Rheumatoid arthritis (RA) is a common condition, familiar to virtually all physicians irrespective of specialty. Recent decades have seen revolutionary changes in our understanding of the disease pathophysiology and, therefore, treatment options. This review will focus particularly on treatment of moderate-to-severe disease, which can be complex, involving various synthetic and biological disease-modifying anti-rheumatic drugs (DMARDs).

Pathophysiology

The pathophysiology of RA is complex, involving several inflammatory cascades. Key to the process is over-production of tumour necrosis factor (TNF) and subsequently cytokines such as interleukin-6 (IL-6).¹ This serves to drive inflammation and joint destruction.²

The majority of patients with RA will have serological evidence of autoantibodies. That classically associated with the condition is rheumatoid factor. The importance of antibodies against cyclic citrullinated peptide (anti-CCP) is increasingly recognised. They have a high positive predictive value for the development of RA in asymptomatic individuals and those with undifferentiated arthritis.³ They are also associated with poor radiographic and functional outcomes.⁴

Natural history/epidemiology

Studies demonstrating a fall in the incidence of RA have been replicated in numerous populations.^5,6 This fall in incidence appears to be paralleled by a fall in disease severity and progression.⁷ Despite these encouraging studies, the burden imposed by RA should not be underestimated. 

In recent years over one-third of patients with RA continue to report work disability because of their condition.⁸ It is worth stating that the condition is not uncommon, affecting 1.16% of women in the UK and 0.44% of men.⁹

Clinical features, diagnosis and grading of disease severity

The predominant clinical features are joint swelling, tenderness and morning stiffness. Extra-articular manifestations are legion, including cardiovascular, pulmonary, neurological and vasculitic changes. Initial diagnosis can be performed objectively using the 2010 ACR-EULAR criteria.¹⁰ 

This classification examines four categories, namely joint involvement, serology, presence of acute phase reactants and duration of symptoms. A score of ≥ 6/10 is needed for classification of a patient as having definite RA. 

Once a diagnosis has been made, several objective measures exist with which the physician can evaluate disease severity. 

Among the most commonly used and extensively valuated are the disease activity score and subsequently developed disease activity score 28 (DAS28). The DAS28 consists of a 28 tender joint count, 28 swollen joint count, ESR and general health assessment on a visual analogue scale. Level of disease activity can be interpreted as low (DAS28 ≤ 3.2), moderate (3.2 ≤ DAS28 ≤ 5.1) or severe (DAS28 > 5.1). A DAS28 < 2.6 is stated to correspond to remission.¹¹

Treatment

Irrespective of disease severity, there are a number of general management principles which should be applied to all individuals with RA. Appropriate treatment comprises the timely use of various synthetic and biological DMARDs, glucocorticoids, NSAIDs and analgesic agents. 

Broadly speaking, synthetic DMARDs should be initiated as soon as the diagnosis of RA is made. Early intervention with such agents is essential as delay is associated with comparatively poor outcomes.¹² The EULAR group recommends methotrexate as the initial DMARD of choice in all patients with RA.¹³ The efficacy of methotrexate is long established.¹⁴ 

Administration is once weekly and a typical starting dose in the individual with severe disease would likely be 15mg. Dose may be titrated upward in the individual with continued high disease activity to a usual maximum of 25mg per week. Practical considerations include the necessity to monitor for lung, liver and bone marrow toxicity.¹⁵ 

Persistent moderate-to-severe disease necessitates the addition of a biological agent (usually a TNF inhibitor). 

This has proven to be more efficacious than addition of sulfasalazine and hydroxychloroquine in individuals who fail to reach low levels of disease activity with three months of methotrexate monotherapy.¹⁶ These agents carry a high risk of tuberculosis (TB) reactivation and therefore pre-treatment TB screening is required. 

