Development and validation of an ama instrument for assessing the disease activity on the basis of constitutional features in Amavata (Rheumatoid Arthritis)

Abstract

Background

Rheumatoid Arthritis (RA), having a striking clinical resemblance to amavata in traditional Indian medicine (Ayurveda) presents an opportunity to look at disease from two different healthcare perspectives. This differential information may potentially supplement one system with the knowledge of the other for optimal application. This study is the first of its kind, where Ayurvedic concepts of amavata have been adopted to enhance the knowledge about RA where optimal care is still beyond the common reach.

Objective

The study was conducted to develop and validate a novel ama score based upon constitutional features of ama as depicted in ayurvedic literature as a disease activity indicator in RA.

Material and methods

The study was conducted in two parts comprising development and textual validation of the ama assessment instrument (AAI) followed by its clinical testing. AAI comprising ten items, was developed where each item was provided with a range of scores to offer the assessment close to the patient's observations. The score obtained through AAI was clinically and statistically tested on 79 RA/amavata patients randomly selected for validity and reliability. The score obtained through AAI was tested for its correlation with the DAS-28 score and ESR.

Results

Ama Assessment Instrument could find a slight correlation with acute phase reactant ESR (r-value between ESR and AMA at baseline is 0.287, and at 1st, 2nd, and 3rd follow-up is 0.276, 0.276 and 0.160 respectively) and DAS-28 (The r value between DAS and AMA at baseline is 0.231, and at 1st, 2nd and 3rd follow up is 0.218, 0.201 and 0.247 respectively). It however emerged as an independent disease status marker since it could mark the changes in the study population on a time scale more precisely as compared to DAS -28 or ESR. When the ama values at different follow-ups were compared, a significant difference was observed consistent with disease activity marker catching constitutional and GI related domain of the patients. When reducing values of ama score were compared to overall improvements as reported by the patients, a similar trend was observed showing that a change in ama score is reflective of a change in disease status and the impact of the disease on the patient.

Conclusion

This study provided a quantitative measure for the abstract concept of ama which could be used to mark the disease activity in amavata or RA. The change in ama based scores can be used to assess disease status and the intervention related benefits. The observations prompt for the possible inclusion of AAI in RA composite score to make it more dynamic in terms of disease activity identification in RA.

1. Introduction

In the management of rheumatoid arthritis (RA), assessment of disease activity plays crucial. The level of disease activity primarily works as a point of reference to predict the course of illness prospectively. Disease activity score (DAS) on its own or in combination with acute phase reactants like ESR and CRP has also been critically utilized to judge the outcome of any intervention in RA [1]. Knowing the disease activity status in rheumatoid arthritis therefore became the first mandate in the current practice of clinical rheumatology.

Although important, we observe that the DAS score is not always reflective of the clinical conditions or the concerns of the RA patients and similarly is not always a reliable reflector of the outcomes observed after any therapeutic intervention in RA [2]. The reason for this mismatch between observed and actual disease status is that DAS largely relies upon observations made by the physician on the domain areas like joint pain, swelling and tenderness. Tenderness, pain or swelling reported by the patient but not elicitable to the physician, obviously leads to a lower disease activity score. To overcome the limitation of DAS score, the use of composite scores having multiple variables have been proposed. Two commonly utilized indices of this kind in RA are the clinical disease activity index (CDAI) and simplified disease activity index (SDAI) [3].

Rheumatoid arthritis is a systemic disorder, with many extra articular and constitutional features that contribute to the status of the disease. Unfortunately, in the conventional disease activity identification done by the tools currently available, such features remain unnoticed irrespective of their importance from the patient's perspective. Finding this gap, recently some suggestions have been made to include fatigue [4] and sleep [5] as disease activity indicators and outcome assessors in RA. Weight loss during the early and active phase of RA is also a key observation during the high disease activity indicative of poor prognosis [6,7]. Recently, the normalization of appetite and resulting weight gain has beenproposed to be one important outcome measure in selected RA patients [8]. However, these new entrants of disease monitoring are yet to find a place in routine assessment of RA.

