- Methotrexate is the gold standard for rheumatoid arthritis (RA) treatment. It can reduce symptoms, limit disease progression and bring RA into clinical remission.
- There is a small ‘window of opportunity’, possibly as short as 3 months, during which therapy has the most impact. Urgent referral to a rheumatologist, and early diagnosis and treatment initiation is essential.
- Consistent messaging from all healthcare professionals can address patient concerns about methotrexate.
- Structured collaboration between patients, GPs, rheumatologists and other healthcare professionals can support an earlier start to treatment, better adherence and better outcomes.
Methotrexate is the ‘gold-standard’ in treating rheumatoid arthritis, however, the medication is much maligned with respect to potential toxicity. In the majority of RA patients, adverse effects can be managed. As low-dose methotrexate has evidence for preventing joint damage and improving quality of life, adherence should be optimised.
Dr Claire Barrett, rheumatologist and president of the Australian Rheumatology Association (Qld)
Many factors contribute to achieving the best possible outcomes for patients with RA, some of which we will examine in this article. What is a ‘good referral’ from a GP to enable early diagnosis and treatment initiation? What support can a rheumatologist give GPs for the management of RA patients? What are the practice gaps that need closing?
DMARDs = disease-modifying antirheumatic drugs
bDMARDs = biological DMARDs
csDMARDs = conventional synthetic DMARDs
tsDMARDs = targeted synthetic DMARDs
CCP = cyclic citrullinated peptide
CRP = C-reactive protein
ESR = erythrocyte sedimentation rate
MBS = Medicare Benefits Schedule
PBS = Pharmaceutical Benefits Scheme
RA = rheumatoid arthritis
RF = rheumatoid factor
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Low-dose methotrexate for RA
Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are the cornerstone of RA treatment, and can minimise or prevent joint damage and induce clinical remission in RA patients.1 Based on efficacy, safety, cost, ability to individualise dose and method of administration, the csDMARD methotrexate is the recommended first-line DMARD for most patients with RA.2,3 Approximately 40% of patients respond to methotrexate monotherapy (using the American College of Rheumatology 50 response criterion),4 with higher response rates possible in combination with other DMARDs,4 albeit with higher risk of adverse effects.2
The 3-month window of opportunity
Prompt diagnosis of RA and early treatment initiation with disease-modifying therapy are crucial to prevent irreversible joint damage.1 Patients with early arthritis who are referred to a specialist within 3 months of disease onset are more likely to experience drug-free remission, have less joint damage seen on X-ray, and have less need for orthopaedic surgery compared to patients referred at a later stage.5
Guidelines recommend methotrexate for the initial treatment of RA (alternative csDMARDs may be used if methotrexate is contraindicated).1,2,6 Corticosteroids, which provide fast-acting symptomatic relief and have disease-modifying properties,1 can be considered at initiation while awaiting a response to csDMARD therapy. However, due to safety issues with long-term use,1 they should be tapered as rapidly as clinically possible (usually within 3 months, and within 6 months in exceptional cases).1,2,6
Clinical remission is the treatment goal
Guidelines recommend a ‘treat to target’ strategy involving regular assessment and adjustment of therapy, including adding and combining DMARDs, to achieve the target of well-controlled disease.1,2,6-8 The target of RA treatment should be clinical remission, or at least low disease activity in long-standing disease.1,2,6-8 Clinical remission is defined by symptom relief, the normalisation of inflammatory markers and the absence of joint swelling.1 Therapy should be adjusted if there is no improvement 3 months after the start of treatment, or if the target has not been reached after 6 months.2
Using this ‘treat-to-target’ strategy, randomised controlled trials show that remission can be achieved for up to 65% of patients, compared with 10%–20% of those treated less intensively.9,10
Further areas for reflection
The role of corticosteroids in RA management
‘Corticosteroids have a role in RA management as a bridge while a csDMARD such as methotrexate is initiated,’ says Dr Barrett. ‘Many patients, however, remain on corticosteroids long-term, where adverse effects are common. A risk-benefit analysis for the individual patient is vital if long-term use is considered, however in general, long-term use is not advocated.’
