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Role of Collagen in Polyarthritis Questioned.

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Company Bnd aispensed to humans under an “educational
investigatien ofrrew drug permit.” However, the patient was
not asked to sign an investigational drug consent form or to
submit to continuing efficacy or toxicity monitoring.
Dimethyl sulfone is a stable oxidation product of
DMSO-odorless, colorless, and water soluble. It is the
major metabolite of DMSO in all species studied, persisting
in tissues long beyond the disappearance of the parent
compound. Bovine meat and milk normally contain DMS02;
however, human intake from these sources would seldom
exceed an average of a few milligrams daily (I). The DMS02
dosage described above was about 4 grams daily.
Studies on DMS02 directly administered to humans
have not been published. In humans given DMSO, DMS02
persisted 3 weeks after topical and 1 week after intravenous
administration (2,3). Some but not all of the well demonstrated biologic effects of DMSO in rats are shared by DMSO2
(4). None of these effects translates easily into the supposed
analgesic effects of these products.
It is probable that “crystalline DMSO” will become
widely used in DMSO clinics, and clinicians should be aware
that these crystals are likely to be DMSO?. Clearly, studies
are needed to determine the effects and toxicity of DMS02 in
Richard Bertken, MD
University of California, San Francisco
and V A Medical Center, Fresno, CA
1. Tiews J, Scharrer E, Harre N, Flogel L: Metabolism and
excretion of dimethyl sulfoxide in cows and calves after topical
and parenteral application. Ann NY Acad Sci 243: 139-150, 1975
2. Kolb KH, Jaenicke G , Kramer M, Schulze PE: Absorption,
distribution, and elimination of labeled dimethyl sulfoxide in man
and animals. Ann NY Acad Sci 141:85-95, 1%7
3. Hucker HB, Miller JK, Hochberg A, Brobyn RD, Riordan FH,
Calesnick B: Studies on the absorption, excretion, and metabolism of dimethylsulfoxide (DMSO) in man. J Pharmacol Exp Ther
155:309-3 17, 1967
4. Kocsis JJ, Harkaway S, Snyder R: Biological effects of the
metabolites of dimethyl sulfoxide. Ann NY Acad Sci 243:104109. 1975
Role of collagen in polyarthritis questioned
To the Editor:
In a recent Letter to the Editor ( l ) , Jarrett and
Roguska-Kyts speculated on a possible relationship between
injectable collagen treatment and polyarthritis in a female
transsexual. In my opinion, this speculation was unsupported both by the data presented on the particular patient, and
by the references cited.
The material referred to in their letter was reportedly
of unknown origin, but was used to “fill in scars from acne.”
Since our product, Zyderm Collagen Implant, is the only
preparation of injectable collagen currently approved for
such use, it is imperative that the implications of their letter
be challenged.
The collagen contained in Zyderm Collagen Implant
(ZCI) is predominantly bovine type I collagen, with up to 5%
type 111 collagen. The references quoted by Jarrett and
Roguska-Kyts are those of Trentham, Kang, and coworkers,
who have shown that only type I1 collagen administered in
adjuvant will produce arthritic-like conditions in rats (2,3).
Furthermore, not all rats which exhibit an immune response
to collagen subsequently developed arthritis; those strains
that did respond appeared to be genetically controlled by the
major histocompatibility complex. Therefore, more than an
immune response to collagen is required for the development
of arthritis, even in the rat model.
At a recent conference sponsored by the Department
of Dermatology, Stanford Medical School, adverse clinical
responses to Zyderm Implant and their immunologic consequences were discussed at length. It was reported that ZCI
has been used in over 20,000 subjects with an adverse
reaction rate of less than 1.3%. Most reactions have been
localized responses at implantation sites, none have been
medically threatening, and most have been self-limiting.
Although a few cases of transient arthralgia have occurred,
no case of arthritis was reported.
Despite this low incidence of adverse responses,
extensive clinical and immunologic studies were performed
on 61 ZCI-exposed subjects in a 1-year prospective study.
Results of this study, which have recently been submitted
for publication, show that ZCI has very low antigenic
activity. Elevated levels of anti-Zyderm antibodies were
found only in subjects previously exhibiting inflammatory
responses at implantation sites. These antibodies did not
appear to cross-react with human dermal collagen and were
neither time nor dosage dependent. No elevated levels of
circulating immune complexes were found, even in reactive
The relationship of collagen to autoimmune disorders
has been the subject of intense investigation for over 2
decades ( 4 3 ) . Several studies have suggested the immunologic involvement of interstitial collagen (type I, 11, and 111)
in rheumatoid arthritis (6). Other studies examined the
presence of autoantibodies to type I collagen in various
autoimmune and nonautoimmune diseases in which an inflammatory component is part of the pathophysiology (7,s).
These studies have shown that significant levels of antibodies were present against denatured collagen but not against
native collagen. Thus, it appears that an immune response to
collagen is secondary to connective tissue destruction that
occurs in these disorders, and is not the inciting event.
