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Synovial tissue responses following treatment of rheumatoid arthritis with the humanized monoclonal antibody CAMPATH-1H.

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LETTERS
that the criteria utilized for its diagnosis are tautological (5).
Others have suggested that the signs and symptoms that we
recognize as FM exist as such because they are acceptable
contemporary expressions of the stresses of daily life. Thus,
it might be argued that the appellation “fibromyalgia” is of
limited value because it describes a loose complex of symptoms rather than a distinct disease state. Nevertheless, the
impact of its symptoms on the patients, as well as the large
number of persons affected make this condition relevant,
irrespective of its moniker.
Besides the widespread pain and increased tenderness at specific nonarticular sites, additional symptomsnonrestorative sleep, severe fatigue, initable bowel syndrome, headache, and affective, anxiety, and somatoform
d i s o r d e r w c c u r with great frequency in patients with FM
(6). Such symptoms are not unique to FM. Other conditions
in which these symptoms commonly occur are chronic
fatigue syndrome and the syndrome of multiple chemical
sensitivities. Aside from the similar symptoms, these 3
conditions (fibromyalgia, chronic fatigue syndrome, multiple
chemical sensitivity) share several demographic, physical,
and laboratory features. All 3 disorders are idiopathic, and
all are associated with substantial disability. Because of their
similarity, it has been suggested that fibromyalgia, chronic
fatigue syndrome, and multiple chemical sensitivity may be
overlapping, if not identical, conditions (7,8). Indeed, the
particular diagnosis a patient receives may depend upon the
most prominent complaint at the time of diagnosis or the
experience and background of the physician the patient
initially encounters.
Recently, rather than using the somewhat pejorative
label “multiple chemical sensitivity” to classify patients,
Cohn has proposed the adoption of the label “multi-organ
dysesthesia” (9). I support this change, and propose it be
expanded to include the similar diagnoses of fibromyalgia
and chronic fatigue syndrome. In this way, patients fulfilling
criteria for fibromyalgia or chronic fatigue syndrome, or
those suspected of having multiple chemical sensitivity,
could be diagnosed instead as having multi-organ dysesthesia. In addition, patients could be subdivided based upon
their predominant symptoms. For example, those patients
satisfying ACR classification criteria for fibromyalgia could be
labeled MODFM (multiagan dysesthesia; fibromyalgia type).
Several benefits might be anticipated from such an
alteration in naming. Such a label would reinforce the
necessity for health caregivers to broaden their focus to
include the diverse symptoms these patients typically experience. Moreover, the pejorative connotations that have
sometimes been associated with each of the labels for these
somewhat ill-defined conditions would be removed. Perhaps
the greatest benefit, and the most compelling reason for the
proposed change, is that it would foster interaction among
the different specialties to whom these patients may present:
rheumatologists for fibromyalgia, allergists for multiple
chemical sensitivity, infectious disease specialists for
chronic fatigue syndrome, and gastroenterologists for irritable bowel syndrome. Such interactions among subspecialists
would be expected to be of substantial benefit in terms of
shared research. By combining what might be learned from
focusing on individual manifestations, substantial progress
would be anticipated in elucidating the pathophysiology,
181
evaluation, and optimal treatment of these similar, common
conditions.
Subspecialists have long been accused of restricting
their focus to individual organ systems while ignoring the
patient as a whole; much as the “blind men examining the
elephant. ” Unifying our classification of fibromyalgia,
chronic fatigue syndrome, and multiple chemical sensitivity
under the common label of multi-organ dysesthesia could
help in correcting that perception.
Arthur F. Kavanaugh, MD
University of Texas Southwestern Medical School
Dallas, TX
I . Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C,
Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P,
Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter M,
Hamaty D, Lessard J, Lichtbroun AS, Masi AT, McGain GA,
Reynolds WJ, Romano TJ, Russell IJ, Sheon RP: The American
College of Rheumatology 1990 criteria for the classification of
fibromyalgia:report of the multicenter criteria committee. Arthritis Rheum 33:160-172, 1990
2. Wolfe F: The epidemiology of fibrornyalgia. J Musculoskeletal
Pain 1:137-148, 1993
3. Makela M, Heliovaara M: Prevalence of primary fibromyalgia in
the Finnish population. Br Med J 303:216-219, 1991
4. Burkhardt CS, Clark SR, Bennett RM: Fibromyalgia and quality
of life: a comparative analysis. J Rheurnatol 20:1821-1824, 1993
5. Cohen ML, Quintner JL: Fibromyalgia syndrome, a problem of
tautology. Lancet 342:906-909, 1993
6. Wolfe F: Fibromyalgia, the clinical syndrome. Rheum Dis Clin
North Am 15:l-18, 1989
7. Goldenberg DL, Simms RW, Geiger A , Komaroff AK: High
frequency of fibromyalgia in patients with chronic fatigue seen in
a primary care practice. Arthritis Rheum 33:381-387, 1990
8. Buchwald D, Ganity D: Comparison of patients with chronic
fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Intern Med 154:2049-2053, 1994
9. Cohn JR: Multiple chemical sensitivity or multi-organ dysesthesia. J Allergy Clin Immunol 93:953-954, 1994
Synovial tissue responses following treatment of
rheumatoid arthritis with the humanized monoclonal
antibody CAMPATH-1H
To the Editor:
We read with interest the paper by Ruderman et al ( I )
describing changes in rheumatoid synovial tissue cells following therapy with the monoclonal antibody CAMPATH@1H. We have carried out a similar study, and have been able
to analyze a small number of synovial biopsies both before
and after exposure to the antibody.
