Less encouraging results were obtained in the French
registry [6], which enrolled 61
patients treated for an average period of 13 months. The rate of treatment
withdrawal for serious side effects was
20%, and a remarkable decrease in the frequency of therapeutic response
between the 3rd and the 12th month of treatment (from 73%
to 39%) was noticed. Other relevant findings were the observation of a number
of severe neurologic and psychiatric adverse events and a significantly lower
efficacy in the subgroup of patients with systemic-onset JIA. The frequency of
clinical response after 6 months (83%) observed in the German study [7], which included 334 patients, was comparable to that
reported in other series. Similarly to the French experience, the therapeutic
effect was poorer in systemic patients. The overall safety profile of
etanercept was satisfactory, although one patient developed a demyelinating
syndrome.
Further evidence that patients with
systemic JIA do not respond as well to etanercept as those with other forms of
JIA was provided by Kimura et al [8], who investigated through a questionnaire survey the
response to etanercept of a cohort of 82 patients with this form of JIA
followed by US pediatric rheumatologists. Forty-five percent of the patients
had a poor response to treatment and an equal percentage experienced one or
more disease flare; 35% discontinued therapy, mostly due to lack of response or
flare. The reasons of the relatively poorer response to etanercept of patients
with systemic JIA have been discussed recently [9]. In a small study, it was suggested that in systemic
patients who do not respond to standard doses the administration of higher
amounts of the drug (0.8 mg/kg/dose or above) may be required to induce
response [10]. Etanercept has been tried with
success in a patient with systemic JIA-associated macrophage activation
syndrome [11]. The rationale for this
intervention came from the demonstration that TNF-α may play a central
role in the pathogenesis of the clinical and laboratory manifestations of this
syndrome. However, there are reports of patients who developed this
complication while taking TNF antagonists [12].
The preliminary results of the controlled
trials with infliximab and adalimumab in JIA, which are ongoing, have been
presented last year during the European Congress of Pediatric Rheumatology and
the American College of Rheumatology meeting. The findings of the first
analyses of the efficacy and safety of the two monoclonal antibodies were not
dissimilar to those obtained with etanercept. The presentation of the final
results of the trials will enable to establish the place of these medications
in the current management of JIA. Recently, the efficacy and safety of
infliximab, in association with methotrexate, have been evaluated in an
open-label, 2-year study in 24 young adults with long-lasting, refractory JIA [13]. After a median treatment duration of 9.1
months, significant improvement was observed in the number of active joints,
pain scores, patient’s and physician’s global assessment of disease status, ESR,
and CRP. The percentage of patients meeting the 20% American College of Rheumatology improvement criteria ranged from 54.2
to 86.7%. Twelve patients (50%) had adverse events, and 5 patients (20.8%)
withdrew. Two patients experienced the transient occurrence of antinuclear
antibodies and low-titer anti-double stranded DNA
antibodies without developing features of systemic lupus erythematosus (SLE).
TNF inhibitors have been used with
encouraging results in juvenile spondyloarthropathies [14-16]. Although evidence is still too
limited to draw definite conclusions, it is likely that these medications will
have a major role in these diseases. The effect of etanercept in
treatment-resistant JIA-associated uveitis is unclear because the few
therapeutic studies have provided conflicting results [17-19]. Furthermore, flares of uveitis during etanercept therapy
in patients who had relapsing uveitis before the institution of treatment have
been observed [16,19].
Following the satisfactory results obtained in chronic arthritides, the
anti-TNF agents have been tested, generally with good results, in several other
rheumatologic conditions refractory to conventional therapies, both in children
and in adults [20]. However, most of
these reports are anecdotal, and confirmation in controlled studies is
warranted. This therapy has been proposed in the TRAPS (TNF receptor
superfamily 1A-associated periodic fever syndrome), which is a hereditary
antinflammatory syndrome due to a specific genetic mutation that may cause a
quantitative or qualitative abnormality of soluble TNF receptor. The resulting
failure to inhibit the cytokine activity, which plays a major role in the
induction of the inflammatory episodes, can be theoretically contrasted by
etanercept, which is an analogue of the soluble physiologic receptor and can,
therefore, compensate its deficiency [21].
Recently, a positive experience with etanercept has been reported in another
antinflammatory condition, the hyperimmunoglobulinemia D and periodic fever
syndrome (HIDS) [22].
In clinical practice, it is important to
consider that the administration of anti-TNF agents has been associated with an
increasing risk of TB infection onset or reactivation. For this reason, an
accurate screening for TB during baseline assessment and a careful monitoring
for the entire duration of treatment are mandatory [23].
