Methotrexate And Infliximab Rheumatoid Arthritis
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There is a perception that biological agents have improved rheumatoid arthritis management so I decided to compare a traditional DMARD (methotrexate) to a biological treatment (infliximab). To analyse the advantages and disadvantages of the drugs I have looked at several features, primarily looking at efficacy but also looking at: cost, method of delivery and safety/side effects of the drug.
Methotrexate an effective s drug in limiting the inflammation from rheumatoid arthritis, it is cost effective with a low toxicity profile. Infliximab is an anti TNF-α drug which is useful in treating patients who have not responded to DMARDs. It has more side effects and a much greater cost but has been shown to be effective
The aim of this SSC is to find the advantages and disadvantages of two commonly used drugs in the treatment of rheumatoid arthritis. There is a perception that biological agents have improved rheumatoid arthritis management so I decided to compare a traditional DMARD (disease modifying antirheumatic drug) to a biological treatment (although often used in conjunction). The reason I chose methotrexate was that it is the most commonly used DMARD and first line treatment. I chose infliximab (a TNF-α inhibitor) because it was one of the first biological treatments to be used.
What is rheumatoid arthritis?
Rheumatoid Arthritis is a chronic autoimmune condition where the body's own immune and inflammatory response attacks the synovial joints. It is first localised to the synovial membrane but can spread into the bone and then damage tissue surrounding the joint such as tendons and ligaments. It causes joint pain and swelling particularly in the hands and feet, which can lead to severe pain, disability and increased mortality.
Within the joint, the synovial membrane becomes inflamed and hyperplasic (known as a pannus). This can invade and erode the bone and articular cartilage, due to release of enzymes such as Matrix matalloproteinases (MMPs). Blood vessels are located in the subintimal area; this becomes filled with immune cells - which arrive through diapedesis (Bathon, 2011). As more immune cells congregate, the synovial membrane becomes hyperplasic and neovascularisation occurs.
Within the synovium there are increased levels of cytokines, with a dominance of pro inflammatory cytokines including TNF-α, IL-1 and IL-6. TNF-α is thought to be a vital cytokine as it can activate macrophages (therefore more TNF-α produced) as well as affecting the production of other pro inflammatory cytokines such as IL-1. This explains why there has been research in to TNF-α inhibitors for rheumatoid arthritis and other inflammatory conditions (Isaacs and Moreland, 2002).
Methotrexate (MTX) is in a class called disease modifying antirheumatic drugs (DMARDs). It is the current first line DMARD in the treatment of active rheumatoid arthritis; it can be part of a combination therapy or as a monotherapy. It is initially given alongside other DMARDs such as hydoxychloroquine and sulfasalazine within 3 months of continual symptoms. The drug has a typical onset of 6-8 weeks but can take longer; glucocorticoids are usually used short term to improve symptoms before it takes effect.
Its mechanism of action in rheumatoid arthritis is not clear but it is known to inhibit Dihydrofolate reductase (DHFR-enzyme involved in folic acid metabolism) and slow the deamination of adenosine. Adenosine can help reduce cytokine production, macrophage activity and neutrophil adhesion (Waller et al, 2010).
Infliximab is a monoclonal antibody which inhibits tumour necrosis factor alpha (TNF-α), given by intravenous infusion. It is a chimeric monoclonal antibody, with the Fc region from a human and the Fab region from a mouse. This binds to the TNF-α molecule neutralizing it. It is normally used alongside methotrexate in a combination therapy and unlike other TNF-α inhibitors it is rarely used on its own (NICE clinical guidelines 79, February 2009). This is due to the patient producing antibodies against the mouse portion of the drug, methotrexate acts as an immunosuppressant reducing the production of these antibodies (Isaacs and Moreland, 2002).
