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Nephrol Dial Transplant (2003) 18: Editorial Comments
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Nephrol Dial Transplant (2003) 18: 13–16
Progress in the treatment of rheumatic disease
Angela Gause
Department of Rheumatology, University of Lübeck, D-23538 Lübeck, Germany
Keywords: COX2 inhibitors; IL-1-receptor antagonist;
rheumatic disease; TNFa neutralizing substances
Introduction
The progress in defining the immunological and
inflammatory mechanisms that lead to the progressive
joint destruction in rheumatoid arthritis (RA) [1,2] has
led to the development of new inhibitory drugs. Large
randomized controlled trials have shown the efficacy of
the new treatments and led to the recent approval of
several new drugs by American and European health
authorities. These are the COX2 inhibitors rofecoxib
and celecoxib, the anti-metabolite leflunomide, and the
‘biologicals’, the TNFa neutralizing substances etanercept and infliximab and the IL1-receptor antagonist
anakinra. At the same time, epidemiological investigations have started to describe the socio-economic
consequences of inflammatory joint diseases, which
often start at a young age and lead to retirement in
50% of the patients in the initial 3 years of the disease
Correspondence and offprint requests to: Angela Gause, Department
of Rheumatology, University of Lübeck, Ratzeburger Allee 160,
D-23538 Lübeck, Germany. Email: [email protected]
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[3]. Analysing the outcome of patients with RA,
responsive or not to methotrexate (MTX) treatment,
it could be shown that compared with age-matched
healthy persons, patients with RA without efficient
treatment have a )4-fold increased standardized
mortality ratio. This is reduced to 1.5-fold by MTX
and probably other efficient treatments [4]. For the
evaluation of the patient before and during treatment,
the DAS28 (disease activity score) has been developed
as a standardized evaluation instrument using the
swollen and tender joint count of 28 joints, the serologic inflammation and the patients self assessment of
pain [5]. Since the nephrologist will see many patients
with rheumatic disorders, it is useful to stay updated
on recent progress in rheumatology.
Cox2 inhibitors in the treatment of rheumatic disease
Selective COX2 inhibitors have been developed with
the aim to treat pain and swelling by inflammation
efficiently and without the side effects, especially at the
gastrointestinal tract, seen with standard non-steroidal
anti-rheumatic (NSAR) drugs. For rofecoxib as well as
for celecoxib, a 50% reduction of the risks for bleeding
of the upper gastrointestinal tract has been shown for
large cohorts. Peripheral oedema, decreased renal
2003 European Renal Association–European Dialysis and Transplant Association
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Nephrol Dial Transplant (2003) 18: Editorial Comments
Fig. 1. Simplified overview of RA therapy in 2002. The drug of choice for erosive RA is MTX, further steps in the case of persistent activity
are ‘triple’ therapy in combination with SSZ and HCQ. Further combinations are MTX with CyA, MTX with LFN, MTX with TNFa
antagonists or with the IL1-receptor antagonist. In the refractory patients, therapy with cyclophosphamide and newer approaches with
autologous stem cell transplantation (ASCT), immuno-adsorption or combination of biologicals are possible. Indications and controls should
be guided by an experienced rheumatologist.
function and cardial insufficiency, however, are also
reported during COX2 inhibitor therapy. For RA the
COX2 inhibitors have a role in the initial phase for
amelioration of arthritis before the definite diagnosis is
established. Especially in patients aged over 60 years,
patients with anti-coagulation and in cases of contraindications against steroids COX2 inhibitors are useful
[6]. In principle, a disease-modifying therapy with the
so-called DMARDs (disease-modifying anti-rheumatic
drugs) or LAARDs (long-acting anti-rheumatic drugs)
is to be instituted in every patient with RA, as soon as
the diagnosis is established. This therapy should be so
effective that glucocorticosteroids (GC) or NSAR are
not necessary. Therefore, the German word ‘Basistherapie’ for the treatment with DMARDs is not a bad
descriptive, because it should be the basis of every
treatment in RA.
patient and has been shown to reduce long-term joint
damage [8]. The dose of prednisolone should be
lowered to -10 mguday as soon as possible and it
should be accompanied by calcium and vitamin D for
prophylaxis of osteoporosis.
If SSZ alone is inefficient, therapy is switched to
MTX. Whenever MTX alone is inefficient it can be
combined with SSZ and HCQ with a significant rate of
improvement without increase in toxicity [9]. A further
efficient combination with MTX is the additional
application of cyclosporine A (CyA) in a dose of
2.5–3 mgukg body weight. The response can already be
expected within 6 weeks, the use of CyA is, however,
limited by its renal toxicity [10].
