Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
TREATMENT OF JUVENILE RHEUMATOID ARTHRITIS BY
ORAL ADMINISTRATION OF POOLED HUMAN
IMMUNOGLOBULIN AND AN ANTACID
FIELD OF THE INVENTION
The present invention relates to the treatment
of juvenile rheumatoid arthritis. More particularly, the
invention relates to the treatment of juvenile rheumatoid
arthritis by oral administration of a pharmaceutical
composition comprising pooled human immunoglobulin and
optionally in conjunction with an antacid.
BACKGROUND OF THE INVENTION
Juvenile rheumatoid arthritis (JRA) affects one
in a thousand children under the age of 17 years and is
more common than diabetes, cystic fibrosis and many other
chronic conditions. Emery (1998) Adolesc. Med., 9(1):45-
48. JRA is most common between 5 and 15 years of age.
JRA is characterised by chronic inflammation of the
connective tissue membranes that line the spaces between
certain bones and moveable joints (synovial membranes).
Clinical manifestations of JRA include high
spiking, daily fevers, rash, arthritis, splenomegaly and
weight loss. JRA effects males and females with equal
frequency.
The immunogenetic associations, clinical
course, and functional outcome of juvenile rheumatoid
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
arthritis are quite different from adult-onset rheumatoid
arthritis. Pediatric Rheumatic Diseases In: Primer on
the Rheumatic Diseases, lied. 1997 (incorporated herein
by reference) .
Juvenile rheumatoid arthritis is most common in
children and includes at least five different forms of
disease. One form of juvenile rheumatoid arthritis, Rf-
positive polyarticular (i.e., more than 4 joints are
involved) juvenile rheumatoid arthritis, bears some
resemblance to adult rheumatoid arthritis. However, only
about 400 of all juvenile rheumatoid arthritis cases are
polyarticular and, of these, only about 5-loo are
rheumatoid factor (Rf) positive. Therefore, only 2-40 of
juvenile rheumatoid arthritis patients suffer from Rf-
positive polyarticular juvenile rheumatoid arthritis.
Another form of JRA is Rf-negative polyarticular juvenile
rheumatoid arthritis. A third form of JRA is positive
antinuclear antibody. A fourth form of JRA is HLA B27
positive and a fifth form is systemic JRA. The onset of
JRA may be slow or very rapid. Acute onset JRA is
referred to as Still's disease.
Still's disease(also known as systemic onset
JRA) is a subset of juvenile rheumatoid arthritis which
has systemic features as the major manifestations which
include fever, rash, leukocytosis, lymphadenopathy,
pleuropericarditis, sore throat and hepatosplenomegaly
-2-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
are common in addition to arteritis. Classic symptoms of
Still's disease include extreme fatique, waves of fevers
that rise to 104°F and rapidly return to normal levels, a
faint salmon-colored skin rash that does not typically
itch. There is also commonly swelling of the lymph
glands, enlargement of the spleen and liver, sore throat,
joint pain and swelling involving many joints
(polyarticular arthritis). Still's disease accounts for
10-200 of all cases of JRA. It affects 25,000 to 50,000
children in the United States and is extremely rare in
adults.
Other types of juvenile arthritis include
lupus, dermatomyositis, vasculitis and scleroderma and
the spondyloarthropathies.
The effective treatment of juvenile rheumatoid
arthritis has generally employed a combination of
medication, exercise, rest and proper joint protection
therapy. The therapy for a particular patient depends on
the severity of the disease and the joints that are
involved. Aspirin is widely used f~r pain and to reduce
inflammation. In addition to aspirin, non-steroidal
anti-inflammatory drugs, corticosteroids, gold salts,
anti-malarials and systemic immuno-suppressants are
widely used in moderate to advanced cases. The use of
steroids and immunosuppressants, however, has significant
risks and side effects both in terms of toxicity and
-3-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
vulnerability to potentially lethal conditions such as
infection and malignancy. Thus, there exists a need for
a method of treating juvenile rheumatoid arthritis which
does not entail the potentially lethal side effects
associated with the treatments described above.
One approach to the treatment of autoimmune
diseases, of which juvenile rheumatoid arthritis is an
example, is tolerization of the patient suffering from
the autoimmune disease to the particular autoantigen(s)
involved in the disease. In Weiner, et al., Science
259:1321-1324 (1993) (incorporated herein by reference),
multiple sclerosis patients were orally administered
bovine myelin protein, which contains two multiple
sclerosis autoantigens. In Trentham, et al., Science
261:1727-1730 (1993) (incorporated herein by reference),
rheumatoid arthritis patients were orally administered
collagen, a presumed autoantigen. One drawback to
tolerization is the identification of the correct
autoantigen to which tolerance is to be induced. Another
drawback to tolerization is the potential to induce onset
of autoimmune disease. (See Blanas, et al. (1999) Int
Rev. Immunol, 18(3):217-228.)
