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| Journal of the New Zealand Medical Association,
28-October-2005, Vol 118 No 1224
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TNF inhibitors for inflammatory arthritis in New
Zealand
Rebecca Grainger, Andrew Harrison
TNF inhibitorsIncreased understanding of the immunopathogenesis of
inflammatory joint disease has recognised tumour necrosis factor (TNF) as a
central cytokine promoting inflammation.3 In humans, TNF antagonists have been
shown to control disease activity in early and established RA, AS, and psoriatic
arthritis. There are currently three TNF antagonists licensed for use in New
Zealand (infliximab, etanercept, and adalimumab) available at a cost of
NZ$20,000 to NZ$30,000 per patient per annum.
InfliximabInfliximab (Remicade®) is a chimeric IgG1 anti–TNF
antibody containing the antigen-binding region of the mouse antibody and the
constant region of the human antibody. Infliximab combined with methotrexate has
been shown to improve disease control in over half of patients with RA failing
methotrexate monotherapy, and to arrest the progression of erosions over 12
months of treatment regardless of the clinical response.4
In AS, infliximab reduced activity of spinal inflammatory
disease by at least 50% in 50% of patients with severe active disease, with
onset of improvement within 2 weeks.5 This benefit was sustained over a 2-year
treatment period.6 Infliximab is given by intravenous infusion: initially 3
infusions over 6 weeks, then at 8-week intervals, with a dose of 3 mg/kg in RA
and 5 mg/kg in AS.
EtanerceptEtanercept (Enbrel®) is a soluble TNF-receptor fused to
the Fc portion of IgG that binds to TNF, preventing interaction with its
receptor. Etanercept, at a dose of 25 mg subcutaneously twice weekly, reduces
arthritis activity in patients with early7 and established RA.8 In AS,
etanercept rapidly reduced both axial and peripheral joint disease;9 and in
psoriatic arthritis, etanercept reduces peripheral arthritis and improves
psoriasis.10
AdalimumabAdalimumab (Humira®)is a recombinant human IgG1
monoclonal antibody that binds to human TNF impairing cytokine binding to its
receptors and lysing cells that express TNF on their surface. In patients with
active RA despite therapy with optimum doses of methotrexate, addition of
adalimumab rapidly reduces disease activity.11 Adalimumab is administered
subcutaneously every other week.
Adverse events and contraindicationsIn clinical trials, all TNF inhibitors have been well
tolerated. Etanercept and adalimumab occasionally cause injection site reactions
which decline over time and are uncommon after 2 months of use.12 Infliximab
infusion can cause fever, nausea, and rash in up to 20% of patients, which is
usually controlled with premedication.13 TNF inhibition has been associated with
the development of serious infectious diseases, both with common Gram-positive
and Gram-negative bacteria and opportunistic organisms such as
Mycobacterium tuberculosis,
Cryptococcus, and
Aspergillus.14 There is a significant
increased risk of reactivation of latent mycobacterial infection (particularly
with infliximab),15 and all patients are screened for latent tuberculosis before
treatment. There are rare reports of demyelinating neurological disease,
pancytopenia, and drug-induced lupus occurring during use of TNF inhibitors.12
TNF inhibition worsens congestive heart failure and there use should be avoided
in patients with class II, III, or IV congestive heart failure. There have been
no studies of safety during pregnancy and therefore adequate contraception
should be used.
TNF inhibitors and PHARMACThe Pharmaceutical Therapeutic Advisory Committee (PTAC)
first considered funding etanercept in August 2002. It recommended that
etanercept be given moderate priority for adult rheumatoid arthritis, which was
regarded as a high cost, high benefit situation, and high priority for juvenile
inflammatory arthritis, which they regarded as a high cost, very high benefit
situation involving many fewer patients.
Etanercept has been funded for juvenile arthritis since
February 2004, but up to now PHARMAC has not funded TNF inhibitors for adult
inflammatory arthritis. This is out of step with countries such as the United
Kingdom, Europe, USA, and Australia where, over the last 7 years, all three TNF
inhibitors have become funded for use in RA, AS, and psoriatic arthritis in
children and adults.
There is considerably more scientific evidence in to support
the use of etanercept in adult RA than in childhood arthritis. The initial PTAC
recommendation for adult RA appears to have been based on projected costs rather
than science. A complaint to the Human Rights Commission that this policy
discriminates on the basis of age has recently been given a favourable
hearing.
In February 2005, PHARMAC published a Hospital
Pharmaceutical Assessment Summary Discussion Document on infliximab and
etanercept for RA.16 In PHARMAC’s view, these drugs are not cost-effective
and fail to achieve an acceptable cost per QALY. Deficiencies in the
methodologies used to reach this conclusion have been highlighted by local and
international commentators. Quite apart from the fact that the RCT-based QALY
calculations are invalidated in clinical practice by entry and exit criteria
that define a high-need high-response target group, the long-term benefit of
erosion reduction is completely overlooked by basing calculations on the
surrogate outcome measure of short-term changes in function. It is particularly
inappropriate to use methotrexate as a comparator given that the proposed
criteria include failure of methotrexate therapy as a prerequisite.
Nevertheless, the document has been circulated to DHBs and, whether intended or
not, has served as a barrier to DHB funding of TNF inhibitors.
Cost-benefit analyses based on randomised control trials
will inevitably underestimate the social and economic gains provided by
successful therapy. It has recently been reported that the cost of arthritis to
the New Zealand economy for 2005 will be NZ$2.35 billion, of which only
one-quarter are health sector costs.1 For the patients who meet the proposed
criteria for funding of a TNF inhibitor, the non-health sector costs are likely
to be proportionately even higher. It seems obvious that targeting this group
with therapy that restores function and arrests joint damage will reap economic
rewards down the line.
In the last few days, PHARMAC has announced a proposal to
list adalimumab on the pharmaceutical schedule. The prospect of TNF inhibitors
for adult RA is greatly welcomed by local rheumatologists and arthritis
patients, but delays in funding have caused considerable harm, and will continue
to do so for New Zealand patients with severe psoriatic arthritis and ankylosing
spondylitis for whom the prospect of relief in the next 2 years is unlikely,
based on the experience with RA.
Author information:
Rebecca Grainger, Senior Rheumatology Registrar, Wellington Regional
Rheumatology Unit, Hutt Hospital, Lower Hutt; Andrew Harrison, Rheumatologist
& Senior Lecturer in Medicine, Wellington School of Medicine & Health
Sciences, Wellington
Correspondence:
Rebecca Grainger, Wellington Regional Rheumatology Unit, Hutt Hospital, Private
Bag 31-907, Lower Hutt. Fax: (04) 570 9231; email: Rebecca.Grainger@huttvalleydhb.org.nz
References:
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