Impact of yoga based mind-body intervention on systemic inflammatory markers and co-morbid depression in active Rheumatoid arthritis patients: A randomized controlled trial

Abstract

Background:

Recovery of patients with rheumatoid arthritis (RA) depends on several physical and psychological factors, besides pharmacological treatment. Co-morbid depression adversely affects the outcome in RA. Usual medical therapies have a limited scope and fail to cure the psychological component of the disease. With advanced therapeutic options, achieving a state of remission has become the treatment goal, yoga based mind body intervention (MBI) may provide a holistic approach in its treatment dimension. Hence, MBIs are the need of hour as majority of diseases have a psychosomatic component.

Objective:

To explore the effect of Yoga based MBI on disease specific inflammatory markers and depression severity in active RA patients on routine disease modifying anti-rheumatic drugs (DMARDs) therapy.

Methods:

A total of 72 RA patients were randomized into 2 groups: yoga group (yoga with DMARDs) and control group (DMARDs only). Blood samples were collected pre and post intervention for primary outcome measurements of systemic biomarkers. Disease activity score 28, erythrocyte sedimentation rate (DAS28ESR) and health assessment questionnaire disability index (HAQ-DI) were used to assess disease activity and functional status respectively at pre and post intervention time-points. Secondary outcome, depression severity, was assessed by Beck Depression Inventory II scale (BDI-II) at 2 weekly intervals during 8 weeks of the study interventional plan.

Results:

After 8 weeks of yoga based MBI, there was significant decrease in the severity of RA as seen by reduction in levels of various systemic inflammatory markers as well as in DAS28ESR (p-value <0.0001; effect size = 0.210) and HAQ-DI (p-value 0.001; effect size = 0.159). Also, yoga group experienced a statistically significant time dependent step-wise decline in depression symptoms over the period of 8 weeks as compared to control group (p-value <0.0001; effect size = 0.5). Regression analysis showed greater reduction in the scores of BDI-II with DAS28ESR (R² = 0.426; p < 0.0001) and HAQ-DI (R² = 0.236; p = 0.003) in yoga group.

Conclusions:

Yoga, a mind body intervention re-established immunological tolerance by aiding remission at molecular and cellular level along with significant reduction in depression. Thus in this severe autoimmune inflammatory arthritis with a major psychosomatic component, yoga can be used as a complementary/adjunct therapy.

Keywords

Rheumatoid arthritis yoga immunomodulation depression inflammation meditation remission oxidative stress

1. Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease which affects both psychological as well as physical health of an individual (Mary Margaretten, Julian, Katz, & Yelin, 2011). It has a bidirectional pathophysiological association with depression as a consequence of accelerated aging, accumulation of oxidatively damaged DNA and systemic inflammatory stress overload(Lu et al., 2016; van Onna & Boonen, 2016; Weyand & Goronzy, 2016). A meta-analysis reported 16.8% higher prevalence of depression in RA patients leading to mental distress (Matcham, Rayner, Steer, & Hotopf, 2013). The co-existence of depression and RA in the same individual poses a significant healthcare burden on the patients, their caregivers, healthcare systems, and society as a whole (Sambamoorthi, Shah, & Zhao, 2017). Depression seems to decrease patients’ compliance and adherence to medical treatment and results in worse health outcomes (DiMatteo, Lepper, & Croghan, 2000; M. Margaretten et al., 2011). High disease activity and underlying depression are associated with increased disability (M. Margaretten et al., 2011), reduced quality of life (Hyphantis et al., 2013; Piccinni et al., 2006), minimized rates of clinical remission and treatment response (Hider, Tanveer, Brownfield, Mattey, & Packham, 2009; Kekow et al., 2011). RA patients with chronic depression may be more likely to discontinue disease modifying anti-rheumatic drugs (DMARDs) against the recommendations of their health-care providers (Sturgeon, Finan, & Zautra, 2016). Facing the egg chicken conundrum of this association of RA with depression, the existing medical treatments can be supplemented with alternative and complementary interventions.

RA, a heterogeneous autoimmune disease, results from interplay between genetic and environmental factors characterized by synovial hyperplasia, cartilage damage, and bony erosions (McInnes & Schett, 2011; Messemaker, Huizinga, & Kurreeman, 2015). The disease is associated with articular and extra-articular manifestations. ‘Active RA’ is a state of high disease activity which is characterized by extensive systemic inflammation, cartilage damage and synovial hyperplasia. Extra articular manifestations because of visceral organ involvement may also contribute to physical disability and psychiatric comorbidity (Cojocaru, Cojocaru, Silosi, Vrabie, & Tanasescu, 2010). Due to disturbed equilibrium between regulatory T (Tregs) cells and T-helper 17 (Th17) cells, there is failure to stop aberrant immune reactions and breakage of self-tolerance. A highly inflammatory microenvironment in RA favours a decreased Foxp3 expression in residential Tregs, hence losing their suppressive activity, and conversion into effector cells. This altered abnormal regulatory network in the immune response, includes human leukocyte antigen-G (HLA-G) and its downstream pathways. HLA-G, a stress-inducible molecule, plays a central role in immune regulation in humans and lower HLA-G levels are associated with increased susceptibility to autoimmune diseases like RA. Inflammatory processes are driven by a plethora of cytokines which are critical in the pathogenesis of RA. A milieu of inflammatory cascade of cytokines cross blood brain barrier leading to altered brain-immune interactions. Pro-inflammatory cytokines or mediators may induce a series of mood and behavioral changes by acting on receptors in the CNS, which are identical to those found on immune cells (Dantzer, 2004).

With accelerated immune ageing in RA, there is decline in immune cell functions (immunosenescence) and persistence of chronic low grade systemic inflammation (inflammaging) (Szarc vel Szic, Declerck, Vidaković, & Vanden Berghe, 2015). Inflammatory response generates free radicals like reactive oxygen species (ROS), induces oxidative stress (OS) and reduces cellular total antioxidant capacity (TAC) (Khojah, Ahmed, Abdel-Rahman, & Hamza, 2016). Overproduction of free radicals induces peroxidative damage to the cell membrane, DNA fragmentation in nuclear/mitochondrial genome, dysregulation in levels of mRNAs/transcripts. This genomic instability may cause genetic mutations, epigenetic alterations and post-translational modifications that negatively affect the cellular function and trigger immune responses Altered epigenetic phenomena like DNA methylation, histone acetylation and micro RNA expressions encompass the association of external stress, environmental stimuli and genetic factors in RA pathogenesis.

