Treating Early Rheumatoid Arthritis: A Guideline Comparison

There is a clear consensus that treatment of rheumatoid arthritis (RA) should begin as early as possible. Because good treatment response early in disease can positively affect disease activity, course, and remission,^1,2  and because irreversible joint damage usually occurs within two years of diagnosis, the existence of a “therapeutic window” for early RA has prompted a shift toward prompt and aggressive treatment with disease-modifying antirheumatic drugs (DMARDs).

Responding to criticism that existing (1987) international criteria for RA lacked sensitivity for early disease, in 2010 the American College of Rheumatology and the European League Against Rheumatism (EULAR) jointly issued an updated classification for RA.³ They proposed a new paradigm that emphasized vigilance for patients with a recent onset of symptoms and a high likelihood of developing persistent or erosive RA, who could benefit from early treatment.

However, no general consensus exists as to the definition of “early RA.” As is evident in the brief summary of guidelines below, the definition ranges from six months to five years after the onset of symptoms.  Also, as yet there is no universally accepted “gold standard” for regimens to counteract early RA. 

In general, methotrexate (MTX) is recommended as the anchoring DMARD in one of two approaches:
1.    Step down-therapy: Starting with a combination of DMARDs and/or TNF modifiers and corticosteroids, then tapering off when the disease is controlled
2.    Dose escalation: Treating initially with DMARD monotherapy, rapidly increasing the dose and/or adding other drugs to achieve disease control.

Adjunctive medications, such as analgesics, NSAIDs, corticosteroids, and omega-3 fatty acids, are
commonly used.

The summary below highlights differences in recommendations from English-language sources for the use of DMARDs to treat early RA.

AMERICAN COLLEGE OF RHEUMATOLOGY2012 Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis ⁴ (Issued 2008, updated May 2012)

Early RA defined as symptom duration of less than 6 months.

Other issues:  Focus on screening for tuberculosis and treatment of high-risk patients, such as those with cardiovascular or liver disease.

Treatment recommendations:

DMARD monotherapy for patients with:
•    early RA and low disease activity
•    moderate to high disease activity without poor prognostic features. 

DMARD combination therapy (double or triple) for:
•    early RA with moderate or high disease activity with poor prognostic features. 

An anti-TNF biologic, with or without methotrexate,  or infliximab plus methotrexate for:
•    early RA with high disease activity and poor prognostic features.

EUROPEAN LEAGUE AGAINST RHEUMATISM (EULAR) Recommendations for the Management of RA⁵  (Issued 2010, updated July 2013)

Treatment recommendations:
 
Methotrexate, as monotherapy or in combination with other DMARDs, as first-line therapy.

Biologics in combination with MTX:
•    for patients with poor prognostic factors and poor response after six months of treatment with a synthetic DMARD. 

A second biologic DMARD:
•    for patients with poor response to an initial biologic DMARD. 

Patients with poor response to an initial TNF-inhibitor should receive another TNF-inhibitor, or a biologic with a different mode of action.

Recommendations for the Management of Early Arthritis⁶ (Issued 2006)

Early RA defined not as a distinct entity but a promptness of response: Patients presenting with arthritis of more than one joint should be seen by a rheumatologist within six weeks after the onset of symptoms.

Treatment recommendations: 

Methotrexate as first-line DMARD for:
•    patients at risk of serious and persistent disease.

DMARDS as early as possible for
•    patients at risk of developing persistent or erosive arthritis.   


NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE (NICE), UK
The management of rheumatoid arthritis in adults⁷ (Issued 2009, modified August 2013)

Early RA defined as disease duration of up to 2 years. 

Treatment recommendations:
       
Combination therapy (MTX plus at least one other DMARD) should be the first-line treatment, ideally starting within 3 months of onset of persistent symptoms. 
       
If combination therapy is contraindicated:  DMARD monotherapy, with rapid dose escalation.

SCOTTISH INTERCOLLEGIATE GUIDELINES NETWORK Management of Early RA⁸  (Issued 2000, updated February 2011)

Early RA defined as disease duration of less than 5 years since symptom onset.  

Treatment recommendations:
      
First-line treatment: DMARD monotherapy, preferably MTX or sulfasalazine.
      
Combination DMARDs (not sequential DMARD monotherapy) for patients with poor response to initial DMARD therapy. 

CANADIAN RHEUMATOLOGY ASSOCIATIONRecommendations for Pharmacological Management of Rheumatoid Arthritis with Traditional and Biologic Disease-modifying Antirheumatic Drugs⁹  (Issued 2011)

Early RA not specifically defined. These guidelines address treatment of RA in general.

Treatment recommendations:

Methotrexate preferred for first-line DMARD therapy, as quickly as possible, for:
•    patients with persistent synovitis.

DMARD combination therapy (with MTX as the drug of choice) should be considered for patients who have:
•    inadequate response to monotherapy,
•    moderate to high disease activity,
•    recent-onset disease, or
•    poor prognostic signs. 

Biologics (co-prescription with MTX recommended) for patients with:
•    inadequate responses to DMARD combination or mono-therapy, and
•    persistent moderate to high disease activity despite being at the target dose for at least 3 months.

Anti-TNF therapy should be considered for patients with:
•    early RA or high disease activity and poor prognostic factors after failure of DMARD monotherapy, or
•    patients with DMARD contraindications.

NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL OF AUSTRALIA Clinical Guideline for the Diagnosis and Management of Early RA¹⁰  (Issued 2009)

Early RA defined as less than 2 years since symptom onset.

Treatment recommendations:

Early treatment with DMARDs for RA patients who:
•    have undifferentiated inflammatory arthritis and
•    are at risk of developing persistent and/or erosive arthritis.

Methotrexate is the first-line drug of choice, especially in:
•    moderate to severe RA, or
•    patients with high risk of erosive disease.

DMARD monotherapy is considered appropriate in mild to moderate RA.

References:

REFERENCES:

1. Verstappen SM, Albada-Kuipers GA, Bijlsma JW, et al, for the Utrecht Rheumatoid Arthritis Cohort Study Group (SRU). A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up.Ann Rheum Dis. (2005)64:38-43.
2. Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients.Arthritis Rheum. 2007;56:3226-3235
3. The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis. Available online at http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp
4. Singh JH Furst DE Bharat A et al. American College of Rheumatology. 2012 Update of the 2008 Recommendations for the use of Disease-Modifying Anti-Rheumatic Drugs and Biologics in the treatment of Rheumatoid Arthritis.Arthritis Care Res (2012) 64:625-639
5. European Union League Against Rheumatism. Press release. EULAR Issues Updated Rheumatoid Arthritis (RA) Recommendations. 3 July 2013. Full guideline not yet available at www.eular.org.
6. B Combe, R Landewe, C Lukas, et al.EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)Ann Rheum Dis. 2007 January; 66(1): 34–45
7. National Institute for Clinical Excellence. The management of rheumatoid arthritis in adults. Issued February 2009; updated August 2013.
8. Scottish Intercollegiate Guidelines Network. Management of early rheumatoid arthritis. February 2011. 9. Bykerk VP, Akhavan P, Hazlewood GS, et al.Canadian Rheumatology Association Recommendations for Pharmacological Management of Rheumatoid Arthritis with Traditional and Biologic Disease-modifying Antirheumatic Drugs J Rheumatol. (2012) 39:1559-1582
10. National Health and Medical Research Council (Australia). Clinical guideline for the diagnosis and management of early rheumatoid arthritis (2009)