There is a perceptual experience that biological agents have improved arthritic arthritis direction so I decided to compare a traditional DMARD ( amethopterin ) to a biological intervention ( Remicade ) . To analyze the advantages and disadvantages of the drugs I have looked at several characteristics, chiefly looking at efficaciousness but besides looking at: cost, method of bringing and safety/side effects of the drug.
Methotrexate an effectual s drug in restricting the redness from arthritic arthritis, it is cost effectual with a low toxicity profile. Infliximab is an anti TNF-? drug which is utile in handling patients who have non responded to DMARDs. It has more side effects and a much greater cost but has been shown to be effectual
Introduction
The purpose of this SSC is to happen the advantages and disadvantages of two commonly used drugs in the intervention of arthritic arthritis. There is a perceptual experience that biological agents have improved arthritic arthritis direction so I decided to compare a traditional DMARD ( disease modifying antirheumatic drug ) to a biological intervention ( although frequently used in concurrence ) . The ground I chose amethopterin was that it is the most normally used DMARD and first line intervention. I chose Remicade ( a TNF-? inhibitor ) because it was one of the first biological interventions to be used.
What is arthritic arthritis?
Rheumatoid Arthritis is a chronic autoimmune status where the organic structure ‘s ain immune and inflammatory response attacks the synovial articulations. It is foremost localised to the synovial membrane but can distribute into the bone and so damage tissue environing the joint such as sinews and ligaments. It causes joint hurting and swelling peculiarly in the custodies and pess, which can take to terrible hurting, disablement and increased mortality.
Within the joint, the synovial membrane becomes inflamed and hyperplasic ( known as a pannus ) . This can occupy and gnaw the bone and articular gristle, due to let go of of enzymes such as Matrix matalloproteinases ( MMPs ) . Blood vass are located in the subintimal country ; 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 synovial membrane there are increased degrees of cytokines, with a laterality of pro inflammatory cytokines including TNF-? , IL-1 and IL-6. TNF-? is thought to be a critical cytokine as it can trip macrophages ( hence more TNF-? produced ) every bit good as impacting the production of other pro inflammatory cytokines such as IL-1. This explains why there has been research in to TNF-? inhibitors for arthritic arthritis and other inflammatory conditions ( Isaacs and Moreland, 2002 ) .
Methotrexate
Methotrexate ( MTX ) is in a category called disease modifying antirheumatic drugs ( DMARDs ) . It is the current first line DMARD in the intervention of active rheumatoid arthritis ; it can be portion of a combination therapy or as a monotherapy. It is ab initio given alongside other DMARDs such as hydoxychloroquine and sulfasalazine within 3 months of continual symptoms. The drug has a typical oncoming of 6-8 hebdomads but can take longer ; glucocorticoids are normally used short term to better symptoms before it takes consequence.
Its mechanism of action in arthritic arthritis is non clear but it is known to suppress Dihydrofolate reductase ( DHFR-enzyme involved in folic acerb metamorphosis ) and decelerate the deaminization of adenosine. Adenosine can assist cut down cytokine production, macrophage activity and neutrophil adhesion ( Waller et al, 2010 ) .
Infliximab
Infliximab is a monoclonal antibody which inhibits tumour mortification factor alpha ( TNF-? ) , given by endovenous extract. It is a chimeral monoclonal antibody, with the Fc part from a human and the Fab part from a mouse. This binds to the TNF-? molecule neutralizing it. It is usually used aboard amethopterin in a combination therapy and unlike other TNF-? inhibitors it is seldom used on its ain ( NICE clinical guidelines 79, February 2009 ) . This is due to the patient bring forthing antibodies against the mouse part of the drug, methotrexate Acts of the Apostless as an immunosuppressant cut downing the production of these antibodies ( Isaacs and Moreland, 2002 ) .
Analysis
To analyze the advantages and disadvantages of the drugs I will be looking at several of their characteristics, chiefly expression at efficaciousness but besides looking at: cost, method of bringing and safety/side effects of the drug. In clinical tests the Paulus standards are frequently used in finding betterment, this is recommended by the American College of Rheumatology ( ACR ) . The standards are: figure of stamp and conceited articulation counts, forenoon stiffness, patient appraisal of disease activity, physician appraisal of disease activity and erythrocyte deposit rate ( ESR ) . A Paulus 20 is a 20 % betterment in 4/6 standards, like wise for Paulus 50. C-reactive protein degrees can be used in the measuring of redness ( John Hopkins Arthritis Centre, 2011 ) .
