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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 1  |  Page : 27-31

Does Delay Matter in Early Rheumatoid Arthritis?


1 Department of Rheumatology, Dubai Hospital, Dubai Health Authority, Dubai, UAE
2 Department of Internal Medicine, Dubai Health Authority, Dubai, UAE

Date of Submission12-May-2019
Date of Acceptance24-Sep-2019
Date of Web Publication20-Feb-2020

Correspondence Address:
Jamal Ali Al-Saleh
Department of Rheumatology, Dubai Hospital, Dubai Health Authority, P.O. Box: 7272, Dubai
UAE
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HMJ.HMJ_42_19

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  Abstract 


Aims: The aims of this study were to explore the effect of delayed presentation to a rheumatologist on the clinical outcomes in patients with early rheumatoid arthritis (RA) after 2 years of follow-up and to determine the predictors of failure to achieve therapeutic targets in those patients. Methods: It is a retrospective study; patients were recruited from Dubai Arthritis Registry (DAR). All patients with symptoms of RA <6months, who attended early arthritis clinic and subsequently completed a follow-up of 2 years in the general rheumatology clinic, were included in the study. We extracted clinical and demographic data from DAR. Results: We have enrolled 78 patients with ERA. Their median age was 49 years (interquartile range [IQR]: 34–52) years, 88.5% were female and 5.2% were current or past smokers. The median delay between symptom onset and seeing a rheumatologist was 34 (IQR: 13–71) days. About 75.4% achieved clinical targets at 24 months of follow-up. Seventy per cent had a good response, 14% had a moderate response and 16% had no response. The proportion of non-responder was higher in the delayed group than those who presented early after the onset of symptoms (odds ratio = 2.6, 95% confidence interval: 1.2–5.9 and P = 0.02). Female gender, Anti-Citrullinated Protein Antibodies (ACPA) positive and Disease Activity Score 28 (DAS28) at baseline are independent predictors of achieving clinical targets after 2-year follow-up. Conclusion: Delayed presentation to rheumatologist adversely affects the clinical outcomes in patients with early RA. Indeed, female gender, DAS28 at baseline and ACPA positivity remain independent predictors of achieving clinical outcomes in patients with ERA.

Keywords: Disease Activity Score 28, early rheumatoid arthritis, gender, referral


How to cite this article:
Al-Saleh JA, Narainen M, Al Marzooqi AM. Does Delay Matter in Early Rheumatoid Arthritis?. Hamdan Med J 2020;13:27-31

How to cite this URL:
Al-Saleh JA, Narainen M, Al Marzooqi AM. Does Delay Matter in Early Rheumatoid Arthritis?. Hamdan Med J [serial online] 2020 [cited 2021 Sep 27];13:27-31. Available from: http://www.hamdanjournal.org/text.asp?2020/13/1/27/278867




  Introduction Top


The treatment goals of rheumatoid arthritis (RA) have evolved in the past two decades from controlling inflammation, symptoms and disease activity to achieve remission and preventing joint damage. The greatest damage occurs in what is so-called 'window of opportunity' early in the disease.[1],[2] Delayed treatment was frequently associated with radiographic damage in RA patients.[3] Hence, the EULAR recommendations for the management of early arthritis in 2007, and 2016, strongly advocate that 'patients presenting with arthritis should be referred to, and seen by, a rheumatologist, within 6 weeks after the onset of symptoms'.[4],[5]

The main aim of starting disease-modifying antirheumatic drug (DMARD) therapy in early RA is to achieve clinical remission. Studies have shown that patients with early RA respond better to treatment than patients with established RA.[6] In fact, disease duration was shown to be an independent predictor of response to DMARD treatment in a meta-analysis of 14 different randomised clinical trials.[7] Given this difference in response, the American College of Rheumatology (ACR) has distinguished the treatment of early RA from established RA based on the available data in the past ACR update on the management of RA.[8]

Few studies in the literature have explored the effect of the delay on patients' outcome in early RA.[9],[10] As the definition of early RA has changed over the years from symptom or disease duration of <2 years to a recent consensus that early RA is patient with symptoms or disease duration of a <6 months. There is a great need to study the effect of delayed presentation on the clinical outcomes, in those who have the symptoms/disease <6 months. Furthermore, there are limited data in the literature published from the Middle East on the predictors of clinical outcomes in patients with early RA.

Objectives

The objectives were to study the effect of delayed presentation to a rheumatologist, as defined by EULAR recommendations,[4],[5] on clinical outcomes after 2 years of follow-up in patients with early RA,[8] and to explore the predictors of failure to achieve therapeutic targets in those patients after 2 years of follow-up.


  Methods Top


Study design

It is a retrospective study. Patients were recruited from Dubai Arthritis Registry (DAR), in Public Hospital that looks after early arthritis in Dubai Health Authority.