On the contrary, the traditional health care system particularly Ayurveda, has a vivid clinical description of amavata, a disease entity resembling to inflammatory arthritis including RA and Spondyloarthritis (SpA) gives a great attention to the systemic features besides adhering to the joint related features. This is observed that the patients diagnosed with RA or SpA on the basis of ACR or EULAR criteria, if simultaneously diagnosed as amavata based on Ayurveda fundamentals and are treated based on such principles, respond well to the Ayurveda interventions [9]. More importantly, in such cases treated with Ayurveda, systemic features respond well and early. RA patients on Ayurveda interventions report less fatigue, stiffness, lethargy, lack of interest, improved appetite and improved weight [10]. Although, this is yet to be understood that to what extent these systemic features can be correlated to the primary joint pathology in RA, their correction simultaneous to the reduction in joint symptoms after the ayurvedic intervention gives a clue for their possible association in altering the primary pathology and thereby in determining the disease activity status.

From Ayurvedic perspective, ama is an important pathogenic produce involved in amavata. This is conceptualized as a product of incomplete digestion and metabolism resulting from impaired metabolic fire (agni) .Ama produced at GIT, tissue or cellular level is proposed to have obliterative properties owing to its stickiness and macromolecular nature. Due to this nature, ama can produce features resulting from the obstruction of the conduits. Ama can be involved in a disease either as a primary factor like in amavata or can secondarily be involved in the disease process because of consequences impairing digestive or metabolic agni [11].

Ama produces pathognomonic GI related or systemic features depending on the site of its primary production and settlement. Its presumed level and associated features often correlate with disease activity. All treatments involving ama are directed towards dissociating of existing ama (ama pachana) and stopping further production and accumulation of ama (agni deepana). For this reason, a treatment focusing on ama leads to the disappearance of ama related features gradually [12].

To ease the understanding of ama related pathogenesis in a clinical setting, various features related to ama association of dosha are described in Ayurvedic texts. Sama (features with ama) and nirama (features without ama) examination make one important point of clinical examination in Ayurveda helping to determine the relative availability of ama in the body and thus determining the appropriate therapeutic action plan.

The association of ama in the body with various dosha and mala may be identified by clinical features representing their association. Once such association is lost, the clinical features also disappear. It is for this reason; ama related features seem to have a high indicator value for ama related disease activity. This can also help assess the therapeutic responses by seeing if the features of ama are reducing in intensity after the appropriate therapeutic interventions in an ama related pathology.

Amavata is a classical prototype of ama related pathogenesis where ama has been involved in the disease process since the beginning. Treatments focusing upon ama dissociation and prevention of its further formation are the first line of management of amavata besides many other interventions aiming to manage other symptoms. Assessing the relative presence or absence of ama in a patient of amavata has a huge, predictive and prognostic value by knowing the disease activity. This also has a high value for it being utilized as a patient-related outcome measure (PROM) occurring as a response to any therapeutic intervention. In rheumatoid arthritis (RA) which represents a subpopulation under the umbrella term of amavata representing most varieties of inflammatory arthritis, PROM has been of renewed interest as dependable measures to assess the outcome of any intervention. Measuring constitutional features like fatigue, stiffness, sleep, appetite etc. have been prompted recently as important indicators of changes in the pathogenesis ofRA in response to any therapeutic intervention. Ama assessment from an ayurvedic perspective therefore presents an opportunity to make a composite measurement of all constitutional features thatare highly sensitive from the patient's perspective and truly reflective of an ama related joint pathogenesis. It is presumed that an ama assessment may not only find its high applicability in ayurvedic clinical practice related to joint diseases but also its high applicability in modern rheumatology practice by providing a composite tool to measure many constitutional features in one go. Despite its high clinical importance, attempts have not been made to make ama assessment among amavata patients suitable for its predictive and prognostic value.

Development and validation of an ama assessment instrument (AAI) for making a quantitative assessment of ama for its use in Ayurveda rheumatology practice therefore is highly desired. Subsequent to its development, this AAI when tested for its clinical reliability and validity against existing disease activity indicators of RA, was found to have a potential to emerge as a high utility index to assess disease activity in RA. This study was done to develop and validate the AAI observations as disease activity indicator and to check its reliability as a disease activity indicator in RA.

2. Materials and methods

2.1. Study setting

This study was conducted at the PG Department of Kaya Chikitsa, State Ayurvedic College and Hospital, Lucknow (PP, SR) in collaboration with the Department of Clinical Immunology and Rheumatology, SGPGI, Lucknow (AL) and Department of Statistics, Lucknow University, Lucknow (GGA). The development and initial validation of the AAI were done in this setting. The face and content validity was partly by inviting domain experts outside the primary research institution. The clinical testing of the instrument was done at Ayurveda –Arthritis Treatment and Advanced Research Center (A-ATARC), State Ayurvedic College and Hospital, Lucknow.