In view of the unsuccessful and disadvantageous
modalities currently employed, there is a continued need
to develop effective methods and compositions for the
treatment of juvenile autoimmune rheumatoid arthritis.
-4-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
SUMMARY OF THE INVENTION
The present invention is directed to a method
and composition for treating juvenile rheumatoid
arthritis patients by orally administering an amount of
pooled human immunoglobulin which is sufficient to
provide a clinically observable improvement in a patient's
rheumatoid arthritic condition. The present invention
also contemplates oral administration of pooled human
immunoglobin in conjunction with an antacid. The present
invention is based on the surprising discovery that the
oral administration of pooled human immunoglobulin to
patients with juvenile rheumatoid arthritis results in a
significant clinical improvement in the rheumatoid
arthritic condition of the patient. The present
invention is also based on the discovery that there are
no toxic effects attributed to the orally administered
pooled human immunoglobulin to treat juvenile rheumatoid
arthritis patients.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention concerns methods for
treating patients with juvenile rheumatoid arthritis.
This is accomplished by orally administering pooled human
immunoglobulin to the patient, optionally in conjunction
-5-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
with an antacid. Pooled human immunoglobin is provided
in an amount sufficient to provide a clinically
observable improvement in the symptoms associated with
the patient's rheumatoid arthritic condition. An
immunoglobulin, introduced into the acidic environment of
the human stomach, may suffer inactivation. To alleviate
such inactivation and/or provide increased therapeutic
efficacy, the pooled human immunoglobulin employed in the
methods and compositions of the present invention is
optionally administered in conjunction with an antacid.
The present invention also contemplates pharmaceutical
compositions comprising pooled human immunoglobulin.
While not wishing to be bound to a particular
mechanism, the acid blocker may neutralise the otherwise
acidic character of the gut thereby shielding the
immunoglobulin from digestion in the stomach.
Alternatively, the acid-blocker and immunoglobulin may
synergistically provide remediation of arthritis symptoms
by suppressing inflammatory mediators or immune-mediated
inf lamination .
A preferred aspect of the present invention
provides pharmaceutical compositions comprising pooled
human immunoglobulin and a pharmaceutically acceptable
carrier. Another preferred aspect of the present
invention provides a pharmaceutical composition
comprising pooled human immunolgloblin, an antacid and a
-6-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
pharmaceutically acceptable carrier. In still another
preferred embodiment the composition comprises
Sandoglobulino, cimetidine and a pharmaceutically
acceptable carrier.
As used herein, "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic
and absorption delaying agents, and the like. The use of
such media and agents for pharmaceutically active
substances is well known in the art. Except insofar as
any conventional media or agent is incompatible with the
active ingredients, its use in the therapeutic
compositions is contemplated.
As used herein, the term "pooled human
immunoglobulin" refers to an immunoglobulin composition
containing polyclonal antibodies obtained from the plasma
of thousands of human donors. The polyclonal antibodies
may include IgG, IgA, IgM, etc. or fragments thereof. A
preferred polyclonal antibody is IgG. A preferred
immunoglobulin composition contains at least about 900
IgG polyclonal antibodies and trace amounts of other
polyclonal antibodies such as, for example, IgA and IgM.
Examples of pooled human immunoglobulin compositions
useful in accordance with the present invention include,
but are not limited to, Sandoglobulino, Gammagardo,
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
Gamimune~ and Gammar~. In accordance with the present
invention any pooled human immunoglobulin can be used.
"Antacid" when used herein denotes an H~-blocker
or acid blocker or other acid neutralizing agent which
neutralizes and/or significantly reduces the acidic
content of the gut. A preferred antacid useful in
accordance with the teachings of the present invention is
cimetidine.
