Case Series
Treatment of Systemic Onset Juvenile
Idiopathic Arthritis with Anakinra
Irigoyen, Patricia1; Olson,
Judyann2, Hom, Christine3; Ilowite, Norman1
Schneider Children’s Hospital1, Medical
College of Wisconsin2, New York Medical College3
Key words: biologics, anakinra, arthritis
Abstract
Objective: To describe the
result of the use of anakinra in 14 patients with systemic onset juvenile idiopathic
arthritis (SOJIA) patients
Methods: We performed a
multi-center retrospective chart review of SOJIA patients who received
anakinra. We asked members of the pediatric rheumatology list-serve to provide
information regarding their experience with the use of anakinra. Five centers,
including our own, provided data. All SOJIA patients in whom anakinra was used
were included in the analysis. N=14
Results: Duration of therapy ranged from
Conclusion: All patients in this study had a good
response and did not have serious side effects.
Most striking was the improvement of joint symptoms in all patients in a
population that was refractory to previous therapy. The study likely has a
selection bias as centers that had success with anakinra may have been more
likely to submit data. Blinded prospective studies on the treatment of systemic
onset JRA with anakinra should be performed.
Introduction
Systemic onset
juvenile idiopathic arthritis (SOJIA) is perhaps the most identifiable, and
potentially most severe, phenotype of the various arthritis subtypes.
Accounting for 10-20 % of children with JIA, the systemic subtype can exhibit a
prolonged course of systemic features with polyarticular joint involvement.
[1]
Children with SOJIA
receive traditional treatment with corticosteroids, NSAIDS, methotrexate, and
other immunosuppressive medications. Despite these therapies, about 30% of
children will develop destructive polyarthritis with long term morbidity and
disability. More recently, TNF α
inhibitors have been used with moderate success to treat patients with SOJIA
and persistent polyarthritis.[2] However, a significant number of children have
persistent polyarticular disease as well as laboratory evidence of chronic
inflammation in spite of aggressive anti-inflammatory or immunosuppressive
therapy. [2] Anakinra is
identical to a naturally occurring nonglycosylated human form of IL-1 Receptor
antagonist (IL-1Ra) with the exception of 1 N-terminal methionine. [3] IL-1Ra
is partly responsible for the regulation of IL-1α and IL-1β by
competitively binding with high avidity to the type 1 IL-1 receptor (IL-1R). Anakinra
is administered subcutaneously, at doses of 1mg/kg up to 100mg daily.
Anakinra blocks the biologic activity of IL-1
by competitively inhibiting IL-1 binding to the IL-1 receptor, preventing
docking of the accessory protein and subsequent intracellular signaling events.
Anakinra consequently has a number of anti-inflammatory effects, including
suppression of proinflammatory cytokine production including TNF and IL-6,
decreased production of collagenases by chondrocytes, decreased production of
adhesion molecules by endothelial cells, fibroblasts, and osteoclast
precursors.
Anakinra has been shown to be safe and
modestly effective in adult rheumatoid arthritis.[4] Preliminary data suggests efficacy in
polyarticular course JIA. [5] Case reports have suggested particular efficacy
of anakinra in refractory cases of SOJIA. [6] Our paper describes a retrospective
chart review analyzing the experience of anakinra in systemic onset JRA
patients who had failed previous therapies, including TNF-alpha
inhibition.
Patients
and Methods
Institutional
review board approval was obtained for this retrospective chart review at each
participating center. The pediatric
rheumatology list-serve, reaching 526 rheumatologists worldwide, established by
Dr. Peter Dent (McMaster University) , was used as a tool to identify
refractory SOJIA patients who had been treated with anakinra. Five centers
agreed to participate, providing data on fourteen patients. All systemic onset
JIA patients who had received anakinra at these centers were included in the
analysis. The diagnosis of SOJIA was
determined by each center, as were criteria for lack of response. We chose the
following significant indicators of response to therapy in SOJIA: rise in hemoglobin and albumin, decrease in
platelet count, Westergren
erythrocyte sedimentation rate (ESR), prednisone dose and number of active
joints. An active joint was defined as having non-bony swelling or, if no
swelling was present, limited range of motion combined with either tenderness
or pain on movement. These data were obtained at the visit preceding initiation
of anakinra therapy, throughout the course of therapy, and at the last
available patient visit while on treatment.
In addition, the centers provided information regarding previous failed
therapy, concomitant therapy, age of disease onset, extra-articular
manifestations, and any adverse events.
All data were collected via retrospective chart review at each
participating institution.
Ten
of 14 patients had extra-articular manifestations at the time of initiation of
anakinra. These included rash (n=9), fever (n=3), myalgia (n=1), hepatomegaly
(n=2), and lymphadenopathy (n=1). All of
the patients had active arthritis, with joint counts ranging from 1 to 49
active joints (mean= 14, median=10). Duration of therapy ranged from
Results
Fourteen of 14
patients had improvement in their arthritis and 10/14 had complete resolution
of arthritis (Figure 1).
Figure 1. Average active joint count following anakinra
therapy.
Anakinra therapy
resulted in complete resolution of extra-articular symptoms within 3 months in
all patients with active systemic features (Figure 2).
Figure 2. Resolution of extraarticular
features
In addition, normalization of laboratory values
was seen in all patients (Figures 3-5).
Figure 3. Average hemoglobin level and
white cell count after anakinra therapy
In most patients who responded the
improvement was immediate (less than two weeks) and sustained.
Figure 4 Average erythrocyte sedimentation
rate (
Fever resolved in the three patients who
were febrile at initiation of therapy.
However, injection site reactions were frequently seen. One patient
chose to discontinue anakinra due to injection site pain. No serious infections
were reported.
Figure 5 Average number of platelets
following anakinra therapy.
Discussion
Between
8,000-30,000 children in the
Predictors of poor outcome (joint damage, poor
functional status) include young age at diagnosis, disease duration of greater
than 5 years, persistent systemic symptoms (defined by prolonged fever or
sustained treatment with corticosteroids) or the presence of thrombocytosis,
high sedimentation rate, and multiple active joints after 3-6 months of
disease. [11-12] Although there is an ever-expanding body of evidence about the
safety and efficacy of various agents in polyarticular JRA, only select
systemic onset patients (those with a polyarticular course but without
significant systemic features) are included in these studies, therefore the
results may not be easily generalized to all SOJIA patients. The current
standard of care is to use methotrexate and etanercept as second and third line
agents in this disease; it can be argued that efficacy has not been proven for
either of these therapies. [13]
The data on
effectiveness of methotrexate in SOJIA are somewhat contradictory. A
collaborative study between the USSR and USA regarding the effectiveness of
methotrexate in JRA found no difference in response rates among the different
subtypes with an overall response rate of 60-89%, however the number of
systemic patients receiving the dose that was found to be effective, was only 9
(20%). [14] Woo et al did not find methotrexate to be effective treatment using
the JRA core criteria in systemic patients. [15] In comparison, Ruperto et al
in their open label uncontrolled study of over 600 patients with JRA treated
with 10mg/m2/week of methotrexate, found that the systemic subset had a
response rate to standard dose methotrexate of 80%. [16] In another
uncontrolled study, al-Sewairy and colleagues found 89% of SOJIA patients had
significant improvement in their joint count, functional class and systemic
features. [17]
There is also a
growing amount of evidence that SOJIA patients’ response to etanercept is less
predictable when compared to other polyarticular JRA patients. In several
studies, when the systemic onset polyarticular course subgroup is examined
separately, more SOJIA patients on etanercept had a disease flare and/or poor
response in comparison to the other JRA subgroups. [18-21] The German
etanercept registry included 66 patients with SOJIA who were evaluated
according to the JRA core set criteria. At 12 months only 24% SOJIA patients
had a 70% response rate compared to 54% of the other subtypes and 14 (21%)
patients had discontinued treatment owing to lack of efficacy. [22]
The initial study
of etanercept in polyarticular course JIA [18] 22 SOJIA patients (without
significant systemic features), 17 (77%) qualified as responders in the open
label phase of the randomized withdrawal trial.
During the blinded phase 7/8 SOJIA patients flared in the placebo group
and 4/9 (44%) flared in the etanercept group.
In contrast, only 18% of children with other subtypes of JIA flared in
the placebo group. In the long-term open
label follow-up study [19], 25% of subjects had SOJIA; only 47% achieved 70%
improvement as compared to 62% with other disease onset subtypes. Less than 50%
of subjects with SOJIA were found to have satisfactory response to
etanercept.
Previous reports
highlight the difficulty of treating SOJIA patients who are refractory to these
standard therapies. Several case series show some response with several
different agents. Drugs which have been tried, with varying levels of success,
have been IVIG, cyclosporine, thalidomide, statins, cyclophosphamide, and stem
cell transplant.[23-28] In light of these studies and reports, the prompt and
sustained response to anakinra and lack of serious adverse events of our
refractory patients is very encouraging.
The different
response rates of JIA subtypes can most likely be attributed to underlying
differences in pathophysiology, which is evidenced by differences in their
cytokine profiles. There have been several studies to evaluate the production
of cytokines and cytokine inhibitors in blood samples from patients with SOJIA,
which have on the whole supported the concept that inflammatory cytokines include
variably IL-1, IL-6, and IL-2 as well as other molecules associated with
inflammatory cytokines (IL-1Ra, sTNFR). [29-37] Gene expression studies have
also suggested increased IL-1 in SOJIA Expression profiling using microarray
technology suggests the presence of inflammatory cytokine signatures unique to
active SOJIA. [38] This is consistent
with the growing evidence that children with SOJIA do not respond to etanercept
as well as other polyarticular JIA patients. Our data, as well as recent case
series, suggest SOJIA is an example of this diversity with generally only
moderate response to TNF inhibitors, but marked rapid improvement in response
to IL-1 inhibition.
In this retrospective chart review we
found that anakinra appeared to be safe and effective in the treatment of
SOJIA. Most striking was the improvement
of joint symptoms in all patients in a population that was refractory to
previous therapy, including TNF alpha inhibition. In addition, anakinra
appeared to be effective in treatment of extra articular manifestations of
SOJIA. The small sample size, retrospective nature, and methods of patient
collection limit our ability to interpret these results to the general
population of SOJIA patients. Our study likely has a selection bias as centers
that had success with anakinra were more likely to participate in the review.
In addition, while our data show improvement of disease, no validated set of
criteria has been determined to evaluate the response of systemic features of
SOJIA. Outcome measures for SOJIA need
to be validated in order to enable blinded prospective studies on the treatment
of systemic onset JIA with anakinra and other promising biologic therapies.
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