Several studies have shown positive effects of mind body interventions (MBIs) in improving patients’ overall well-being and quality of life (Fernros, Furhoff, & Wändell, 2008; Pradhan et al., 2007; Wahbeh, Elsas, & Oken, 2008), reducing their psychological distress (Maddux, Daukantaité, & Tellhed, 2018; Pradhan et al., 2007; M. R. Tolahunase, Sagar, Faiq, & Dada, 2018) and decreasing their pain intensity (Zautra et al., 2008). Yoga, MBI of Indian origin, is gaining rapid popularity due to its beneficial effects seen on myriad aspects of overall wellbeing and disease management. Yoga includes a set of mind body based physical activities including various asanas (physical postures), pranayama (breathing exercises), and dhayna (meditation). Yoga practice facilitates self-regulation and maintains a behavioral change via conditioning of higher-level and lower-level brain networks during stress related physical and emotional change (Gard, Noggle, Park, Vago, & Wilson, 2014). Self-regulation results from integration of autonomic, cognitive, behavioral, and affective processes for adaptive functioning at a multi-system level. Various studies evaluated the role of yoga as an effective intervention to assist the management of rheumatoid arthritis with respect to clinical symptoms, quality of life, psychosocial outcomes and functional ability. Further research is needed for the exploration of possible mechanism underlying the cumulative effect of yoga on multiple pathways at a cellular level. Current evidence is limited regarding how yoga practice affects the systemic biomarkers of inflammation, cellular aging and OS, especially in RA.

Thus the present study was designed to assess the impact of 8 weeks yoga based MBI on severity of RA and depression through evaluation of biomarkers associated with RA outcome at a cellular and molecular level. Our study included a combination of biomarkers which are associated with systemic and local inflammation, neuroplasticity and cellular health, which include: biomarkers of systemic inflammation – acute phase reactant, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), pro-inflammatory & anti-inflammatory cytokines -Interleukin (IL)-6, IL-17A, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β and immunomodulatory marker – soluble HLA-G; biomarkers of neuroplasticity – brain-derived neurotrophic factor (BDNF), serotonin, β endorphins; biomarkers for cellular health – oxidative stress by ROS and TAC, DNA damage by 8-hydroxy-2^′ -deoxyguanosine (8OHdG), health span & longevity by sirtuin 1(SIRT1) and cellular aging by telomerase activity and telomere length. We assessed disease severity by disease activity score 28 erythrocyte sedimentation rate (DAS28 ESR), functional status by health assessment questionnaire disability index (HAQ – DI) and depression severity by Beck Depression Inventory – II (BDI-II).

2. Materials and methods

2.1. Participants

Study participants were recruited from the outpatient unit of Rheumatology department of AIIMS, New Delhi during April 2016 to June 2018. The study inclusion criteria included 18–60 years old RA patients diagnosed as per 2010 ACR/EULAR RA classification criteria, whose DAS28ESR was >2.6 and were on routine medical treatment for at least 6 months. The exclusion criteria included any other autoimmune diseases, pregnant women or lactating mothers, history of recent intake of oral/ intra-articular steroids in past 6 months, and those who were physically unfit for yoga.

2.2. Study design

2.2.1. Type of trial

The study was interventional type of randomized controlled trial analyzing the effects of 8-week yoga based MBI on depression severity and systemic biomarkers associated with active RA patients on routine DMARDs.

2.2.2. Ethical consideration

The study was initiated after obtaining ethical clearance (IECPG-211/24.02.2016) from institute ethics committee and registration under clinical trials registry, India (REF/2016/01/010500).

2.2.3. Sample size

The sample size was obtained on G power software by fixing the alpha at 0.05 powered at 0.8 for a medium effect size (as per Cohen’s d) considering the mean and SD of a previous study (Subhadra Evans et al., 2011). The attrition rate was assumed to be 15–20% which was consistent with previous yoga studies (Subhadra Evans et al., 2011; M. R. Tolahunase et al., 2018), we decided to recruit 35 participants for each group (total n = 70).

2.2.4. Randomization and blinding

Sequence of random numbers was generated by permuted block randomization of variable block size with the assistance of the web tool research randomizer ( https://www.randomizer.org/). For this investigator blinded study, sequentially numbered sealed opaque envelopes were used for the concealment of random numbers. As each patient was enrolled, he or she was assigned to the next numbered envelop and the associated group, yoga or control. The statistician and the researcher were blinded to the group status of the subjects.

2.3. Intervention

2.3.1. Yoga based mind body based intervention (MBI)

Patients of yoga group underwent 8 weeks pre-tested yoga based MBI program which was designed in such a way that it least likely created any further irritation in inflamed joints. Yoga based MBI program incorporated the components of classical Yoga which are a derivative of 8 limbs of Patanjali’s Raj yoga. It included a set of different asanas (physical postures), pranayama (breathing practices) and dhyana (meditation) suitably modified for active RA patients, which aimed to promote circulation, stimulate endocrine system and enhance muscular activity. Each session of this program lasted for approximately 120 min per day (Table 1) and 5 sessions per week for 8 weeks. The sessions were held under the supervision of certified and well qualified Yoga instructors in Laboratory for Molecular Reproduction & Genetics, Department of Anatomy, AIIMS, New Delhi. Due to the extensive time commitment for yoga based MBI program, there were no instructions for home practice. They were also advised to integrate yoga into their daily lifestyle for the rest of their lives following 8 weeks of intervention. The whole aim of this program was to develop an integrated approach for a holistic lifestyle to build positive health at physical, mental, emotional and intellectual level.

Table 1
Details of activities in a single day session of Yoga based MBI program

S.No. Practice to be done Duration

1. Session preparation instructions 2 min

5 min

Starting Prayer

Yogic sukshma vyama Finger loosening, Wrist loosening, Elbow loosening, Shoulder loosening, Toe bending, Ankle bending, Knee cap tightening, patella movement, Knee bending & Hip rotation 10 min

Yogic sthool vyama Rekhagati, Sarvaangpushti

2. Yogasana Standing Trikonasana 5 min

Katichakrasana

Tadasana

Veerabhadrasana

Sitting Gomukhasana 5 min

Paschim-utaanasana

Shashaankasana

Vakrasana

Prone Ek-pada-shalabhasana 5 min

Bhujangasana

Poorna-shalabhasana

Makarasana

Supine Uttanapadasana 5 min

Setubhandhasana

Pavanmuktasana

Matsyasana

3. Relaxation Savasana 10 min

4. Pranayama Kapalbhati (Kriya) 20 min

Ujjayi

Nadishodhana

Bhramari

5. Nada anusandhana, AUM-Aumkar recitation 3 min

6. Dhyana (meditation) 15 min

7. Shanti mantra-Closing prayer 5 min

8. Interactive Session/ Self-directed learning 30 min

Total 120 min

2.3.2. Usual care control

Patients in the control group were advised to follow normal day to day physical activities along with the prescribed medicines by the physicians. There was no change in their daily routine.

2.4. Outcome measures

2.4.1. Primary outcome

The primary outcome was to assess the change in RA severity which was detected by evaluating levels of systemic biomarkers and assessment of functional status and disease activity.

The systemic biomarkers include: biomarkers of systemic inflammation – acute phase reactants (ESR and CRP), pro-inflammatory & anti-inflammatory cytokines (IL-6, IL-17A, TNF-α and TGF-β) and immunomodulatory marker – soluble HLA-G; biomarkers of neuroplasticity – BDNF, serotonin, β endorphins; biomarkers for cellular health – oxidative stress (ROS and TAC), DNA damage (8OHdG), health span & longevity (SIRT1) and cellular aging – telomerase activity and telomere length.

