Treatment paradigms for Rheumatoid Arthritis (RA) have drastically changed in the last two to three decades. Rather than beginning with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), followed by a cautiously progressive addition of Disease-Modifying Antirheumatic Drugs (DMARDs), patients now aggressively begin DMARD therapy as soon as a RA diagnosis has been made. Growing evidence demonstrating improved prognosis and outcomes with the start of DMARD therapy early in the course of symptomatic disease has led to this revolution in RA care. Understanding the effect that starting the right treatment at the early stages of RA has on these outcomes is crucial because the goals in RA management include not just disease remission but also improved functional status, which is closely associated with radiographic joint destruction. The main studies that support the effectiveness and significance of early DMARD initiation in the management of RA will be covered in this review, along with concerns about the definitions and diagnosis of early RA.

Defining Rheumatoid Arthritis

Clear definitions of RA and early are necessary for an accurate diagnosis of the disease. The time period used to define early RA varies widely throughout the literature [1]. It is now obvious that a shorter time interval for classifying early RA is clinically meaningful. Previous intervention studies in early RA have considered early RA as disease duration from 3 months to 3 years; however, with knowledge of improved results with earlier treatment in RA, it is challenging to pinpoint the precise time period that constitutes early RA. Although it may be challenging for rheumatologists to evaluate patients within that 3-month window due to a number of factors, including delays in referring patients with early symptoms of Inflammatory Arthritis (IA) or delays in patients seeking medical attention for their symptoms [2], early RA is now generally accepted to be the onset of joint (typically polyarticular) pain, stiffness, or swelling within the past 3 months [3].

Benefits of Early DMARD Treatment for Response to Therapy in RA

Numerous studies have examined the advantages of treating RA early, including those that looked at how early DMARD treatment affected a patient's ability to respond successfully to medication. A shorter disease duration at the time of treatment initiation was found to be one of the greatest indicators of response to therapy in a meta-analysis of about 1,400 RA patients from 14 randomised controlled trials. Regardless of the individual DMARD used, treatment response in this meta-analysis was defined as achievement of an ACR20 response and 53% of RA patients with disease duration 1 year and only 35-43% of those with disease duration >1 year obtained an ACR20 response [4]. Additionally, subgroup analyses of the adalimumab, etanercept and infliximab studies showed increased ACR20 response rates in patients treated who had a disease duration of 2-3 years as compared to individuals with disease durations of 2-3 years in a 2007 review article by Cush [5].

Reduction of Joint Damage and Improved Function With Early Treatment in RA

The prevention of functional deterioration and disability is a crucial long-term goal in the therapy of RA. Inhibiting progressive joint deterioration is a crucial part of treating RA since function in the disease is closely related to radiographic joint damage [6].

Lard et al. [7] retrospectively compared early and delayed DMARD treatment beginning in an early-RA group in 2001. 109 patients received DMARDs only after many months of an insufficient NSAID response, based on different treatment paradigms at the time of diagnosis. This "delayed" treatment group was compared to 97 patients who began DMARD therapy as soon as possible. In contrast to the delayed DMARD treatment group with a median symptom duration of 4 months, those who started taking DMARDs quickly (within 2 weeks of symptom onset) experienced decreased progression of radiographic joint deterioration from baseline at 2 years of follow-up (p.05).

The absence of long-term follow-up data for joint deterioration makes it difficult to use the currently available data to suggest earlier start of treatment in RA. Most studies had a maximum follow-up of two years, which may be insufficient to fully grasp the effects of early treatment on function and joint deterioration. In order to address this issue, Finckh et al. conducted a meta-analysis in 2006 in which they assessed the degree of radiographic joint deterioration in more than 1,000 RA patients taking DMARDs up to 5 years (median 3 years) following the start of treatment. In comparison to RA patients who began receiving DMARD therapy more than a year after their symptoms began, they discovered that the radiographic joint damage in those treated within a year of the onset of symptoms was reduced by 33%. In addition, a recent study by van der Linden et al. [8] discovered that, compared to those assessed >3 months after the onset of symptoms, clinical assessment by a rheumatologist resulted in a 1.34-fold decrease in the progression of radiographic joint damage at 6 years (median 4 years).