The risk of TB reactivation is three to fourfold higher in patients receiving infliximab or adalimumab than those receiving etanercept.¹⁷ A number of studies examining the role of TNF inhibitors in early RA are ongoing but evidence remains insufficient to alter current practice as outlined above.

In the event that disease activity remains high, EULAR recommends initiation of an alternative biological agent, typically an alternative TNF inhibitor, with or without a synthetic DMARD.¹³ In the event of failure, treatment with agents such as abatacept, rituximab and tocilizumab is indicated. These drugs have different mechanisms of action, interacting with T-cells, B-cells, and IL6 receptors, respectively.

It is important to note that glucocorticoids have an important role in conjunction with stepwise DMARD therapy as outlined above. They are particularly useful as a bridging measure while awaiting therapeutic response from a DMARD. Medium-to-long-term use has traditionally been discouraged given the myriad of associated side-effects.

In cases of refractory RA, it may rarely be necessary to resort to agents such as azathioprine, cyclosporin A or cyclophosphamide. The latter is rarely used due to concerns regarding toxicities including haemorrhagic cystitis, nausea, alopecia, thrombocytopenia and leucopenia.¹⁸

Conclusion

Rheumatoid arthritis continues to impose a significant burden on affected patients despite evidence to suggest that the condition may be, broadly speaking, in recession. Precise objective criteria exist for the purposes of diagnosis and assessment of disease severity. 

Management is based on synthetic and biological DMARDS, the repertoire of which continues to grow. We await new drug targets as pathophysiological advances are brought from bench to bedside.

References

1. Maini RN, Taylor PC, Paleolog E et al. Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the pathophysiology of rheumatoid arthritis. Ann Rheum Dis 1999; 58(1): I56-1 60
2. Choy E. Interleukin 6 receptor as a target for the treatment of rheumatoid arthritis. Ann Rheum Dis 2003; 62(2): ii686-9
3. van der Linden MP, van der Woude D, Ioan-Facsinay A et al. Value of anti-modified citrullinated vimentin and third-generation anti-cyclic citrullinated peptide compared with second-generation anti-cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis. Arthritis Rheum 2009; 60(8): 2232-2241
4. Quinn MA, Gough AK, Green MJ et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford) 2006; 45(4): 478-480
5. Doran MF, Pond GR, Crowson CS et al. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002; 46(3): 625-631
6. Shichikawa K, Inoue K, Hirota S et al. Changes in the incidence and prevalence of rheumatoid arthritis in Kamitonda, Wakayama, Japan, 1965-1996. Ann Rheum Dis 1999; 58(12): 751-756
7. Sokka T, Kautiainen H, Häkkinen A et al. Radiographic progression is getting milder in patients with early rheumatoid arthritis. Results of 3 cohorts over 5 years. J Rheumatol 2004; 31(6): 1073-1082
8. Sokka T, Kautiainen H, Pincus T et al. QUEST-RA. Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study. Arthritis Res Ther 2010; 12(2): R42
9. Symmons D, Turner G, Webb R et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford) 2002; 41(7): 793-800
10. Aletaha D, Neogi T, Silman AJ et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9): 2569-2581
11. Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005; 23(5[39]): S93-299 
12. Lard LR, Visser H, Speyer I et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 2001; 111(6): 446-451
13. Smolen JS, Landewé R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69(6): 964-975
14. Weinblatt ME, Coblyn JS, Fox DA et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985; 312(13): 818-822
15. Chakravarty K, McDonald H, Pullar T et al; British Society for Rheumatology, British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group; British Association of Dermatologists (BAD). BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology (Oxford) 2008; 47(6): 924-5
16. van Vollenhoven RF, Ernestam S, Geborek P et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 2009; 8: 37
17. Dixon WG, Hyrich KL, Watson KD et al; BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register(BSRBR). Ann Rheum Dis 2010; 69(3): 522-528
18. Suarez-Almazor ME, Belseck E, Shea B et al. Cyclophosphamide for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000; 4: CD001157