Corticosteroids have anti-inflammatory and disease-modifying effects with a rapid onset of action.1 Their use is, however, limited to the short term due to a high risk of serious adverse effects including weight gain, hypertension, diabetes, cataracts and osteoporosis.5 They can be used as a bridging therapy when initiating methotrexate (or other csDMARDs), or for short-term treatment of flare-ups,6 but their use should be gradually reduced and ultimately stopped, usually within 3 months.2
‘One of the questions I am most frequently asked by GPs is how to deal with flare-ups,’ says Dr Barrett.
A flare-up is an episode of increased disease activity beyond normal day-to-day variation.25
‘This is a good example of shared care,’ says Dr Barrett. ‘The patient should have a plan for handling flare-ups including using simple analgesics, NSAIDs and non-pharmacological aids. The GP can assess the situation using history, examination and blood tests. If simple analgesia or NSAIDs are ineffective, prescribing corticosteroids for short-term relief may be indicated. If the disease control does not improve, a request for an earlier rheumatology review to reassess the DMARD treatment regime is vital.’
Subcutaneous methotrexate improves tolerability
Analysis of PBS and MBS data (based on dispensed prescriptions) shows that only a small percentage of patients with RA trial both oral and subcutaneous methotrexate before treatment is escalated. Of patients who started a bDMARD or a tsDMARD for RA between January 2015 and December 2016, only 3.3% had trialled both oral and subcutaneous methotrexate in the previous 2 years. (Calculated from data supplied by the Department of Human Services.)
‘I anticipate that with greater awareness of the potential benefits, and education from practice staff on the correct administration, Australian patients will be afforded the opportunity of the increased efficacy and lower incidence of adverse effects of subcutaneous methotrexate,’ says Dr Barrett.
The optimal dosing strategy for methotrexate starts at 15–20 mg/week, with prompt escalation to 25–30 mg/week, or the highest tolerable dose, and a switch to subcutaneous methotrexate for patients with inadequate response or poor tolerance.22,24,26,27 Subcutaneous methotrexate, with a higher bioavailability and lower variability than oral methotrexate,24 is more effective and associated with fewer gastrointestinal adverse effects.24
Folic acid supplementation and methotrexate dosage timing are further methods to improve the tolerability of methotrexate16 (See ‘Prescribing points for methotrexate’ above).
Maintain methotrexate when intensifying DMARD treatment
If the treatment target is not reached with methotrexate monotherapy, other csDMARDs and subsequently biological DMARDs (bDMARDs) or targeted synthetic DMARDS (tsDMARDs) may be trialled, usually in addition to methotrexate.1,2,6
Despite proven benefits of continuing methotrexate when starting bDMARDs or tsDMARDs, Australian evidence shows that up to a third of patients do not have continuing prescriptions for csDMARDs, including methotrexate.28
There is no consensus on when to begin combination therapy, or on the optimal combination of csDMARDs for patients with RA, but combining csDMARDs is frequently used as a first-line strategy, particularly for those with poor prognostic factors.1,3
The PBS requires that before starting a bDMARD or tsDMARD, patients must have failed a 6-month intensive DMARD treatment trial with a minimum of two csDMARDs, used for a minimum of 3 months each, (including ≥ 20 mg per week of methotrexate, unless contraindicated or not tolerated at required minimum dose).29
All bDMARD and tsDMARD treatments have superior efficacy for the treatment of RA when combined with methotrexate, compared with when used as monotherapy,2 and for some bDMARDS (abatacept, golimumab, infliximab, rituximab), maintaining methotrexate is a PBS requirement for their use.29
Getting the most out of DMARDs for RA
The use of DMARDs, with methotrexate as the backbone of the treatment, has revolutionised RA management, but there is still room to maximise the benefit.
Rheumatologists, GPs, nurses, pharmacists and other allied health professionals can each play a role in improving coordinated care for RA patients. This can help to initiate treatment earlier, keep patients on optimal treatment, and enable regular monitoring to maintain the prolonged benefit of disease-modifying treatment.