During this 8-week study, the participants were evaluated for these parameters at baseline and week 8. Fasting venous blood samples (10 ml) were collected and divided into two halves. From the first half, one part was allowed to clot, and the serum was separated within 30 min, and the other part was transferred to heparinized and EDTA vials and was centrifuged at 2000 g for 15 minutes at 4°C. Both serum and plasma were stored at – 80°C until analyzed. From the second half, one part was used for whole genomic DNA isolation of peripheral leukocytes as per manufacturer’s protocol (QIAamp DNA Mini Kit, Qiagen, Hilden, Germany) and the rest of the sample was used for peripheral blood mononuclear cell (PBMC) isolation using Ficoll Histopaque (Sigma, Aldrich). Peripheral blood leucocyte telomere length was measured by the qPCR method as described by Cawthon (2002). Telomerase activity was estimated by using a telomerase assay kit with PBMC’s as a starting material as per manufacture’s protocol (Roche, Switzerland). ESR was estimated at laboratory medicine department by Westergren method. ROS detection was done by chemiluminescence assay (Berthold detection luminometer, USA). TAC was estimated by a colorimetric assay (Cayman Chemical, Ann Arbor, USA). ELISA kits were used for the levels of 8-OHdG (Cayman’s EIA kit), BDNF (Raybiotech, Inc), sirtuin 1 (Qayee Bio-Technology), CRP (Immunology Consultants Laboratory, Inc.), β-endorphin (Phoenix Pharmaceuticals, Inc.), serotonin (Elabscience, USA), BDNF (Raybiotech, Inc), soluble HLA-G (Bioassay Tech Laboratory, China), IL-17A (Gen-Asia Biotech, China), TNF-α (Gen-Probe, Diaclone Diagnostic, France) and IL-6 (Gen-Probe, Diaclone Diagnostic, France). Serum TGF-β levels were estimated by magnetic bead-based multiplex assay using Bio-Plex Pro TGF-β Assays (Bio-Rad Laboratories Inc., USA) according to manufacturer’s guidelines. Quality-control assays for biomarkers and validation were performed.

The functional status and disease activity were assessed by health assessment questionnaire disability index (HAQ–DI) (Bruce & Fries, 2003) and disease activity score (DAS28 ESR) (Nishimoto & Takagi, 2010) respectively.

2.4.2. Secondary outcome

The secondary outcome was to assess the change in severity of depression in RA patients which was measured by Beck Depression Inventory – II scale (BDI-II) scores from baseline to 8th week. It was completed by participants of both the groups just prior to baseline session and just after sessions at weeks 2, 4, 6 and 8. The BDI scale is a 21 item multiple choice question self-inventory report of depressive symptoms and one of the most widely used psychometric tests with score ranging from 0–63.

2.5. Data analysis

All statistical analyses were performed using IBM SPSS Statistics for Macintosh, Version 25.0. (IBM Corp. Armonk, NY). A p value of <0.05 was considered to be statistically significant. Analyses were carried out on an intent-to-treat basis, with all available participant data included, regardless of compliance with the protocol. To examine whether clinical and demographic characteristics of randomized participants were distributed equally between the two groups, Chi-square test and Fisher’s exact tests were used to compare categorical characteristics at baseline; student’s t-test and Wilcoxon rank-sum test to compare normally distributed continuous variables and nonparametric continuous data respectively (Table 2). For within group analysis to see the difference between pre-to post-intervention we used paired t-tests for continuous variables, or Wilcoxon signed rank test for continuous variables without normal distribution. For between-group differences over time the assessments were made using independent samples t-test. Following tests of statistical significance, study outcomes were analyzed for clinical significance via estimates of effect size. For each outcome measure, the magnitude and direction of the 8 week yoga based MBI’s effect, relative to the control, was then calculated for each outcome via the formula for Cohen’s d (Lakens, 2013). According to conventions proposed by Cohen, (1992), an effect size with an absolute value of ≥0.2 and <0.5 was considered to be small but appreciable clinical effect; an absolute value of ≥0.5 and <0.8 for a moderate clinical effect; and an absolute value ≥0.8 to represent a large clinical effect. A general linear model was created for subject within univariate analysis of variances conducted to assess the impact of the yoga intervention on BDI-II scores, across 5 time points (pre-intervention, 2 weeks post-intervention, 4 weeks post-intervention, 6 weeks post-intervention and 8 weeks post-intervention). Multiple regression analysis was used to determine the association and interaction of disease activity and functional ability with change in depression severity. Different regression models using stepwise, forward, or enter methods were used for this.

3. Results

3.1. Overview of enrolment

A total of 104 individuals were screened for eligibility, out of which 72 were randomized into 2 groups (each group n = 36). Figure 1 shows the CONSORT flowchart of intervention. All 36 randomized participants were included in intent-to-treat analyses of outcome measures.

Fig.1

A CONSORT study flow chart.

3.2. Baseline characteristics

Baseline demographic and clinical characteristics (presenting symptoms, depression severity, disease activity and functional status) of all randomized participants are shown in Table 2. There were no statistically significant differences between the two intervention groups.

Table 2
Baseline characteristics

Variable Group P value

Yoga (n = 36) Control (n = 36)

Demographic Characteristics

Age (years) 45.7 (1.6) 42.1 (1.7) 0.1198

Sex 0.57075

Male 7 (19.4) 9 (25)

Female 29 (80.6) 27 (70)

Disease duration (years) 6.32 (0.8) 5.61 (0.7) 0.5076

BMI (kg/m²) 25.72 (0.8) 24.03 (0.7) 0.1434

Presenting symptoms

Early morning stiffness (minutes) 24.7 (3.7) 24.4 (3.7) 0.9583

Tender joint count (TJC) 5.97 (0.7) 6.36 (0.6) 0.7074

Swollen joint count (SJC) 3.81 (0.7) 3.58 (0.5) 0.7945

Depression Severity

BDI-II Score 19.14 (1.0) 18.33 (0.9) 0.5682

RA Activity

DAS28-ESR 5.13 (0.2) 4.95 (0.1) 0.4406

Functional Status

HAQ-DI 0.59 (0.06) 0.53 (0.06) 0.4995

Variable	Group	P value
Demographic Characteristics
Age (years)	45.7 (1.6)	42.1 (1.7)	0.1198
Sex	0.57075
Male	7 (19.4)	9 (25)
Female	29 (80.6)	27 (70)
Disease duration (years)	6.32 (0.8)	5.61 (0.7)	0.5076
BMI (kg/m²)	25.72 (0.8)	24.03 (0.7)	0.1434
Presenting symptoms
Early morning stiffness (minutes)	24.7 (3.7)	24.4 (3.7)	0.9583
Tender joint count (TJC)	5.97 (0.7)	6.36 (0.6)	0.7074
Swollen joint count (SJC)	3.81 (0.7)	3.58 (0.5)	0.7945
Depression Severity
BDI-II Score	19.14 (1.0)	18.33 (0.9)	0.5682
RA Activity
DAS28-ESR	5.13 (0.2)	4.95 (0.1)	0.4406
Functional Status
HAQ-DI	0.59 (0.06)	0.53 (0.06)	0.4995

Data were described as frequency (%) for sex and mean (SD) for others.

