Journal of Hematology - Supplements - Haematologica

90
pro-drug of mycophenolic acid, which inhibits
purine biosynthesis and the proliferation of B-
and T-lymphocytes. Clinical improvement has
been seen in many mycophenolate mofetil-treated
patients with rheumatoid arthritis who had
been refractory to treatment with a variety of other
disease-modifying anti-rheumatic drugs. 13
The most frequent side-effects of mycophenolate
mofetil are of gastrointestinal type. No
clinically significant nephrotoxicity, hepatotoxicity
or bone marrow toxicity attributable to this
drug has been demonstrated. 13
Another treatment possibility for refractory
rheumatic diseases is combination therapy, for
example methotrexate plus cyclosporine, or
methotrexate plus salazopyrine plus steroids.
O'Dell et al. 14 demonstrated that a combination
of methotrexate and hydroxychloroquine is
more effective than methotrexate alone in adult
rheumatoid arthritis and this enhanced effectiveness
occurred with no increase in toxicity during
the two years of treatment.
Tugwell et al. 15 showed that adults with severe
rheumatoid arthritis and only partial response to
methotrexate experienced a clinically important
improvement after combination therapy with
cyclosporine and methotrexate with substantially
similar side-effects.
Wallace et al. 16 used monthly intravenous pulses
of cyclophosphamide and methylprednisone
to treat four patients with systemic-onset juvenile
idiopathic arthritis that had remained active
despite therapy with combination of methotrexate,
sulfasalazine and hydroxychloroquine. Three
patients achieved remission and all had an
increase in linear growth. Pulsed cyclophosphamide
could be added to methotrexate in
severe, refractory JIA with growth retardation.
The benefits of pulsed compared with oral
cyclophosphamide include: 1) lower total dose
and risk of secondary malignancy; 2) ability to
ensure adequate hydration and drugs that protect
the bladder from hemorrhagic cystitis; 3)
reduced risk of gonadal dysfunction.
In the last few years the pathogenetic studies on
rheumatic inflammatory processes have brought
to light new therapeutic possibilities for severe,
intractable forms of JIA.
Tumor necrosis factor (TNF) is a pro-inflammmatory
cytokine that has an important, complex
role in the pathogenesis of rheumatic diseases.
Two distinct inhibitors of this cytokine have
recently been licensed in USA. Etanercept
(Enbrel, Immmunex, Seattle), a genetically engineered
fusion protein consisting of two identical
chains of the recombinant TNF-receptor p75
monomer fused with the Fc domain of human
IgG1, binds and deactivates TNF 17 and infliximab
(chimeric human-mouse anti TNF-alpha monoclonal
antibody). 18
Weinblat et al. 17 employed etanercept and
methotrexate to treat a group of patients with
adult rheumatoid arthritis not responsive to
methotrexate alone in a double-blind trial. This
combined therapy resulted in a rapid and sustained
improvement and the only adverse effects
associated with etanercept were mild injectionsite
reactions. More recently, Lovell et al. 19 used
this drug in patients with polyarticular JIA who
did not tolerate or had an inadequate response
to methotrexate. In the first part of the study
(open-label study) 74% of children had a good
response to etanercept treatment. In the second
part (double-blind study) 81% of cases who
received placebo relapsed against 28% of patients
who received etanercept. The drug was also effective
in psoriatic arthritis. 20 A combination of
infliximab plus methotrexate was also more effective
than methotrexate alone in patients with
active rheumatoid arthritis who have not previously
responded to methotrexate. 18 This drug
proved effective in an open-label pilot study in
active spondyloarthropathy and in the treatment
of Crohn’s disease. 22
Both these drugs may be able to induce remission
in severe, non-responsive JIA. They are well
tolerated and safe, but the follow-up in the different
studies is too short to establish their ability
to achieve long-term remission and to change
the natural history of this disease, that should be
considered the principal aim of this kind of therapy.
Only a stable remission actually allows a
resumption of growth, a reduction of osteoporosis
and can put a stop to progressive articular
damage.
In our opinion, only after having tried mediumhigh
doses of methotrexate, in some cases associated
with other immunosuppressive drugs
and/or TNF-inhibitors, and when faced with an
inadequate response or with a relapse within a
short time, can it be justified to suggest a bone
marrow transplantation (BMT).
Autologous hemopoietic stem cell transplantation
has been proposed in a consensus report
published by the European League Against Rheumatism
23 as a possible treatment for severe autoimmune
diseases such as rheumatoid arthritis, systemic
sclerosis, and systemic lupus erythematosus.
Only a few pediatric patients have undergone
this treatment, so it is very difficult to decide
when BMT can be proposed to children with
intractable autoimmune diseases, especially in
those with non-fatal inflammatory disorders.
The most important experience is that of Wulffraat
who initially described a small series of four
patients with refractory juvenile chronic arthritis
24 and more recently presented a series of 12
haematologica vol. 85(supplement to n. 11):November 2000