2.2. Time frame of the study

AAI development began in December 2020 and was completed in June 2021. After the instrument's initial validation, the AAI clinical testig was done from July 2021 to April 2022. The data was subsequently statistically analyzed in June 2022.

2.3. Ethical clearance

The study had an ethical clearance issued by Institutional Ethics Committee wide letter no. SAC/IEC/2020/Dated 23.10.2020.

2.4. Conduction of the study

The study was conducted in two steps. The first was about developing the ama assessment instrument (AAI) for quantitative measurement of ama (index test) based on available classical literature. This step involved multiple small steps, from screening the available literature to finalizing tool components after pilot testing. The second step of the study was related to the validation of developed AAI on various parameters and correlating the AAI observations with standard biomarkers or disease activity scores (reference test) in RA both before and after a given intervention for a certain time period. The process utilized in this study for the development and validation of a new tool was tested and proven reliable through earlier studies having their relevance to Ayurveda [13,14].

2.5. Development of ama assessment instrument (AAI)

The process utilized for the development of AAI was done by utilizing following steps related to the construction of Instrument-

• 1.Domain specification: This involved the specification of “what” is to be measured in the evaluation.
• 2.Scaling: This involved the conversion of qualitative characteristics in quantitative terms. This was done by identifying the two extremes of responses against a given question and subsequently dividing the range of responses into 10 clearly definable categories.
• 3.Item generation: This involved the specific question formation pertaining to the specific domain area.

2.6. Literature survey

To begin the process of development of AAI, nine classical texts (Table 1) of Ayurveda were thoroughly screened for the inscription of ama related features. After thoroughly reviewing all texts, 51 signs/symptoms were identified for relevance to ama related pathology. These symptoms were subsequently listed to identifycommonly agreed upon by all texts consulted for the process. In this process 27 features were found to be described by almost every text either in a similar language or with partially rephrased language having a similar meaning. From the shortlist, the symptoms pertaining to the joint were eliminated to keep the focus on the constitutional features of ama. This exercise has eliminated six joint-related features and finally identified 21 features for their relation to the systemic presentation of ama.

Table 1.

Classical texts of Ayurveda reviewed for AAI development.

Number	Name of the text book
1.	Charak Samhita
2	Sushruta Samhita
3	Astanga Samgraha
4	Astanga Hridaya
5	Bhava Prakash
6	Sharangadhara Samhita
7	Madhava Nidana
8	Yoga Ratnakar
9	Bhisahjya Ratnavali

2.7. Finding the standard ayurvedic terms (SAT)/morbidity code and English equivalents for selected items

The selected 21 items had their standard ayurvedic terminologies (SAT) and morbidity identified with the help of the NAMSTP (National Ayurveda Morbidity Code and Standard Terminology Portal) application developed by Ministry of Ayush, Govt of India [15] (Table 2).

Table 2.

Features suggestive of ama status in RA/amavata patients and summated score given by the cohort of amavata experts.

S.n.	Specific features	SAT code/morbidity code	Interpretation in Englisha	Summated score by 10 experts	Average score
1.	सदन	SAT-D.8547	With body pain	45	4.5
2.	पृष्ठकटिग्रह	SAT-D.1894	Stiffness of the lumber region or lower back	39	3.9
3.	तृष्णा	EK-2	Polydipsia	36	3.6
4.	अरोचक	SAT-D.8171	Tastelessness	45	4.5
5.	व्याकुलता	SAT-D.7404	Restlessness	37	3.7
6.	आलस्य	SAT-D.914	laziness	44	4.4
7.	मूत्राधिक्य	ACB-9	Polyurea	29	2.9
8.	उदर गुरुता	SAT-D.1579	Heaviness in abdomen	40	4.0
9.	स्रोतोरोध	SAT-C.159	Obstructive pathology occurring in channels	47	4.7
10.	बलभ्रंश	SAT-D.5483	Diminution of physical strength	45	4.5
11.	गौरव	SAT-D.8463	Heaviness of the body	45	4.5
12.	क्लम	SAT-D.2521	Exhaustion without exertion	39	3.9
13.	वायुविबंध			37	3.7
14.	वेदना	SAT-D.7358	Pain/sensation	46	4.6
15.	शोथ	EK-3	Edema/inflammation	45	4.5
16.	अंग पीडन	SAT-D.167	Bodyache	39	3.9
17.	स्तैमित्य	SAT-D.8875	A sensation of dampness/feeling as if wrapped with wet clothes	33	3.3
18.	अरति	SAT-D.817	Restlessness/distress	42	4.2
19.	अतिनिद्रा	SAT-D.301	Excessive sleep	39	3.9
20.	अशन मे विव्देष	No information available	Disliking of food	39	3.9
21.	गात्र पाण्डुता	No information available	Pallor/paleness of body	28	2.8