Briefly, frozen sections (8 pm thickness) were cut
and processed for immunolocalization of CD3 (T cells), CD68
(macrophages), and CDw52 (CAMPATH- 1H antigen). Binding of the primary antibodies was detected following incubation with rabbit anti-mouse Ig, murine alkaline phosphatasel
anti-alkaline phosphatase complex, and substrate (naphthol
AS-MX phosphate coupled to fast red TR). In some experiments, dual fluorescence was used to determine surface
phenotype markers on CDw52-positive cells. This was carried out using fluorescein isothiocyanateconjugated F(ab’),
182
LETTERS
Table 1. Synovial biopsy findings before and after CAMPATH-IH therapy in 3 patients
Patient 1
Before
After
Patient 2
Before
After
Patient 3
Before
After
Time since
previous
Present
CAMPATH-IH
treatment
CAMPATH1H dose
Synovial cell scores
CD3
CD68
CDw52
Circulating
lymphocytes
at biopsy
lO’/liter)
Clinical
response
(X
6 months
-
10 mg IV
-
0
2
1
4
0
1
0.71
0.38
Poor
3 months
25mg/dayIV
( X 10days)
2
3
1
0.59
-
-
1
3
0
0.05
Good
1 month
60 mg IV
I
-
2
1
4
-
3
1
0.54
0.30
None
-
anti-CDw52 in association with the other antibodies visualized with tetramethyl rhodamine isothiocyanate-conjugated
second antibody.
Antigen expression was determined by estimating
the percent positivity for each marker, and scoring each
section from 0-4, as follows (2): 0 = marker absent, 1 =
<5% cells positive, 2 = 5-33% cells positive, 3 = 3 3 4 6 %
cells positive, and 4 = >66% cells positive.
All 3 patients reported here received CAMPATH-1H
by intravenous (IV) infusion as part of a multicenter, open,
dose-ranging study ( 3 ) . In 2 patients, matched pairs of
synovial biopsy samples were obtained before and 15 days
after a single IV infusion of CAMPATH-IH, and in the third
patient, before and 20 days after a IO-day course of daily
CAMPATH-1H infusions (see Table 1). Each patient had
previously received CAMPATH-1H infusions before the
initial synovial biopsy, with the intervening period varying
from 1-6 months.
In general, our results showed that, despite the
presence of very few mononuclear cells in the peripheral
circulation, significant numbers of T cells and, in particular,
macrophages remained in the synovium after IV infusion of
CAMPATH- 1H. The lymphocyte infiltrate scores were
lower than those reported by other investigators (21, perhaps
reflecting the exposure of our patients to the antibody prior
to biopsy. Essentially all the T lymphocytes present in the
synovial samples expressed CDw52, suggesting that failure
to deplete these cells was not due to lack of antigen expression. Our observations agree with those of Ruderman et a1
(I), in that no correlations could be found between the
numbers of circulating cells and the clinical response. Our
patient 2, who showed a marked decrease in CDw52-positive
cells in the synovium following CAMPATH-IH treatment,
was the only patient analyzed after receiving a course of
daily CAMPATH-1H infusions, and was also the only pa-
-
tient who demonstrated an unequivocal, good clinical response.
In conclusion, we agree with Ruderman and colleagues that monitoring peripheral blood mononuclear cell
numbers is not helpful in predicting the outcome of monoclonal antibody therapy, and does not address what is
happening in tissues such as the synovial membrane. Repeated infusions of such reagents may be required to deplete
tissue sites of infiltrating antigen-positive cells. Tantalizingly,
the one patient in this study in whom this was achieved using
CAMPATH- 1H showed a marked clinical improvement following antibody therapy, perhaps supporting the concept of
synovial T cell depletion as a valid therapeutic goal.
Bath Instirurefor Rheumatic Diseases receivedjinancial supporffor
this study .from Wellcome Research Laboratories. Beckenham. Kent, U K .
Enrique R. Soriano, MD
Jonathan Dixey, BSc
Nicolas D. Hall, PhD
Joan Davies, MB
Peter J. Maddison, MD
Bath Institute for Rheumatic Diseases
Bath, UK
1. Ruderman EM, Weinblatt ME, Thurmond LM, Pinkus GS,
Gravallese EM: Synovial tissue response to treatment with
CAMPATH-1H. Arthritis Rheum 38:25&258, 1995
2. Rooney M, Whelan A, Feighery C, Bresnihan B: Changes in
lymphocyte infiltration of the synovial membrane and the clinical
course of rheumatoid arthritis. Arthritis Rheum 32:361-369,
1989
3. Soriano E, Davies J, Maddison PJ, Hall ND: Preliminary experience with single infusion CAMPATH-IH in the treatment of refixtory rheumatoid arthritis (abstract). Br J Rheumatol32 (suppl 1):54,
1993
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humanized, treatment, response, following, monoclonal, arthritis, tissue, antibody, synovial, rheumatoid, campath
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