Diagnostic and therapeutic delay in Rheumatoid Arthritis patients: Impact on disease outcome

Objective: To identify factors causing diagnostic and therapeutic delay in patients with rheumatoid arthritis, and to evaluate relationship of diagnostic and therapeutic delay with disease outcome. Methods: This cross-sectional study was conducted in Rheumatology Department, Fatima Memorial Hospital, Lahore, Pakistan, from May 2018 to July 2018. In this study 102 patients fulfilling ACR/EULAR criteria 2010 were enrolled. Lag times were calculated in months: lag-1 (delay in initial medical consultation); lag-2 (delay in consulting rheumatologists); lag-3 (diagnostic delay); lag-4 (therapeutic delay). Disease activity and functional outcome were measured by DAS28, HAQ-DI respectively. Association of lag-3 and lag-4 with HAQ-DI and DAS28 was calculated by Pearson correlation. Results: Median (IQR) disease duration of study group was 6(2-10) years. Initial consultations were with; orthopedic surgeon 40(39.2%), general practitioner 27(26.5%), rheumatologist 13(12.7%), medical specialists 14(13.7%). Median (IQR) lag times in months: lag-1 (delayed initial consultation): 2(0-5), lag-2 (delay in consulting rheumatologist): 30(7.7-72), lag-3 (diagnostic delay): 12(3-48), lag-4 (therapeutic delay):18(5.7-72). Factors attributed to lag-3 (diagnostic delay) and lag-4 (therapeutic delay) (p<0.05): older Age (r= 0.2), education level(r= - 0.2), initial consultation (non-rheumatologist) (r=0.2), lag-2(r=0.8), >three doctors visited before diagnosis(r=0.6). Positive anti-CCP antibodies(r=0.2) and lag-1 (delayed initial consultation) (r=1) were associated with lag-3 (diagnostic delay) only; no association was found with positive RA factor. Significant correlation (p=<0.05) of lag-3 (diagnostic delay) was found with both DAS28(r=0.2) & HAQ-DI(r=0.2). Similarly lag-4 (therapeutic delay) also correlated with both & DAS28(r=0.2) & HAQ-DI(r=0.3) (p=<0.05). Conclusion: Diagnostic and therapeutic delay were associated with older age, lower education and delayed consultation with rheumatologist but not with positive RA factor. Positive anti-CCP antibodies were associated with diagnostic delay only. Diagnostic and therapeutic delay led to high disease activity and poor functional outcome in RA patients.


INTRODUCTION
Rheumatoid arthritis (RA) is an autoimmune, systemic, chronic inflammatory disorder with articular and extra-articular manifestations. 1 Worldwide RA affects 0.24 to 1% adult population 2 with female to male ratio 3:1. Peek age of onset in females is late childbearing years while in males is in sixth to seventh decade. 1 Point prevalence of RA reported from Karachi has increased from 12.9% in 2011 to 26.9% in 2015. 3 Musculoskeletal disorders contribute to 6.7% of "total overall global burden" of disease. 4 Damage is irreversible once erosions develop on radiograph leading to deformities within one to two years. 1 In 2013 average cost of illness of RA patient in South India was estimated as 2229.99 ($34)/month. 5 Regarding health economics, long term studies reported that 50% RA patients have had to stop working after 10 years of disease which is 10-times the average rate caused by other medical conditions. 1 In RA the overall mortality is 2.5 times higher than that of the general agematched population. 6 RA is associated with fatty liver and comorbidities like metabolic syndrome, diabetes mellitus and hypertension. 7 Hypertension, smoking and self-use NSAIDS/ Hakeem medication lead to impaired renal function in RA patients. 8 Initiating treatment within 12 weeks of symptoms onset (therapeutic window of opportunity) 9 doubles the chances of achieving remission and decreases necessity of using biologics in RA treatment from 32.24% to 10% 10,11 leading to better functional outcome (lower HAQ-DI values) with good radiographic outcome and lower disease progression rate. 9,12 Main objective of this study was to identify factors contributing to diagnostic and therapeutic delay in RA patients and to evaluate relationship of diagnostic and therapeutic delay with disease outcome, previously never studied in Pakistan. Considering the data available on disease burden and disability 2,3,6 as well as economic burden caused by RA, 5 it is need of the hour to address these factors to improve outcome of RA in Pakistani milieu. Delays in diagnosis and initiation of treatment for Rheumatoid arthritis leads to poor disease outcome in terms of disability and quality of life, early diagnosis and treatment will result in improved quality of life and prevention of complications of Rheumatoid arthritis.