A "clinically observable improvement" when used
herein refers to a significant subjective remediation
and/or objective remediation of symptoms associated with
the patient's rheumatoid arthritic condition including,
but not limited to, tender joint(s), swollen joints) and
stiffness assessments. Significant subjective remediation
of symptoms denotes a patient's self-assessment or a
physician's assessment of stiffness, joint tenderness,
swelling and the like. For example, an observable
difference in swelling or tenderness in even one
arthritic joint is significant. Absence of swelling or
tenderness in a previously affected joint is most
significant. Significant objective remediation of
symptoms is characterized by healing of bone cysts
confirmed radiographically and decreased erythrocyte
sedimentation rate (ESR) relative to normal levels (i.e.,
an ESR less than about 20 mm/hr is considered normal in
accordance with the present invention).
_g_
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
"Treating" as used herein includes any measure
to ameliorate, suppress, mitigate or eliminate the
clinical symptoms after the onset (i.e., clinical
manifestation) of juvenile rheumatoid arthritis.
"Oral" administration as used herein includes
oral, enteral or intragastric administration.
"In conjunction with" as used herein means
before, substantially simultaneously with or after oral
administration of antacid. Of course, the immunoglobulin
composition can not precede or follow administration of
an antacid by so long an interval of time that the
relevant effects of the substance administered first have
expired. Therefore, the immunoglobulin composition
should usually be administered within a therapeutically
effective time. By "therapeutically effective time," as
used herein, is meant a time frame in which the antacid
or immunoglobulin is still active within the patient.
In a preferred embodiment, the pooled human
immunoglobulin is produced by cold alcohol (e. g.,
ethanol) fractionation from the plasma of thousands of
human volunteers according to the method of Cohn et al.
(1946) J.~Am. Chem. Soc., 68:459-475, incorporated herein
by reference.
In another preferred embodiment, pooled human
immunoglobulin is purchased from Novartis
Pharmaceuticals, where it is sold under the name Immune
-9-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
Globulin Intravenous (Human) Sandoglobulino.
Sandoglobulin~ is a sterile, highly purified polyvalent
antibody product containing, in concentrated form, all
the IgG antibodies which regularly occur in the donor
population. This immunoglobulin preparation is produced
by cold alcohol fractionation from the plasma of over
16,000 volunteer donors. Sandoglobulin~ (IGIV) is made
suitable for intravenous use by treatment at acid pH in
the presence of trace amounts of pepsin. The preparation
contains at least 960 of IgG and with a neutral
unbuffered diluent has a pH of 6.6 ~ 0.2. Most of the
immunoglobulins are monomeric (7 S) IgG; the remainder
consists of dimeric IgG and a small amount of polymeric
IgG, traces of IgA and IgM and immunoglobulin fragments
Romer J, Spath PJ: Molecular composition of
immunoglobulin preparations and its relation to
complement activation, in Nydegger UE (ed):
Immunohemotherapy: A Guide to Immunoqlobulin Prophylaxis
and Therapy. London, Academic Press, 1981, p. 123. The
distribution of the IgG subclasses corresponds to that of
normal serum. Final container lyophilized units are
prepared so as to contain 1, 3 or 6 g protein with 1.67 g
sucrose and less than 20 mg NaCl per gram of protein.
The lyophilized preparation is devoid of any preservative
and may be reconstituted with sterile water.
-10-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
In still another preferred embodiment, pooled
human immunoglobulin is purchased from the Baxter
Healthcare Corporation, where it is sold under the name
Immune Globulin Intravenous (Human) Gammagardo.
Gammagardo is a sterile, freeze dried preparation of
highly purified immunoglobulin G (IgG) derived from large
pools of human plasma. Gammagard~ is manufactured by
cold ethanol fractionation. Gammagard~ contains at least
about 90o IgG and trace amounts of IgA and IgM.
Gammagard~, reconstituted to 5%, contains a physiological
concentration of sodium chloride (approx. 8.5 mg/mL) and
has a pH of 6.8 ~ 0.4. The distribution of IgG
subclasses is similar to that in normal plasma.
Gammagard~ is supplied lyophilized in 2.5, 5 or 10 g
single use bottles. Each bottle of Gammagardo is
furnished with a suitable volume of sterile water for
reconstitution.
In yet another preferred embodiment, pooled
human immunoglobulin is purchased from the Bayer
Corporation, where it is sold under the name Gamimuneo.
Gamimune~ is a sterile solution of highly purified human
protein. Gamimune~ contains 9-11% protein in 0.16-0.24 M
glycine. At least about 900 of the protein is IgG
monomer Gamimune~ also contains traces of IgA and IgM.
The distribution of TgG subclasses is similar to that
found in normal human serum. Gamimuneo like Gammagard~
-21-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
and Sandoglobulin~ is made by cold ethanol fractionation
of pools of human plasma obtained from thousands of
volunteers.