3.3. Evaluation of primary outcomes: Systemic biomarkers & measures of RA outcome

As shown in Table 3 and Fig. 2 (A-F), there were significant changes observed in all the systemic outcomes (except telomere length (Fig. 2E) and disease activity in RA after 8 weeks of yoga based MBI as compared to usual care control group. Among the cardinal biomarkers of neuroplasticity, there was a significant increase in BDNF, serotonin, β endorphins in yoga group as compared to control group from its baseline measurements. Biomarkers of systemic inflammation including acute phase reactants, pro-inflammatory cytokines – ESR, CRP, IL-6, IL-17A and TNF-α showed a significant decline; whereas anti-inflammatory cytokine and immunomodulatory marker – TGF-β and soluble HLA-G showed a significant increase in yoga group as compared to control group. Among the biomarkers for cellular health & integrity – there was a significant decrease in OS as there was decrease in ROS (p < 0.05) and increase in TAC (p < 0.05); 8OHdG levels (marker of oxidative DNA damage) also showed significant reduction (p < 0.05); SIRT1 (marker for health span & longevity showed an increase (p < 0.05) after yoga based MBI as compared to control group. However, for biomarkers of cellular aging only telomerase activity showed significant increase in yoga group and change in telomere length was not significant in either group. A total of 8 weeks yoga based MBI showed improvement in clinical outcomes for RA that included – significant decrease in DAS28ESR and HAQ-DI scores as compared to control group (all p < 0. 05) (Fig. 2(F)). Small effect size (0.2 to 0.5) of the yoga based MBI was observed on – TAC, Telomerase activity, SIRT1, TNF-α, β-endorphins, IL-17A and disease activity whereas serotonin (marker of neuroplasticity) showed a moderate effect size of 0.59. Also, the control group showed significantly increased IL-17A levels and decreased β-endorphins, SIRT1, serotonin levels compared to baseline (p < 0.001).

Table 3
Means (SD) and results of within-group and between-group analysis of primary outcomes (n = 72; Yoga, 36; Control, 36)

Outcome Measure Group Baseline measurement Mean±SD Post 8 week measurement Mean±SD p-value Within groups Change from Baseline Mean [95% CI] Effect size p-value Between the groups

Systemic Biomarkers

ROS (RLU/min/10⁴ neutrophils) Yoga 1605.17±1392.73 1151.95±1049.36 0.001 453.22 [229.26, 677.17] 0.105 0.006

Control 1612.39±1090.26 1613.15±876.44 0.993 –0.754 [–224.7, 223.2]

8OHdG (pg/ml) Yoga 1363.59±168.53 1287.47±192.48 0.001 76.12 [35.95, 116.26] 0.108 0.005

Control 1307.04±199.92 1313.59±218.49 0.749 –6.55 [–46.69, 33.59]

TAC (mmol Trolox equiv/L) Yoga 1.23±0.61 2.37±0.89 <0.0001 –1.136 [–1.34, –0.924] 0.466 <0.0001

Control 1.04±0.507 1.01±0.56 0.418 0.039 [–0.173, 0.251]

CRP (ng/ml) Yoga 5652.44±1467.17 4984.12±1389.60 <0.0001 668.32 [328.31, 1008.33] 0.08 0.016

Control 5769.04±1148.47 5697.53±1113.82 0.745 71.51 [–268.49, 411.52]

ESR (mm/1st hour) Yoga 42.41±9.16 38.00±8.37 <0.0001 4.42 [2.52, 6.32] 0.12 0.003

Control 43.63±7.75 43.38±6.7 0.790 0.25 [–1.65, 2.15]

Telomerase Activity (IU/cell) Yoga 0.79±0.29 1.26±0.51 <0.0001 –0.46 [–0.57, –0.36] 0.386 <0.0001

Control 0.81±0.22 0.77±0.25 0.216 0.038 [–0.069, 0.144]

Telomere length Yoga 0.44±0.21 0.47±0.19 0.250 –0.027 [–0.084,0.031] 0.005 0.566

Control 0.43±0.13 0.43±0.16 0.929 –0.003 [–0.06, 0.05]

Serotonin (ng/ml) Yoga 78.64±8.67 96.21±15.48 <0.0001 –17.56 [–20.9, – 14.14] 0.590 <0.0001

Control 81.59±6.38 74.78±5.08 <0.0001 6.81 [3.38, 10.24]

BDNF (ng/ml) Yoga 13.33±3.9 16.48±6.01 <0.0001 –3.51 [–4.68, – 2.33] 0.172 <0.0001

Control 13.61±4.29 13.93±4.66 0.412 –0.32 [–1.5, 0.86]

Sirtuin (ng/ml) Yoga 31.64±1.94 36.21±6.08 <0.0001 –4.58 [–5.9, – 3.2] 0.332 <0.0001

Control 30.60±2.41 29.52±2.38 0.005 1.08 [–0.27, 2.44]

β endorphins (ng/ml) Yoga 3.71±1.31 5.15±1.82 <0.0001 –1.44 [–1.88, – 1.00] 0.408 <0.0001

Control 3.81±0.58 3.07±0.75 <0.0001 0.74 [0.29, 1.18]

IL-17A (pg/ml) Yoga 195.66±30.16 78.22±30.43 <0.0001 17.44 [9.64, 25.24] 0.368 <0.0001

Control 192.50±41.25 210.34±43.29 <0.0001 –17.83 [–25.63, – 10.03]

IL-6 (pg/ml) Yoga 3.3±1.26 2.4±1.6 <0.0001 0.93 [0.52, 1.34] 0.128 0.002

Control 3.77±1.09 3.76±1.41 0.981 0.006 [–0.402, 0.413]

TNF-α (pg/ml) Yoga 17.04±3.4 14.06±3.7 <0.0001 2.98 [1.93, 4.031] 0.297 <0.0001

Control 17.33±6.74 18.38±5.27 0.063 –1.04 [–2.09, –0.003]

TGF-β (ng/ml) Yoga 42.20±16.75 50.81±15.53 <0.0001 –8.6 [–13.27, – 3.9] 0.128 0.003

Control 43.61±15.35 42.00±14.64 0.513 1.61 [–3.04, 6.27]

s HLA-G (U/ml) Yoga 12.77±2.56 17.73±12.4 <0.0001 –4.96 [–7.81, – 2.11] 0.089 0.011

Control 11.91±1.66 11.56±2.3 0.156 0.34 [–2.51, 3.19]

RA Outcomes

DAS28-ESR Yoga 5.13±1.14 4.42±0.93 <0.0001 0.71 [0.52, 0.91] 0.210 <0.0001

Control 4.9±0.83 4.8±0.87 0.256 0.12 [–0.07, 0.31]

HAQ-DI Yoga 0.59±0.41 0.44±0.36 <0.0001 0.15 [0.09, 0.20] 0.159 0.001

Control 0.53±0.38 0.50±0.38 0.671 0.01 [–0.04, 0.06]

