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Thyroidstimulating immunoglobulins in mixed type II cryoglobulinemia associated with thyrotoxicosis.

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acid, and ethionamide generally has been unsuccessful.
Although there have been no controlled or prospective
studies, recent clinical experience suggests that rifampin and
ethambutol is the drug combination of choice (2,5,6). The
optimum duration of therapy is unknown, but treatment for
a minimum of 3-6 months is usually required. Increased
awareness of the circumstances in which M marinum infections occur may result in early diagnosis, expeditious drug
therapy, and avoidance of the necessity for surgical intervention.
Michael Aubrey, MD, FRCP(C)
Adel G. Fam, MD, FRCP(C)
Sunnybrook Medical Centre
University of Toronto
Toronto, Ontario, Canada
I . Collins CH, Grange JM, Noble WC, Yates MD: Mycobacterium
marinum infections in man. J Hyg [Camb] 94: 135-149, 1985
2. Chow SP, Stroebel AB, Lau JHK, Collins RJ: Mycobacterium
marinum infection of the hand involving deep structures. J Hand
Surg [Am] 8568-573. 1983
3. Travis WD, Travis LB, Roberts GD, Su DW, Weiland LW: The
histopathologic spectrum in Mycobacterium marinum infection.
Arch Pathol Lab Med 109: 1109-1 113, 1985
4. Littlejohn GO, Dixon PL: Fish fancier's finger. J Rheumatot
11:390-391, 1984
5. Bailey JP, Stevens SJ, Bell WM, Mealing HG, Loebl DH, Cook
EH: Mycobacterium marinum infection: a fishy story. JAMA
247:1314, 1982
6. Donta ST, Smith PW, Levitz RE, Quintiliani R: Therapy of
Mycobacterium marinum infections: use of tetracyclines vs rifampin. Arch Intern Med 146:902-904, 1986
Thyroid-stimulating immunoglobulins in mixed (type
11) cryoglobulinemia associated with thyrotoxicosis
To the Editor:
Mixed cryoglobulinemia may occur in a variety of
lymphoproliferative, infectious, or autoimmune diseases (1).
In some cases, it has been possible to characterize the
antibody activity of the cryoglobulins. Thus, autoantibodies,
such as anti-DNA antibodies, or antibodies directed against
infectious agents, such as the hepatitis B virus (2), have been
demonstrated in isolated cryoglobulins. We describe a patient with mixed (type 11) cryoglobulinemia associated with
thyrotoxicosis. Analysis of the cryoprecipitate showed that
the same antibodies were probably involved in both diseases.
The patient, a 52-year-old woman, was admitted for
a nephrotic syndrome that was associated with moderate
renal failure. Eight months before admission, a diagnosis of
thyrotoxicosis had been made, and she took methimazole 20
mglday for 10 weeks. Physical examination disclosed arterial
hypertension (200/100 mm Hg), a thyroid goiter, ankle
edema, and purpura on both legs. Blood analyses revealed a
mixed cryoglobulin consisting of monoclonal IgMK and
polyclonal IgG, hypocomplementemia (CH5O 65% [normal
80-1201, C4 3 mgldl [normal 15-501, and C3 66 mgldl [normal
80-2001), a positive result on the latex fixation test (titer
I :2,5OO), an elevated erythrocyte sedimentation rate (40
m d h o u r [normal 1-18]), and moderate renal failure (blood
urea nitrogen 55 mg/dl and creatinine 1.5 mg/dl). Antinuclear, antithyroglobulin, and antimicrosomal antibodies
were absent, and a direct Coombs' test gave results that
were negative. Hyperthyroidism was still present: Levels of
triiodothyronine were 239 ng/dl (normal 85-195), and thyroid-stimulating hormone levels were undetectable. Urinalysis revealed granular casts and proteinuria (5.2 gm/day).
A renal biopsy showed membranoproliferative glomerulonephritis with hyaline thrombi in some capillaries. The
nephrotic syndrome was treated symptomatically with diuretics, and the proteinuria, as well as renal function,
remained stable. Administration of radioiodine brought her
thyroid function to normal. The persistence of cryoglobulinemia was associated with occasional episodes of purpura
over the following months.
Analysis of serum cryoglobulin (1.1 mg/ml) by immunoelectrophoresis and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) showed the presence
of IgM and IgG without other normal human serum proteins.
For isolation of the IgG and IgM components, the cryoprecipitate was solubilized in 0.1M acetic acid and applied to a
Sephadex (3200 filtration gel column (Pharmacia, Uppsala,
Sweden). Two peaks were obtained and dialyzed against
phosphate buffered saline. The IgM and the IgG fractions
were found to be homogeneous by SDS-PAGE analysis.
Rheumatoid factor activity, as assessed by a latex agglutination test, was present in the monoclonal IgM fraction and
absent in the IgG fraction. The thyroid-stimulating activity
of the IgG fraction was first evaluated in a biologic assay
based on the uptake of radioiodine by rat thyroid cells in
culture (3), and was compared with the thyroid-stimulating
activity of the IgG fraction of the patient's serum purified by
DEAE ion-exchange chromatography. The IgG fraction purified from a pool of sera from normal blood donors was used
as a control. Results presented in Table 1 indicate the
presence of thyroid-stimulating immunoglobulins concentrated in the cryoprecipitate, whereas other antithyroid
antibodies and thyroglobulin were undetectable in this cryoprecipitate. The thyroid-stimulating activity of the cryoimmunoglobulins was confirmed in a test based on CAMP
release by human thyroid cells.