In still another preferred embodiment, pooled
human immunoglobulin is purchase from Centeon, L.L.C.,
where it is sold under the name Immune Globulin
Intravenous (Human) Gammar~. Gammar~ is a sterile
solution of immunoglobulin, primarily immunoglobulin G
(IgG), containing 16.5 ~ 15% protein. Gammar~ is
prepared by cold alcohol fractionation of plasma pooled
from at least 1000 donors. The pH of Gammar~ is 6.8 ~
0.4. Gammar~ also contains approximately 0.450 sodium
chloride, thimerosal, at a concentration of O.Olo and
0.3M glycine. The above-described pooled human
immunoglobulin preparations are merely exemplary of the
class of pooled human primarily immunoglobulin G
preparations useful in accordance with the present
invention.
In order to enhance the effectiveness of the
introduced immunoglobulin in the treated patient and
provide a clinically observable improvement, an antacid
is administered in conjunction with the pooled
immunoglobulin. In a preferred embodiment the
immunoglobulin composition and the antacid are
administered simultaneously in a unitary pharmaceutical
composition. In another preferred embodiment the
-12-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
immunoglobulin composition is administered at a
therapeutically effective time after administration of
the antacid. Preferably, the antacid is aluminum
hydroxide or magnesium hydroxide such as Maaloxo,
Mylanta~ or Tagamet~ which are available commercially.
Most preferably the antacid is an H2 blocker, such as
Cimetidine or Ranitidine.
The dosage of antacid administered in
conjunction with immunoglobulin depends on the particular
HZ-blocker used. When the antacid is Mylantao, between 15
ml and 30 ml is preferred. Most preferably the dosage of
Mylanta~ is 15 ml. When the cimetidine H2 blocker is
used, the preferred dosage is between 400 and 800 mg per
day.
The dosage of pooled human immunoglobulin
administered to the patient may be varied dependent upon
severity of the patient's arthritic condition and other
clinical factors. Preferably, the dosage will be as
small as possible while still providing a clinically
observable result. The most preferable doses are those
that have the largest effect in terms of alleviating the
patient's arthritic condition. Dosages of the
immunoglobulin composition may range from as little as
100 mg per day up to as much as 10 g per day. Dosages of
300 mg of pooled human immunoglobulin per day have been
found to result in significant improvement in the
-13-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
condition of patients with rheumatoid arthritis and cause
little or no adverse side effects. Accordingly, 300 mg
per day is a preferred dose. The present invention also
contemplates dosages ranging from 3 mg/kg to about 100
mg/kg.
Although the chosen dose may be given in
increments, it also may be given as a single dose.
Further, although the dose of immunoglobulin may be
administered at any time during the day, it is preferred
that it be administered at bedtime. The patient's
arthritic condition can be determined, for example, by
the patient's self-assessment of his or her pain,
stiffness, etc. Another way to determine the patient's
arthritic condition is for a physician to examine a
patient's joint tenderness, swelling and cystic growth.
It is especially advantageous to formulate the
pooled human immunoglobulin in dosage unit form for ease
of administration and uniformity of dosage. Dosage unit
form as used herein refers to physically discrete units
suited as unitary dosages for the rheumatoid arthritic
subjects to be treated, each unit containing a
predetermined quantity of pooled human immunoglobulin
with or without an antacid calculated to produce the
desired therapeutic effect in association with the
required pharmaceutical carrier. The specifics for the
novel dosage unit forms of the invention are dictated by
-14-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
and directly dependent on (a) the unique characteristics
of the pooled human immunoglobulin, antacid and the
particular therapeutic effect to be achieved, and (b) the
limitations inherent in the art of compounding such a
pooled human immunoglobulin for the treatment of juvenile
rheumatoid arthritis herein disclosed in detail.
The pooled human immunoglobulin with or without
an antacid is compounded for convenient and effective
administration in effective amounts with a suitable
pharmaceutically acceptable carrier in dosage unit form
as hereinbefore described. A unit dosage form can, for
example, contain the pooled human immunoglobulin in
amounts ranging from about 100 mg to about 10 g and, if
desired, an antacid in an amount ranging from about 400
to 800 mg.
Clinically observable results from the
administration of immunoglobulin in conjunction with
antacid may be observed. in as little as 2 weeks.
However, it may take up to 6 weeks to obtain measurable
benefit. Initial dose levels used during the first few
weeks of treatment may be reduced once clinical
improvement has been observed. Reductions in dose levels
of up to 90o may be made after the first few weeks.