^aThe English translation of specific features are in accordance of Standardized Ayurveda Terminology (SAT) & National Ayurveda Morbidity Code described by Ministry of Ayush.

2.8. Content validity of the selected items

After making the preliminary selection of items reflective of the clinical presentation of ama related systemic pathology, the selected items were further reviewed against a relevance scale of 1–5 showing minimum to maximum relevance by a national cohort of 12 clinical experts of Ayurveda selected based on their experience and expertise in rheumatology. Each expert in the process was provided with a detailed item sheet consisting of all 21 items and was asked to mark the relevance of the individual item in reference to disease activity status of amavata on a scale ranging from 1 to 5 representing minimum and maximum relevance respectively.

The relevance identification was made by approaching the experts physically or through email. Responses from ten experts were obtained within the stipulated time whereas two experts could not comply with the time specified for the responses. Based on summated responses of all ten experts, the items having an average score four or higher were selected to frame the final index tool. This process has finally identified ten items agreed upon by all experts for having high relevance as the systemic clinical feature related to ama pathology (Table 2, Table 3).

Table 3.

Finally selected list of clinical features for their relevance in assessing the disease activity status in amavata.

S.n.	Specific features	English interpretation
1	सदन	With body pain
2	अरोचक	Tastelessness
3	आलस्य	laziness
4	उदर गुरुता	Heaviness in abdomen
5	स्रोतोरोध	Obstructive pathology occurring in channels
6	बलभ्रंश	Diminution of physical strength
7	गौरव	Heaviness of the body
8	वेदना	Pain/sensation
9	शोथ	Edema/inflammation
10	अरति	Restlessness/distress

2.9. Formatting the questions for practical application of AAI and determining the scores for individual observations

Once clearly identified for their relevance and being selected through a process of consensus of a cohort of experts, selected items were expanded into the question to make them comprehensible by the RA patients when attempted for ama examination in individual cases (Table 4). Selected items after formatting of appropriate questions were allocated a range of score from 1 to 10 in order to get a closer opinion from the respondent. For this purpose 1 was considered to be minimum intensity of a specific feature whereas 10 was considered the highest intensity of the same selected feature. Based upon this scoring pattern, 100 had been postulated as the highest and 10 as the lowest ama score in any given case.

Table 4.

Formatting of the questions for selected items for assessment of ama.

S.n.	Specific features	English interpretation	Proposed question to be asked for enquiry (Hindi)	English translation for the proposed question to be asked for enquiry
1.	सदन	With body pain	क्या आप इन दिनों थका हुआ सा महसूस करते हैं?	Do you feel excessively tired these days?
2.	अरोचक	Tastelessness	क्या आपको इन दिनों भोजन रुचिकर नहीं लगता हैं?	Do you feel disliking/tastelessness in your favorite food recently?
3.	आलस्य	Laziness	क्या आप इन दिनों अधिक आलस्य महसूस करते हैं?	Do you feel lazy these days?
4.	उदर गुरुता	Heaviness of abdomen	क्या आपको इन दिनों पेट में भारीपन जैसा महसूस होता हैं?	Do you feel heaviness in your abdomen these days?
5.	स्रोतोरोध	Obstructive pathology occurring in channels	क्या आपको इन दिनों शरीर में जकडन सी महसूस होती हैं?	Do you feel any stiffness in your body/body parts these days?
6.	बलभ्रंश	Diminution of physical strength	क्या आपको इन दिनों अधिक शारीरिक कमजोरी सी महसूस होतो हैं?	Do you feel weakness in these days?
7.	गौरव	Heaviness of the body	क्या आपको इन दिनों शरीर में भारीपन सा महसूस होता हैं?	Do you feel heaviness in your body these days?
8.	वेदना	Pain/sensation	क्या आपको इन दिनों शरीर में दर्द सा महसूस होता हैं?	Do you feel pain in your body/body parts these days?
9.	शोथ	Edema/Inflammation	क्या आपको इन दिनों शरीर के किसी भाग में सूजन सी महसूस होती हैं?	Do you feel any kind of swelling in your body/body parts these days?
10.	अरति	Restlessness/Distress	क्या आपको इन दिनों बेचैनी, घबराहट अथवा तनाव सा महसूस होता है?	Do you feel any kind of stress, anxiety or restlessness these days?