To analyse the advantages and disadvantages of the drugs I will be looking at several of their features, primarily look at efficacy but also looking at: cost, method of delivery and safety/side effects of the drug. In clinical trials the Paulus criteria are often used in determining improvement, this is recommended by the American College of Rheumatology (ACR). The criteria are: number of tender and swollen joint counts, morning stiffness, patient assessment of disease activity, physician assessment of disease activity and erythrocyte sedimentation rate (ESR). A Paulus 20 is a 20% improvement in 4/6 criteria, like wise for Paulus 50. C-reactive protein levels can be used in the measurement of inflammation (John Hopkins Arthritis Centre, 2011).
Infliximab seems to show a reduction in symptoms in patients who have an incomplete response to methotrexate. In a study by Maini et al (1998) infliximab was trialled in 3 different doses (1mg/kg, 3mg/kg and 10mg/kg). These were with and without low doses of methotrexate as well as a control group on a placebo and a low dose of methotrexate (7.5-15 mg/week). Patients were eligible for the study if they were showing resistance to methotrexate or had a disease flare.
There was a 70-90% reduction in swollen and tender joint counts and C-reactive protein levels for the whole 26 weeks in patients receiving 10mg/kg and methotrexate. One area that was of interest was how well the treatment would be tolerated. It was found that there were stable blood levels of the drug in all groups except in the 1mg/kg of infliximab, without methotrexate, were antibodies against the drug were found in nearly 50% of patients.
The data shows a clear indication that infliximab, especially in doses of 10mg/kg with methotrexate, can reduce the symptoms of active rheumatoid arthritis. The study tried to eliminate other factors, for example other DMARDs were stopped 4 weeks in advance of the trial. By having the study as a double blind randomised control trial it aimed to reduce bias. However patients used were from a narrow ethnic and gender mix, with a mean of 73% female in each group (67-86% range) and 96% white (93-100%). It also analysed short term efficacy so it is not clear if patients would develop a resistance to the chimeric antibody longer term.
A Cochrane review article (Singh et al, 2009) found that infliximab achieved a Paulus 50 result in 43 of 100 patients compared to 21 of 100 patients on a placebo; this was a 22% improvement. It was comparing the effectiveness of different biological treatments and shows the benefit of infliximab over a placebo. It also shows infliximab has a similar efficacy to other biologics. However this study compares many trials which had individual parameters and objectives so it is not easy to definitively rule on their effectiveness.
The efficacy of methotrexate was examined in a meta-analysis study in a Cochrane review (Suarez-Almazor et al, 1998) which concluded that there was significant evidence for methotrexate use in the short term for rheumatoid arthritis patients. However the study could not analyse the long term efficacy of the drug.
A long term retrospective study (Varatharajan et al, 2009) of 518 patients it was found that 247 patients, 47.5% went into complete remission on methotrexate (but often in combination therapies). Patients who went into remission were on the drug for longer on average 6.8 years compared 5.4 years for those not in complete remission to. In practice in the USA more than 50% of patients continue to take methotrexate longer than 5 years, this is higher than other DMARDs (Isaacs and Moreland, 2002).
The safety and side effects of the drugs are an important consideration for both physicians and patients. Infliximab can cause symptoms such as: nausea, headache, raised blood pressure and abdominal pain. As it is given by a transfusion it can have additional side effects including joint and muscle pain, pruitis, fever, rash. It works by restricting the immune system so patients can become more susceptible to a higher frequency and severity of infections (Drugs.com). One way of analysing the impact of side effects is the amount if people who drop out of research studies due to them. A study (Singh et al, 2009) found that 11 out of 100 dropped out due to the impact of side effects compared to 5 out of 100 on the placebo, this is a 6% difference.
Infliximab has also been thought to lead to higher levels of hospitalization and mortality from congestive heart failure (CHF). In a report for the European Agency for the Evaluation of Medicinal Products (EMEA), patients who had moderate to severe CHF were given infliximab. These were at 2 different doses: 5mg/kg, 10mg/kg or a placebo. There was a higher incidence of hospitalization or mortality in the groups on the drug, 7 out of 101 patients compared to 0 from 49 in the placebo group. As such, patients with CHF are not started on infliximab, and discontinued if patients develop worsening CHF (EMEA, 2001).
