Ray Fitzpatrick PhD FRPharmS
Clinical Director of Pharmacy,
Royal Wolverhampton Hospitals NHS Trust
and Professor of Pharmacy,
Rheumatoid arthritis (RA) is an inflammatory disease that exerts its greatest impact on those joints of the body that are lined with a synovium. Therefore, it typically affects the small joints of the hands and feet. The inflammation results in pain and swelling of the joint, loss of muscle around the affected area and subsequently loss of joint function. In addition, as a result of the release of large amounts of proteins driving the inflammatory process, patients also suffer systemic fatigue and flu-like symptoms.
The disease affects between 0.5% and 1% of the population and there are more than 400,000 people with RA in the UK.(1) The considerable morbidity associated with the disease has a significant impact on the lives of patients and represents an enormous cost to the UK economy.
In 1987 the American College of Rheumatology (ACR) published a classification system based on symptoms to aid the diagnosis of RA, as there are no simple biological markers of the disease.(1) The disease activity score (DAS) is an alternative scoring system developed in Europe. It is calculated using a formula that includes counts for tender and swollen joints (53 and 44 joints, respectively), an evaluation of general health by the patient (on a scale of 0 to 100) and a measure of circulating inflammatory markers. DAS28 is similar to DAS above but uses only 28 joints for assessment. A DAS28 score greater than 5.1 is considered to be indicative of high disease activity, between 5.1 and 3.2 of moderate disease activity and less than 3.2 of low disease activity.(1) A patient scoring less than 2.6 is defined as being in remission.
Initial treatment of symptoms of RA is with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). However, NICE recommends that patients be offered a combination of disease-modifying anti-rheumatic drugs (DMARD) and short-term glucocorticoids as soon as possible (and ideally within three months) of the onset of persistent symptoms.(1) The DMARD combination should include Methotrexate and at least one other DMARD. If the disease is still active (DAS 28 score > 5.1) after six months treatment, anti-tumour necrosis factor inhibitors (biologics) may be introduced, usually in combination with methotrexate.
While it is clear that methotrexate is central to the treatment of RA, the use of oral methotrexate is limited in some patients by lack of efficacy owing to poor absorption, and side-effects, typically gastrointestinal tract-related. Once patients have failed oral methotrexate, they are escalated to treatment with a biologic.(1)
Subcutaneous (sc) methotrexate (Metoject) has been licensed since 2007, and offers an alternative treatment for those patients who cannot tolerate, or exhibit poor response to, oral methotrexate. Parenteral methotrexate therapy is clinically superior to oral methotrexate,(2) and with fewer side-effects.(3) These differences result from the improved bioavailability of sc methotrexate compared with the oral formulation.(4–6)
NICE recommends that biologic use be delayed until after failure of methotrexate and at least one other DMARD.(1) Therefore, the option to use sc methotrexate in patients who have failed oral methotrexate and would otherwise proceed to biologic therapy may have significant cost advantages.(7) This paper describes in more detail a pharmacoeconomic model to test this.
Current NICE guidance1 was used to develop the management model using the following principles:
- Biologic therapy, in the form of adalimumab, etanercept or infliximab, should be used in conjunction with methotrexate unless contraindicated.(1)
- Upon efficacy failure of biologic therapy assessed at six months of therapy, patients would be switched to rituximab.(8) All patients would receive the licensed dosage schedule of two 1000mg doses a fortnight apart. Patients suffering an adverse event prior to the six month efficacy assessment are eligible to receive an alternative tumour necrosis factor alpha (TNFα) inhibitor.
- Failure of sc methotrexate will result in the introduction of a biologic, which will be added to existing oral methotrexate therapy, in line with current NICE guidance.(1)
This approach is described in the decision model shown in Figure 1.
Calculation of patient numbers
The current UK population is 62,300,000 and, based on the Office of National Statistics (ONS) population statistics by gender, the model assumed that the UK population is 49.2% male and 50.8% female.(9)
A number of studies in the literature have attempted to calculate the incidence of RA in various countries around the world, including the UK. Data from one U.K study(10) estimated the incidence as 54.0 per 100,000 in women and 24.5 per 100,000 in men and were used in the analysis (Table 1). It was assumed that only 95% of new RA patients would receive oral methotrexate therapy, as it will be contraindicated in approximately 5% of patients.
All patients of a child-bearing age were excluded from the estimates as per the special product characteristics for methotrexate. The study calculating the incidence of RA in the UK showed that 13.34% of men and 26.84% of women diagnosed with RA are aged between 15–44 years.(10) Applying this to the ONS population statistics gave an estimate of just over 19,000 patients eligible to receive methotrexate per year (Table 1).
It was then necessary to estimate the number of these patients who were likely to fail on oral methotrexate, in order to apply the decision model in Figure 1.
Several studies were identified that reported rates of oral methotrexate discontinuation. However, these rates varied greatly, depending on the patient types being studied and the study design. Therefore, available data from a systematic review(11) and meta-analysis(12) were combined to provide an overall estimate of oral methotrexate failure rates.