Dr Claire Barrett
Rheumatologist, Redcliffe Hospital, Queensland
Senior Lecturer, University of Queensland
Associate Professor Morton Rawlin
General practitioner, Templestone
Adjunct Associate Professor, General Practice, University of Sydney
- Rheumatology Expert Group. Therapeutic Guidelines: Rheumatoid arthritis. West Melbourne: Therapeutic Guidelines Ltd, 2017 (accessed 14 December 2017).
- Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Diseases 2017;76:960-77.
- Wilsdon TD, Hill CL. Managing the drug treatment of rheumatoid arthritis. Aust Prescr 2017;40:51-8.
- Hazlewood GS, Barnabe C, Tomlinson G, et al. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ 2016;353:i1777.
- Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis 2017;76:948-59.
- Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016;68:1-26.
- Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016;75:3-15.
- Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388:2023-38.
- Ledingham J, Snowden N, Ide Z. Diagnosis and early management of inflammatory arthritis. BMJ 2017;358:j3248.
- Bakker MF, Jacobs JW, Verstappen SM, et al. Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis 2007;66 Suppl 3:iii56-60.
- Tay SH, Lim AY, Lee TL, et al. The value of referral letter information in predicting inflammatory arthritis--factors important for effective triaging. Clin Rheumatol 2014;33:409-13.
- Ong SP, Lim LT, Barnsley L, et al. General practitioners' referral letters--Do they meet the expectations of gastroenterologists and rheumatologists? Aust Fam Physician 2006;35:920-2.
- Royal Australian College of General Practitioners. Clinical guideline for the diagnosis and management of early rheumatoid arthritis. South Melbourne: RACGP, 2009 (accessed 12 January 2018).
- Harnden K, Pease C, Jackson A. Rheumatoid arthritis. BMJ 2016;352:i387.
- Arnold MH, Bleasel J, Haq I. Nocebo effects in practice: methotrexate myths and misconceptions. Med J Aust 2016;205:440-2.
- Rheumatology Expert Group. Therapeutic Guidelines: Principles of immunomodulatory drug use for rheumatological diseases in adults. West Melbourne: Therapeutic Guidelines Ltd, 2017 (accessed 15 December 2017).
- Ngian GS, Briggs AM, Ackerman IN, et al. Management of pregnancy in women with rheumatoid arthritis. Med J Aust 2016;204:62-3.
- Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford) 2016;55:1693-7.
- Australian Rheumatology Association. Notes on prescribing medications for rheumatic diseases in pregnancy. Sydney: ARA, 2017 (accessed 9 February 2018).
- Kavanaugh A, Cush JJ, Ahmed MS, et al. Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases. Arthritis Care Res (Hoboken) 2015;67:313-25.
- Australian Rheumatology Association. Patient iInformation on Methotrexate. 2017 (accessed 1 February 2018).
- Claire Barrett. Personal communication, 18 February 2018.
- Australian Rheumatology Association. Notes for prescribers of low dose once weekly methotrexate (MTX). Sydney: ARA, 2017 (accessed 16 January 2018).
- Bianchi G, Caporali R, Todoerti M, et al. Methotrexate and rheumatoid arthritis: Current evidence regarding subcutaneous versus oral routes of administration. Adv Ther 2016;33:369-78.
- Bartlett SJ, Hewlett S, Bingham CO, 3rd, et al. Identifying core domains to assess flare in rheumatoid arthritis: an OMERACT international patient and provider combined Delphi consensus. Ann Rheum Dis 2012;71:1855-60.
- Mouterde G, Baillet A, Gaujoux-Viala C, et al. Optimizing methotrexate therapy in rheumatoid arthritis: a systematic literature review. Joint Bone Spine 2011;78:587-92.
- Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009;68:1094-9.
- Jones G, Nash P, Hall S. Advances in rheumatoid arthritis. Med J Aust 2017;206:221-4.
- Australian Government Department of Human Services. Rheumatoid arthritis Initial PBS authority application form (PB109). 2017 (accessed 20 September 2017).