Diane Langleben, BPharm, MRPharmS
Pharmacuetical writer and editor
“Subcutaneous (SC) methotrexate has a significant place in the treatment of rheumatoid arthritis (RA),” claimed Professor David GI Scott, consultant rheumatologist at Norfolk and Norwich University Hospital in the UK. Professor Scott’s presentation on methotrexate use in the real world was introduced at a EULAR satellite symposium, which focused on optimising clinical outcomes and resources in rheumatology.
Current clinical practice is to start patients on oral methotrexate, and if they exhibit an intolerant or poor response to methotrexate, to switch or add another disease-modifying antirheumatic drug (DMARD) or a biologic, often without trying SC methotrexate. Professor Scott went on to give an interim analysis of the data set from the Methotrexate Evaluation of Norwich Treatment Outcomes in RA study he is conducting. The study, which began in December 2010, involves approximately 300 RA patients who were initially prescribed oral methotrexate, and has been designed to evaluate clinical outcomes following a change in therapy to SC injections. So far, findings have been analysed retrospectively in 150 patients. The data indicate that patients had been on a wide dose range of oral methotrexate: with a mean of 17.7mg in males and 18.2mg in females, taken weekly. Upon switching to the injection, the weekly dose was similar: with a mean of 17.9mg in males and 15.8mg in females. A relative minority were also taking other DMARDs before and after the switch, while some patients went on to take a biologic. Around one third of patients were placed on injections as they suffered an adverse reaction and two-thirds for reasons of efficacy. Professor Scott said that once the switch was made, 80% of patients were still on SC treatment after several years and were doing well.
If SC methotrexate had to be stopped, the main reasons were an adverse reaction (59%) or efficacy (12%); reasons for the remainder discontinuing included patients who were to undergo major surgery, start a family, or wanted to go back to the oral form because of the inconvenience of being injected.
Professor Scott said that there was very little literature comparing oral and SC methotrexate. The conclusion he draws from his study is that a switch from oral to SC is successful. The majority of patients will stay on methotrexate; however, the disease may not be completely controlled and other treatment may be necessary.
Optimising first-line therapy
“At one time RA was regarded, in the majority of patients, as a disease with a poor prognosis,” declared Dr Tuulikki Sokka, head of rheumatology at Jyväsklä Central Hospital in Finland, during her session on optimising first-line therapy in RA treatment and patient care. Although Dr Sokka stated that trials do not reflect what happens in clinical practice, she nevertheless discussed several clinical studies and the Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis database, which have led to current treatment strategies.
In the 1950s and 1960s, studies such as the Bath Cohort, UK, showed that methotrexate was only prescribed for 4% of RA patients. Since then, there has been a steady rise in its popularity; by the 1980s patients in the clinical setting were shown to respond well to methotrexate. In a study conducted by Dr Sokka in Finland, and Dr Pincus in the US, it was shown that in the early 1980s, only 10% of patients were still taking methotrexate after five years in Finland, but 30% in the US. By the 1990s this had risen to 50% in Finland and 80% in the US.
In many European countries at that time, more patients were taking sulfasalazine than methotrexate. However, by the end of that decade this changed, with more patients receiving methotrexate.
From the 1990s to the present day, it has been shown that methotrexate, sulfasalazine, leflunomide and the biologics have equivalent evidence-based efficacy. However, Dr Sokka stressed that this may be inaccurate in terms of clinical care. From her experience, in which patients are given methotrexate, sulfasalazine, hydroxychloroquine and prednisolone on the day of diagnosis, 68% are in remission after two years.
Dr Sokka discussed a few cases from her own clinic: one 44-year-old patient with high rheumatoid factor who was started on 25mg SC methotrexate weekly as well as hydroxychloroquine and prednisolone, went into remission
after three months; an 81-year-old given weekly SC methotrexate 20mg with prednisolone 2.5mg also went into remission after three months.
Dr Sokka invariably recommends methotrexate monotherapy or in combination with other DMARDs. Patients are given SC methotrexate 10mg at the clinic on diagnosis, before there are any erosions, to initiate aggressive treatment of RA. The patient then continues to self-inject methotrexate
from week 2 onwards with a dose of 25mg weekly. In conclusion, Dr Sokka reminded delegates that the aim of RA treatment should be to achieve remission as soon as possible by early and aggressive therapy.
Vascular comorbidity in RA
“Why do people with RA still die prematurely?” was the rhetorical question posed by Professor Markus Gaubitz,
Head of Rheumatology at the University Hospital in Münster, Germany, as an opening to his presentation on the protective effect of methotrexate in patients with RA who also have vascular problems. Professor Gaubitz said that many studies have shown that mortality in RA patients is high; in fact, life expectancy is lower than in people with diabetes. “RA is not only a disease of the joints, but also causes systemic inflammation, leading to, for example, cardiovascular complications,” he continued. Cardiovascular disease (CVD)
is the most prevalent cause of death in RA patients. Professor Gaubitz discussed similarities in the pathogenesis between RA and atherosclerosis in which the same cytokines are present; he suggested that mortality could be linked to an increase in the traditional factors for atherosclerosis as well as the presence of chronic inflammation. Although cardiovascular risk factors are the same as in the general population – for example, age, obesity, hypertension and smoking – RA itself
is a risk factor. Professor Gaubitz said that for this reason it is important to treat intensely; for example, to lower cytokine levels.