Outcome Measure	Group	Baseline measurement Mean±SD	Post 8 week measurement Mean±SD	p-value Within groups	Change from Baseline Mean [95% CI]	Effect size	p-value Between the groups
Systemic Biomarkers
ROS (RLU/min/10⁴ neutrophils)	Yoga	1605.17±1392.73	1151.95±1049.36	0.001	453.22 [229.26, 677.17]	0.105	0.006
	Control	1612.39±1090.26	1613.15±876.44	0.993	–0.754 [–224.7, 223.2]
8OHdG (pg/ml)	Yoga	1363.59±168.53	1287.47±192.48	0.001	76.12 [35.95, 116.26]	0.108	0.005
	Control	1307.04±199.92	1313.59±218.49	0.749	–6.55 [–46.69, 33.59]
TAC (mmol Trolox equiv/L)	Yoga	1.23±0.61	2.37±0.89	<0.0001	–1.136 [–1.34, –0.924]	0.466	<0.0001
	Control	1.04±0.507	1.01±0.56	0.418	0.039 [–0.173, 0.251]
CRP (ng/ml)	Yoga	5652.44±1467.17	4984.12±1389.60	<0.0001	668.32 [328.31, 1008.33]	0.08	0.016
	Control	5769.04±1148.47	5697.53±1113.82	0.745	71.51 [–268.49, 411.52]
ESR (mm/1st hour)	Yoga	42.41±9.16	38.00±8.37	<0.0001	4.42 [2.52, 6.32]	0.12	0.003
	Control	43.63±7.75	43.38±6.7	0.790	0.25 [–1.65, 2.15]
Telomerase Activity (IU/cell)	Yoga	0.79±0.29	1.26±0.51	<0.0001	–0.46 [–0.57, –0.36]	0.386	<0.0001
	Control	0.81±0.22	0.77±0.25	0.216	0.038 [–0.069, 0.144]
Telomere length	Yoga	0.44±0.21	0.47±0.19	0.250	–0.027 [–0.084,0.031]	0.005	0.566
	Control	0.43±0.13	0.43±0.16	0.929	–0.003 [–0.06, 0.05]
Serotonin (ng/ml)	Yoga	78.64±8.67	96.21±15.48	<0.0001	–17.56 [–20.9, – 14.14]	0.590	<0.0001
	Control	81.59±6.38	74.78±5.08	<0.0001	6.81 [3.38, 10.24]
BDNF (ng/ml)	Yoga	13.33±3.9	16.48±6.01	<0.0001	–3.51 [–4.68, – 2.33]	0.172	<0.0001
	Control	13.61±4.29	13.93±4.66	0.412	–0.32 [–1.5, 0.86]
Sirtuin (ng/ml)	Yoga	31.64±1.94	36.21±6.08	<0.0001	–4.58 [–5.9, – 3.2]	0.332	<0.0001
	Control	30.60±2.41	29.52±2.38	0.005	1.08 [–0.27, 2.44]
β endorphins (ng/ml)	Yoga	3.71±1.31	5.15±1.82	<0.0001	–1.44 [–1.88, – 1.00]	0.408	<0.0001
	Control	3.81±0.58	3.07±0.75	<0.0001	0.74 [0.29, 1.18]
IL-17A (pg/ml)	Yoga	195.66±30.16	78.22±30.43	<0.0001	17.44 [9.64, 25.24]	0.368	<0.0001
	Control	192.50±41.25	210.34±43.29	<0.0001	–17.83 [–25.63, – 10.03]
IL-6 (pg/ml)	Yoga	3.3±1.26	2.4±1.6	<0.0001	0.93 [0.52, 1.34]	0.128	0.002
	Control	3.77±1.09	3.76±1.41	0.981	0.006 [–0.402, 0.413]
TNF-α (pg/ml)	Yoga	17.04±3.4	14.06±3.7	<0.0001	2.98 [1.93, 4.031]	0.297	<0.0001
	Control	17.33±6.74	18.38±5.27	0.063	–1.04 [–2.09, –0.003]
TGF-β (ng/ml)	Yoga	42.20±16.75	50.81±15.53	<0.0001	–8.6 [–13.27, – 3.9]	0.128	0.003
	Control	43.61±15.35	42.00±14.64	0.513	1.61 [–3.04, 6.27]
s HLA-G (U/ml)	Yoga	12.77±2.56	17.73±12.4	<0.0001	–4.96 [–7.81, – 2.11]	0.089	0.011
	Control	11.91±1.66	11.56±2.3	0.156	0.34 [–2.51, 3.19]
RA Outcomes
DAS28-ESR	Yoga	5.13±1.14	4.42±0.93	<0.0001	0.71 [0.52, 0.91]	0.210	<0.0001
	Control	4.9±0.83	4.8±0.87	0.256	0.12 [–0.07, 0.31]
HAQ-DI	Yoga	0.59±0.41	0.44±0.36	<0.0001	0.15 [0.09, 0.20]	0.159	0.001
	Control	0.53±0.38	0.50±0.38	0.671	0.01 [–0.04, 0.06]

Fig.2

(A-F): Between and within group analysis of Primary outcome measures pre and post 8 weeks intervention; Systemic Biomarkers (A–E) (A) Acute phase reactants; (B) Inflammatory & immune-modulatory markers; (C) Markers of neuroplasticity & cellular health span; (D) Markers of Oxidative stress and DNA damage; (E) Markers of Cellular aging (TL = Telomere length; TA = Telomerase activity); (F) RA health outcome -clinical parameters (DAS28ESR and HAQ-DI).

3.4. Evaluation of secondary outcome: Depression severity

BDI-II scores from all randomized participants (n = 72) were evaluated from baseline till study completion at 2 week intervals in between. Figure 3(A) depicts time-plots of the mean BDI scores, along with 95% confidence intervals, for each intervention group at each assessment point. The yoga group experienced a statistically significant step-wise decline in depression symptoms over the period of 8 weeks as compared to usual care group (p-value < 0.0001) with moderate effect size of 0.5 (Table 4).

Fig.3

(A-B): Between and within group analysis of Secondary outcome meausres pre and post 8 weeks intervention; (A) Mean BDI-II scores plotted by time between the yoga and control groups; (B) Association of ΔDAS28ESR and ΔHAQ-DI with ΔBDI-II across total study participants (n = 72) and among groups (n = 36).

Table 4

Intent-to-treat analysis: Mean BDI scores [SD] by time, with 8-wk change scores

Between groups analysis {8-wk BDI Change Score [95% CI]}
Difference from pre intervention to post intervention
Yoga Group		Control Group	Effect Size	P value
(n = 36)		(n = 36)
7.33 [5.93, 8.74]		–0.94 [–2.35, 0.46]	0.5	0.000
Within group analysis
BDI-II Score	Mean±S.D	Mean±S.D	Mean±S.D	Mean±S.D	Mean±S.D
	(Baseline)	(2 weeks)	(4 weeks)	(6 weeks)	(8 weeks)
Yoga Group (n = 36)	19.13±6.09	16.13±5.4	14.13±4.9	12.77±4.8	11.88±4.6
P value	<0.0001	<0.0001	<0.0001	<0.0001
Control Group (n = 36)	18.33±5.81	18.16±5.2	18.66±5.6	19.11±5.5	19.27±5.9
P value	0.5637	0.3990	0.1319	0.0784

3.5. Association of RA outcome with depression severity

There is a correlation between the pre and post intervention change (Δ) in DAS28ESR scores and BDI-II scores across study participants (R² = 0.521; p < 0.0001). In Fig. 3(B), the correlation between the ΔHAQ-DI scores and ΔBDI-II scores across study participants can be appreciated (R² = 0.306; p < 0.0001). The dependent variable is RA health outcome (ΔDAS28ESR and ΔHAQ-DI scores) with constant, ΔBDI-II scores as predictors. There was a clear-cut variance seen in regression lines of BDI-II scores of both the groups with respect to change in DAS28ESR (F = 76.125; p < 0.0001) and HAQ-DI (F = 30.807; p < 0.0001) scores, using different methods of linear regression analysis. Results of regression model using stepwise method are listed in Table 5. Yoga group showed greater reduction in BDI-II scores as DAS28ESR scores decreased (R² = 0.426; p < 0.0001); whereas, for controls higher DAS28ESR scores unexpectedly corresponded to increased BDI-II scores (R² = 0.439; p < 0.0001). Also, greater reduction was seen in BDI-II scores in yoga group as HAQ-DI scores were reduced with time (R² = 0.236; p = 0.003); whereas higher HAQ-DI scores corresponded to increased BDI-II scores (R² = 0.106; p = 0.053).

