural products. Undenatured collagen type II demonstrated positive results with substantially lower therapeutic doses. Hence, the present study was designed to determine the efficacy and safety of Native CT-II®, an undenatured type II collagen, on the symptomatic effects in individuals having joint pain due to OA.
Methods
A randomized, double-blinded, placebo-controlled, parallel study was conducted on 101 slightly overweight volunteers, whose knee joint pain VAS score was ≥ 60 had been included in the study for at least three months. The participants were divided into three groups, with similar demographic and baseline characteristics. The test product containing Native CT-II®, positive control containing G+C, and the placebo were taken six tablets per day for 84 consecutive days (Three capsules to be taken post-breakfast and three capsules post-dinner). Improvement in overall joint health in each participant from baseline to end of the study was measured by WOMAC, self-administered questionnaire in Native CT-II® as compared to G+C and placebo group.
Results
This study demonstrated that Native CT-II® had an effective impact on the symptomatic effects of knee impairment associated with OA and in the quality of life of the participants. After 84 days, participants receiving Native CT-II® and G+C had significant improvement in overall joint health as compared to participants receiving placebo.
Conclusion
Native CT-II® was shown to be effective in relieving symptoms and improving quality of life for patients with knee joint pain associated with OA.
Trial registration
The trial was registered with the clinical trial registry of the U.S. National Library of Medicine under National Institutes of Health (NIH) (https://clinicaltrials.gov/) with the National Clinical Trial (NCT) No: NCT04470336, Date of first registration: 14/07/2020.
Zusammenfassung
Methoden der komplementären und alternativen Medizin („complementary and alternative medicine“ [CAM]) stoßen bei vielen Patienten mit rheumatischen Erkrankungen auf Interesse. Die wissenschaftliche Datenlage ist durch eine große Anzahl von Publikationen bei einem eklatanten Mangel an verwertbaren klinischen Studien gekennzeichnet. Anwendungen der CAM stehen im Spannungsfeld zwischen dem Bemühen um eine evidenzbasierte Medizin und um qualitativ hochwertige Therapiekonzepte auf der einen und wenig fundierten bis eindeutig unseriösen Angeboten auf der anderen Seite. Die Deutsche Gesellschaft für Rheumatologie (DGRh) hat 2021 eine Kommission Komplementäre Heilverfahren und Ernährung ins Leben gerufen, welche die aktuelle Evidenz für CAM-Anwendungen und ernährungsmedizinische Maßnahmen in der Rheumatologie sichten und in praktisch anwendbare Empfehlungen einarbeiten soll. Für die vorliegende Publikation wurden für 4 Bereiche Empfehlungen für den rheumatologischen Praxisalltag erstellt: Ernährung, mediterrane Kost, ayurvedische Medizin und Homöopathie.
A study was conducted to develop criteria for clinical remission in rheumatoid arthritis (RA). Data were provided by 35 rheumatologists on 175 RA patients considered to be in complete remission (with or without antirheumatic therapy) and 169 RA patients in partial remission or with active disease. Six criteria yielded optimal discrimination: morning stiffness absent or not exceeding 15 minutes, no fatigue, no joint pain by history, no joint tenderness, no joint or tendon sheath swelling, and no elevation of erythrocyte sedimentation rate. In this study sample, the presence of five or more of these criteria in an individual patient yielded 72% sensitivity for clinical remission and 100% specificity in discriminating RA patients with active disease. In a population sample, it is estimated that the overall accuracy of these criteria would be more than 90% in RA patients.
The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
Objective. To develop a set of disease activity measures for use in rheumatoid arthritis (RA) clinical trials, as well as to recommend specific methods for assessing each outcome measure. This is not intended to be a restrictive list, but rather, a core set of measures that should be included in all trials.
Methods. We evaluated disease activity measures commonly used in RA trials, to determine which measures best met each of 5 types of validity: construct, face, content, criterion, and discriminant. The evaluation consisted of an initial structured review of the literature on the validity of measures, with an analysis of data obtained from clinical trials to fill in gaps in this literature. A committee of experts in clinical trials, health services research, and biostatistics reviewed the validity data. A nominal group process method was used to reach consensus on a core set of disease activity measures. This set was then reviewed and finalized at an international conference on outcome measures for RA clinical trials. The committee also selected specific ways to assess each outcome.
Results. The core set of disease activity measures consists of a tender joint count, swollen joint count, patient's assessment of pain, patient's and physician's global assessments of disease activity, patient's assessment of physical function, and laboratory evaluation of 1 acute-phase reactant. Together, these measures sample the broad range of improvement in RA (have content validity), and all are at least moderately sensitive to change (have discriminant validity). Many of them predict other important long-term outcomes in RA, including physical disability, radiographic damage, and death. Other disease activity measures frequently used in clinical trials were not chosen for any one of several reasons, including insensitivity to change or duplication of information provided by one of the core measures (e.g., tender joint score and tender joint count) The committee also proposes specific ways of measuring each outcome.
Conclusion. We propose a core set of outcome measures for RA clinical trials. We hope this will decrease the number of outcomes assessed and standardize outcomes assessments. Further, we hope that these measures will be found useful in long-term studies.
One hundred eighty-six patients with active rheumatoid arthritis were evaluated in a double-blind, randomized study that compared treatment with sulfasalazine (SSZ) (2 gm/day), gold sodium thiomalate (GST) (50 mg/week), and placebo (PBO). The 37—week course of therapy was completed by 109 patients. While marked improvement was seen in all 3 treatment groups, the only statistically significant differences between SSZ or GST and PBO were in a decreased erythrocyte sedimentation rate and increased grip strength in the right hand. GST is known to be superior to PBO, and the response of the GST-treated group was similar to that seen in other trials. The response of the PBO group, however, was much greater than in other placebo groups we have studied. SSZ was similar in efficacy to injectable gold, but was better tolerated. Because of adverse drug reactions (most commonly, rash, stomatitis, and proteinuria), 41% of patients were withdrawn from the GST treatment. Untoward drug effects (most frequently, rash and gastrointestinal distress) caused 16% of patients to be withdrawn from SSZ therapy.
Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.
Evaluation of polyarthritis in 110 patients in civilian and armed force life revealed 89 with rheumatoid arthritis (RA). In
the Indian population, RA seems milder and confined to the joints. A substantial number of male patients appeared to share
features with spondarthritis, often in HLA-B27 positive individuals.
In this article the relationship between the cellular elements of the immune response and inflammation are examined with reference to the B lymphocyte repertoire. Evidence is presented that, in addition to an environment in the joint that favors localization and activation of auto-reactive B lymphocytes, the circulating B lymphocyte pool in rheumatoid arthritis is abnormally enriched in cells that bear a receptor for mouse erythrocytes and possess CD5 antigen. B lymphocytes with these novel phenotypic markers secrete autoantibodies and are found in abundance in fetal lymphoid tissues and cord blood; analogous cells in the mouse belong to a distinct lineage and are implicated in allotype- and idiotype-restricted interactions. It is postulated that a subset of B lymphocytes is of primary importance in the etiopathogenesis of rheumatoid disease.