Anakinra
Several studies have shown that interleukin (IL)-1 is
a key mediator of inflammation, bone resorption and cartilage destruction,
which are the main determinants of joint damage in chronic arthritis. The
proinflammatory action of IL-1 is contrasted by a natural inhibitor which, when
present in excess, blocks the interaction of the cytokine with its receptor
and, consequently, the transduction of the signal to the effector cells.
Anakinra is a recombinant homolog of the human IL-1 receptor antagonist
(IL-1Ra) that competitively inhibits binding of IL-1 with its receptor [24].
Anakinra has been evaluated in JIA in a non controlled
trial [25]. This study has included 60 patients with polyarthritis who were
treated for 12 weeks with daily subcutaneous injections of 1 mg/Kg/die. At the
end of the treatment period, a significant response was observed in 61%
patients. Anakinra was generally well tolerated and the most frequent adverse
events were injection site reactions. Ten percent of the patients were
discontinued prematurely from treatment. Nevertheless, IL-1 blockade with
recombinant IL-1Ra did not gain much popularity in the treatment of JIA.
Similarly, this approach did not prove to be significantly advantageous over
anti-TNF blockade in adult rheumatoid arthritis, and did not show efficacy in
patients who were failing anti-TNF treatment [26,27].
Recently, however, a number of reports have appeared
regarding the excellent response of patients with the systemic subtype of JIA to
anakinra [28-31]. Most patients cleared symptoms and laboratory abnormalities
within days to week of therapy initiation, and prednisone dose was
significantly tapered or discontinued in all. Many of these patients had failed
etanercept. This effect has been related to an intrinsic dysregulation in the
production of IL-1, which may play a critical role in the pathogenesis of this
condition [31]. Interestingly, IL-Ra therapy has been found to be effective in
patients with refractory adult-onset Still’s disease, which is the adult
equivalent of systemic JIA [32]. The therapeutic effect of anakinra and the
clinical similarities that exist between systemic JIA and autoinflammatory
syndromes (see below) has led to postulate that al least some cases of systemic
JIA could be due to gene mutations leading to uncontrolled IL-1 production
[33]. Controlled clinical trials are likely to begin shortly for anakinra in
systemic JIA.
Anakinra has demonstrated a remarkable efficacy in the
autoinflammatory diseases that are associated with CIAS1 gene mutations, which include Muckle-Wells syndrome, familiar
cold autoinflammatory syndrome (FCAS), and chronic infantile neurological
cutaneous and articular syndrome/neonatal-onset multisystem inflammatory
disease (CINCA/NOMID). In 3 members of a family, all of whom had Muckle-Wells
syndrome, anakinra led to rapid and complete resolution of clinical and
serologic evidences of active inflammatory disease [34]. IL1-Ra administration
was found to prevent cold-induced symptoms and hematological and biochemical
changes in patients with FCAS [35]. In two series of patients with CINCA/NOMID,
this treatment was followed by rapid improvement in clinical symptoms and
laboratory markers of inflammation [36,37]. The distinctive efficacy of treatment
was confirmed by the reoccurrence of symptoms and laboratory abnormalities
within few days from its discontinuation [38]. The mechanisms that lead to
abnormalities in IL-1 release in autoinflammatory diseases and the rationale
for their treatment with IL1-Ra have been reviewed recently [33].
Interleukin-6 inhibitor
As stated above, children with systemic JIA do not
respond as well to etanercept as those with other forms of JIA. This poorer
therapeutic effect is likely due to differences in the characteristics of the
inflammatory response. A growing body of evidence suggests that in active
systemic JIA the proinflammatory cytokine that plays a major role is IL-6
rather than TNF-α. IL-6 is a pleiotropic cytokine, which is believed to be
responsible of the induction of fever, of the synthesis of several acute phase
proteins, and of the development of the main complications of systemic JIA,
such as growth failure, osteoporosis, and anemia [36].
IL-6 exerts its biologic activities through
interaction with the transmembrane glycoprotein gp130, which mediates the
activation of the intracellular signal. The cytokine molecule, however, is not
able to bind directly to gp130, but can only do so after the link with its own
receptor, either membrane (IL-6R) or soluble (sIL-6R), to form heterodimeric
IL-6/IL6R complexes, which can bind to gp130. Of the various approaches that
have been considered to block the biologic activity of IL-6, the most
advantageous has been the one aimed at inactivating the cytokine receptors
through the development of a humanized recombinant monoclonal antibody, named
MRA [39].
Recently, Yokota et al [40] reported impressive
clinical responses with the short-term use of escalating doses of MRA in 11
patients with corticosteroid-dependent systemic JIA. MRA administration led to
prompt abatement of active disease manifestations, namely fever and active
arthritis, and quick reduction of acute-phase reactants. No serious adverse
events were recorded. This study confirms indirectly the pathogenetic role of
IL-6 and suggests that this medication may have an important role in the future
treatment of this disease, especially in corticosteroid-resistant patients.
