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Penicillin in the treatment of Beh┬зet's diseaseComment on the article by бalgUneri et al.

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LETTERS
1728
with a normal ESR, the response to corticosteroids may hold
greater clinical utility in determining the diagnosis of PMR.
Simon M. Helfgott, MD
Haward Medical School
Boston, M A
Raphael I. Kieval, MD
Brockton Hospital
Brockton, M A
1. Jones JG, Hazleman BL: ESR in polymyalgia rheumaticd and
giant cell arteritis. Ann Rheum Dis 42:702-703, 1983
2. Ellis ME, Ralston S: The ESR in the diagnosis and management of
the polymyalgiaigiant cell arteritis syndrome. Ann Rheum Dis
421168-170, 1983
3. Gonzalez-Gay MA, Rodriguez-Valvarde V, Bianco R, FernandezSueiro JL, Armona J, Figueroa M, Martinez-Taboada VM: Polymyalgia rheumatica without significantly increased erythrocyte
sedimentation rate. Arch Intern Med 157:317-320, 1997
4. Olsson AT, Elling H, Elling P: Frequency of a normal erythrocyte
sedimentation rate in patients with active, untreated arteritis
temporalis and polymyalgia rheumatica: comment on the article by
Helfgott and Kieval (letter). Arthritis Rheum 40:191-192, 1997
5. Kyle V, Cawston TE, Hazleman BL: Erythrocyte sedimentation
rate and C-reactive protein in the assessment of polymyalgia
rheumatica giant cell arteritis presentation and during follow-up.
Ann Rheum Dis 48:667-671, 1989
6. Spector TD, Hart DJ, Nandra D, Doyle DV, Mackillop N,
Gallimore JR, Pepys MB: Low-level increases in serum C-reactive
protein are present in early osteoarthritis of the knee and predict
progressive disease. Arthritis Rheum 40:723-727, 1997
7 . Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens
CH: Inflammation. aspirin, and the risk of cardiovascular disease
in apparently healthy men. N Engl J Med 336373-979, 1997
8. Kuller LH, Tracy RP, Shaten J, Mellahn EN: Relationship of
C-reactive protein and coronary heart disease in the MRFIT
nested case control study. Am J Epidemiol 144:537-547, 1996
9. Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo
JCW: Hemostatic factors and the risk of myocardial infarction or
sudden death in patients with angina pectoris. N Engl J Med
332:635-641, 1995
10. Salvarani C, Boiardi C, Macchioni G, Olivieri I, Portioli I:
Polymyalgia rheumatica (letter). Lancet 348:550-551, 1996
Penicillin in the treatment of Behget’s disease:
comment on the article by Calgiineri et al
To the Editor:
We read with great interest the article by Calgiineri et
a1 on penicillin treatment of BehEet’s disease (BD) (1). They
compared the efficacy of colchicine alone versus colchicine
plus penicillin in the prophylaxis of recurrent arthritis of BD.
The etiology of BD has not yet been definitely established (2). Although viruses, environmental factors, racial and
familial tendency, and autoimmunity have been implicated in
the pathogenesis of the disease, none of these factors has been
proven to be causative. It has been emphasized in recent years
that the manifestations of the disease are due to humoral and
cell-mediated immune reactions against streptococcal infections (3,4). We have made an interesting observation on the
interrelationship between streptococcal infections and BD
symptomatology (5). We observed 2 patients with BD who
developed chronic neutropenia. The manifestations of BD,
such as orogenital ulcers, erythema nodosum, papulopustular
skin lesions, and arthritis, had shown exacerbations following
attacks with these pathogens. We assumed that recurrent
streptococcal infections were the result of decreased immunity
caused by the neutropenic state. We treated these patients with
granulocyte colony-stimulating factor to increase absolute neutrophil counts. With this treatment, neutrophil counts returned
to normal and streptococcal infections did not recur. With the
disappearance of recurrent streptococcal infections, the attack
rates of BD decreased considerably. We believe that, rather
than being a direct etiologic factor, streptococcal infections
have a permissive action for the recurrence of the manifestations of BD.
The proposed relationship between BD and streptococcal infections is the rationale for the use of penicillin. We
wish to share our own experience with the use of penicillin in
BD. Since 1988, we have been prescribing benzathine penicillin
(1.2 million units intramuscularly every 3 weeks) alone or in
combination with colchicine (1.5 mgiday orally). We reported
our preliminary results at the Mediterranean Congress of
Rheumatology meeting held in Athens, Greece in 1994 (6).
Although penicillin was effective in the prevention of articular
attacks, its effect was more marked in the prophylaxis of oral
and genital ulcers.