2.10. Validity testing of the formatted prototype questionnaire

During the process of AAI development, the prototype questionnaire including all items and their scales of quantitative measurement was taken up for its content and construct validity. For content validity each item in the questionnaire was reviewed by a team of in-house Ayurveda experts (having a minimum standard decided before the start of the study) in ama assessment through clinical examination and was evaluated if each of the items had the possibility of predicting the ama status in Amavata patients.

Construct validity was done through an exploration of each item for their construct and showing if the construct of the item and the scale assigned to measure it quantitatively is able to find the answer it is aiming at.

2.11. Pilot testing of the prototype questionnaire

The pilot testing of the prototype AAI was done on 10 RA patients fulfilling the specific inclusion and exclusion criteria for selecting cases for clinical validation of the instrument. The participants of the pilot testing were selected from A-ATARC outpatient clinic on routine OP days. Such patients were given the AAI to obtain a response from them and see if there were any interpretational problems. This pilot testing was done by the lead investigator (PP) of this study. After this exercise, one item and the question framed to evaluate this (Q 2) were found ambiguous. This question was therefore elaborated and expanded in the final questionnaire to give a clear meaning and response selection. The questionnaire approved after pilot testing was subsequently taken up for further clinical validation study of the instrument.

2.12. Clinical validation study against existing benchmarks of disease activity parameters in RA

The ama assessment instrument was subsequently validated against standard disease activity indicators in RA (amavata). These standard disease activity scores and markers comprised ESR and DAS 28 scores. Following were the inclusion criteria of the selection of patients of RA (amavata) for the validity testing of the instrument –

• 1.Age between 20 and 60 years, of either gender
• 2.Diagnosable as amavata as per ayurvedic criteria and RA as per ACR criteria
• 3.Having the symptoms for not less than 3 months and not more than 5 years
• 4.Should not have taken any long acting steroids or disease modifying anti rheumatic drugs in past three months which may have modified the status of ama related features
• 5.Should not have taken any NSAID or short acting steroids during past 24 h from the time of actual interrogation.

2.13. Exclusion criteria

• 1.Patients having any other joint pathology besides RA (amavata)
• 2.Patients having ama related systemic pathology eg. Obesity, hypothyroidism, diabetes, Hepato-stetosis etc. To rule out such conditions, every prospective participant was screened for Random Blood Sugar, BMI, TSH and Serum Alkaline Phosphatase and only those coming under the strict inclusion and exclusion criteria were taken into the study.

2.14. Participant's sample for the clinical validation study

The reliability and validity of the instrument were tested on 79 participants fulfilling the inclusion and exclusion criteria.

Construct and content validity was tested with the help of ∼10 domain experts fulfilling predetermined inclusion criteria.

3. Results

79 patients duly diagnosed with RA and amavata fulfilling the inclusion and exclusion criteria having attended the A-ATARC OPD were enrolled in the study (Fig. 1). The study population included 14 male (17.72%) and 65 female (82.27%) with mean age of 44.68 years (SD ± 12.68 Years). Mean duration of illness in study population was 3.01 Year.

Fig. 1.

Study flow chart.

All study participants were examined at baseline for DAS-28 score, ESR (reference tests) and AMA score (index test). The participants were further examined at follow–ups every month and finally on completion of the study after three months.

Ama instrument was tested statistically for reliability using Cronbach's Alpha and Spearman–Brown Coefficient (split half method) (Table 5) and validity using Pearson Correlation and Sig. (2-tailed) (Table 6). Considering Chronbach's Alpha, the reliability of Baseline (0.724) is maximum, whereas minimum for Follow-up 3 (0.689). Similarly, considering split half method, the reliability of Follow-up 3 (0.803) is maximum, whereas minimum for Follow-up 1 (0.750). For the scores computed, the reliabilities obtained are acceptable. Based on the significance value obtained by the Sig. (2 tailed), the sig. (2 tailed) values obtained are less than 0.05, so it can be concluded that the items are valid.

