Treating rheumatoid arthritis with tumour necrosis factor α blockadeBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7333.312 (Published 09 February 2002) Cite this as: BMJ 2002;324:312
All rapid responses
A possible alternative treatment for rheumatoid arthritis
The editorial “Treating rheumatoid arthritis with tumor necrosis
factor á blockade”1 describes a medical problem for which there is
apparently no satisfactory solution. Although drugs that block tumor
necrosis factor á have proven to be effective treatments, they are also
associated with serious adverse side effects. Without these drugs many
patients will be left to deteriorate and eventually will no longer be able
to work but the very high cost of the treatment limits their use to a
restricted patient population.
One tumor necrosis factor á blocker, not mentioned by the authors of
the editorial, is the antidepressant drug moclobemide. In a small
controlled study, involving human subjects, moclobemide significantly
suppressed the unstimulated production of the proinflammatory cytokine
tumor necrosis factor á.2 The serum concentrations of moclobemide that
were used in the study were comparable to oral dosing in human subjects of
100-200 mg three times per day (within the dosage recommendations of the
manufacturer), 3, Moclobemide is an effective antidepressant drug, when
taken pursuant to that dosage schedule 4
Rheumatoid arthritis is also associated with depression. One 18 year
study of 1290 outpatients with rheumatoid arthritis found a 17.9%
incidence of co-morbid depression. The study also found that co-morbid
depression was an independent risk factor for mortality.5 Moclobemide
overdose, in combination with a serotonergic agent, can cause severe
serotonin toxicity but when taken alone, even in overdose, moclobemide is
a safe drug for the treatment of depression, 6
More research has yet to been done on the use of moclobemide to treat
rheumatoid arthritis before it may be used clinically as a drug for that
purpose. Following a thorough investigation of the matter, I would hope
that it might eventually prove to be a safe, effective and relatively
inexpensive therapeutic alternative.
1. Emery P, Buch M. Treating rheumatoid arthritis with tumour
necrosis factor alpha blockade BMJ 2004; 324: 312-313.
2. Lin A, Song C, Kenis G, Bosmans E, De Jongh R, Scharpe S, Maes
M. The in vitro immunosuppressive effects of moclobemide in healthy
volunteers. J Affect Disord. 2000 Apr; 58(1):69-74.
3. Mayersohn M, Guentert TW. Clinical pharmacokinetics of the
monoamine oxidase-A inhibitor moclobemide. Clin Pharmacokinet. 199;
4. Gagiano CA, Muller FG, Berk M, Joubert PM, Brown RG, Schall R.
Moclobemide twice daily in the treatment of major depressive episode: a
double-blind, multicenter comparison with different three times daily
dosage schedules. J Clin Psychopharmacol. 1995 Aug; 15(4 Suppl 2):4S-9S.
5. Ang DC, Choi M, Kroenke K, Wolfe F. Comorbid depression is an
independent risk factor for mortality in patients with rheumatoid
arthritis. J. Rheumatol. 2005 Jun; 32(6):1013-9.
6. Isbister JK, Hackett LP, Dawson AH, Whyte IM, Smith AJ.
Moclobemide poisoning: toxicokinetics and occurrence of serotonin
toxicity. Br J Clin Pharmacol. 2003; 56(4):441-50.
Competing interests: No competing interests
ECONOMIC APPROPRIATENESS OF THE EXPENDITURE FOR INFLIXIMAB IN RHEUMATOID ARTHRITIS : ANALYSIS OF NATIONAL PRESCRIPTION DATA IN ITALY
The editorial by Emery
and Buch (1) discusses the use of infliximab for rheumatoid arthritis(RA) and addresses the issue of the high cost of this treatment.
In Italy, the association of infliximab and
methotrexate is widely prescribed to patients with RA. To
the data of national expenditure
(EXPEND) for a given drug class per year (or for single pharmacological agent),
an innovative method has recently been proposed that assigns an index of
“economic appropriateness” to the treatment(s) under examination (2-6). This
index is based on the comparison between the health gain theoretically expected
from EXPEND (expected health gain, EHG) according to current cost effectiveness
benchmarks and the amount of health that is thought to be gained in the “real”
patients (real health gain, or RHG). The value of RHG is estimated using both
epidemiological data and evidence-based information. In this rapid response, we
apply this analysis to the use of infliximab in RA.
In the period from 16 December 2002 to 15 December 2003, Euros
37,103,181 have been spent on infliximab in Italy (personal communication by Bruzzone M and
Puca E, Italian Ministry of Health, December 2003). To interpret this value of EXPEND=37.1 million Euros, our analysis
proceeds as shown in Table 1. Using the benchmark Euros 10,000 per life year
gained (or QALY gained), our results indicate that the EHG is 3,710 years,
while the RHG is 1,553 years; hence, these findings suggest that the amount of
health really obtained using infliximab in RA is less than the amount that
would be expected using the benchmark mentioned above (RHG/EHG=0.42). On the
other hand, the two values of EHG and RHG give a ratio slightly higher than 2
(RHG/EHG=2.09) when the benchmark of 50,000 Euros per life year gained is used.
There are several important
limitations in this simplified ranking approach (2). Anyhow, this method
can be a starting point to improve our ability to interpret national
prescription data and, in particular, to identify areas of poor cost-effectiveness (where the decision
of changing the current reimbursement status might be made in some cases on the
basis of “reasonably good” data of economic appropriateness).
Emery P, Buch M. Treating rheumatoid arthritis with tumour necrosis
factor alpha-blockade BMJ 2002; 324: 312-3.