Efficacy
Infliximab seems to demo a decrease in symptoms in patients who have an uncomplete response to methotrexate. In a survey by Maini et Al ( 1998 ) Remicade was trialled in 3 different doses ( 1mg/kg, 3mg/kg and 10mg/kg ) . These were with and without low doses of amethopterin every bit good as a control group on a placebo and a low dosage of amethopterin ( 7.5-15 mg/week ) . Patients were eligible for the survey if they were demoing opposition to methotrexate or had a disease flair.
There was a 70-90 % decrease in swollen and stamp articulation counts and C-reactive protein degrees for the whole 26 hebdomads in patients having 10mg/kg and amethopterin. One country that was of involvement was how good the intervention would be tolerated. It was found that there were stable blood degrees of the drug in all groups except in the 1mg/kg of Remicade, without amethopterin, were antibodies against the drug were found in about 50 % of patients.
The information shows a clear indicant that Remicade, particularly in doses of 10mg/kg with amethopterin, can cut down the symptoms of active rheumatoid arthritis. The survey tried to extinguish other factors, for illustration other DMARDs were stopped 4 hebdomads in progress of the test. By holding the survey as a dual blind randomised control test it aimed to cut down prejudice. However patients used were from a narrow cultural and gender mix, with a mean of 73 % female in each group ( 67-86 % scope ) and 96 % white ( 93-100 % ) . It besides analysed short term efficaciousness so it is non clear if patients would develop a opposition to the chimeric antibody longer term.
A Cochrane reappraisal article ( Singh et al, 2009 ) found that Remicade achieved a Paulus 50 consequence in 43 of 100 patients compared to 21 of 100 patients on a placebo ; this was a 22 % betterment. It was comparing the effectivity of different biological interventions and shows the benefit of Remicade over a placebo. It besides shows Remicade has a similar efficaciousness to other biologics. However this survey compares many tests which had single parametric quantities and aims so it is non easy to definitively govern on their effectivity.
The efficaciousness of amethopterin was examined in a meta-analysis survey in a Cochrane reappraisal ( Suarez-Almazor et Al, 1998 ) which concluded that there was important grounds for amethopterin usage in the short term for arthritic arthritis patients. However the survey could non analyze the long term efficaciousness of the drug.
A long term retrospective survey ( Varatharajan et al, 2009 ) of 518 patients it was found that 247 patients, 47.5 % went into complete remittal on amethopterin ( but frequently in combination therapies ) . Patients who went into remittal were on the drug for longer on mean 6.8 old ages compared 5.4 old ages for those non in complete remittal to. In pattern in the USA more than 50 % of patients continue to take amethopterin longer than 5 old ages, this is higher than other DMARDs ( Isaacs and Moreland, 2002 ) .
Safety/Side effects
The safety and side effects of the drugs are an of import consideration for both doctors and patients. Infliximab can do symptoms such as: sickness, concern, raised blood force per unit area and abdominal hurting. As it is given by a transfusion it can hold extra side effects including joint and musculus hurting, pruitis, febrility, roseola. It works by curtailing the immune system so patients can go more susceptible to a higher frequence and badness of infections ( Drugs.com ) . One manner of analyzing the impact of side effects is the sum if people who drop out of research surveies due to them. A survey ( 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 besides been thought to take to higher degrees of hospitalization and mortality from congestive bosom failure ( CHF ) . In a study for the European Agency for the Evaluation of Medicinal Products ( EMEA ) , patients who had moderate to severe CHF were given Remicades. 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 non started on Remicade, and discontinued if patients develop declining CHF ( EMEA, 2001 ) .
Methotrexate
Infliximab
Hepatic harm
Nausea
Gastrointestinal jobs: abdominal hurting, diarrhea, oral cavity ulcers
Fatigue
Pneumonic jobs: Pneumonitis, fibrosis, cough
Rash
Hair loss
More terrible infections peculiarly in the respiratory piece of land
More terrible infections peculiarly in the respiratory piece of land
Fatigue
Fever
Cardiopulmonary jobs: high blood pressure, dyspnea, thorax hurting, irregular pulse
Rash
Nausea
Oedema
Seizures
Back hurting
Methotrexate has a comparatively low toxicity profile but does hold some serious side effects such as hepatic harm and pneumonic jobs ( peculiarly pneumonitis ) . As it is non given as an extract ( normally ) there is none of the transfusion side effects. Folic acerb addendums should be prescribed to patients as it helps cut down the harm to the GI piece of land and hepatic enzymes.
