• Conventional DMARDs
• Biological DMARDs
• Regular monitoring essential
• Involving patients
• Insert: Disease modifying arthritis drugs - contraindications, toxicities and monitoring
  
• Case Study 45: DMARDs in rheumatoid arthritis - pdf

Helping patients achieve remission of rheumatoid arthritis

Rheumatoid arthritis is the most common autoimmune disease in Australia. Over 400 000 people, mostly women, are affected.[1] It is a disabling condition that impacts on quality of life and increases mortality, mainly through cardiovascular disease.[1] Around 25% of people may stop working, or have a reduced capacity to work, 6 years after diagnosis.[1]

Primary care practitioners have a role in early referral for treatment (which improves patient outcomes), monitoring disease-modifying antirheumatic drugs (DMARDs) and providing advice to patients on managing their disease.

Early referral for early treatment

Consider referral to a rheumatologist, within 6 weeks of the onset of symptoms, for patients with:

• two or more swollen joints, and/or
• morning stiffness for > 30 minutes, and/or
• involvement of metacarpophalangeal and/or metatarsophalangeal joints.[2]

Joint damage occurs early in the disease and is progressive.[2–4] Patients who are diagnosed and managed earlier have a better prognosis.[2–5]

Joint swelling (synovitis) associated with pain or stiffness is a feature of early arthritis.[2,5] Tenderness of the joint line is insufficient to detect synovitis.[5] Determine the total number of affected hand and foot joints by a 'squeeze test', involving gentle palpation of individual joints (Figure 1).[4,6]

Figure 1: 'Squeeze test' for joints of the hands and feet[4]

Diagnosis may be established when there are at least 4 of 7 features.[7] This may be difficult in early arthritis, because the signs and symptoms vary and may develop over time.[2–4] Referring patients with less severe symptoms may facilitate early intervention by a specialist before the disease progresses.[4]

Box 1: Features suggesting rheumatoid arthritis[5,7]

DMARDs — reduce symptoms and disease progression

Conventional disease-modifying antirheumatic drugs — or DMARDs — (e.g. methotrexate) and the newer, biological DMARDs are the only drug treatments that can minimise or prevent joint damage, preserve function and induce clinical remission (symptom relief, normal inflammatory markers and no joint swelling).[5]

Clinical remission is the treatment goal

Starting DMARDs early improves clinical remission.[2–4] Patients at risk of persistent and/or erosive arthritis should be started on DMARDs as early as possible (Box 2).[2,5]

Figure 2: [3]
(shaded area represents permanent joint damage)

Roberts LJ, et al. Early combination disease modifying antirheumatic drug treatment for rheumatoid arthritis. MJA 2006;184:122–5. © Copyright 2006. The Medical Journal of Australia — reproduced with permission.

Methotrexate — a first-choice DMARD

Use methotrexate in moderate to severe disease, or in patients at risk of persistent and/or erosive arthritis.[2,5,9] Sulfasalazine or hydroxychloroquine may be considered in mild disease.[5]

Methotrexate has similar efficacy to other DMARDs, but has a better long-term benefit–harm profile.[2,10,11] One review of observational and randomised controlled trials found that more patients continued treatment with methotrexate for 5 years than with either sulfasalazine or injectable gold.[12]

Methotrexate makes up over 20% of the medications for rheumatoid arthritis prescribed by GPs.[13] It may be used with other conventional DMARDs. Combining treatment with biological DMARDs can lead to greater reductions in disease activity.

Intensify treatment if clinical remission is not achieved

Combine sulfasalazine, hydroxychloroquine or both with methotrexate.[3,5,11] Consider combination therapy as initial treatment for those with a poorer prognosis.[5] In patients with severe disease, or who have not responded to monotherapy, combining two or more DMARDs improves clinical efficacy compared with a single DMARD.[2,5,15–17]

If initial combination therapy is ineffective or not tolerated, leflunomide may be used alone or with methotrexate.[5,8,11] Leflunomide is as effective as methotrexate in slowing progression of joint damage, but may be less tolerated.[18] If clinical remission is still not achieved, biological DMARDs may be started.

Box 2: Indicators of poorer outcome in rheumatoid arthritis[2,4,5,8]

[a]  Major indicators

Biological DMARDs

Biological DMARDs target pro-inflammatory cytokines that are involved in joint destruction, in particular tumour necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1).[5] There are 4 biological DMARDs available in Australia — etanercept, infliximab and adalimumab (TNF-alpha inhibitors), and anakinra (IL-1 receptor antagonist).

Where do they fit?

Systematic reviews of randomised controlled trials have shown a large effect of biological DMARDs on disease activity compared with placebo.[19–23] This is mainly in patients with severe disease who have not responded to at least one conventional DMARD.[19–23] Combining treatment with methotrexate provides greater efficacy compared with methotrexate alone.[19–23]

There is no direct evidence from randomised controlled trials that biological DMARDs differ in their efficacy. Indirect comparisons suggest that etanercept, infliximab and adalimumab have similar effectiveness, while anakinra may be less effective.[19,23] Choice of treatment depends on patient preference.[24]

Biological DMARDs are generally well tolerated[19–23], but some patients may stop treatment due to adverse effects (e.g. injection site reactions).

PBS eligibility

The PBS listing for biological DMARDs reflects their place in therapy. Patients are only subsidised if they have severe disease (e.g. at least 20 affected joints) and do not respond to, or cannot tolerate, conventional DMARDs.

