An observational study on Assessment of disease activity in Rheumatoid Arthritis patients using Patient based Disease Activity Score 2 (PDAS 2)

Objective To assess the utility of Patient Based Disease Activity Score 2 (PDAS 2) in assessing the disease activity in Rheumatoid arthritis (RA). Methods A prospective cohort study was conducted on 80 patients of RA. The demographic and clinical characteristics of the patients were recorded. They were assessed for disease activity using “Disease Activity Score 28” (DAS 28), “Clinical Disease Activity Index” (CDAI) and PDAS 2 score at baseline (M0), at 2 months (M2) and at 4 months(M4) while they were on treatment. Data was analyzed for correlation of PDAS-2 with other scores and internal reliability. P < 0.05 was considered for statistical signi�cance. Results


Introduction
The disease activity in Rheumatoid arthritis (RA) needs regular assessment due to regular uctuations and guidance of treatment. 1Clinically, the physicians have the prime focus of controlling the ongoing in ammation, 2 to achieve a low disease activity. 3,4][7][8][9][10] But since the Indian rheumatology are too busy with time constraints, the physician gets little time to assess the disease holistically.So there is an increasing focus on patient-centered care.This has shifted the focus on the tools which are patient dependent rather than physician dependent.
Patient-reported outcome measures (PROMs) have been found to be patient-friendly, non-speci c to location and time e cient.[13][14] Previous studies on the psychometric properties of composite indices based purely on PROMs, such as Patient Activity Scale (PAS), the RADAI 11,12 or RAPID-3 13,14 index, have demonstrated adequate reliability, validity and responsiveness of these indices among patients with RA and proven them to be feasible, informative quantitative measures in busy clinical settings 12,14 .In RA, self-monitoring of disease at home can make patient self-aware in availing medical advice during increasing disease activity.These considerations inculcated in the development of an index, termed Patient Based Disease Activity Score (PDAS) 15 .
Earnest H. Choy et al developed and validated PDAS 1 (with ESR) and PDAS 2 (without ESR) in 2008 15,16 .The application of PDAS 2 without any laboratory parameter increases the feasibility of its use by the patients themselves at home 15 .However there is paucity of data on the correlation of DAS 28 and CDAI and PDAS 2 in RA in Indian population.Thus the current study was undertaken to assess the correlation of PDAS-2 with the routinely applied DAS28 and CDAI.

Methods
The study was a prospective observational cohort study over a period of one year where a total of Eighty patients of RA as per ACR criteria (1987) 17 and on regular treatment reporting to the Out Patient Department of Rheumatology Clinic of a tertiary care hospital, Rohtak were enrolled.Patients with severe anemia, hypothyroidism, renal, hepatic, cardiac, or pulmonary disease were excluded.A written informed consent was obtained from all eligible patients.The detailed history and clinical examination along with relevant hematological and biochemical evaluation was done.The patients were primarily on treatment with steroids and conventional synthetic Disease-modifying antirheumatic drugs (csDMARDs) such as sulfasalazine, methotrexate, gold salts, le unomide and hydroxychloroquine (HCQ).No intra-articular injections or biologicals were given to the study patients.Among all patients, DAS28, CDAI and PDAS-2 scores were calculated (Annexure I) using the formulas: a) DAS28 score = 0.56√TJC + 0.28√SJC + 0.70 (log ESR) + 0.014 (GH) 8,9 Where, TJC = tender joint count (range, 0-28) SJC = swollen joint count (range, 0-28) ESR = Erythrocyte sedimentation rate in mm rst hr by Wintrobe method GH = General health as assessed by physician (0-100 mm) b) CDAI score = SJC + TJC + PGA (VAS, 0 to 10 cm) + EGA (VAS, 0 to 10 cm) 10 Where, SJC = swollen joint count (range, 0-28) TJC = tender joint count (range, 0-28) PGA = patient global assessment of disease activity (on VAS, 0 to 10 cm) EGA = evaluator global assessment of disease activity (on VAS, 0 to 10 cm) c) PDAS 2 score = 2.667 + 0.021*(PGA) + 0.483*(HAQ) + 0.033*(patient 28 SJC) + 0.002*(EMS) 15 Where, PGA -Patient Global Assessment of disease activity (0-100 mm) HAQ -Health Assessment Questionnaire 18,19 Patient 28 Self SJC -Swollen Joint Count of 28 joints as assessed by the patient him/her-self (Supplementary Fig. 1).

EMS -Early Morning Stiffness (in minute).
All subjects were on their medication and all the three mentioned scores were reassessed at baseline (M0) and at follow up of two months (M2) and four months (M4).During the follow up ongoing therapy was changed according to the disease activity (CDAI scores).

Statistical analysis
Data was collected, plotted on Microsoft excel sheet and analyzed statistically by using SPSS software.The PDAS 2 score was compared with DAS-28, CDAI score; and with disease activity variables of DAS28 and CDAI.Pearson Correlation test was used to assess the correlation between two quantitative variables.Cronbach's alpha test was used to check the internal consistency of the indicators used in PDAS-2.Inter class correlation co-e cient was measured to assess the agreement between PDAS-2 and DAS-28/CDAI.For all tests con dence interval was kept at 95 percent.Statistical signi cance was measured by p-value < 0.05.

Results
The mean age of study group was 40.13 ± 11.74 year and there 70 females and 10 males.(Table I).The mean duration of the disease was 67.5 ± 57.8 months.