He cited a study by Choi et al that followed 1,240 RA patients for almost 20 years. Of the 191 who died during the study, 44% of the deaths were caused by cardiovascular events. In patients treated with methotrexate, the overall mortality rate decreased by 60%; in deaths caused specifically by CVD, mortality decreased by 70%. Professor Gaubitz declared that the findings are convincing evidence of the efficacy of methotrexate.
This observation has been underlined in other studies, including that by Prodanovich et al. Their retrospective cohort study on 7,615 patients with psoriasis and 6,707 with RA looked at the development of CVD and signs of atherosclerosis. In patients treated with methotrexate alone, the incidence of vascular disease was reduced by 17% in RA patients (27% in those with psoriasis). Where therapy also included folic acid, the incidence of vascular disease was reduced by 23% in RA patients (44% in those with psoriasis). Professor Gaubitz recommends the addition of folic acid because it enhances the positive effect on hyperhomocysteinemia, which is also a risk factor for coronary heart disease.
According to Professor Gaubitz, results with methotrexate to reduce CVD are better than with other DMARDs, even if only taken for a short time. The value of treatment with methotrexate was confirmed in a meta-analysis conducted by Westlake et al, published in 2010. The mechanisms involved are not yet fully known but are probably multifactorial. Methotrexate has no significant influence on hypercholesterolaemia, lipid profile, hypertension, or insulin resistance. It may have no direct influence on atherosclerosis but is effective against inflammatory factors; for example, suppression of cytokines endothelial dysfunction and coagulation.
Professor Gaubitz stated that all future studies to evaluate DMARDs should not only focus on joint counts and inflammation parameters but also collect data on CVD factors and the effect on long-term mortality. He also believes that rheumatologists should be aware of the risk of CVD in RA patients; in future, they should consider prescribing drugs such as statins and ACE inhibitors to lower CVD risk.
Professor Gaubitz’s final message was that rigorous suppression of inflammation is a pivotal aim of therapy, and methotrexate reduces CVD events significantly.
Using resources wisely
A pragmatic approach and powerful argument for methotrexate use in RA treatment was put forward by Professor Ray Fitzpatrick, the clinical director of pharmacy at Royal Wolverhampton Hospitals NHS Trust in the UK. Professor Fitzpatrick’s presentation was on optimal use of resource utilisation. He stated that RA has a substantial impact on patients and healthcare systems. In the UK and elsewhere in Europe, governments were looking at ways to make enormous savings in their healthcare budgets. Certainly in the case of RA, Professor Fitzpatrick was able to demonstrate that money could be saved without compromising patient care.
When patients did not respond to oral methotrexate, either alone or with another DMARD, many clinicians then switched straight to a biologic; however, clinicians did not then get the full benefit of methotrexate.
As was shown in a study by Mainman et al, it is better to switch to SC methotrexate if the oral drug fails because of low efficacy or intolerance. The study concludes that SC methotrexate should be considered in all RA patients unresponsive to or unable to tolerate oral therapy before changing to anti-TNF therapy.
Professor Fitzpatrick continued by describing the cost minimisation study he had devised in the UK over a 12-month period, with the objective to model the economic impact of a switch from oral methotrexate to either SC methotrexate (Metoject) or a biologic.
He calculated that the RA population is approximately 24,733 patients (7,500 male and 17,000 female) per year. Not
all would be eligible to take methotrexate; for example, the 5% of patients who have a contraindication to its use and women contemplating pregnancy.
Professor Fitzpatrick excluded all women of childbearing age giving a figure of approximately 18,000 who are eligible to take methotrexate. However, a number of patients would fail to respond or be intolerant of oral methotrexate.
Professor Fitzpatrick explained that he estimated the number by consulting studies showing efficacy dropout rates and intolerability dropout rates, giving the combined dropout rate of 21%, which amounts to 3,800 patients.
Around 2,900 of the 3,800 would be eligible for biologic therapy, according to the National Institute for Health and Clinical Excellence recommendations. Using these figures, the treatment costs were worked out, based on the British National Formulary prices for drugs, and hospital outpatient and monitoring costs based on the standard NHS tariff. This gives a figure of £10,167 (€11,522) per patient per year, assuming
non-responders would be prescribed rituximab.
This is significantly higher than the £3,606 (€4,088) it would cost if patients were switched instead to SC methotrexate, assuming non-responders would then take a biologic. If the saving of £6,561 (€7,439) equivalent per patient in the first year is extrapolated to the whole population that can be prescribed methotrexate, it can be seen that this equates to a potential saving of £19 (€21.5) million per annum.
Professor Fitzpatrick also applied a sensitivity analysis looking at the best-case and worst-case scenarios. For example, he examined the economics if the assumed biologic failure rate was higher than expected, if patients stopped Metoject injections at three months not six months (as assumed for the economic model), or if the Metoject failure rate was not the assumed 26% but better than 12.5%, or worse than 50%. The best-case scenario gives a saving of £28 (€31.7) million and the worst-case still gives a saving of £11 (€12.5) million.
Professor Fitzpatrick concluded: “The study is based on published studies, not numbers that I have just plucked out of the air.
The sensitivity analysis gives us some confidence that the savings are real and there is clear evidence that SC methotrexate, certainly from a cost perspective, is definitely worthwhile trying because it reduces cost of treatment without compromising patient care”.