How Should Early RA Be Managed?

It is obvious that early RA patients should be identified and treated, but as was previously mentioned, it can be challenging to determine the best initial treatment plan for a specific patient. While some studies, including the FIN-RACo, BeST and PREMIER trials, suggest that early combination DMARD/biologic therapy is preferable, other studies, including the TEAR and SWEFOT trials, demonstrate that a certain proportion of patients respond favourably to initial therapy with MTX or do not appear to experience significant long-term adverse events if their disease requires additions to initial MTX monotherapy over time. Therefore, it is still unknown what the best initial therapy should be for a patient with early RA. The 2012 changes to the ACR's guidelines for treating RA more officially address this issue and propose starting DMARD monotherapy in any early-RA patient without poor prognostic markers (functional restrictions, extra-articular disease, seropositivity, or erosions). However, they advise starting treatment with combination DMARDs or anti-TNF Medication (MTX) within the first 6 months of disease in early-RA patients with moderate to high disease activity and poor prognostic characteristics. Although they agree that some patients with high disease activity may benefit from DMARD monotherapy, they advise more aggressive treatment due to the existence of unfavourable prognostic variables in order to prevent irreparable joint damage and maintain function over the long term.

This approach to the management of early RA as recommended by the ACR is reasonable; however, there are several caveats to it, which include (1) difficulty in practical clinical experience of identifying and treating patients with “early RA” (and especially of disease of <6-month duration since symptom onset; in particular, a 2011 study of European patients found that the median duration from onset of symptoms to assessment by a rheumatologist was ~24 weeks) [9], (2) limited head-to-head randomized trials comparing early and delayed institution of specific treatment regimens in RA, (3) limitations in excluding spontaneous disease remission and avoiding potential overtreatment with early therapy in using current definitions of RA, especially the 2010 criteria and (4) a limited understanding of the specific prognostic factors and biomarkers that should be used to guide initial therapy of individuals with early RA (e.g., what specific findings would indicate that use of MTX monotherapy is adequate, as compared with MTX plus a biologic agent?). Future studies that, hopefully, will identify the best practises for diagnosing and treating RA patients as soon as symptoms appear as well as techniques (biomarker or otherwise) for determining which particular early treatments are best for specific patients will need to address these issues.

1. van der Helm-van Mil, A.H. et al. “A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: How to guide individual treatment decisions.” Arthritis and Rheumatism, vol. 56, 2007, pp. 433–440.

2. Singh, J.A. et al. “2012 Update of the 2008 American college of rheumatology recommendations for the use of disease-modifying Antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis.” Arthritis Care and Research, vol. 64, 2012, pp. 625–639.

3. Aletaha, D. et al. “Attitudes to early rheumatoid arthritis: changing patterns: Results of a survey.” Annals of the Rheumatic Diseases, vol. 63, 2004, pp. 1269–1275.

4. Anderson, J.J. et al. “Factors predicting response to treatment in rheumatoid arthritis: The importance of disease duration.” Arthritis and Rheumatism, vol. 43, 2000, pp. 22–29.

5. Cush, J.J. “Early rheumatoid arthritis-is there a window of opportunity?” The Journal of Rheumatology Supplement, vol. 80, 2007, pp. 1–7.

6. Smolen, J.S. et al. “Treating rheumatoid arthritis to target: recommendations of an international task force.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 631–637.

7. Lard, L.R. et al. “Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: Comparison of two cohorts who received different treatment strategies.” The American Journal of Medicine, vol. 111, 2001, pp. 446–451.

8. van der Linden, M.P. et al. “Repair of joint erosions in rheumatoid arthritis: prevalence and patient characteristics in a large inception cohort.” Annals of the Rheumatic Diseases, vol. 69, 2010, pp. 727–729.

9. Raza, K. et al. “Delays in assessment of patients with rheumatoid arthritis: variations across Europe.” Annals of the Rheumatic Diseases, vol. 70, 2011, pp. 1822–1825.