METHODS
This cross-sectional study was conducted in Rheumatology department, Fatima Memorial Hospital, Lahore, Pakistan, from May 2018 to July 2018. After receiving approval from Hospital Ethical Committee (dated June 01, 2018, IRB FMH-O4-2018-IRB-419-M), total one hundred and two patients, both male and female with RA fulfilling ACR/EULAR (annex-1) classification criteria 2010, with age ≥18 years, and disease duration of ≥3 months were included using 95% Confidence level (SD=1.96), 10% margin of error (SE=0.1), keeping 31% patients (P=0.31) assessed within 12 weeks, showed less joint destruction and higher chances of remission, 9 Q=1-P, using following formula: n= SD 2 x P x Q SE 2 Exclusion criteria: • RA overlapping other connective tissue diseases. • Comorbidity/medical illness leading to functional impairment. • Pregnancy. Operational definitions: Diagnostic and treatment delay was defined as delay in establishing RA diagnosis and initiating treatment after 12 weeks (therapeutic window of opportunity) 9 and was calculated in lag times. 13 • Lag-1: delay in initial consultation from symptoms onset. • Lag-2: delay in consulting rheumatologist from symptoms onset. • Lag-3 (diagnostic delay): delay in diagnosis from symptoms onset. • Lag-4 (therapeutic delay): delay in initiating 1st DMARD from symptoms onset. Impact on disease outcome was measured by calculating disease activity and functional disability; DAS28 (annex2) and HAQ-DI (annex3, 4,5) respectively. Threshold of disease activity with DAS28 was interpreted as follow: Remission <2.6, low activity >2.6-<3.2, moderate activity ≥3.2-≤5.1, high activity >5.1. 14 HAQ-DI index was interpreted in three categories: 0-1: mild to moderate disability, 1-2: moderate to severe disability, 2-3: severe to very severe disability. 15 Data was analyzed by SPSS version 17 and quantitative study variables like age were presented as mean and standard deviation. Qualitative variables like gender and factors were presented as frequency and percentages. Lag time1-4 and disease duration were calculated in median and interquartile range (IQR). All patients were divided into three groups according to diagnostic and therapeutic delay (lag-3 & lag-4) of ≤1 year, >1-≤5 years and >5 years. Mean DAS28 & HAQ-DI values were calculated for each group and were compared among them by applying ANNOVA. Lag-3 and lag-4 were correlated with both DAS28 and HAQ -DI by using Pearson correlation. Spearman correlation was used to correlate all factors with both lag3 and lag4. P<0.05 was taken as significant.