Table 5.

Reliability testing for ama score.

Reliability
	Cronbach's Alpha	Spearman–Brown coefficient (split half method)
Baseline	0.724	0.776
Followup1	0.695	0.750
Followup2	0.695	0.782
Followup3	0.689	0.803

Table 6.

Validity testing for ama score.

		Ama SCORE_B	Ama SCORE_1	Ama SCORE_2	Ama SCORE_3
Tiredness	Pearson correlation	0.751	0.636	0.675	0.740
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Tastelessness	Pearson correlation	0.461	0.384	0.528	0.579
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Laziness	Pearson correlation	0.678	0.667	0.649	0.704
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Heaviness in abdomen	Pearson correlation	0.394	0.351	0.449	0.461
	Sig. (2-tailed)	0.000	0.002	0.000	0.000
Stiffness in body	Pearson correlation	0.576	0.544	0.424	0.501
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Diminution of physical strength	Pearson correlation	0.496	0.496	0.596	0.492
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Heaviness of the body	Pearson correlation	0.514	0.539	0.505	0.447
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Body pain	Pearson correlation	0.487	0.532	0.504	0.587
	Sig. (2-tailed)	0.000	0.000	0.000	0.000
Swelling in the body/body part	Pearson correlation	0.447	0.477	0.427	0.237
	Sig. (2-tailed)	0.000	0.000	0.000	0.036
Anxiety	Pearson correlation	0.611	0.602	0.501	0.407
	Sig. (2-tailed)	0.000	0.000	0.000	0.000

3.1. Correlation between ama score and disease activity markers in RA

A Pearson Correlation was obtained at different timelines (baseline, follow-ups and final follow-up) between Ama score and DAS score and also ESR. At each of such observations DAS and ESR were found moderately correlated on the basis of r value whereas Ama was only slightly related to both DAS and ESR at all 4 observation time points (Table 7).

Table 7.

Correlations between DAS, ESR and ama score at followup1.

		Disease activity score	Erythrocyte sedimentation rate	Ama SCORE
Disease activity score	Pearson correlation		0.485	0.218
Erythrocyte sedimentation rate	Pearson correlation			0.276

The r value between DAS and ESR obtained is 0.572 which means the DAS and ESR is moderately correlated. The r value between DAS and AMA obtained is 0.231 which means DAS and AMA are slightly correlated. The r value between ESR and AMA obtained is 0.287 which means ESR and AMA are slightly correlated.

The r value between DAS and ESR obtained is 0.485 which means the DAS and ESR is moderately correlated. The r value between DAS and AMA obtained is 0.218 which means DAS and AMA are slightly correlated. The r value between ESR and AMA obtained is 0.276 which means ESR and AMA are slightly correlated.

The r value between DAS and ESR obtained is 0.400 which means the DAS and ESR is moderately correlated. The r value between DAS and AMA obtained is 0.201 which means DAS and AMA are slightly correlated. The r value between ESR and AMA obtained is 0.276 which means ESR and AMA are slightly correlated.

The r value between DAS and ESR obtained is 0.439 which means the DAS and ESR is moderately correlated. The r value between DAS and AMA obtained is 0.247 which means DAS and AMA are slightly correlated. The r value between ESR and AMA obtained is 0.160 which means ESR and AMA are slightly correlated.

3.2. Analyzing ama score for their possibility of being considered as an independent disease variable indicating the disease activity

It the study population mean Ama score was found to be 57.15 (SD 8.476) at base line which was subsequently reduced to 49.39 (SD 7.155), 42.03 (SD 6.577) and 34.91 (SD 5.359) at 1st, 2nd and final follow up subsequently (Table 8).

Table 8.

Descriptive statistics of cumulative ama scores at various time points.

	Mean	Std. deviation	N
AMA score (baseline)	57.15	8.476	79
AMA score (1st follow up)	49.39	7.155	79
AMA score (2nd follow up)	42.03	6.577	79
AMA score (3rd follow up)	34.91	5.359	79

Multivariate tests

Effect		Sig.
factor1	Hotelling's Trace	<0.001

The p-value for AMA obtained is <0.05 which is significant at 5% level of significance; hence there is difference in different levels of AMA.