Cryoglobulinemia and immune complex glomerulonephritis have been previously described in association with
Table 1. Antithyroid antibodies and thyroglobulin in serum and
antibodies (% "'I uptake)*
Antimicrosomal antibodies
Antith yroglobulin
Thyroglobulin (ng/ml)
* Assayed on FRTL-5 cells with IgG fractions at a concentration of
0.5 mg/ml.
autoimmune thyroid disease (4) and, in some of those
observations, thyroglobulin was identified as the antigenic
comiponent of the nephritogenic immune complexes (4). In
our patient, thyroglobulin was not involved in the formation
of the cryoglobulin which consisted of monoclonal IgMK
complexed with polyclonal IgG. The IgM component exhibited rheumatoid factor activity, which is a usual finding in
mixed (type 11) cryoglobulinemia (2). The demonstration of
thyroid-stimulating activity concentrated in the IgG fraction
would suggest that the same immunoglobulins are involved
in thle thyroid disease and in the cryoglobulinemia.
Indeed, thyroid-stimulating immunoglobulins are
known to play a major role in Graves’ disease, and the
formation of mixed (type 11) cryoglobulins is thought to
result from specific reactions between monoclonal IgM and
selected IgG molecules, with the possible participation of
idiotypic interactions (2). The simultaneous occurrence of a
monoclonal IgM rheumatoid factor and of cryoprecipitable
thyroid-stimulating immunoglobulins in this patient may be
fortuitous, but the possible role of B cell hyperactivity,
which has been shown to be associated with thyrotoxicosis
should be considered.
Michel Goldman, MD
Philippe Lambert, MT
Nicole Tasiaux, PhD
Pierre Vereerstraeten, MD
Jean-Pierre Sabot, MD
Yvette Thoua, MD
Charles Toussaint, MD
Hdpital Erasme
Brussels, Belgium
Stephen Bidey, MD
Middlesex Hospital
London, UK
1. Giorevic PD, Kassab HJ, Lev0 Y, Kohn R, Meltzer M, Prose P,
Franklin EC: Mixed cryoglobulinemia: clinical aspects and longterm follow-up of 40 patients. Am J Med 69:287-307, 1980
2. Geltner D, Franklin EC, Frangione B: Anti-idiotypic activity of
the IgM fraction of cryoglobulins. J Imrnunol 125: 1530-1535.
3. hlarcocci C, Valente WA, Pinchera A, Aloj SM, Kohn LD,
Ckollman EF: Graves’ IgG stimulation of iodide uptake in
FRTL-5 rat thyroid cells: a clinical assay complementingFRTL-5
assays measuring adenylate cyclase and growth-stimulatingantibodies in autoimmune thryoid disease. J Endocrinol Invest
6:463-471, 1983
4. J’ordanS, Buckingham B, Sakai R, Olson D: Studies of immunecomplex glomerulonephritis mediated by human thyroglobulin.
PI Engl J Med 304:1212-1215, 1981
5. Mori T: Increase of peripheral B lymphocytes in Graves’ disease.
Clin Exp Immunol42:33-37, 1980
Comment on article by Strauss et a1
To ,the Editor:
In an article in Arthritis and Rheumatism, Strauss et
al reported a lack of improvement in psychological symptoms of depression and anxiety in a group of patients with
rheumatoid arthritis (RA) (Strauss GD, Spiegel JS, Daniels
M, Spiegel T, Landsverk J, Roy-Byrne P, Edelstein C,
Ehlhardt J, Falke R, Hindin L, Zackler L: Group therapies
for rheumatoid arthritis: a controlled study of two approaches. Arthritis Rheum 29: 1203-1209,1986). This lack of
improvement may well be due to the lack of significant
symptoms to begin with.
The authors did not assess the presence of diagnosable depression or anxiety disorder. Their questionnaire was
not suitable for diagnostic purposes. No comparison was
made between the results on the depression and anxiety
scales in the study population (RA patients) versus a healthy
population. Thus, the scores attained by the RA patients,
which are near midpoint on the authors’ scale, could well
represent good mental health.
Before attempting to conduct research studies that
incorporate psychological treatments, investigators should
first determine whether significant psychological problems
exist in their subjects. The authors’ suggestion that medications might be tried next, without mentioning the need for
better assessment, is a cause for concern.
Saralynn H. Allaire, MS, RN
Boston University
Multipurpose Arthritis Center
Boston, M A
To the Editor:
Ms Allaire’s letter raises several important issues,
and these deserve further discussion. She is quite right that
my colleagues and I did not use any of the usual instruments
to assess depression and anxiety, such as the Beck (1) or
Hamilton depression scales (2) or the Spielberger Anxiety
Scale (3). Instead, we used items from the Arthritis Impact
Measurement Scales (AIMS) (4) and from the Rand Health
Insurance Study for Mental Health (5). We proceeded in this
manner for 2 reasons: 1) The anxiety and depression items
from the Rand study and AIMS were few, and we were
concerned about the physical burden to rheumatoid arthritis
(RA)patients in filling out an already lengthy written questionnaire; 2) The Rand study and AIMS scales were developed in general medical populations, as well as rheumatic
disease populations, and were therefore designed to be as
free as possible of items that might confound somatic symptoms of depression or anxiety with the symptoms of chronic
disease. Unfortunately, most of the commonly used selfreporting measures of’depression and anxiety suffer from
this limitation.
Ms Allaire suggests that our patients may not have
been depressed or anxious. While we would disagree that
our patients’ baseline scores represented “good mental
health,” it is true that depression, anxiety, and pain scores
were less extreme in this ambulatory population than were
those found with the same scales in a study of RA patients
admitted to an inpatient rehabilitation unit (6). The pain and
physical activity scores at baseline, however, suggest that
our study population was not a mildly affected or symptomfree group of RA patients.
A point related to those raised by Ms Allaire is the
virtual absence of data in the literature on the relation of
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associates, immunoglobulin, typed, thyroidstimulating, mixed, thyrotoxicosis, cryoglobulinemia
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