Since no definite therapy is established in BD, new
agents are being evaluated. Interferon is gaining popularity for
its antiviral and immunomodulatory properties ( 7 ) . In another
study evaluating the role of interferon, we showed that this
agent was more effective than penicillin in the treatment and
prophylaxis of vascular and ocular complications (8).
Penicillin is a new agent for BD, and further studies are
required to definitely establish its role in the management of
the disease. The only convincing proof that streptococcal
infections are the cause of BD would be the documentation of
disappearance of all manifestations of the disease with antistreptococcal therapy alone. The cause-and-effect relationship
between streptococcal infections and BD is not as definite as in
the case of acute rheumatic fever and p-hemolytic streptococci.
In the latter interaction, penicillin prophylaxis will completely
prevent recurrent attacks. However, the effect of prophylactic
penicillin in the prevention of arthritis attacks in BD is not as
dramatic as that seen in acute rheumatic fever. Moreover, it
has no effect in the prevention of vascular and ocular disease
(6). Vascular involvement such as deep vein thrombosis and
ocular lesions seems to occur more commonly in patients who
are 5 3 0 years of age, have central nervous system disease, and
are within the first 2 years of disease onset (Y-11).
At present, we suggest that penicillin should especially
not be prescribed to patients who are at high risk for vascular
and ocular involvement. However, in patients with mucocutaneous lesions and articular manifestations dominating the
clinical picture, a trial with benzathine penicillin alone or in
combination with colchicine may be justified.
HalClk Demiroglu, MD
Semra Dundar, MD
Hacettepe University Medical School
Ankara, Turkey
1. Calguneri M, Kiraz S, Ertenli I, Benekli M, Karaarslan Y, Celik I:
The effect of prophylactic penicillin treatment on the course of
1729
LETTERS
arthritis episodes in patients with Behqet’s disease: a randomized
clinical trial. Arthritis Rheum 39:2062-2065, 1996
2. O’Duffy JD: Behcet’s disease. Curr Opin Rheumatol 6:39-43,
1994
3. The BehGet’s Disease Research Committee of Japan: Skin hypersensitivity to streptococcal antigens and the induction of systemic
symptoms by the antigens in Behqet’s disease-a multicenter
study. J Rheumatol 16:506-511, 1989
4. Namba K, Ogawa T: Antibody titer to streptococcal L-form in
Behqet’s disease. In, Behcet’s Disease-Basic and Clinical Aspects. Edited by JD O’Duffy, E Kokmen. New York, Marcel
Dekker, 1991
5. Demiroglu H, Diindar S: Behqet’s disease and chronic neutropenia. Scand J Rheumatol 26:130;132, 1997
6. Haznedaroglu IC, Demiroglu H, Ozcebe 01, Ozdemir 0, Diindar
SV: Benzathine penicillin in the prophylaxis and treatment of
Behget’s disease. In, Proceedings of the Seventh Mediterranean
Congress of Rheumatology, Athens (Greece). Edited by KA Boki,
AA Drosos, HM Moutsopoulos, AG Tzioufas, PG Vlachoyiannopoulos. Bologna, Monduzzi Editore, 1994
7. Alpsoy E, Yilmaz E, BaSaran E: Interferon therapy for Behcet’s
disease. J Am Acad Dermatol 31:617-61.9, 1994
8. Diindar S, Demiroglu H, Ozcebe 0, Ozdemir 0, CaliSkan S,
Eldem B: Alpha interferon in Behqet’s disease. Hematol Rev
9~285-290, 1996
9. Demiroglu H, BariSta I, Diindar S: Assessing the risk of deep vein
thrombosis in Behqet’s disease. Thromb Res 84:297-298, 1996
10. Demiroglu H, BariSta I, Dundar S: Risk factor assessment and
prognosis of eye involvement in BehGet’s disease in Turkey.
Ophthalmology 104:701-705, 1997
11. Demiroglu H, Diindar S: Effects of age, sex, and initial presentation on the clinical course of Behqet’s syndrome. South Med J
90567, 1997
,,
Reply
To the Editor:
We appreciate the comments of Demiroglu and
Dundar concerning our trial of prophylactic penicillin in BD.
They describe 2 BD patients who were given recombinant
granulocyte colony-stimulating factor (G-CSF) for the coexistent neutropenia, and G-CSF was observed to be effective for
the treatment of streptococcal infection in these patients. As
the authors also state, in contrast to acute rheumatic fever, no
direct causal relationship with overt streptococcal infection in
BD exists; rather, disease symptoms are often triggered or
exacerbated by occult streptococcal antigenemia (1,2). G-CSF
might be beneficial in such cases of incidental neutropenia in
BD. However, considering the still-unclarified pathogenetic
mechanisms of BD and the neutrophilic hyperfunction suggested to be responsible for many of the clinical manifestations
of the disease (3), further amplification of already augmented
leukocyte functions by G-CSF may, in fact, lead to deleterious
consequences.
