Anuradha Venugopalan

Effectiveness of Chloroquine and Inflammatory Cytokine Response in Patients With Early Persistent Musculoskeletal Pain and Arthritis Following Chikungunya Virus Infection

To evaluate whether chloroquine (CQ) is more effective than meloxicam for treating early musculoskeletal pain and arthritis following acute chikungunya (CHIK) virus infection.

Profile of Indian Patients with Juvenile Onset Chronic Inflammatory Joint Disease Using the ILAR Classification Criteria for JIA: A Community-based Cohort Study

Objective. To assess the current International League of Associations for Rheumatology (ILAR) classification criteria (Edmonton, 2001) for juvenile idiopathic arthritis (JIA) in Indian patients. Methods. Out of 441 children, 330 with chronic joint pains were diagnosed with juvenile onset chronic inflammatory arthritis and followed in an observational cohort. Our study was carried out from 1994 to 2006 in a community rheumatology clinic. Emphasis was placed on obtaining data required by the ILAR system. Of the original group, 235 children were eventually classified as having JIA; 108 were examined during the first year of illness. Results. We assigned 224 children (95%) to discrete JIA categories: enthesitis-related arthritis (ERA; 36%), oligoarthritis (OLA-persistent; 17%), polyarthritis rheumatoid factor (RF)-negative (17%), polyarthritis RF-positive (12%), systemic arthritis (8%), OLA-extended (4%), and psoriatic arthritis (1%). The remaining 11 children (5%) were classified with undifferentiated arthritis (mostly an overlap due to seropositive RF and/or HLA-B27). The prevalence of ERA (89% HLA-B27-positive) and seropositive RF was unexpectedly high. Although agreement (κ > 0.79) with the American College of Rheumatology criteria and the European Spondylarthropathy Study Group criteria was good to excellent, the ILAR system was found to be more comprehensive and clinically homogeneous. However, some problems appear unique in our scenario. Conclusion. A wide-spectrum phenotype of JIA is demonstrated by an Indian cohort. Although useful, RF and HLA-B27 in this population proved problematic to the ILAR classification.

Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: a randomized, double-blind, controlled equivalence drug trial

OBJECTIVE To demonstrate clinical equivalence between two standardized Ayurveda (India) formulations (SGCG and SGC), glucosamine and celecoxib (NSAID). METHODS Ayurvedic formulations (extracts of Tinospora cordifolia, Zingiber officinale, Emblica officinalis, Boswellia serrata), glucosamine sulphate (2 g daily) and celecoxib (200 mg daily) were evaluated in a randomized, double-blind, parallel-efficacy, four-arm, multicentre equivalence drug trial of 24 weeks duration. A total of 440 eligible patients suffering from symptomatic knee OA were enrolled and monitored as per protocol. Primary efficacy variables were active body weight-bearing pain (visual analogue scale) and modified WOMAC pain and functional difficulty Likert score (for knee and hip); the corresponding a priori equivalence ranges were ±1.5 cm, ±2.5 and ±8.5. RESULTS Differences between the intervention arms for mean changes in primary efficacy variables were within the equivalence range by intent-to-treat and per protocol analysis. Twenty-six patients showed asymptomatic increased serum glutamic pyruvic transaminase (SGPT) with otherwise normal liver function; seven patients (Ayurvedic intervention) were withdrawn and SGPT normalized after stopping the drug. Other adverse events were mild and did not differ by intervention. Overall, 28% of patients withdrew from the study. CONCLUSION In this 6-month controlled study of knee OA, Ayurvedic formulations (especially SGCG) significantly reduced knee pain and improved knee function and were equivalent to glucosamine and celecoxib. The unexpected SGPT rise requires further safety assessment. TRIAL REGISTRATION Clinical Drug Trial Registry-India, www.ctri.nic.in, CTRI/2008/091/000063.

Cytokines in acute chikungunya.