Table 5
The stepwise relationship between change in RA outcome and BDI-II (depression severity) scores across participants of different groups

Dependent Variable (RA Outcome) Group Variable B SEb β t P value

ΔDAS28ESR Yoga Constant 0.183 0.127 1.436 0.160

ΔBDI-II 0.072 0.014 0.652 5.019 <0.0001

Control Constant 0.238 0.080 2.965 0.005

ΔBDI-II 0.129 0.025 0.663 5.161 <0.0001

ΔHAQ Yoga Constant 0.033 0.043 0.752 0.457

ΔBDI-II 0.016 0.005 0.485 3.238 0.003

Control Constant 0.026 0.026 1.015 0.317

ΔBDI-II 0.016 0.008 0.325 2.005 0.053

Dependent Variable (RA Outcome)	Group	Variable	B	SEb	β	t	P value
ΔDAS28ESR	Yoga	Constant	0.183	0.127		1.436	0.160
		ΔBDI-II	0.072	0.014	0.652	5.019	<0.0001
	Control	Constant	0.238	0.080		2.965	0.005
		ΔBDI-II	0.129	0.025	0.663	5.161	<0.0001
ΔHAQ	Yoga	Constant	0.033	0.043		0.752	0.457
		ΔBDI-II	0.016	0.005	0.485	3.238	0.003
	Control	Constant	0.026	0.026		1.015	0.317
		ΔBDI-II	0.016	0.008	0.325	2.005	0.053

Δ indicates pre-post intervention change i.e. difference from pre intervention to post intervention.

4. Discussion

Our study highlights for the first time, the positive impact of 8 weeks yoga based mind body intervention on molecular remission; decline in RA severity which further influences psychological health via changes in biomarkers at a systemic level. Improvement in psychological health and reduction in depression severity made the yoga group more compliant and were able to perform daily chores without much difficulty. RA outcome reveals current disease activity and functional abilities of the patients which are dependent on the ongoing systemic inflammatory pathways directly associated with the depression severity. Our findings suggest that yoga facilitates the mind’s capacity to affect bodily function and symptoms mediated through a variety of downstream pathways like – increasing joint flexibility, maintaining a steady state optimal OS balance, reducing the rate of telomere attrition and cellular aging via telomere metabolism, bringing genomic stability, regulation of OS via regression of inflammatory responses, reducing the sustained acute phase response, improving neuroplasticity and balancing the levels of neurotransmitters, harmonizing the circadian rhythm and optimizing the levels of immune regulatory molecules. These mechanisms aid to improve overall RA health outcome measures with reduction in co-morbid depression and to bring about natural immunological tolerance. Improvement in systemic biomarkers of neuroplasticity, systemic inflammation, cellular health integrity and aging in association with the positive clinical outcome of reduction in depression severity, disease activity and disability quotient suggests that yoga may provide long-term clinical remission in RA and reduced episodes of relapses. Yoga may positively modify the pathobiology of autoimmunity at a cellular and molecular level by targeting mind-body communications.

4.1. Yoga based immune-modulation in RA

RA serves as a model for systemic inflammation with dysfunctional intracellular signaling involved in deregulated activation of pro-inflammatory cytokine-mediated pathways thus adversely impacts many organ systems (Malemud, 2013). The recent advances in the pathogenesis of RA has led to development of biologic agents which are engineered to target specific inflammatory cells, cellular interactions, and cytokines that mediate RA-related tissue damage (Curtis & Singh, 2011). Both conventional DMARDs (Cannon et al., 2004) and targeted biologic agents (Curtis & Singh, 2011) have multiple side-effects on various systems of body with increased risk of serious infections. Moreover, there is substantial financial burden on the healthcare systems and individual patients which itself increases the stress to patient and their caregivers. Dysregulation of immune response triggers stress vicious cycle and precipitation of autoimmunity (Stojanovich & Marisavljevich, 2008). Current treatment mainly focusses to treat joint manifestations rather to eliminate systemic inflammation. Yoga buffers the effect of stress mediated immune responses (Arora & Bhattacharjee, 2008), stimulates the dominance of parasympathetic nervous system (Pilkington, Kirkwood, Rampes, & Richardson, 2005) and upregulates cardio-vagal tone (Innes, Bourguignon, & Taylor, 2005). According to Bhasin MK et al., 2013, transcriptional profiling results from a study on elicitation of relaxation response by an 8 weeks meditation practices in healthy subjects showed a transcriptional downregulation in genes associated with regulation of apoptosis, nuclear transport, metabolic processes, T-and B-cell activation, regulation of cell cycle, insulin sensitivity, glucose transport, DNA replication, chemokine signaling and stress response (Bhasin et al., 2013). Yoga intervention upregulates the expression of DNA repair genes, and the levels of anti-inflammatory cytokines such as IL-2 and IL-4 and decreases the levels of inflammatory cytokines such as Interleukin-6 (IL-6), mitogen activated protein kinases etc. (M. Tolahunase, Sagar, & Dada, 2017).

Our results highlight that yoga based MBI suppresses the acute phase responses, reduces inflammatory markers and aids in suppression of hyperactive immune system by – downregulation of acute phase reactants (ESR and CRP) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-17A), co-stimulation of anti-inflammatory cytokines (TGF-β) and immune-modulatory molecule (sHLA-G). Yoga not only relaxes the body and mind but also maintains homeostasis at internal organ system level and regulation of metabolic processes. Yoga intervention induces proper absorption of iron from small intestine and its combination with a beta globulin in blood plasma leading to decreased ESR and also optimizes the increased hepcidin levels leading to a decline in CRP (Tiwari, Mishra, Chaudhary, & Pandey, 2017). Cytokines like IL-6, IL-1, IL-17, TNF-α etc. send inflammatory signals to central nervous system leading to precipitation of stress as well high disease activity (Bellavance & Rivest, 2014; Shepherd, Downing, & Miyan, 2005). The pleiotropic cytokine transforming growth factor (TGF)-β and forkhead box P3 (Foxp3), an X-chromosome-linked transcription factor expressing Tregs cells helps in active immunosuppression, a function that is critical to maintain immune homeostasis and prevent autoimmunity. Our results are in concordance with other studies which suggested the role of yoga in downregulation of inflammatory processes by reduced pro-inflammatory cytokines and increase anti-inflammatory cytokines (Rajbhoj, Shete, Verma, & Bhogal, 2015; Shete, Verma, Kulkarni, & Bhogal, 2017). In present study increased levels of TGF-β post 8 weeks of yoga was found to suppress the activity of this autoimmune disease by influencing a number of downstream immunological phenomena. Regression of inflammatory processes and modulation of hyperactive immune system by yoga in turn aids in significantly reducing disease activity much early in time as compared to the usual care control group. To the best of our knowledge, the present study is the first to report the upregulation of soluble HLA-G levels in RA patients followed by yoga based MBI. HLA-G, a non-classical HLA class I molecule, possesses immune-modulatory and anti-inflammatory properties. It is a good reference parameter for prevention, diagnosis and a potential treatment target in autoimmune and inflammatory diseases since its elevated levels are associated with reduced severity and fewer relapses in RA patients.