Regular monitoring is essential — for all DMARDs

Monitor disease activity and drug toxicity to guide choice of and changes in treatment.[2,5] Review patients every 1–3 months, until clinical remission is achieved, for measures of disease activity including:

• number of tender and swollen joints
• duration of morning stiffness
• elevated ESR and CRP levels
• functional status (e.g. activities of daily living).[2,5,9]

Joint damage may be assessed by X-ray every 6–12 months during the first few years.[2]

Maximal response to conventional DMARDs usually occurs within 3 months, but varies depending on the drug (e.g. methotrexate: 1–2 months).[5,14] Biological DMARDs can have a more rapid onset of effect.[14] Drug toxicity is specific for each DMARD. Most conventional DMARDs have an established toxicity profile, but biological DMARDs are new drugs and their long-term risks are unknown. Reports of serious adverse effects are emerging, such as tuberculosis (reactivation and community-acquired), lymphoproliferative disease (e.g. lymphoma), blood dyscrasias, demyelinating disease (e.g. multiple sclerosis, Guillain–Barré syndrome), lupus-like autoimmune disease and precipitation of heart failure.[25–28]

Specific steps to monitor for rare but serious adverse effects are important, because rheumatoid arthritis already predisposes to infection, lymphoma and cardiovascular disease.[8,27]

In rural areas, access to specialists may be limited, so the primary care practitioner may play a greater role in monitoring patients. A management plan should be agreed between the patient, primary care practitioner and specialist.[5]

Involving patients in their management

Rheumatoid arthritis impacts on quality of life and self-management is important for patients.[5] Educational programs, such as the arthritis self-management course (ASMC) reduce pain, fatigue and distress about the disease.[5] The Arthritis Foundation delivers the ASMC in every Australian State and Territory.[5]

Provide an opportunity for patients to ask questions about their disease, and involve them in decisions about choice of treatment.[5] Offer advice on non-pharmacological management, such as exercise and occupational therapy. Information for patients about lifestyle measures and managing rheumatoid arthritis is available from the Arthritis Australia website.

Expert Reviewer

Dr Paul Kubler, Clinical Pharmacologist/Rheumatologist, Royal Brisbane and Women's Hospital, Brisbane

Reviewers

Dr Richard Abbott, General Practitioner
Dr James Best, General Practitioner
A/Prof Nick Buckley, Clinical Pharmacologist, The Canberra Hospital
Ms Jan Donovan, Consumer
Dr John Dowden, Editor, Australian Prescriber
Ms Susan Parker, Head of Medical Affairs, Pfizer Australia
Ms Simone Rossi, Editor, Australian Medicines Handbook

Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been sought from all reviewers.

References

1. Australian Institute of Health and Welfare (AIHW). Arthritis and musculoskeletal conditions in Australia, 2005. Canberra: AIHW, 2005. (accessed 1 August 2006).
2. Combe B, et al. Ann Rheum Dis 2006; published online first: 5 January 2006. doi:10.1136/ard.2005.044354.
3. Roberts LJ, et al. Med J Aust 2006;184:122–5.
4. Emery P, et al. Ann Rheum Dis 2002;61:290–7.
5. Therapeutic Guidelines: Rheumatology, Version 1. 2006.
6. Visser H, et al. Arth Rheum 2002;46:357–65.
7. Arnett FC, et al. Arth Rheum 1988;31:315–24.
8. Prodigy Knowledge. Rheumatoid arthritis. Newcastle (UK): Sowerby Centre for Health Informatics, 2005. (accessed 2 August 2006).
9. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arth Rheum 2002;46:328–46.
10. Emery P, Suarez-Almazor M. Clin Evid 2003;10:1454–76.
11. O'Dell JR. N Engl J Med 2004;350:2591–602.
12. Maetzel A, et al. Rheumatology 2000;39:975–81.
13. BEACH data. Australian General Practice Statistics and Classification Centre, a collaborating unit of the Family Medicine Research Centre, University of Sydney and the Australian Institute of Health and Welfare. August 2006.
14. Australian Medicines Handbook, 2006.
15. O'Dell JR, et al. N Engl J Med 1996;334:1287–91.
16. O'Dell JR, et al. Arth Rheum 2002;46:1164–70.
17. Korpela M, et al. Arth Rheum 2004;50:2072–81.
18. Osiri M, et al. Cochrane Database Syst Rev 2002;(3):CD002047.
19. Gartlehner G, et al. Drug Class Review on Targeted Immune Modulators. Portland: Oregon Health and Science University, 2005. (accessed 9 August 2006).
20. Blumenauer B, et al. Cochrane Database Syst Rev 2002;(3):CD003785.
21. Blumenauer B, et al. Cochrane Database Syst Rev 2003;(3):CD004525.
22. Navarro-Sarabia F, et al. Cochrane Database Syst Rev 2005;(3):CD005113.
23. Clark W, et al. Health Technol Assess 2004;8. (accessed 9 August 2006).
24. Scott D, Kingsley G. N Engl J Med 2006;355:704–12.
25. Keane J, et al. N Engl J Med 2001;345:1098–104.
26. Bongartz T, et al. JAMA 2006;295:2275–85.
27. Lu TY-T, Hill C. Aust Prescr 2006;29:67–70.
28. Shin I-S, et al. Arth Rheum 2006;54:1429–34.

The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.