Introduction Acute chikungunya (CHIKV) is predominantly an acute onset of excruciatingly painful, self-limiting musculoskeletal (MSK) arbovirus illness and this was further reported by us during the 2006 Indian epidemic [Chopra et al. Epidemiol Infect 2012]. Selected serum cytokines profile in subjects within one month of onset of illness is being presented. Methods Out of 509 clinical CHIKV cases (43% population) identified during a rural population survey, 225 subjects consented blood investigations. 132 examined within 30 days of febrile onset are the study cohort. Anti-CHIKV IgM and IgG antibodies tested by immunochromatography and indirect immunofluorescence respectively. Interferons (IFN)-α, -β and -γ, Interferon Gamma-Induced Protein-10 (CXCL-10/IP-10), Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-13 (IL-13), Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin–4 (IL-4) and Interleukin–10 (IL-10) performed by ELISA. Samples collected from neighboring community a year prior to the epidemic used as healthy controls. Results Seropositivity for anti-CHIKV IgM and IgG was 65% and 52% respectively. IFN-α, IFN-β, IFN-γ, CXCL10/IP-10 and IL-1β showed intense response in early acute phase. Cytokines (particularly TNF-α, MCP-1, IL-4, IL-6 and IL-10) was maximum in extended symptomatic phase and remained elevated in recovered subjects. Higher (p<0.05) IFN and IL-4 seen in patients seropositive for anti-CHIKV IgG. Elderly cases (≥65 years) showed elevated cytokines (except IFN) and anti-CHIKV antibodies near similar to younger subjects. Significant correlations (p<0.05) found between cytokines and clinical features (fatigue, low back ache, myalgia) and anti-CHIKV antibodies. Conclusion An intense cytokine milieu was evident in the early and immediate persistent symptomatic phase and in recovered subjects. Early persistent IgM and lower IgG to anti-CHKV and intense Th2 cytokine phenotype seem to be associated with delay in resolution of MSK symptoms. Intriguingly, maximum TNF-α, IL-6 and IL-13 with low anti-CHIKV IgM response found in subjects recovered from CHIKV within one month of illness.

A Randomized Controlled Exploratory Evaluation of Standardized Ayurvedic Formulations in Symptomatic Osteoarthritis Knees: A Government of India NMITLI Project

The multidisciplinary “New Millennium Indian Technology Leadership Initiative” Arthritis Project was undertaken to validate Ayurvedic medicines. Herbal formulations in popular use were selected by expert consensus and standardized using modern tools. Our clinical strategy evolved from simple exploratory evaluations to better powered statistically designed drug trials. The results of the first drug trial are presented here. Five oral formulations (coded A, B, C, D and E), with a common base of Zingiber officinale and Tinospora cordifolia with a maximum of four plant extracts, were evaluated; with placebo and glucosamine as controls. 245 patients suffering from symptomatic OA knees were randomized into seven arms (35 patients per arm) of a double blind, parallel efficacy, multicentric trial of sixteen weeks duration. The groups matched well at baseline. There were no differences for patient withdrawals (17.5%) or adverse events (AE) of mild nature. Intention-to-treat efficacy analysis, demonstrated no significant differences (P < .05) for pain (weight bearing) and WOMAC questionnaire (knee function); placebo response was high. Based on better pain relief, significant (P < .05) least analgesic consumption and improved knee status, “C” formulation was selected for further development. Controlled exploratory drug trials with multiple treatment arms may be used to economically evaluate several candidate standardized formulations.

Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project

Background: Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination)-based formulations in the treatment of Osteoarthritis (OA) Knees. These formulations were “platform combination+Withania somnifera+Tribulus terrestris” (formulation B) and “platform combination+Emblica officinale” (formulation C). This paper reports safety of these formulations when used in higher doses (1.5–2 times) along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation). Materials and Methods: Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I) formulation B, 2 t.i.d.; (II) formulation B, 2 q.i.d.; (III) platform combination+Sallaki Guggul; (IV) Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE) and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5) was used for analysis. Results: None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut–related (mostly epigastric burning) AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT)] without any other hepatic abnormality was reported in 2 patients (group IV). Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5–2.22), WOMAC (functional activity questionnaire) pain score (1.37, CI 0.22–2.5), and urinary C-TAX (cartilage collagen breakdown product) assay was maximum (NS) in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. Conclusion: The results suggested that despite higher doses, standardized Ayurvedic formulations demonstrated a good safety profile. An improved efficacy and likely chondroprotective effect was shown by group IV intervention. A confirmatory drug trial with adequate power and sample size was planned based on the learning from this trial.

Persistent rheumatic musculoskeletal pain and disorders at one year post-chikungunya epidemic in south Maharashtra—a rural community based observational study with special focus on naïve persistent rheumatic musculoskeletal cases and selected cytokine expression