The oral treatment method in accordance with
the present invention may be used to treat juvenile
rheumatoid arthritis, including systemic onset,
-15-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
oligoarticular and polyarticular types and other closely
related autoimmune diseases such as lupus,
dermatomyositis, vasculitis, scleroderma and the
spondyloarthropathies. The treatment of e.g.,
spondyloarthropathies according to the present invention
would employ the same dosages as for junveile rheumatoid
arthritis and the same treatment protocol.
Demonstrations of the treatment of patients in
accordance with the present invention are set forth in
the following non-limiting examples.
-16-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
T1T! 7~ ~llT T T 1
An open-label study was conducted to evaluate
the safety and efficacy of oral gammaglobulin. Two
patients, a six year old and a 10'/2 year old, exhibiting
severe, unremitting juvenile rheumatoid arthritis and
unresponsive to conventional therapy were selected and
for investigation. The patients discontinued their
prescribed medical regimen, which was replaced by the
administration of 300 mg of lyophilized gammaglobulin
(dissolved in sterile water) daily in a single dose for
six weeks. There was no evidence of toxicity as a result
of receiving oral gammaglobulin. Surprisingly, both
patients showed marked improvement as described fully
below.
A 10'/2 year old boy developed systemic onset JRA
at age 6 characterized by high spiking fever,
intermittent rashes, polyarticular arthritis, fatigue,
weight loss, and ESR of 117 mm/hr. For 4 years the
patient received various medications and combinations of
medications. These included pulse medrol 250 mg/day,
oral prednisone 20 mg/day over prolonged periods of time,
methotrexate 22.5 mg/week, cyclosporin 50 mg/day,
ibuprofen 1200 mg/day, indomethacin 25 mg/day and enbrel
15 mg twice weekly. Adequate control of disease activity
was not achieved. In spite of optimum therapy, the
-17-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
patient experienced recurrent fevers and unrelenting
polyarthritis. At age 10, the patient discontinued
methotrexate due to a lack of efficacy. The patient also
was administered Enbrelo, but was unresponsive to enbrel
as well. At this time the patient was administered 300
mg gammaglobulin orally once daily at bedtime. Within 3
to 4 weeks, the patient experienced a feeling of well
being; the patient's fevers and arthritis subsided. The
boy was seen by his physical therapist after 6 weeks of
oral gammaglobulin. Notably, the patient was able to
walk without crutches or a walker and after 3 months of
therapy the patient was able to run and jump; he had been
unable to walk without assistance since the onset of his
disease. At this time the patient's ESR was ~0 mm/hr
compared to an ESR of greater than 100 mm/hr before
taking oral gammaglobulin. After 6 months of therapy,
the patient remains in remission. X-rays were taken
after 6 months of oral gammaglobulin and showed complete
healing of multiple large bone cysts. The patient
continues to take 300 mg oral gammaglobulin daily without
any side effects.
PATIENT 2
A 6-year old girl developed polyarticular onset
JRA at age 1~~2. For the past 4 years she was treated with
multiple drug therapy, and her current therapy included
prednisone, methotrexate, cyclosporin, and Enbrel~. In
-18-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
spite of this aggressive therapy, the patient was
resistant to therapy, exhibiting a poor clinical
response. The patient had to be carried upstairs to her
bedroom and she could not descend the stairs without
help. The patient's pain was so severe that she was
unable to sleep due to severe pain from turning in bed.
At age six she was started on 300 mg of oral
gammaglobulin at bedtime. Within one week of therapy the
patient informed her mother that she was beginning to
feel well. After 2 weeks of therapy she began to sleep
through the night for the first time in 4 years. The
patient reported that the oral gammaglobulin was
responsible for her improvement and requested the
medication at night. After 3 weeks of therapy dramatic
improvement in the swelling of the patient's ankles were
observed by the patient's mother, and the girl was able
to climb and descend stairs without help for the first
time in 4 years.
The child was able to ambulate better with less
pain, and her play was more vigorous. The patient's
physician evaluated her and documented at least 500
clinical improvement in only 3 weeks. Because the
patient was scheduled to enter another clinical trial,
the oral gammaglobulin was discontinued. She was
examined again two weeks after discontinuing the oral
gammaglobulin, and the same physician documented a 200
-19-
CA 02424623 2003-04-03
WO 02/28430 PCT/USO1/31240
flare of her arthritis. The patient did not experience
any side effects from the oral gammaglobulin.
-20-