Diagnostic & therapeutic delay (Lag-3 & Lag-4) with disease outcome:
Patients having diagnostic and therapeutic delay of one year or less were found to have lower disease activity and better functional outcome. (Table-III).
This study showed that median lag-3 (diagnostic delay) was one year while median lag-4 (therapeutic delay) was one and half years but initial consultations were done within "window period of opportunity". On average >three physicians were consulted before RA diagnosis was reached (Table-I). Median lag-2 (delay in consulting rheumatologists) was 30(7.7-72) months. Rheumatologists were ultimately responsible for diagnosing RA.
Initial consultation with rheumatologists was done by 12.7% patients only. Major causes of delay in seeking initial consultation with rheumatologist were lack of awareness and lack of referral. One study conducted in Rawalpindi reported that even in diagnosed RA patients only 1.5% patients had knowledge on disease. 18 Current study shows only 47.1% of cases were diagnosed by rheumatologist hence this lack of initial rheumatologist consultation led to lag-3(r=0.2, p=0.04) and lag-4(r=0.29, p=0.08) ( Table-II). This was in contrast to study by Hussain W et al, where rheumatologists diagnosed RA in 75.6% patients. 16 Even though non-rheumatologists diagnosed RA, they did not initiate DMARD's. Initiation of DMARD's in   Table-II). Similar pattern was reported from Saudi Arabia (p=<0.00). 16 Gender and geographical region (rural vs. urban), presence of initial symptoms (hand/wrist, knees involvement) were not found to be associated with lag-3 and lag-4. Delay in initial consultation led to diagnostic delay (r=0.25, p=0.01). Older age was associated with lag-3 (r=0.2, p=0.02) and lag-4 (r=0.21, p=0.03) ( Table-II). Hussain W et al, reported that patients presenting initially with hand/wrist involvement and fatigue as well as those belonging to urban population were associated with early diagnosis but no association of diagnostic delay was found with gender and age. 16 Both lag-3 and lag-4 correlated with lower education status (r=-0.20, p=0.04 &r=-0.29, p=0.03 respectively) ( Table-II). Cho et al, reported that older age at onset, higher education level and higher income led to early diagnosis. 21 We did not find any association of RA factor+/with diagnostic and therapeutic delay. Positive anti-CCP antibodies were associated with diagnostic delay (r=0.20, p=0.03) but not with therapeutic delay (r=0.07, p=0.43) ( Table-II). Pratt et al, described that insidious onset of symptoms in patients with RA factor + /anti-CCP + led to delay in seeking medical care which in turn led to diagnostic delay. Diagnostic and therapeutic delay in RA factor -/anti-CCPpatients occurred in secondary care. 22 One study conducted in Karachi reported that RA factor-patients had diagnostic delay and hence delayed rheumatology referral. 23 All the other possible factor causing diagnostic and therapeutic delay were not determined previously Fig.1: Association of Lag-3 and Lag-4 with DAS28 and HAQ-D1 (Impact on disease outcome) Pearson correlation was used to correlate lag-3 and lag-4 with HAQ-D1. Significant correlation between lag 3 (diagnostic delay) and DAS28 was found (r=0.2, p=0.02) (Fig. a) as well as between lag3 and HAQ (r=0.2, p= 0.003), (Fig. b) Similarly significant correlation between leg 4 (therapeutic delay) and DAS28 (r=0.2, p=0.03) (Fig. c) as well as between lag4 and HAQ (r=0.3, P=0.001) was found (Fig. d)  in Pakistan as we have tried to find out to reduce lag times in order to improve disease outcome in RA patients. Significant statistical correlation of lag-3 was found with both DAS28 (r=0.2, p=0.02), and HAQ-DI (r=0.2, p=0.003) (Fig. 1a & 1b). Correlation of lag-4 with both DAS28 (r=0.2, p=0.03) and HAQ-DI (r=0.3, p=0.001) was found (Fig. 1c & 1d). Badsha et al, reported high disease activity (DAS28) in patients with diagnostic delay (r=0.323, p=0.025). 20 Kim 24 reported lower HAQ-DI and DAS28 value in patients having started treatment within six months of symptom onset than those starting treatment later(p=0.01).

Strength and limitations:
This single concise study gives true insight into the lag times along with different factors causing diagnostic and therapeutic delay in RA patients and their impact on disease outcome in Pakistan. This study is first of its kind ever done in Pakistan.

Limitations of the study:
All patients in this study belonged to lower socioeconomic status. Other factors e.g. myths and fears of patients regarding disease and treatment, adherence to treatment, and reason of delay in patient with better socioeconomic status were not evaluated in this study. This study needs to be repeated after few years in same population to evaluate any decline in lag times and improvement in disease outcome.

CONCLUSION
Older age, lower education and delayed consultation with rheumatologist were the factors associated with both diagnostic and therapeutic delay. Positive RA factor did not impact on diagnostic and therapeutic delay. Positive anti-CCP antibodies were associated with diagnostic delay only. Diagnostic and therapeutic delay ultimately led to high disease activity and poor functional outcome in RA patients. It is essential to address these factors to minimise diagnostic and therapeutic delay in RA patients to improve their physical wellbeing and to decrease burden of disease, disability and economic burden in our patients.