4.2. Yoga improves cellular health and longevity

Our results demonstrated that yoga maintains the integrity of cellular health and longevity. Achieving optimum cellular health and longevity depends on maintaining optimal OS levels (Mishra, Kumar, Malhotra, Singh, & Dada, 2016), genomic stability, chromosomal integrity and telomere length maintenance. OS is a pathogenic hallmark in RA, as evident by increased ROS and reduced anti-oxidants levels (Quiñonez-Flores, González-Chávez, Del Río Nájera, & Pacheco-Tena, 2016). This redox imbalance impairs cellular integrity and causes cellular toxicity leading to activation of abortive apoptosis, growth signal impairment, and initiation of stress signaling by causing oxidative damage to the nuclear and mitochondrial DNA (mtDNA), to cellular membrane structures. Mt DNA damage is more severe and persistent and further worsens the OS state. Supplementation of various synthetic anti-oxidants could help in relieving OS, however, by its indiscriminate usage a cell may undergo reductive stress, due to disruption of the intricate oxidation-reduction balance and though it may improve membrane parameters but its impact on DNA is still controversial. Physical aerobic exercises also help in reducing free radical generation and upregulation of endogenous anti-oxidant defenses (Bloomer, 2008; Campbell et al., 2010). Our results showed that yoga aids in maintenance of OS as indicated by a significant reduction in ROS levels and elevation of TAC levels in yoga group as compared to control group. 8-hydroxy-2’-deoxyguanosine (8-OHdG), major product of DNA oxidation, leads to DNA breaks, base modifications, DNA mutations, genomic instability in nuclear and mt DNA (Dizdaroglu, 2012). In addition, accumulation of this DNA adduct not only induces mutations but also causes epigenetic alterations by causing genome wide hypomethylation by preventing methylation at CpG sites in promotor regions of genes (Bisht, Faiq, Tolahunase, & Dada, 2017). According to Dhawan et al., the dysregulation of transcripts caused by OS is also regularized by yoga (Dhawan, Kumar, & Dada, 2017). Maintaining optimum oxidative eustress, even under extremes of stress associated with lifestyle and environmental challenges, is a highly challenging task and needs a regulated redressal. Previous studies from our laboratory have documented that yoga based lifestyle intervention improves mitochondrial integrity as evident from increased COX activity, upregulating the total anti-oxidant capacity and telomerase enzymes in healthy population (M. Tolahunase et al., 2017), thus reducing and delaying onset of age-related chronic diseases and complex lifestyle disorders and their sequelae (Bisht & Dada, 2017; Gautam, Chawla, Bisht, Tolahunase, & Dada, 2018; Gautam, Kumar, Kumar, Chaudhary, & Dada, 2017; Rima, Shiv, Bhavna, Shilpa, & Saima, 2016). In addition yoga increases melatonin levels, a master regulatory molecule which a both oncostatic and a strong antioxidant. The subcelluar concentrations of melatonin are highest in mitochondria, thus preventing them from oxidative injury and improving their integrity. Present study showed that yoga based MBI helps to maintain an intricate balance between ROS and TAC with downregulation of highly mutagenic oxidative product, 8OHdG and upregulation of cell regulator, SIRT1, which promotes longevity by deactivating p53 mediated pathways.

RA patients have insufficient amounts of telomerase enzyme due to insufficient induction of telomerase reverse transcriptase (Fujii, Shao, Colmegna, Goronzy, & Weyand, 2009) and telomere shortening may predict the impending disease (Costenbader, Prescott, Zee, & De Vivo, 2011). Several hallmarks of cellular aging have been seen in RA T cells which include accumulation of DNA double-strand breaks, reduction in DNA repair protein kinase, lack in activation of p53-dependent pathways, premature telomere shortening even in naïve T cells, loss of co-stimulatory receptor CD28 on T cells and diminished ATP production (Chalan, van den Berg, Kroesen, Brouwer, & Boots, 2015). Present study showed an upregulation in telomerase enzyme and maintenance of telomere length in RA patients with 8 week yoga based MBI. Hence, yoga aids in slowing the rate of cellular aging. Previous studies have shown an upregulation in telomerase enzyme levels followed by yoga based lifestyle intervention (YBLI) in apparently healthy individuals (M. Tolahunase et al., 2017). This may be one of the underlying phenomena for the reduced disease activity and reduced disability consequently followed by yoga therapy along with drugs.