Leflunomide
Standard therapy and combination therapy of RA
The introduction of MTX into the therapy of RA
has been the most important improvement in antirheumatic therapy in the last 30 years [7]. MTX is the
drug of choice for every patient with the diagnosis
of RA with bone erosions. In early non-erosive RA,
sulfasalazine (SSZ) is efficient and safe; in very mild
forms the anti-malarial hydroxychloroquine (HCQ)
can also be used. A disadvantage of SSZ and HCQ is
that both medications need to be applied for at least
12 weeks before they can be judged as ineffective.
Furthermore, SSZ must often be given in a dose of
3 guday. As long as there are no contraindications
against GC all DMARDs are initially combined with
prednisolone, which targets pain and stiffness of the
As an inhibitor of the de novo pyrimidine synthesis,
leflunomide (LFN) has been shown to block the
proliferation of activated lymphocytes, an additional
inhibitory effect on TNFa production in vitro has been
demonstrated. For the treatment of RA, LFN is
characterized by its fast onset of action after
;4 weeks with further improvement up to 1 year. Its
effect on swollen and tender joint counts and on
radiologic progression has been demonstrated [11,12].
Main side effects are diarrhea, nausea, rash and
alopecia. LFN is a first line drug in patients with
intolerance of MTX and those with renal insufficiency,
because of its main gastrointestinal mode of excretion.
The combination with MTX is possible when liver
function and peripheral blood counts are carefully
monitored.
Nephrol Dial Transplant (2003) 18: Editorial Comments
TNFa neutralizing substances
TNFa has a key function in the inflammatory process
by its action on macrophages for the production of
further proinflammatory cytokines and chemokines,
on endothelial cells for expression of adhesion molecules, on hepatocytes for production of acute phase
reactants, and on fibroblasts and chondrocytes for the
synthesis of growth factors (e.g. VEGF). It leads to
increased activity of matrix metalloproteinases and
decreased collagen production [1,2].
Neutralization of TNFa by the TNF-receptorconstruct etanercept [13,14] as well as the chimeric
monoclonal antibody infliximab [15,16] has profound
effects on all activity parameters of RA with often
extremely fast remission of inflammation and joint
counts. Also, in the long term, the effect on inflammatory activity is sustained and the radiologic
progression as a parameter of joint destruction is
significantly reduced. The rate of infections in patients
with etanercept is not increased compared with the
control group treated with conventional DMARDS in
the clinical trials [17]. An alarming high absolute
number of cases with tuberculosis has been registered
under the treatment with infliximab mainly in Europe
[18]. The tuberculosis occurs mainly in the first
3 months after the start of infliximab treatment and
is thought to be due to reactivation. It is recommended
that an X-ray of the thorax and a purified protein
derivative of tuberculosis (PPD) test are performed
before treatment, and that only negative patients
are treated or when treatment is inevitable INH
prophylaxis is administered.
As anti-TNF therapy is expensive and long-term
toxicities unknown, it is recommended by the German
Society for Rheumatology that besides the firmly
established diagnosis, patients should have been
treated with at least two DMARDS, one of the two
being MTX, with an adequate dose and duration (in
general 6 months).
Extremely positive results have been obtained with
anti-TNF treatment of ankylosing spondylitis and
psoriatic arthritis. A third TNFa neutralizing fully
humanized antibody will be available in the near
future. Etanercept as well as infliximab have been used
successfully in ANCA-associated vasculitis and should
be further investigated for these indications.
Immuno-adsorption
For refractory cases of RA, immuno-adsorption with a
protein A column has been applied with reasonable
success and without major side effects [19]. The use of
this treatment can be offered in desperate cases.
IL-1-receptor antagonist and further perspectives
Since this year, the recombinant IL-1-receptor antagonist anakinra [20] is available as another biological
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treatment option for patients still active under classical
DMARDs. This drug has to be injected every day and
is applied in addition to any other DMARD, mainly
MTX. The most important adverse events are strong
skin reactions at the injection site. Long-term effects
have not yet been reported.
For desperate disease courses the application of
autologous bone marrow transplantation is already
applied, here further controlled studies are justified
[21]. Further therapeutic approaches for the future
imply the application of recombinant IL10, IL4 and
antibodies against CD20 and CD40. Combinations of
the classical DMARDS with new immunosuppressive
drugs as mycophenolate mofetil and rapamycine are
discussed and oral inhibitors of the TNF processing
enzyme [TACE (TNFa-converting-enzyme) inhibitor]
are in development [22,23]. Immunologic approaches
also aim at vaccine development with T-cell receptor or
MHC specific peptides and somatic gene therapy for
local interference with inflammation is being developed
in animal models [2,24]
Conclusions
The modern therapy of inflammatory arthritis (Figure 1)
has improved the prognosis for many patients. For
those (;5%) also unresponsive to modern treatment,
special care and research is necessary [25].
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2003 European Renal Association–European Dialysis and Transplant Association