However, this favorable preliminary experience warrants further investigation
in a controlled clinical trial.
Abatacept
CTLA4-Ig or abatacept belongs to a
new generation of medications that act
at the beginning of the cytokines’ pathway,
blocking T-lymphocyte activation [41]. T-cells request at least two different signals to reach
complete activation: the first generates after the presentation of the
processed peptide to the T-cell receptor, in the contest of a specific HLA
antigen; the second is the so-called co-stimulatory signal, which is provided
by the link between the CD28 receptor expressed on T-lymphocytes and the
CD80/86 (B7-1 or B72) receptor expressed on the surface of the antigen
presenting cells. The CTLA-4 is a second receptor that binds to both CD80 and
CD86 with an affinity 500 to 2500 times higher than CD28.
Abatacept
is a soluble protein that is composed by the extra-cellular portion of human
CTLA4 and a fragment of the Fc region of a human IgG1. The binding between
abatacept and the CD80/86 molecules prevents their interaction with the CD28
receptor and, therefore, blocks the second signal necessary for T-cell
activation. The method of artificial modulation of the immunological response
followed in the development of this drug is very interesting because it allows,
at least theoretically, to avoid toxicity associated to cellular lysis through
the specific block of the sole T-cells that have been stimulated to activation.
No information still exists on the use of this medication in the pediatric age.
A multicenter controlled trail is under way in JIA.
Rituximab
Rituximab
is a humanized chimeric monoclonal antibody specific for the B-lymphocyte CD20
antigen. It is composed by the variable regions of a murine
anti-human CD 20 B cell hybridoma fused to human IgG and κ constant
regions [42]. Its administration produces a profound B lymphocyte depletion and its use is
theoretically indicated in autoimmune diseases in which there is a pathogenetic
autoantibody production, namely SLE. However, this drug doesn't seem to be completely adequate to decrease
autoantibody generation because plasma cells, which are the main producers, do
not express CD20 antigen. It has been hypothesized that the clinical
improvement caused by rituximab in immune-mediated diseases is more related to
the inhibition of others immunologic functions of B cells potentially
implicated in the pathogenic process, such as the ability of behaving as
antigen presenting cells, of producing cytokines and of stimulating T cells
activation [43]. The mechanisms through which rituximab destroys target cells is not clear, but it may involve
antibody-dependent cytotoxicity, complement-mediated lysis, or apoptosis.
There
are reports of the efficacy of this medication, either as monotherapy or in combination with immunosuppressive drugs, in patients
with juvenile SLE who had severe clinical manifestations which were refractory
to corticosteroids or conventional immunosuppressive treatments. These
manifestations include autoimmune hemolytic anemia, thrombocytopenia,
proliferative nephritis, and central nervous system involvement (isolated or associated
with the presence of antiphospholipid antibodies) [44-46].
Although rituximab
has generally been well tolerated in the few treated cases, it may produce a
number of side effects, such as infusion reactions, hypogammaglobulinemia, anti-chimerical
antibodies, and increased susceptibility to
infection. Furthermore, although there is evidence that it may not affect the
protective antibody levels induced by prior vaccination, presumably due to the
lack of effects on long-lived plasma cells [47],
there is the concern that children receiving treatment may not mount an
effective response to vaccinations.
Anecdotal
reports in refractory juvenile SLE and recent clinical trials in adult patients
with proliferative lupus nephritis [48] suggest that rituximab may have an attractive safety and
efficacy profile and may be associated with less risk than current regimens
with cyclophosphamide, which may have a superior potential of impairing
defenses from infection and is responsible for a significant risk of ovarian
failure. However, further investigations in larger number of patients are
required to support this hypothesis.
Conclusion
The
introduction of biologic agents has led to a dramatic change in the approach to
the treatment of childhood rheumatic diseases. For the first time, clinicians
may target specific aspects of the pathologic process that produces the
disease. It should be kept in mind, however, that, at the present time, these
medications do not represent an alternative to the traditional anti-rheumatic
drugs and that their use should be considered only in patients with the most
severe and refractory forms, who are at risk of developing sustained active
disease with impairment of quality of life, irreversible organ damage, or
unacceptable drug toxicity [49].
The challenge for the next future will be to conduct trials and accumulate
clinical information that will help to establish which patients are most likely
to benefit from these treatments and when in the course of disease these therapies
should be introduced in order to achieve a right balance among efficacy,
toxicity, and cost. Furthermore, data in larger number of patients treated for
sufficiently protracted periods are needed to define the long-term safety of
biologic therapies in childhood.
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