Mucocutaneous manifestations, which also constitute
the classification criteria for BD, are the most frequent and
presenting symptoms of BD (4). Because of the growing
evidence that exposure to streptococcal antigens may be a
major initiating and/or provoking factor for BD, we formerly
instituted a randomized trial of colchicine with or without
benzathine penicillin for the prophylaxis of mucocutaneous
manifestations in BD, and observed a reduced frequency of
mucocutaneous symptoms in the penicillin group (5). In our
most recent study, prophylactic penicillin was further documented to offer adjunctive benefits in the prevention of
arthritis episodes in BD. Being the first in the literature, the
results of our 2 randomized trials could be accepted as
additional evidence for a streptococcal antigen-triggered
pathogenetic explanation for BD. Therefore, one could expect
prophylactic penicillin to also be beneficial in treating the
other manifestations of BD, including vascular, neurologic,
and ocular symptoms, as we have observed by using prophylactic penicillin in our BD patients since 1985 (a randomized
trial is still in progress). At present, we prefer to utilize
adjunctive prophylactic penicillin for all BD patients at the
time of diagnosis in our clinic, since it is an agent that is
inexpensive, safe, and effective for mucocutaneous and arthritic
symptoms. The treatment of BD activation episodes encountered
during followup is managed by appropriate multimodal therapeutic options, depending on the system involved.
In contrast to the mucocutaneous and arthritic manifestations, vascular and ocular involvement can lead to more
disabling and even life-threatening symptoms in BD. Although
Diindar et a1 argue for interferon monotherapy to alleviate
mucocutaneous, arthritic, and ocular symptoms based on the
results of their open trial ( 6 ) , further recurrent vascular events
are still the major cause of morbidity and mortality in BD. The
high therapeutic cost and serious side effect profiles of the
currently available immunosuppressive agents, which leads to a
dubious cost-benefit ratio, and the lack of randomized clinical
trials make it difficult to recommend the long-term use of these
agents for the prophylaxis of vascular complications of BD.
Since vasculitic manifestations could be encountered at any
time during the natural course of disease, it is of utmost
importance to prevent these complications, and the settlement
of such a therapy would be an evolutionary step in BD.
Moreover, one would be eager to administer such a safe and
potentially efficacious agent to all BD patients, rather than try
to determine an arbitrary discrimination of high-risk patients.
Meral Calguneri, MD
Sedat Kiraz, MD
Ihsan Ertenli, MD
Mustafa Benekli, MD
YaSar Karaarslan, MD
Ismail Celik, MD
Hacettepe University
Ankara, Turkey
1. Mizushima Y, Matsuda T, Hoshi K, Ohno S: Induction of Behqet’s
2.
3.
4.
5.
disease symptoms after dental treatment and streptococcal antigen
skin test. J Rheumatol 15:1029-1030, 1988
Namba K, Ueno T, Okita M: BehGet’s disease and streptococcal
infection. Jpn J Ophthalmol 30:385-401, 1986
Niwa Y, Mizushima Y: Neutrophil-potentiating factors released
from stimulated lymphocytes; special reference to the increase in
neutrophil-potentiating factors from streptococcus-stimulated
lymphocytes of patients with Behset’s disease. Clin Exp Immunoi
79:353-360, 1990
International Study Group for Behqet’s disease: Criteria for diagnosis of Behqet’s disease. Lancet 335:1078-1080, 1990
Calgiineri M, Ertenli I, Kiraz S, Erman M, Celik I: Effect of
prophylactic benzathine penicillin on mucocutaneous symptoms of
Behqet’s disease. Dermatology 192:125-128, 1996
1730
6. Dundar S, Demiroglu H, Ozcebe 0, Ozdemir 0,CaliSkan S, Eldem
B: Alpha interferon in BehGet’s disease. Hematol Rev 9:285-290,
1996
Analytic review of the scientific literature on silicone
immune responses: comment on the article by Marcus
To the Editor:
In a recently published review article (l), Marcus raises
several subjective points that warrant response. First, he states
that silica has been associated with induction of autoimmune
syndromes including scleroderma, but he also says that crystalline silica comes from neither the amorphous silica in the
implant nor silicone degrading to silica. He fails to cite at least
2 studies that demonstrated conclusively that silicone degrades
to silica in nature in the presence of water (2,3). Why should he
consider the complex potential of biologic systems to be more
protective? In addition, polarized microscopy of various tissues
from silicone breast implant patients often shows birefringent
crystals that are morphologically consistent with crystalline
silica and identical to those seen in occupational silicotic
tissues (43). Neither silicone nor amorphous silica is made
visible by this technique.