In a long term retrospective survey ( Varatharajan et al, 2009 ) of 790 patients, 93 withdrew from amethopterin intervention due inauspicious effects ( 11.8 % ) . The average clip for patients to be on the intervention was 9.2 old ages, with an mean dosage of 17.5mg/week. The survey was analyzing long term effects by looking retrospectively over an 18 twelvemonth period. It provides critical information which can merely be obtained in clinical pattern non in a randomized control test. Whilst the bulk of the patients had rheumatoid arthritis ( 518 ) it was non sole with patients with other conditions besides in the survey. This may hold deductions for the consequences as it does non take into history the consequence of other medicines and conditions.
Cost
Infliximab is a monoclonal antibody so it requires expensive engineering and installations to bring forth. After initial doses at 0, 2 and 6 hebdomads the drug is infused routinely every 8 hebdomads. This adds to the cost, as the drug needs to be administered in a infirmary under supervising. In a study into costs of tumour mortification factor inhibitor usage ( Harrison, 2010 ) it was found that Remicade had higher costs than Etanercept and Adalimumab ( other biological agents ) ; this was due to the cost of patients coming in to hospital for their extracts. The average cost of Remicade with all costs accounted for was $ 25,943 for new patients and $ 30,018 for go oning patients per twelvemonth.
As Methotrexate is administered by unwritten tablet at place there are no extra costs of coming into infirmary. It can besides be given by injection ( subcutaneously, intramuscularly, and intravenously ) which require a wellness attention professional. A 20mg/week dose of amethopterin costs $ 638 per twelvemonth ; it can decelerate the disease 20-30 % at a cost of $ 665 ( Choi et al, 2000 ) . The cost and effectivity are the grounds why it is frequently prescribed by rheumatologists, unless a patient has an implicit in status e.g. hepatic harm.
Discussion
Methotrexate is an highly utile drug in handling arthritic arthritis. It has been used normally in the intervention of it since the 1980s ; as such there is long term grounds for both its efficaciousness and safety ( low toxicity profile ) . This is an of import factor in drugs for chronic conditions as patients may necessitate to be on them for a long period of clip. Bing in an unwritten tablet it is easier for a patient to take so other drugs. Another advantage of amethopterin is its cost ; at merely $ 638 for 20mg/week it is well cheaper than any biological interventions.
Due to its low toxicity profile it can be used alongside other DMARDs such as sulfasalazine and hydoxychloroquine in combination therapy. If this proves uneffective amethopterin is usually used aboard biological interventions.
However amethopterin can do serious side effects, particularly in patients with preexistent liver and GI harm. As many drug protocols are based around amethopterin this can intend that patients have to be put on drugs with higher toxicity profiles earlier in their intervention. It can besides take a long clip to hold an consequence in patients ; glucocorticoids can be used short term to pull off the hurting.
Infliximab has proved to be an effectual intervention in patients who do non react to DMARD combination therapy. It is recommended for usage alongside amethopterin if the disease has non responded to 2 tests of DMARDs or there is a important disease flair ( NICE guidelines ) . Tender and conceited articulation counts were reduced by 70-90 % ( 10mg/kg ) , when used in concurrence with amethopterin ( Maini, 1998 ) . Despite its effectivity it is a really expensive drug so would be used after DMARD therapy had been tried. Infliximab can hold serious side effects which can do patients stop the intervention. The extract is besides clip devouring and an incommodiousness for the patient, and an extra disbursal for the infirmary. This makes it one of the more expensive drugs in rheumatoid arthritis attention ( Harrison, 2010 ) .
Infliximab was one of the first biological interventions available, so there are more surveies into its effects than other biological agents. However it still takes old ages for the information from clinicians to be collaborated to happen long term effects. How long it takes patients to develop opposition to the drug is one of the purposes for future research.
Text Mentions
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Choi HK, Seeger JD, Kuntz KM ( 2000 ) . A cost effectual analysis of intervention options for patients with methotrexate-resistant rheumatoid arthritis. Arthritis and Rheumatism vol.43 pp2316-2327
Drugs.com ( 2011 ) , side effects of Remicade & A ; lt ; hypertext transfer protocol: //www.drugs.com/sfx/infliximab-side-effects.html & A ; gt ; ( Accessed 23/3/11 )
European Agency for the Evaluation of Medicinal Products ( EMEA ) . Public statement on Remicade ; increased incidence of mortality and hospitalization for declining bosom failure ( 2001 ) .
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