Based on these results, the model used a figure of 21% to estimate the number of newly diagnosed patients who will fail oral methotrexate per year, which, when applied to the final numbers from Table 1 (19,007), gives a figure of 3991 patients. However, NICE guidelines recommend that only patients with a DAS baseline of >5.1 are eligible for biologic therapy. A recent paper comparing the efficacy of parenteral methotrexate in patients who had failed oral methotrexate with those continuing to take oral methotrexate found that 76% of patients on parenteral methotrexate had DAS28 scores of >5.1, which would make them eligible to receive a biologic.(13) Therefore, applying this proportion of 76% to the 3991 patients gives a population of 3033 patients where the decision model described in Figure 1 could be applied.
The costs for the various treatment options were then calculated for a single patient per year. The costs of the medicines were calculated using British National Formulary basic NHS costs plus VAT (as these are generally hospital-only medicines). For methotrexate an average weekly dose of 17.5mg was assumed. The cost of biologic therapy was based on the average cost of adalibumab, etanercept and infliximab. The cost of rituximab was based on a single course of treatment as per NICE guidance.(8) The costs of monitoring were based on NHS outpatient tariff costs for 2012-13.14 These individual patient costs are shown in Table 2.
In order to scale these costs to the patient population identified in Table 1 it was necessary to identify the likely continuation rate with sc methotrexate and biologic therapy.
A review of the literature identified a number of studies where the continuation rate of sc methotrexate was described, which varied from 58% to 96%. The most recent study, which was UK based, estimated a continuation rate of 76%.(13) This rate was used in the analysis. Similarly a review of the literature indicated a continuation rate for biologic therapy of between 70% and 87%. In this case, the figure of 80% was taken, as this was not only the mid range, but a large multicentre trial.(15)
Therefore, the proportion of eligible patients following each arm of the model is shown in Figure 2.
Applying these proportions to the cost per patient for each arm identified in Figure 2 and extrapolating the costs per patient in Table 2 for the UK population of RA patients for whom continued treatment with oral methotrexate is not possible gives an overall cost for each option as shown in Table 3.
The results of the pharmacoeconomic modelling shown in Table 3 demonstrate that starting oral methotrexate failures on sc methotrexate rather than immediately commencing treatment with a biologic is approximately £25m less expensive, even after taking into account that some patients will fail sc methotrexate. This cost difference is larger than demonstrated in an earlier conference report, as the analysis described here includes VAT in the medicines costs and a higher biologic success rate.
Methotrexate is a well-established and important treatment in RA However, some patients fail oral methotrexate, either because of poor absorption or because of side effects (usually gastrointestinal). A frequent approach to treatment failure is to commence these patients on a biologic, which is supported by NICE guidance. However, the availability of sc methotrexate offers an alternative step before commencing biologic therapy. This pharmacoeconomic analysis has demonstrated that, by using sc methotrexate after failure or intolerance to oral methotrexate, but before introducing a biologic, the NHS could save in excess of £25m per year. Given the current pressures on NHS resources this is a treatment option that must be considered.
- NICE Technology Appraisal 130. Adalibumab, etanercept, and infliximab for the treatment of rheumatoid arthritis. National Institute for Health and Clinical Excellence 2007, London UK.
- Braun J et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis. Arthritis Rheum 2008; 58:73–81.
- Rutkowska-Sak L, Rell-Bakalarska M, Lisowska B. Oral vs. subcutaneous low-dose Methotrexate treatment in reducing gastrointestinal side effects. Rheumatologia, 2009;47:207–11.
- Hamilton RA, Kremer JM. Why intramuscular Methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. Br J Rheumatology 1997;36:86–90.
- Jundt JW et al. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 1993;20:1845–9.
- Hoekstra M et al. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol 2004;31:645–8.
- Langleben D. Optimising outcomes and resources in rheumatology: Report on a Satellite Symposium of the EULAR Congress London. Hospital Pharmacy Europe 2011;57:31–3.
- NICE Technology Appraisal 195. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. National Institute for Health and Clinical Excellence, 2010, London UK.
- Office for National Statistics. Mid Year Population Estimates 2010. www.ons.gov.uk
- Wiles N et al. Estimating the incidence of rheumatoid arthritis: Trying to hit a moving target? Arthritis Rheum 1999;42:1339–46.
- Katchamart W et al. Efficacy and toxicity of Methotrexate monotherapy vs methotrexate combination therapy with non-biological disease-modifying anti rheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2009;68:1105–12.
- Choy EH et al. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology 2005;44:1414–21.
- Mainman H et al. When should we use parenteral methotrexate? Clin Rheumatol 2010;29:1093–8.
- Payment by Results NHS outpatient Tariff 2012/13. Department of Health. www.dh.gov.uk.
- Emery P et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active early and moderate to severe rheumatoid arthritis (COMET); A randomised, double blind, parallel treatment trial. Lancet 2008;372:375–82.