Marcus refers to studies by Chang (6) and by Brantley
et al (7) as providing evidence of a lack of immune responsiveness; both were published in a plastic surgery journal not
commonly read by immunologists. Nevertheless, he uses these
2 reports to criticize other studies that independently showed
positive responses. Chang’s report, which was poorly written,
had significant limitations such as small numbers of animals
studied (only 7), inappropriate controls, short time periods (16
days), and uninterpretable low volumes of silicone administered. Chang also failed to examine the tissue microscopically,
and only looked at the animals grossly. Objectively, this study,
funded by a silicone devices manufacturer, failed to fit Marcus’
outline of rigorous professional standards. The results of this
study also are in direct conflict with those of a similar study by
Yoshino (8), who found both acute and chronic arthritis and T
cell response in an animal model; Yoshino’s manuscript was
reviewed by and published in an internationally recognized
immunology journal. In studies of proliferative response to
silicone, Brantley and colleagues (7) demonstrated thymidine
counts per minute in a positive control to be actually less than
background counts. The background counts varied from 500 to
>10,000 cpm. This study was short-term, had limited sample
size, and the mitogen controls had cpm varying from 7,500 to
nearly 100,000, technically unacceptable results. A controlled
study would have provided consistency in isotope labeling,
pulsing time, and other technical features; the extensive variation of background and control counts raises questions about
this study. Analytic review for editorial purposes should be
balanced.
With regard to our study (9), Marcus considers the
background thymidine incorporation to be lower than is usually attained with automated harvest techniques (1). O u r
report stated clearly that we used a manual washing and
harvest method, the predecessor of the semiautomated and
automated harvest systems. One should expect the counts to be
lower when washing the unincorporated isotope from the cells
before harvest to the filter. Automated methods wash the
unincorporated isotope through the filter, which traps some,
LETTERS
raising the background counts. Second, Marcus states that no
recall antigen was used in our study; however, this is neither
required nor necessary in seeking the differences between two
populations, one silicone exposed and the other not exposed.
The major point of our study was that there is a significant
difference between the T cell response to silicon dioxide in
implant recipients and that in controls, regardless of background or harvest technique. Recall antigens have no effect on
the response in testing for putative agent responses. Further
study of these effects shows they are T cells by immunophenotyping (lo), that the reactions can be blocked by antibody to
interleukin-2 (ll), and that the implant population did not
respond to other common provocative agents such as beryllium
or titanium (11).
Marcus also cites a non-peer-reviewed letter to the
editor by Young (12) that appeared last year in a plastic
surgery journal. The letter, as Marcus reviews it, stated that
saline implant recipients showed positive T cell responses to
stimulation by silicon dioxide. However, it should be noted that
the outer shell of the saline implant is silicone surface, particle
shedding is common, and T cell response in non-gel implants
has been reported by others (13). Basically, the letter stated
that of the 6 alleged patients who were not breast implant
recipients, 1 did have another type of silicone implant, and the
author failed to review the possibilities of other silicaceous
exposures in the other subjects, e.g., from tuba1 ligation
clamps, stents, or other devices or environmentalioccupational
exposures. Given the fact that hundreds of normal controls
have been tested in our system and were found to be nonreactive to silica, it is unlikely that one could select a responsive
population as well as Young did without prior thought as to
exposure. In addition, had Young been correct in his speculation of proliferative response to silicon dioxide in anyone, this
would be considered evidence of a mitogenic response, and no
one would knowingly place a mitogen in the human body.
This letter is not an appropriate forum by which to
review all corroborating data on immune responses to siliconbased molecules. Studies conducted since 1980 have demonstrated a lymphocyte stimulation role of silicon-based substances. Most of these studies have been published in either
immunology journals or other outstanding scientific journals.
A list of the articles can be made available upon request.
Finally, can an objective scientist neglect the fact that chronic
inflammatory reactions are found in at least 90% of tissue
where silicone and its metabolites are located (14), and the fact
that many patients’ biopsies demonstrate immune vasculitis (a
pathognomonic lesion of autoimmunity)? We agree that further studies are necessary to define the details of these
reactions, but scientific fact is based on reproducible, independent studies, whether by the same or similar technique. The
fact that numerous independent studics from several countries,
that have been peer-reviewed and published in good scientific
format, have all reached the same conclusion is determinative:
silicon-based molecules do elicit cellular immune reactions.
Both authors have served as expert witnesses in silicone implant
cases in the past, mainly forplaintiffs. Dr. Smalley has testified in court in
3 cases in 4 years, Dr. Shanklin in 5 cases in I 1 years.
David L. Smalley, PhD
Douglas R. Shanklin, MD, FRSM
University of Tennessee
Memphis, TN
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