4.3. Yoga reduces depression severity in RA

We observed a time dependent reduction in depressive symptoms of RA patients who practiced yoga along with the routine medications as compared to control groups in which depressive symptoms aggravated overtime, indicating efficacy of yoga in disease and stress management over the other treatment options. RA and depression are mind body diseases and thus need a holistic approach in its management. Although other forms of yoga like Iyenger yoga performed twice weekly for 6 weeks did not produce significant changes in disease activity or pain, whereas quality of life, mood and fatigue improved significantly (Subhadra Evans et al., 2011). Duration, frequency and intensity of yoga intervention according to severity of patients’ symptomatology are a critical factor in producing desirable clinical response. Long-term yoga and meditation practitioners exhibited immediate gene expression changes as compared to short-term practitioners (Bhasin et al., 2013). Data from randomized trials suggest that yoga reduces symptoms of anxiety and depression (Pilkington et al., 2005; Woolery, Myers, Sternlieb, & Zeltzer, 2004) along with positive benefits on inflammation (Shete et al., 2017; Vijayaraghava, Doreswamy, Narasipur, Kunnavil, & Srinivasamurthy, 2015), reduction in sympathetic nervous system activity (Riley, 2004), and increases in vagal activity (Bernardi et al., 2001). Yoga improves concentration, attention, learning and memory by promoting neuroplasticity. It positively affects mitochondrial metabolism by improving COX activity, reducing ROS production, improving energy metabolism and maintaining telomere length. In addition, yoga and meditation stimulates the left prefrontal cortex, the seat of positive emotion, attention and reward centers which is associated with increased size of hippocampus and cerebellum. Also, there is improvement in cardiovagal tone and upregulation in various repair mechanisms (Dada et al., 2018; Gagrani et al., 2018). Our patients showed a significant improvement in RA health outcomes in yoga group over control group and also, a strong association of greater reduction of BDI-II scores with disease activity and disability index. Deficiency of neurotransmitters like dopamine (Schneier et al., 2000), serotonin (Kim & Gorman, 2005) and norepinephrine (Selden, Robbins, & Everitt, 1990) is associated with anxiety, social phobia and depression. However, our results showed that markers associated with neuroplasticity like BDNF, serotonin and β-endorphins have also shown significant elevations post 8 week yoga based MBI which were in concordance with other studies (Brown & Gerbarg, 2005; Kinser, Goehler, & Taylor, 2012; Lee, Moon, & Kim, 2014; Yadav, Magan, Mehta, Sharma, & Mahapatra, 2012). Our findings suggest that yoga has the ability to adapt and reorganize the structure and function of central nervous system which was manifested at both biological and clinical levels by upregulation of markers of neuroplasticity like BDNF, serotonin and β-endorphins and reduction in BDI-II scores respectively. Yoga is being now popularly used as an adjunct to modern medicine (Halappa et al., 2018; Prathikanti et al., 2017; M.R. Tolahunase et al., 2018; Wahbeh et al., 2008; Yadav et al., 2012). Yoga, an ancient Indian science includes a set of postural exercise and mental/emotional focus which aims to bring overall relaxation with respect to health and disease. Psychological stress can be curbed by acquiring attentional control by focusing on breath, thoughts, and emotions etc. at the current moment with nonjudgmental acceptance by meditation (dhyana) (Wahbeh et al., 2008). Meditation is a physiological state of reduced metabolic activity which increases deep relaxation during sleep and increases alertness, awareness and attention and improves mood. There is a pathophysiological association between RA and depression (Lu et al., 2016), possibly through a dysfunctional neuro-endocrine system (Kemeny & Schedlowski, 2007; Straub, Dhabhar, Bijlsma, & Cutolo, 2005). Hence, many behavioral approaches including the gold standard cognitive-behavioral therapy (CBT), aims to change maladaptive ways of thinking, psychological response to illness and reduction of anxiety (Hofmann & Smits, 2008). Many CBT trials left patients symptomatic and non-respondents (Evans et al., 2008). Pharmacological therapies for RA have been effective in controlling symptoms of inflammation but fail to address key psychosocial vulnerabilities that worsens the condition (Irwin, Davis, & Zautra, 2008). Studies indicated yoga’s potential role in increasing BDNF, a key regulator of neuroplasticity hence downregulating the stress cascades and promoting neurogenesis (Naveen et al., 2016; M.R. Tolahunase et al., 2018).

Our study showed a significant association in the reduction of disease activity and depression severity over 8 weeks of yoga based MBI in RA patients. Previous study from our laboratory showed a decline in depression severity after yoga based lifestyle intervention in major depressive disorder patients and associated improvement in systemic biomarkers of neuroplasticity (M.R. Tolahunase et al., 2018). According to Su Qu et al., a yoga program had a rapid and significantly more pronounced gene expression effect in peripheral blood mononuclear cells (PBMCs) (Qu, Olafsrud, Meza-Zepeda, & Saatcioglu, 2013). Bhasin et al. stated that long-term relaxation response practitioners were found to have upregulated pathways associated with genomic stability such as telomere packaging, telomere maintenance and tight junction interaction whereas downregulated pathways that were associated with the inflammatory responses (Bhasin et al., 2013). Yoga aids in maintenance of genomic stability and chromosomal integrity, reducing the rate of cellular ageing by maintaining telomere length and upregulation of telomerase activity. Rima D have documented that yoga reduces mt and oxidative DNA damage and upregulates activity and levels of Telomerase, a reverse transcriptase (Rima et al., 2016). Yoga normalizes the levels of transcripts involved in DNA repair, cell cycle checkpoint control and causes down regulation of pro-inflammatory genes (Dhawan et al., 2017; Dada T et al., 2018). Microarray studies on effect of YBLI from our lab showed an upregulation in expression levels of various anti-inflammatory, cell cycle control, DNA repair and genes responsible for regulation of OS. Therefore, adoption of yoga as a lifestyle intervention is beneficial in reducing the disease activity, severity of psychosomatic symptoms and sequelae of this debilitating disease by its immune-modulatory potential. Thus yoga has promotive, curative and rehabilitative potential and may be used as an adjunct therapy.

4.4. Limitations

There was a lack of an active control group in our study, as control group was only on drugs and not exposed to any control intervention whereas yoga intervention group practiced asanas, dhyana and pranayama. To rule out the anti-inflammatory changes of yoga alone, future studies require an addition of the third group with physical exercise as an intervention. Apart from BDI-II scores, interpretation of systemic biomarkers at 2 weekly intervals during intervention could provide a clear picture of changing trends at cellular level. Further large-scale studies focusing on the effect of yoga on individual immune effector cells and complete cytokine profile would provide a more comprehensive picture on its role in the management of RA.

5. Conclusions

Yoga, an integrative health technology, comprises of both psychological and physical components and is thus ideal as an adjunct management system of severe painful disabling autoimmune disease like RA. Yoga has a significant effect on RA as it aids in reduction of articular and extra-articular symptoms with improvement in systemic biomarkers of inflammation, OS and maintenance of cellular health. Yoga acts via psycho-neuro-immunological mechanisms which aim to achieve a homeostatic balance for life. Yoga based MBI significantly reduced pain perception, disability quotient, disease activity and depression severity resulting in an improved quality of life in active RA patients. Yoga is a profound science based health discipline and can be used as a complementary, integrative and adjunct medical therapy which impacts the body, mind as a whole and results in promoting physical and mental health and improving quality of life. Moreover, it is a cost effective MBI, unlike drugs has no side-effects, which positively impacts body as a whole and aids in prolonging the periods of remission with fewer relapses. Thus yoga may aid in achieving immunological tolerance and molecular remission and hence can be beneficial as an adjunct therapy in the management of this severe debilitating disorder.

Footnotes

Acknowledgments

The authors would like to thank all participants for participating in the study and yoga instructors: Amit Kumar, Sudhir Chaudhary and Sneha Chandna for their guidance.

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S.No.		Practice to be done		Duration
1.	Session preparation instructions			2 min
				5 min
	Starting Prayer
	Yogic sukshma vyama	Finger loosening, Wrist loosening, Elbow loosening, Shoulder loosening, Toe bending, Ankle bending, Knee cap tightening, patella movement, Knee bending & Hip rotation		10 min
	Yogic sthool vyama	Rekhagati, Sarvaangpushti
2.	Yogasana	Standing	Trikonasana	5 min
			Katichakrasana
			Tadasana
			Veerabhadrasana
		Sitting	Gomukhasana	5 min
			Paschim-utaanasana
			Shashaankasana
			Vakrasana
		Prone	Ek-pada-shalabhasana	5 min
			Bhujangasana
			Poorna-shalabhasana
			Makarasana
		Supine	Uttanapadasana	5 min
			Setubhandhasana
			Pavanmuktasana
			Matsyasana
3.	Relaxation	Savasana	10 min
4.	Pranayama	Kapalbhati (Kriya)	20 min
			Ujjayi
			Nadishodhana
			Bhramari
5.	Nada anusandhana, AUM-Aumkar recitation			3 min
6.	Dhyana (meditation)			15 min
7.	Shanti mantra-Closing prayer			5 min
8.	Interactive Session/ Self-directed learning			30 min
	Total			120 min