Messori A et al. Spending on
20 Oct 2003
Messori A et al. Economic
appropriateness of the expenditure for coxibs: cost-effectiveness analysis of
national prescription data in Italy. http://bmj.com/cgi/eletters/327/7420/933-b#39700
Santarlasci B. Economic appropriateness of national drug expenditures:
improved estimation of cost-effectiveness ranking for coxibs. http://bmj.com/cgi/eletters/327/7420/933-b#42273
Messori A et al. Economic
appropriateness of the expenditure for alendronate: cost-effectiveness analysis
of national prescription data in Italy. http://bmj.com/cgi/eletters/327/7406/89#40333
Messori A et al. Questionable
cost-effectiveness of statins for primary
prevention of cardiovascular events. http://bmj.com/cgi/eletters/326/7404/1407#34612
Wong JB, Singh G, Kavanaugh A. Estimating the cost-effectiveness of 54
weeks of infliximab for rheumatoid arthritis. Am J Med. 2002 Oct 1;113(5):400-8
HEALTH GAIN (EHG)
HEALTH GAIN (RHG)
EHG (years or QALYs)* = EXPEND /10,000
Nexposed patients = EXPEND/ (COST1DDD x DAYSexpend)
Nbeginners = Nexposedpatients / (DAYStreatment / DAYSexpend)
RHG = N beginners x GAINQALYs
-analysis on infliximab:
EHG = 37,103,181/10,000 = 3,710 years or QALYs
EHG = 37,103,181/50,000 = 742 years or QALYs
Nexposed patients**= 37,103,181/ (21.4 x 365) = 4,750
Nbeginners = 4,750/ [(54 x 7) / (52 x 7)]=4,567
RHG*** = 4,567x 0.34=1,553 QALYs
*This calculation can also be made using the benchmark of Euros 50,000 per life year gained (or QALY
**The COST1DDD = Euros 21.4
***The gain (in QALYs per patient) has
Emery`s and Buch`s editorial about drug treatment of rheumatoid
arthritis states that after ten years 50% of people with the disease no
longer work, most losing their jobs in the first 12 months after diagnosis
(1). However, it is not necessarily rheumatoid arthritis that causes job
loss: it is likely also to be due to the barriers in society that exclude
disabled people from full employment.
I`ve had rheumatoid arthritis for over ten years, and have written
this letter using voice-activated software, originally provided through
the government's Access to Work programme. This provides funding for
equipment and other means of overcoming barriers that would exclude people
from work. Health professionals and employers generally aren`t familiar
with such provision, therefore it`s likely that some people give up their
jobs without knowing about any of the support and funding that is
available, nor about protection afforded them by the Disability
Discrimination Act 1995.
My continued employment is also influenced by the fact that my job
attracts a high salary. Therefore I can pay for what I need to overcome
barriers to employment and to live a full life outside work. For example,
my car has automatic gears and power assisted steering; I can afford
taxis; I live in a city-centre flat with a lift that works; I pay a
cleaner; I eat out a lot.
Tumour necrosis factor alpha blockade costs about £6000-£8000 a year
per patient (1). If every year that money (or even half!) was given
directly to the patient tax-free, I expect that for most, their quality of
life would improve far more substantially than if they take the drugs.
The government recently required every local authority to develop, in
conjunction with health authorities, a Welfare to Work Plan for Disabled
People, to increase their opportunities for employment. In Liverpool, this
was drafted mainly by disabled employees of the local authority, health
service, and voluntary agencies (2). It was informed by work carried out
locally by and with disabled people about the barriers they face in
According to the editorial`s subheading, the drugs discussed could be
only “a small expensive step” (1). A giant leap would be to address the
disabling barriers in society; this approach is increasingly recognised as
important in tackling inequalities faced by disabled people, but health
professionals, the medical profession in particular, are slow to recognise
1. Emery P, Buch M., Treating rheumatoid arthritis with tumour necrosis
factor alpha blockade. British Medical Journal 2002;324:312-3
2. Liverpool City Council, Liverpool Health Authority. Liverpool`s
Joint Investment Plan on Welfare to Work for Disabled People. Liverpool
3. Liverpool Independent/Integrated Living Project. Report to the
joint care planning subgroup for disabled people. Manchester: Greater
Manchester Coalition of Disabled People, 1999
4. Liverpool Association of Disabled People. What disabled people
need to achieve independent and inclusive living. Conference report.
Liverpool March 1999.
5. Carter JM, Markham N. Disability discrimination. British Medical
Competing interests: No competing interests
Juvenile Idiopathic Arthritis affects approximately one in every
thousand children .It varies considerably in its clinical manifestations
and severity .Some patients will not have their disease controlled with
standard treatment including high dose weekly parenteral
methotrexate.These children will require joint surgery including total hip
and knee replacements.Etanercept given twice weekly by subcutaneous
injection is licenced for children with polyarthritis .Infliximab is still
undergoing trials in children.Evidence supports the value of this
treatment and offers a hope of remission for these patients 1).
Guidelines for prescribing biologic therapies in children and young
people with Juvenile Idiopathic Arthritis'was produced by consensus and
approved by the British Paediatric Rheumatology Group (April
2000).Currently many children who fulfil these guidelines are not
receiving Etanercept because of postcode prescribing .NICE is shortly to
publish their appraisal for its use in children.It is not only adults with
Rheumatoid Arthritis but also children who could be benefitting from this
1)Lovell DJ,Giannini EH,Reiff A,Cawkwell GD,Siverman ED,Nocton
JJ,Stein LD,Gedalia A,Ilowite NT,Wallace CA,Whitmore J,Fincki BK
,Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis
.NEJM 2000; 342 763-9 .
convenor British Paediatric Rheumatology Group
(Royal College of Paediatrics and Child Health)
HV has received support in attending 2 International meetings .
Competing interests: No competing interests