Abstract The recent Chikungunya (CHIKV) epidemic (2006) unleashed an unrecognized spectrum of rheumatic musculoskeletal (RMSK) pain and disorders. The data on persistent RMSK is lacking. About 10% clinical acute cases are considered to suffer from chronic arthritis. We used an arthritis camp approach in a 9000 populated village Modnimb (district Sholapur) in December 2007 to identify naive cases of RMSK following symptomatic CHIKV outbreak in December 2006. A 10-day intensive publicity through public announcement and media pamphlet distribution program was carried out to attract villagers with persistent aches and pains and a past history of acute CHIKV illness to attend a 3 day free of cost evaluation arthritis camps. Blood samples were collected from consenting patients. Village volunteers and health workers participated in it. 1.4 percent (95% confidence interval 1.13, 1.60) village population was found to suffer from naive persistent RMSK pain and disorders at 1 year following acute CHIKV infection. Patients were generally >45 years age and females were predominant. Knee was the predominant pain site in 79% cases. Though 27% cases suffered from non-specific arthralgias (NSA), the diagnosis in 48% and 15% cases respectively was consistent with OA (often knee and spine) and undifferentiated inflammatory arthritis (0.2% crude prevalence). Overall, the clinical RMSK profile was benign and none reported any significant functional disability or mobility impairment. Seventy-three percent patients tested seropositive for anti-CHIKV IgG antibody; none for IgM antibody. None showed any abnormality on routine laboratory haematology and biochemistry testing; seropositive RF, ANA and anti-CCP was infrequent. Though CRP values were low, IL-6 was elevated and was not associated with any clinical phenotype. As compared to normal healthy population values assayed a year prior to the epidemic in a neighboring village, cases with persistent RMSK showed elevated IFN-γ, TNF-α and IL-13. Also, the clinical phenotype and cytokine expression did not seem to differ between the seropositive and seronegative groups for anti-CIKV IgG antibody. Conclusion In this rural community study, at least 1.4% population continued to suffer from some form of RMSK at 1 year following acute CHIKV epidemic. Though clinically unimpressive, a large number showed elevated pro-inflammatory cytokine expression. A longer follow-up may explain this disconnect.

Salivary immunoglobulin A in rheumatoid arthritis (RA) with focus on dental caries: a cross-sectional study

Salivary secretory immunoglobulin A (sIgA) is postulated to protect against dental caries. Dental hygiene and health are usually poor in rheumatoid arthritis (RA) due to several factors. We hypothesized higher salivary sIgA in caries-free subjects and a higher extent of caries in RA. A protocol-driven cross-sectional pilot study was carried out to determine salivary sIgA in 48 patients with RA and 102 non-RA, healthy case controls. Standard of care in clinical and dental assessments were done by experts. A decay, missing teeth, filled teeth (DMFT) index was used to classify caries. Whole unstimulated saliva was collected to assay sIgA using a commercial ELISA kit. Dental caries was diagnosed in 67% and 86% of the RA and healthy subjects, respectively. Eight percent of RA patients had visited a dental surgeon. Though they tend to be higher in caries-free status, there were no statistically significant differences (p > 0.05) between RA and non-RA subjects with respect to salivary sIgA and extent of caries. The salivary sIgA levels for both RA and healthy case control subjects in this ethnic Indian (Asian) study were much higher than that reported in literature and need further validation. Rheumatologists ought to educate patients on dental matters.

Long term effectiveness of RA-1, a standardized Ayurvedic medicine as a monotherapy and in combination with disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis

Background: Data on long term use of Ayurvedic drugs is sparse. They may prove useful if combined with modern medicine in certain clinical situations (integrative medicine). We present the results of a long term observational study of RA-1 (Ayurvedic drug) used in the treatment of rheumatoid arthritis (RA). Objective The objective was to study safety of long term use of RA-1 for treatment of rheumatoid arthritis (RA). Materials and methods On completion of a 16 week randomized controlled study, 165 consenting volunteer patients were enrolled into a three year open label phase (OLP) study. Patients were symptomatic with persistent active disease and naïve for disease modifying anti-rheumatic drugs (DMARD). 57 patients were on fixed low dose prednisone. Patients were examined every 10–14 weeks in a routine rheumatology practice using standard care norms. They continued RA-1 (Artrex ™, 2 tablets twice daily) throughout the study period and were generally advised to lead a healthy life style. Based on clinical judgment, rheumatologist added DMARD and/or steroids (modified if already in use) to patients with inadequate response; chloroquine and/or methotrexate commonly used. Treatment response was assessed using American College of Rheumatology (ACR) efficacy measures and ACR 20% improvement index standard update statistical software (SAS and SPSS) were used; significant at p < 0.05. Results 158, 130 and 122 patients respectively completed evaluations at 1, 2 and 3 year primary end point. The ACR 20 response (range 34–40%) remained stable over three years (p = 0.33). Patients improved optimum for several measures by one year (p < 0.05) and this was sustained. The use of steroids varied from 42 to 49% patients at yearly end points (mean daily dose 5 mg prednisone); correspondingly the use of DMARD varied from 20 to 34% patients. 40% patients on RA-1 did not require DMARD/steroids for control of disease. 77% patients reported adverse events, albeit mild and mostly gut related, and not causing withdrawal. Several study limitations (especially self-selection) were reduced by the high patient retention and consistency in drug use. Conclusion RA-1 is safe and effective in the long term management of symptomatic active chronic RA. DMARDs and/or steroids can be used judiciously along with RA-1 to treat difficult disease/flares. Further studies are required to evaluate RA-1 in early RA. This paves way for research and application of integrative therapeutic approach in clinical medicine.