Gastrointestinal problems: abdominal pain, diarrhoea, mouth ulcers
Pulmonary problems: Pneumonitis, fibrosis, cough
More severe infections particularly in the respiratory tract
More severe infections particularly in the respiratory tract
Cardiopulmonary problems: hypertension, dyspnoea, chest pain, irregular heartbeat
Methotrexate has a relatively low toxicity profile but does have some serious side effects such as hepatic damage and pulmonary problems (particularly pneumonitis). As it is not given as an infusion (commonly) there is none of the transfusion side effects. Folic acid supplements should be prescribed to patients as it helps reduce the damage to the gastrointestinal tract and hepatic enzymes.
In a long term retrospective study (Varatharajan et al, 2009) of 790 patients, 93 withdrew from methotrexate treatment due adverse effects (11.8%). The median time for patients to be on the treatment was 9.2 years, with an average dose of 17.5mg/week. The study was analysing long term effects by looking retrospectively over an 18 year period. It provides vital information which can only be obtained in clinical practice not in a randomised control trial. Whilst the majority of the patients had rheumatoid arthritis (518) it was not exclusive with patients with other conditions also in the study. This may have implications for the results as it does not take into account the effect of other medications and conditions.
Infliximab is a monoclonal antibody so it requires expensive technology and facilities to produce. After initial doses at 0, 2 and 6 weeks the drug is infused routinely every 8 weeks. This adds to the cost, as the drug needs to be administered in a hospital under supervision. In a report into costs of tumour necrosis factor inhibitor use (Harrison, 2010) it was found that infliximab had higher costs than Etanercept and Adalimumab (other biological agents); this was due to the cost of patients coming in to hospital for their infusions. The mean cost of infliximab with all costs accounted for was $25,943 for new patients and $30,018 for continuing patients per year.
As Methotrexate is administered by oral tablet at home there are no additional costs of coming into hospital. It can also be given by injection (subcutaneously, intramuscularly, and intravenously) which require a health care professional. A 20mg/week dosage of methotrexate costs $638 per year; it can slow the disease 20-30% at a cost of $665(Choi et al, 2000). The cost and effectiveness are the reasons why it is often prescribed by rheumatologists, unless a patient has an underlying condition e.g. hepatic damage.
Methotrexate is an extremely useful drug in treating rheumatoid arthritis. It has been used commonly in the treatment of it since the 1980s; as such there is long term evidence for both its efficacy and safety (low toxicity profile). This is an important factor in drugs for chronic conditions as patients may need to be on them for a long period of time. Being in an oral tablet it is easier for a patient to take then other drugs. Another advantage of methotrexate is its cost; at only $638 for 20mg/week it is substantially cheaper than any biological treatments.
Due to its low toxicity profile it can be used alongside other DMARDs such as sulfasalazine and hydoxychloroquine in combination therapy. If this proves ineffective methotrexate is normally used alongside biological treatments.
However methotrexate can cause serious side effects, especially in patients with pre-existing liver and gastrointestinal damage. As many drug protocols are based around methotrexate this can mean that patients have to be put on drugs with higher toxicity profiles earlier in their treatment. It can also take a long time to have an effect in patients; glucocorticoids can be used short term to manage the pain.
Infliximab has proved to be an effective treatment in patients who do not respond to DMARD combination therapy. It is recommended for use alongside methotrexate if the disease has not responded to 2 trials of DMARDs or there is a significant disease flare (NICE guidelines). Tender and swollen joint counts were reduced by 70-90% (10mg/kg), when used in conjunction with methotrexate (Maini, 1998). Despite its effectiveness it is a very expensive drug so would be used after DMARD therapy had been tried. Infliximab can have serious side effects which can make patients discontinue the treatment. The infusion is also time consuming and an inconvenience for the patient, and an additional expense for the hospital. This makes it one of the more expensive drugs in rheumatoid arthritis care (Harrison, 2010).
Infliximab was one of the first biological treatments available, so there are more studies into its effects than other biological agents. However it still takes years for the data from clinicians to be collaborated to find long term effects. How long it takes patients to develop resistance to the drug is one of the aims for future research.
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