Tests of within-subjects effects
Measure: MEASURE_1
Source		Sig.
factor1	Greenhouse–Geisser	<0.001

For test of within subjects effects, the p-value obtained is <0.05 for all levels which is significant at 5% level of significance, hence we reject the null hypothesis and conclude that there is significant difference between different levels of AMA.

Table 9 (Supplementary file) makes a pairwise comparison compares the different level of AMA. The p-value <0.05 shows that there is significant difference between means of AMA at different level for the considered pairs.

When a similar descriptive statistics was applied to various levels of DAS scores and ESR and their pair wise comparison was made, a similar trend of reducing values was observed and a similar significance was observed at pair wise comparison of all values in both of these variables (Tables 10–13 in supplementary file and Fig. 2).

Fig. 2.

Correlation between ama score, DAS score and ESR at various time points.

The p-value for DAS obtained is <0.05 which is significant at 5% level of significance; hence there is difference in different levels of DAS.

For test of within subjects effects, the p-value obtained is <0.05 for all levels which is significant at 5% level of significance, hence we reject the null hypothesis and conclude that there is significant difference between different levels of DAS.

The p-value for ESR obtained is <0.05 which is significant at 5% level of significance; hence there is difference in different levels of ESR.

For test of within subjects effects, the p-value obtained is <0.05 for all levels which is significant at 5% level of significance, hence we reject the null hypothesis and conclude that there is significant difference between different levels of ESR.

The above table pairwise comparison compares the different level of ESR. The p-value obtained is <0.05 shows that there is significant difference between means of ESR at different level for the considered pairs. The p-value >0.05 shows no significant difference between means of ESR at different level.

4. Discussion

Clinical rheumatology faces a dearth of parameters that can precisely reflect the clinical activity of the disease. This seems highly important in conditions like Rheumatoid Arthritis, where high disease activity predicts a bad prognosis warranting urgent actions to arrest the disease progression and joint destruction. Various disease activity parameters currently used for evaluating the clinical staging of RA are either joint-based, defining the joint counts in terms of swelling, tenderness, and stiffness, or the levels of inflammatory markers like ESR and CRP reflecting the underlying inflammatory process in an individual. Scores like DAS which rely heavily upon joint status actually fail to appreciate the systemic features which might be of substantial importance to the patient for the level of discomfort they might pose. Similarly, the inflammatory biomarkers are not specific to RA alone and are obtainable in many conditions other than joint diseases. The level of inflammatory biomarkers can also be misleading for it being a cumulative score for a summated time period. Therefore changes in such scores do not reflect the changes in the clinical status in the case of RA precisely.

Besides being unable to reflect the disease condition through various domain areas precisely, currently utilized RA disease activity indicators also have a poor translational capacity to be considered a dependable outcome reporting measure. Changes in the joint counts in relation to its swelling, pain, and tenderness or even changes in ESR or CRP like inflammatory biomarkers do not necessarily reflect the changes the patient perceives in response to a therapeutic intervention. In RA what is meaningful to a patient may differ much from what is meaningful to a physician in terms of observations.

This delusion about proposing the most appropriate measures to define the disease status and the intervention-related outcome has long been faced in clinical rhematology practice. To overcome this, a composite scoring pattern was proposed, developed, and utilized in clinical trials related to RA [16].

Composite outcome measures have become very popular in assessing RMDs, because of their claim to catch all relevant dimensions of the disease into one convenient measure.

Composite scores are proposed to reflect multidimensionality and heterogeneity in disease pathogenesis, manifestations, and outcome. Multidimensional composites usually include several disease manifestations and outcome dimensions into one index. It is however noticed that multidimensional composites are not free of errors in terms of their use for treat-to-target and window of opportunity like strategies of modern rheumatology. Using multidimensional composites in clinical trials is found to have a different notion when the same is used in clinical practice. Moreover, many aspects of disease impact have not yet been covered in any of the components of the commonly utilized composite scores.

Patients with rheumatoid arthritis are found to differ from controls in their emotion-related personality traits, leading to their increased susceptibility to chronic stress and hypothalamic–pituitary–adrenal axis dysregulation. Such dysregulations make a substantial impact on a patient's well-being and net outcome of a given intervention [17].

Evidence suggests RA is a highly heterogeneous disease with many subtypes characterized by personality, psychiatric and immunological differences. Such complexities associated RA again warrants for a more comprehensive scoring method inclusive of every dimension reflecting the disease activity and outcome status.