Patients

We recruited all patients who have attended the early arthritis clinic after the launch of DAR in December 2014. Those patients who fulfilled the inclusion criteria and completed 2 years of regular follow-up in general rheumatology clinic were included in the study.

The inclusion criteria were as follows: age between 18 years and 80 years, meeting ACR/EULAR 2010 RA classification criteria for RA and symptom/disease onset<6 months from the initial presentation (early RA). We have excluded patients with established RA, patients with undifferentiated or other rheumatological disorders and those who lost follow-up for ≥6 months.

Demographic and referral data and clinical assessments

Patients who attended early arthritis clinic were assessed at baseline and enrolled in DAR. Their regular visits to the rheumatology clinic, which is usually once every 3 months over a period of 2 years, were also entered in the registry. To answer our research question, we extracted the following information from DAR including demographic data, date of symptom onset, date of referral, date of initial rheumatologist consultation, rheumatoid factor, ACPA positive, baseline Disease Activity Score 28 (DAS28) within 2 weeks from the first presentation, number of conventional DMARDs and biologics used over the 2 years, the number of hospitalisation day and sick days, the Health Assessment Questionnaire after 2 years of follow-up and DAS28 after 2 years of follow-up.

Grouping

Eligible participants were grouped into one of the two groups: the early group: those who seen within 6 weeks of their symptom onset to a rheumatologist and the delayed group: those who presented after 6 weeks after their symptom onset. We compared the demographic, clinical and immunological features of the groups at baseline and after 2 years of regular follow-up with rheumatologist.

Clinical targets

At the end of the 2 years, patients were assessed for achieving clinical targets, namely DAS28 of<2.6, i.e., remission, or DAS28<3.2, i.e., low disease activity (LDA).[11] Furthermore, we compared the fraction of patients in the early and delayed groups for achieving EULAR response criteria.[12],[13]

Statistical analysis

Descriptive statistics, Student's t-test and Fisher's exact test were used as appropriate. Demographic data and disease and treatment characteristics are described as median and 25th–75th interquartile range (IQR). 2 ×2 tables were used to calculate the odds ratio and 95% confidence interval on comparing the fractions in the early and delayed groups.

Multivariate regression analysis was used to investigate the effect of delay of presentation to rheumatologist on achieving clinical targets after two years of follow up defined by DAS28 <3.2, taking in to account; patient demographic and clinical characteristics at baseline and during follow-up. Variables included in the different models tested were selected based on their statistical significance in the univariate analysis and also on their clinical relevance. Significant variables were finally isolated using stepwise forward selection. In all statistical tests used; Student's t-test, Fisher 's exact test, and multivariate regression, we considered the results are statistically significant if the P-value < 0.05. Statistical analysis was performed using Minitab software version 18.1, Minitab, LLC, State College, Pennsylvania, USA.


  Results Top


We identified 78 RA patients who presented with symptoms <6-month duration and completed 2-year follow-up in general rheumatology clinic. The median age was 49 years (IQR: 34–52 years), 88.5% were female and 5.2% were current or past smokers. The median delay between symptom onset and seeing a rheumatologist was 34 days (IQR: 13–71 days). The baseline characteristics of enrolled patients enrolled in the study and subgroups are outlined in [Table 1]. About 75.4% achieved clinical targets at 24 months of follow-up, 49.4% had a DAS28 <2.6 and 26% had DAS28>2.6 but <3.2. The median reduction of DAS28 since the initial presentation to a rheumatologist was 1.65 (IQR: 1–2.3). Applying EULAR response criteria, we found that 70% had a good response, 14% had a moderate response and 16% had no response.[12]
Table 1: Baseline characteristics of all patients enrolled in the study and the subgroups

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Early presentation versus delayed presentation

The median time lag between symptom onset and the first presentation to a rheumatologist in the early group was 19 days (IQR: 10–32 days) and the delayed group was 90 days (68–116) (P < 0.0001). On comparing the early group with the delayed group, there was no significant difference between the groups at baseline or after 2 years for follow-up. The median reduction of DAS28 after 24 months was 1.7 (IQR: 1.1–2.4) in the early group and 1.5 (IQR: 0.6–2.3) in the delayed group (P = 0.13).

However, on exploring the clinical targets, the delayed group had a higher proportion of patients in remission (DAS28 <2.6) than the early group (60.0% vs. 41.7%, respectively, P = 0.02), whereas the early group had a higher proportion of patients in LDA (DAS28 ≥2.6 but<3.2) than the delayed group (31.3% vs. 16.7%, respectively, P = 0.03) [Table 2].
Table 2: Summary of treatment and clinical outcomes after two years of follow up

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Similarly, there was no difference between the groups in the frequency of EULAR good response. Nevertheless, patients in the early group had a statistically significantly higher proportion in moderate response and a lower proportion in no response categories than patients in the delayed group [Table 3].
Table 3: The proportion of EULAR response after 24 months of follow up in the early & delayed group

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Predictors of clinical in patients with early rheumatoid arthritis

Univariate analysis showed that achieving clinical targets after 2 years of follow-up was dependent on the age at presentation, female gender, ACPA positive, rheumatoid factor positive, DAS28 at baseline and number of DMARDs used over 2 years.