In summary then, these data suggest that polyarthritis is unlikely to develop secondary to exposure to injectable
collagen. Furthermore, the presence of polyarthritis in the
patient described by Jarrett and Roguska-Kyts is unsubstantiated. The patient was examined only after resolution of her
symptoms, and all of her laboratory results were within
normal limits. Indeed, the important distinction between
arthritis and arthralgia cannot be made from the available
data. In addition, the fact that no anti-collagen antibodies
could be measured in this patient suggests that the chance
that a serum sickness reaction ensued is extremely remote.
The additional fact that there was no inflammatory response
at injection sites makes it unlikely that a significant immune
response occurred.
Finally, the title assigned to this letter, “Collageninduced arthritis in a human” signifies a conclusion that
exceeds the information contained in the letter. The editors
are reaching a conclusion that would not be made by the
careful reader.
Bruce B. Pharriss, PhD
Linda Cooperman
Collagen Corporation
Palo Alto C A
1. Jarrett MP, Roguska-Kyts J: Collagen-induced arthritis in a
human (letter). Arthritis Rheum 25:1024-1025, 1982
2. Trentham DE, Townes AS, Kang AH: Autoimmunity to type I1
collagen: an experimental model of arthritis. J Exp Med 146:857868, 1977
3. Trentham DE. Townes AS, Kang AH, David JR: Humoral and
cellular sensitivity to collagen in type I1 collagen-induced arthritis in rats. J Clin Invest 61239-96, 1978
4. Steffen C: Tissue antibodies in rheumatoid arthritis and other
connective tissue diseases. Ann Immunol 1 :47-58, 1969
5 . Michaeli D, Fudenberg HH: The incidence and antigenic specificity against denatured human collagen in rheumatoid arthritis.
Clin Immunol Immunopathol 2: 153-159, 1974
6. Andropoulos NA, Mestecky J. Miller EJ, Bradley EL: Antibodies to native and denatured collagen in sera of patients with
rheumatoid arthritis. Arthritis Rheum 19:613-617. 1976
7. McAdam KPWY. Fudenberg HH, Michaeli D: Antibodies to
collagen in patients with leprosy. Clin Immunol Immunopathol
9:1&21, 1978
8. Michaeli D, Fudenberg HH: Antibodies to collagen in patients
with emphysema. Clin Immunol Immunopathol 3: 187-192, 1974
Olecranon bursitis related to calcium pyrophosphate
dihydrate crystal deposition disease
To the Editor:
We were interested to read the report of olecranon
bursitis related to calcium pyrophosphate dihydrate (CPPD)
crystal deposition disease (Gerster J-C, Lagier R, Boivin G:
Olecranon bursitis related to calcium pyrophosphate dihydrate crystal deposition disease: clinical and pathologic
study. Arthritis Rheum 25:989-996, 1982), because we recently treated a patient who developed infrapatellar bursitis
as an extraarticular manifestation of CPPD crystal deposition.
A 58-year-old white woman was admitted to the
hospital to be treated with continuous neck traction for
cervical spondylosis. Two days before admission she had
developed an acutely tender swelling below the left knee,
which was diagnosed clinically as infrapatellar bursitis.
There was no history of previous trauma, nor was there an
effusion or other abnormality in the knee joint. The bursa
was aspirated and examination of the fluid under polarized
light microscopy showed positively birefringent calcium
pyrophosphate crystals. Radiographs of the knee did not
show any signs of chondrocalcinosis or tendon calcification.
There was no clinical or investigational evidence of a background inflammatory or metabolic arthropathy.
Isolated acute bursitis is often treated without exhaustive investigation of its cause. These 2 cases, in which
calcium pyrophosphate crystal deposition produced isolated
bursitis, suggest that a search for such crystals should be
made in the aspirate from all bursae. Only if this procedure is
adopted as routine will the true incidence of this condition be
Peter T. Dawes, MRCP
D. Raman, MRCP
Ian Haslock, MD
Middlesbrough General Hospital
Middlesbrough, Cleveland
The value of pharmaceutical conferences
To the Editor:
I finally made it, and feel I must share the news of my
good fortune. A recognized specialist on a selected list! In
1982 I received invitations to New Orleans, San Francisco,
and now Bermuda. Not only have I been invited to privileged symposia, but I now have the opportunity to conduct
my own mini trial.
After years of nonrecognition, low pay, and contending with a population of patients whose conditions seem to
steadily worsen, the travel and support seem too good to be
true. Nevertheless, crass money considerations can’t be
overlooked. Who is paying, and for what? Drug companies
are paying obviously, but not, it seems, for my clinical
expertise. They claim education is the main objective, but do
they know enough? At the time of the conferences on
benoxaprofen, the main danger of that drug was not appreciated. Do brief intensive trials make up for inadequate post
marketing surveillance? And one usually pays for education,
rather than having it underwritten.
The main point of zero order kinetics is difficult to
ferret out, as most of the literature is of the usual glowing
“effective with no side effects” variety. Will I learn anything
from a brief open trial? Will my patients appreciate trying a
“new” drug from a “selected” rheumatologist? Or will they
simply end up paying more for yet another form of aspirin,
and offsetting the cost of a rheumatologist’s trip to Bermuda?
Lorne A. Runge, MD
State University Hospital
Syracuse, N Y
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role, polyarthritis, questions, collagen
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