Currently used measures of rheumatoid arthritis disease activity are the following: Patient (PtGA) and Provider (PrGA) Global Assessment of Disease Activity, Disease Activity Score (DAS) and Disease Activity Score with 28-Joint Counts (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Patient Activity Score (PAS) and Patient Activity Score-II (PASII), Routine Assessment of Patient Index Data (RAPID), Rheumatoid Arthritis Disease Activity Index (RADAI) and Rheumatoid Arthritis Disease Activity Index-5 (RADAI-5), Chronic Arthritis Systemic Index (CASI), Patient-Based Disease Activity Score With ESR (PDAS1) and Patient-Based Disease Activity Score without ESR (PDAS2), and Mean Overall Index for Rheumatoid Arthritis (MOI-RA). We see that despite such a plethora of single and composite indexes, the disease activity in RA and its outcome assessment is still far from being perfect [18].

RA patients are found to have intriguing constitutional features related to general well-being, sleep, energy status, appetite, and GI functioning [19]. This has been observed that such features find little place in the currently used composite score meant for evaluating RA disease activity. Clinical observation on RA patients has revealed that while receiving the Ayurveda treatment, these are the features that are addressed first within 1–3 months before actual improvements in joint related features are observed. This is also observed that during high disease activity, most RA patients report a loss in weight [20] accounting for a loss of appetite and after ayurvedic treatment the improvements in a loss of appetite and weight are reported [8]. Such clinical observations made in ayurveda rheumatology clinics when matched with a near absence of any such parameter or observation in modern rheumatology practice, warrant a serious thought of including these constitutional features in the composite scores meant for a comprehensive clinical evaluation of RA. Finding a parallel to RA in Ayurveda was the first problem to be addressed before any such measure could be developed based on Ayurvedic fundamentals explaining the pathogenesis of RA kind of diseases. A dual diagnosis approach was adopted to overcome this intrigue where the study population was diagnosed simultaneously as having RA and Amavata by the standard parameters of diagnosis adopted by both the systems. After finding this parallelism, this was easy to extrapolate the observations made in one context to be inferred in the other.

Subsequent to the establishment of this parallelism, what done was to explore the extra articular and constitutional features in RA which are otherwise the hallmarks of ama. A thorough literature search helped extensively identify and determine the most appropriate features reflective of ama and check their reliability and validity on established parameters.

After initial textual validation of the instrument which was meant to check the presence and level of ama related features in rheumatoid arthritis, its testing as an index test on the sample population was quite rewarding. Although the newly developed ama assessment instrument could find only a slight correlation with the reference tests like acute phase reactant ESR and disease activity score based upon 28 joint counts (DAS-28), it stood apart as an independent disease status marker since it was able to mark the changes in the population on a time scale more precisely comparing to DAS -28 or ESR. When the succeeding ama values of follow-ups were compared with preceding values, a significant difference was observed, showing it to be a consistent and reliable disease activity marker catching constitutional and GI-related domain of the patients. When reducing values of ama score were compared to overall improvements as reported by the patients, a similar trend was observed showing that a change in ama score reflects of a change in disease status and the impact of the disease on the patient.

The study however had its limitations. Question framing always has a scope to be refined further, and so is in this study. Ama score, the index test used in this study, also needs to be further tested for its sensitivity, specificity and predictive values in reference to RA. Ama, the progenitor of various ama induced pathogenesis also prompts the test to be evaluated for ama diseases other than amavata.

5. Conclusion

This study provided a quantifiable measure for the abstract concept of ama and helped utilize this percept as a reliable measure to mark the disease activity in amavata. This came as a great help in determining the course of ayurvedic therapy based upon ama scores reflecting the disease activity status. This ama based scoring also came as a help in quantifying the intervention-related benefits in terms of the significance of changes in baseline ama score. This study leads to future studies in this area focusing upon the development of ama score as a patient-related outcome measure (PROM) in Ayurveda.

Funding

None.

CRediT author statement

Preeti Pandey: Conceptualization, Methodology, Data Collection; Sanjeev Rastogi: Data curation, Writing – Original draft preparation; Able Lawrence: Visualization, Review; Girdhar G Agrawal: Software, Analysis, Supervision.

Conflict of interest

We declare no conflict of interest.

Appendix A. Supplementary data

The following is the supplementary data to this article: