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COMMENTARY
Current questions in the
treatment of childhood SLE.
There are three key issues for those
who care for children with SLE. The first is early identification of those
children who have ‘high risk’ disease. Appropriate selection of those likely to
do poorly if not aggressively treated with immunosuppressive therapy is
essential if we are to obtain the best quality of life for the largest number.
The second issue is maximization of the immunosuppressive therapy. We must give
those who need immunosuppressive therapy enough to minimize the risk of
recurrence while simultaneously balancing the risk of therapy related toxicity.
The third issue is treatment of those who fail initial immunosuppressive
therapy. What can we do for those children? Is there a regimen with an
acceptable ratio of efficacy to toxicity? Further, we must ask ourselves what
is acceptable toxicity in this situation?
You will not find the answers to
these questions in any text. Nor will you find uniform agreement among those
who treat children or adults with SLE. However, a simple, well-considered
approach with a clear understanding of the questions, which must be answered,
quickly resolves many of the ‘dilemmas’ broached in clinical discussions of
individual patients on rounds, in clinics, and on bulletin boards.
Most recognize that the child with
class IV DPGN and a creatinine of 2.0 is already in trouble. However, serial
renal biopsy studies clearly indicate that adults with a relatively low
chronicity index will progress to renal failure despite treatment [1,2]. We
cannot wait until the patient is obviously in trouble to begin therapy. Too
often we are like the careless mother at the scenic overlook. There is a
guardrail and two feet beyond it is a steep cliff dropping off to rocks
hundreds of feet below. Little Johnny is playing on the railing, but he’s still
two feet short of the cliff. Now little Johnny is on the other side of the
railing, but he’s still a foot and a half from the edge. Now Johnny’s looking
down over the edge, but he’s still a foot back. Why did those silly engineers
put the fence two feet back and make it hard for people to look over the edge?
Now Johnny’s trying to get just a little closer to look at the rocks at the
bottom. Now Johnny’s – Oh my gosh!!!!! How did that happen? What a tragedy!!
Well of course if we’d known that was going to happen we would have kept Johnny
on this side of the guardrail, but it looked like he was still so far from the
edge. All of us would be sympathetic to Johnny’s mother for her loss, but all
would say she was foolish to let Johnny climb over the guardrail. Do you initiate
immunosuppressive therapy as soon as you see someone headed near the edge? How
close do you let them get? Are you waiting till they are already over the edge?
Faulting therapy for its inability to catch people once they’ve fallen is like
saying the designers of the scenic overlook should have put netting on the side
of the cliff to catch anyone who fell. Our emphasis must be on keeping everyone
away from the edge. It is true that every Johnny doesn’t fall, but does that
make it safe to go past the guardrail?
In deciding where the ‘edge’ is we
must balance probability of disease progression, if left untreated, versus
efficacy of treatment and probability of toxicity from treatment. Each of these
issues remains controversial. Again you won’t find answers in books. From the
perspective of twenty-five plus years experience, the simplest answer is the
most informative. Children with recurrent lupus-related problems (e.g.
infections, neurologic complications, hypertension, pulmonary hemorrhage, nephritis/nephrotic
syndrome) do poorly over the long term if not aggressively treated. Not only do
the problems keep recurring, but also with recurrent use of moderate to high
dose corticosteroids to control these problems, steroid toxicity becomes a
major issue. You do not need class IV DPGN, or a creatinine greater than 2.0,
or in fact any nephritis at all to recognize the child at high risk. You simply
need to recognize the child who is recurrently having problems that force you
to raise the steroids above 0.5 mg/kg/day.
The breadth of the current
recommendations for when to initiate IV cyclophosphamide is quite wide. The
most aggressive would be my recommendation that any child with recurrent
hypocomplementemia that you are unable to maintain satisfactorily on less than
0.5 mg/kg/day (I use 20 mg/day as the cutoff for ‘normal sized’ patients),
should be given immunosuppressive therapy. The least aggressive is that IV
cyclophosphamide is rarely indicated, but most investigators agree it is
appropriate for anyone with biopsy proven DPGN. Some may be tempted to disagree
with this recommendation. However, it takes more than a few years to recognize
the cumulative toxicity recurrently increasing and decreasing the steroid
dosage inflicts on a growing child. Over a five-year horizon children will
generally do well without aggressive therapy, but in the five to ten year gap
there is a dramatic separation between the children I have treated with IV
cyclophosphamide and minimal steroids and the children who have chosen to be
treated with steroids alone. A typical child who received IV cyclophosphamide
reports, ‘I only remember I have lupus when I come to the hospital for my
checkups.’ Similar results have been reported in studies of adults with lupus
[3]
The major concern of most physicians
is long-term toxicity of intravenous cyclophosphamide therapy. The answer is
clear. In our long term experience at the Hospital for Special Surgery only one
female (who received two full courses of therapy - 34 gms/M2 of
cyclophosphamide over 6 years) has developed amenorrhea. Extensive studies of
children receiving intravenous cyclophosphamide for malignant conditions
estimate the frequency of amenorrhea to range from a high of 16% in children
receiving high dose chemotherapeutic regimens with irradiation to a low of 6%
in children treated with intravenous cyclophosphamide alone [4,5] Thus the risk
of amenorrhea for children with SLE is probably 1/16 with the highest estimate
being 1/6 [6]. The risk of death from SLE over ten years of follow-up in a
similarly selected group of children for whom intravenous cyclophosphamide was
avoided was 1/4. If one considers not only death, but failure to reproduce
because of the cosmetic and psychological effects of chronic corticosteroids as
well, the risk of ‘reproductive failure’ was far higher for those who avoided
cyclophosphamide.
The risks of intravenous
cyclophosphamide therapy are not limited to infertility. Additional risks
include infection, hemorrhagic cystitis, and an increased incidence of late
onset neoplastic diseases. With careful evaluation of the patient prior to
cyclophosphamide administration and proper inpatient hydration and
administration of MESNA our incidence of all these complications remains
negligible in children who have received less than 20 gms/M2 of
cyclophosphamide. One child with long-term recalcitrant lupus who had received
in excess of 60 gms/M2 of intravenous cyclophosphamide developed a renal
papillary cell carcinoma during his seventh year of therapy. However, as with
amenorrhea there have been no neoplastic complications in children receiving
the standard therapeutic regimen of 17 gms/M2. Again this reflects the
published adult data [7]
At every meeting I am asked about
using less cyclophosphamide, using it for a shorter period, or waiting until
the patient is doing very poorly to start. Often the question is followed by a
complaint that their experience using cyclophosphamide in the past, has been
poor. Their experience is poor because they use less cyclophosphamide, use it
for a shorter period, or wait until the patient is doing very poorly. Even the
best guardrail will not catch someone who has already fallen over the
cliff.
The current regimen of intravenous
cyclophosphamide is not the final answer. However, it clearly works well and
with minimal toxicity. Our patients deserve the best shot a getting better and
staying better. When I began in pediatric rheumatology the prognosis for ALL
was far worse than for lupus. Now the prognosis for ALL is far better. The
oncologists stick to their protocols. Do children with lupus deserve less?
There are reported abstracts and in
a few cases manuscripts describing the use of mycophenolate mofetil,
azathioprine, methotrexate, and cyclosporine in the treatment of children with
lupus. None of these initial reports of these therapies has been followed by a
report of continued efficacy. To date intravenous cyclophosphamide is the only
therapy with long term follow-up data and repeated studies demonstrating
consistent efficacy in a significant number of children. That doesn’t mean
intravenous cyclophosphamide is perfect. Only that at present it is the best we
have.
Since 1983 I have treated more than
fifty children with intravenous cyclophosphamide with SLE. The majority for
whom follow-up is available are doing well on low dose prednisone without the
stigmata of Cushing’s syndrome. With long-term follow up it has become evident
that not every child with lupus will respond completely to intravenous
cyclophosphamide. Our recurrence rate is approximately 20%. Again this is
similar to the published adult experience [8]. Most of these cases are children
who flare within the first year of completing intravenous cyclophosphamide therapy.
A few are children who flare during the initial course of intravenous
cyclophosphamide therapy, usually when the frequency of cyclophosphamide
administration changes from monthly to every three months. Since our two cases
of significant toxicity (one amenorrhea and one renal carcinoma) occurred in
children with recurrent disease who were continued on monthly intravenous
cyclophosphamide it is clear this is not a satisfactory approach.
At the present time children with
recurrent disease are treated with a nine-month course of monthly intravenous
cyclophosphamide and monthly intravenous methotrexate (dose slowly increased
from 50 mg/M2 to 300 mg/M2, given four hours after the intravenous
cyclophosphamide). This dose of combine chemotherapy has brought continued
active disease under control in all of the children so treated [9]. This
regimen clearly causes more nausea and cytopenia than IV cyclophosphamide
alone. It is also carries a higher risk of ultimate sterility and neoplasia.
However, these are children with severe disease that has not remitted with
intravenous cyclophosphamide alone. We continue to explore alternative
therapies for this group.
For children who fail even this
salvage therapy there is no ‘standard’ regimen. Bone marrow transplantation and
IV cyclophosphamide marrow ablation without transplantation have both been
utilized in adults and some teenagers [10]. The utility of these regimens
remains unclear. Everyone who cares for children with SLE anxiously awaits a
more effective and less toxic therapy than intravenous cyclophosphamide.
However, until one is demonstrated, I am committed to giving the children in my
care the best possible chance of long-term disease remission without
significant corticosteroid toxicity. At present intravenous cyclophosphamide
remains the only therapy proven to achieve that goal consistently.
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References
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Plotz PH Decker JL Effect of treatment on the evolution of renal abnormalities
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