Assessment of disease activity
Disease activity was assessed using DAS 28, CDAI and PDAS 2 score at baseline (M0), at 2 months (M2) and at 4 months (M4) follow up (Table II).There was a statistically signi cant reduction (all p values < 0.001) in DAS28, CDAI and PDAS 2 score over 4 month duration of therapy (Table-III).This may be because of the introduction of steroids in the early phase of the treatment.PDAS 2 score showed signi cant (all p value < 0.001) correlation with DAS28 and CDAI score at M0, M2 and M4 as assessed by Pearson's coe cient (Table IV).Cronbach's Alpha was used to calculate internal reliability of scores.It was 0.799 for DAS28, 0.794 for CDAI and 0.578 for PDAS 2 score.(Table V).It was noticed that if early morning stiffness was excluded from PDAS-2, its Cronbach's Alpha value turned to be highly signi cant 0.757 (Table VI).To measure the agreement between disease activity categories of PDAS 2, DAS28 and CDAI, the inter-class coe cient (ICC) was used.The agreement between DAS 28 and PDSA 2 was 0.788 (p < 0.001) and between CDAI and PDAS 2 was 0.766 (p < 0.001) (Table VII), which is comparable to agreement between DAS 28 and CDAI, that is, 0.757 (p < 0.001).

Discussion
The ongoing advancements in therapeutics require continuous upgrade in disease activity measurement tools.The present study holds strength in showing the positive correlation of PDAS-2 with the currently applied physician centered clinical tools (DAS-28 and CDAI).
In the normal outpatient departments it is very di cult and time consuming to assess the RA disease activity using well known score (e.g.DAS28, CDAI).All indices to assess disease activity in RA have some shortcomings.DAS 28 includes 4 variables and it requires complex calculations like square root and logarithm.Further, DAS 28, SDAI, CDAI do not include patient functional status {Health assessment Questionnaire (HAQ)}, which is the best predictor of most severe long term outcomes of RA.
These shortcoming are overcome with the use of PDAS-2 where the clinical symptoms of the disease are self-assessed by the patients at home.It includes all the clinical symptoms of RA like fatigue, early morning stiffness, tender joint count and swollen joint count.In comparison to PDAS-1, PDAS-2 has an advantage of not including ESR measurement which is a laboratory baaed test. 20 our study PDAS 2 was signi cantly correlated with DAS28 with Pearson's coe cient 0.792, 0.757 and 0.669 and with CDAI with Pearson's coe cient 0.861, 0.832 and 0.695 respectively at M0, M2, M4 intervals which is comparable to the correlation shown in study done by Earnest H choy et al (2008)  15 (between DAS28 and PDAS 2 score was 0.76 and between CDAI and PDAS 2 score was 0.73).In our study the agreement between DAS 28 and PDSA 2 was 0.788 (p < 0.001) and between CDAI and PDAS 2 was 0.766 (p < 0.001) which is comparable to agreement between DAS 28 and CDAI 0.757 (p < 0.001).
The study by Alexander M.H. Leung et al 16 depicted similar results (correlation between DAS 28 and PDAS 2 was 0.650; between CDAI and PDAS 2 score was 0.680 and between CDAI and DAS28 was 0.810).In our study, the cronbach's alpha for PDAS 2 was 0.578.It was noticed that if early morning stiffness was excluded from PDAS 2 its Cronbach's Alpha value turned to be highly signi cant 0.757 suggesting a good internal consistency.In the study of Earnest H Choy et al cronbach's alpha of PDAS 2 was 0.400.They also opined that early morning stiffness score can be omitted without signi cantly affecting the validity and sensitivity of the instrument 15 .
The PDAS-2 holds strength since the subjects found it very easy to ll.Subjects, by self assessing their disease activity using PDAS 2 questionnaire, improved their overall understanding of the disease.Many of them agreed that their understanding and involvement helped optimizing medication; as using PDAS 2 they could assess disease activity on that very day; an early and prompt medical attention could be sought which is important in line of management.However the score suffers from the limitation that the it requires the patient to be well educated and with a good common sense.The ignorant behaviour or the lack of understanding of the clinical assessment tool may cause an underestimation of the disease activity as well, leading to worse consequences.

Conclusion
Use of PDAS 2 may be a novel approach for RA as the other disease activity scores (DAS28 and CDAI) assess the in ammatory part of disease objectively, but do not assess the impact on activity of daily living.Single-handed practitioners and clinicians working in an environment in which resources are limited could adopt patient-derived measures of disease activity such as the PDAS 2. It could also be used in Web-based recording of disease activity in future years.Nonetheless, it is suggested that larger and longer duration studies are needed to establish the rmness of the above correlation between PDAS 2 (PRO) and DAS 28 and CDAI (conventional method) to assess disease activity.

Table I :
11. Stucki G, Liang MH, Stucki S, Bruhlmann P, Michel BA : A self-administered rheumatoid arthritis disease activity index (RADAI) for epidemiologic research.Psychometric properties and correlation with parameters of disease activity.Arthritis Rheum.1995;38:795-8.12. Veehof MM, Ten Klooster PM, Taal E, van Riel P L C M, van de Laar M A F J: Psychometric properties of the rheumatoid arthritis disease activity index (RADAI) in a cohort of consecutive Dutch patients with RA starting antitumor necrosis factor treatment.Ann Rheum Dis.2008;67;789-93.Khoshaba B, Cooper D,MacGregor A, Scott DL.Development and validation of a patientbased disease activity score in rheumatoid arthritis that can be used in clinical trials and routine practice.Arthritis Rheum.2008;59:192-9. 1 .Alexander MH.Farewell LD, Lau CS, Ernest HS.De ning criteria for rheumatoid arthritis patientderived disease activity score that correspond to Disease Activity Score 28 and Clinical Disease Activity Index based disease states and response criteria.Rheumatology.2016;55:1954-8.Showing age distribution.

Table II :
Mean values of the disease activity characteristics of the study

Table III :
Table showing values of disease activity score.