Multiple regression analysis showed that female gender, ACPA positive and DAS28 at baseline were independent predictors of achieving clinical targets after 2-year follow-up [Table 4].
Table 4: Results of Multiple regression analysis

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  Discussion Top


Our study showed that delayed presentation to a rheumatologist of 6 weeks or more in patients with early RA, symptoms<6 months, can influence the response to treatment after 2 years. Overall, almost three-quarters of the patients achieved clinical targets defined as LDA or remission after 2 years in both the groups. This can be attributed to the tight control strategy used in our centre in daily practice, and physicians are keenness to treat patients with RA to reach the recommended clinical targets. This is in line with what is reported by others.[14]

There was no significant difference in the use of conventional DMARDS, biologics and the percentage of patients achieving good clinical response at the end of 2-year follow-up between those who presented in the early and delayed groups. However, a higher proportion of patients in the delayed group were classified as non-responder, as per EULAR criteria for response, than those who presented early. This is comparable to what is described in the literature. In a study including 487 patients with early RA, symptom duration of 1 year, all were treated with methotrexate monotherapy. The investigator found that long symptom duration decreases the likelihood of EULAR response in methotrexate-naive ERA patients.[15] Similarly, in another multicenter study, included 1,795 patients with arthritis for <12 months of different etiology, of which 711 patients were diagnosed to have early RA. A shorter time lag between symptom onset and initiation of treatment was important determinants of achieving EULAR and ACR remission criteria.[16]

We have shown that in patients with early RA, female gender, ACPA positive and DAS28 at initial presentation were important predictors of DAS28 after 2 years of follow-up. Indeed, several studies have shown a strong association between female gender and adverse clinical outcomes in patients with early RA.[15],[17],[18],[19],[20],[21],[22] Probably, this reflects considerable differences in the measures between genders, including normal ESR levels, which tend to be slightly higher in females than males.[23] Furthermore, women report more symptoms and poorer scores on most questionnaires,[24] including pain scores.[25]

DAS28 at baseline was found to be a predictor of clinical outcomes in patients with early RA and in established RA.[20],[22],[26] This is in line with our findings. However, others have described that good EULAR response to treatment at 6 months is a stronger predictor of clinical and radiographic outcome than DAS28 at baseline at the end of 5-year follow-up.[27]

ACPA positive was a predictor of DAS28 after 2 years of follow-up in our cohort. This is in correlation with a 2-year prospective study that included 105 patients with early RA (disease duration<2 years), who underwent the same structured therapeutic protocol including DMARDs in a step-up strategy; ACPA positive and female gender were found to be most important predictors of radiographic progression at the end of follow-up period. Interesting, DAS28 at baseline did not influence the radiographic damage after 2 years probably due to the tight control exhibited in this study with target to achieve ACR50, and the use of glucocorticoid therapy was left to clinical judgement.[22]

Although rheumatoid factor was described to be a strong predictor of radiographic damage in patients with early RA, it did influence DAS28 at the end of 5-year follow-up.[27] Several studies, like our study, reported an insignificant association between rheumatoid factor positivity and adverse clinical outcome in patients with early RA.[18],[20] In fact, some have found that a negative rheumatoid factor is an independent predictor of remission in patients with RA.[28]

The strengths of this study can be summarised in the following. It is a considerable size study for a single centre in a relatively small population. Data are extracted from standardised electronic medical record completed by rheumatologists in each outpatient visit. Moreover, our study has examined the predictors of achieving clinical targets in patients with early RA, <6 months. However, there are few limitations in the study worth mentioning; patient compliance was not assessed neither the use of corticosteroids was controlled; both might influence the outcome of the study. Furthermore, there was no follow-up radiographic data to demonstrate a possible subclinical difference in outcome between those who presented early and the delayed group.


  Conclusion Top


The delayed presentation to rheumatologist adversely affects the clinical outcomes in patients with early RA. Indeed, female gender, DAS28 at baseline and ACPA positivity remain independent predictors of achieving clinical outcomes in patients with ERA.

Ethi cal approval

The study was approved by Dubai Scientific Research Ethics Committee (Ref: DSREC-08/2018_11).

Consent

All participants have orally consented to use their clinical information anonymously for the purpose of this study as per the regulation of Dubai Scientific Research Ethics Committee.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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