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Thoracic Duct Drainage in Sle with Cutaneous Vasculitis.

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1129
THORACIC DUCT DRAINAGE IN SLE
WITH CUTANEOUS VASCULITIS
A CASE REPORT
KENNETH E. NYMAN, RUTH BANGERT, HERBERT MACHLEDER. and HAROLD E. PAULUS
A 25-year-old woman had systemic lupus erythematosus manifested primarily by severe cutaneous
vasculitis that was unresponsive to oral prednisone and
azathioprine. She was treated with thoracic duct drainage
(TDD). Her course was followed by serial photographs,
skin biopsies, and serum immunoglobulin, antinuclear antibody, and complement levels. After 1 week of drainage
there was obvious clinical improvement. During the remainder of her drainage, the vasculitis continued to improve. It was possible to taper oral corticosteroids and to
discontinue azathioprine during TDD without any clinical
or laboratory evidence of exacerbation. The patient had
no recurrence of vasculitis 22 weeks after the termination
of TDD.
We report a patient with systemic lupus erythematosus (SLE) with severe cutaneous vasculitis
who was treated with prolonged thoracic duct drainage.
To our knowledge this is the first reported case of SLE
with cutaneous vasculitis successfully treated with thoFrom the Departments of Medicine and Surgery, UCLA
School of Medicine, Los Angeles. California.
Supported by USPHS grants G M 15759 and RR-865.
Kenneth E. Nyman, M.D.: Adjunct Assistant Professor of
Medicine, UCLA. and Chief Medical Resident, Sepulveda VA Hospital; Ruth Bangert, R.N.: Staff Nurse, UCLA; Herbert 1. Machleder.
M.D.: Associate Professor of Surgery, UCLA; Harold E. Paulus.
M.D.: Associate Professor of Medicine, UCLA.
Address reprint requests to Harold E. Paulus, M.D., Department of Medicine, UCLA School of Medicine, 1000 Veteran Avenue,
Los Angeles, California 90024.
Submitted for publication November 17, 1976; accepted December 21, 1976.
Arthritis and Rheumatism, Vol. 20, No. 5 (June 1977)
rack duct drainage (TDD). Two patients with SLE have
been treated for arthritic complaints with T D D for 8
days by Olhagen and Franksson (1); joint pain and
synovitis subsided during the period of drainage but
recurred with its termination.
T D D was considered for the treatment of cutaneous vasculitis in this patient for the following reasons. Cutaneous vasculitis is a well-recognized manifestation of SLE. It is particularly suited for serial study
because of the ready availability of skin for photography
and biopsy. Deposition of immune complexes and complement in blood vessel walls, in the connective tissue of
the subepidermal papillae, at the dermal-epidermal
junction, and in the nuclei of the deeper layer of the
epidermis has been described in SLE (2,3). These immune complex deposits at the dermal-epidermal junction and in vessel walls may play a pathogenic role.
Gilliam et a1 (4) have reported the disappearance of
immunoglobulin deposits at the dermal-epidermal junction in the uninvolved skin of patients with SLE treated
with immunosuppressive doses of cyclophosphamide.
These observations suggested that immunosuppression
by lymphocyte depletion via thoracic duct drainage may
be effective therapy and could help to delineate the role
of thoracic duct lymphocytes in this condition. Lymphocyte depletion previously has been demonstrated to
produce a significant immunosuppressive effect on various immune system responses (5-12).
Photographs, skin biopsies studied by light microscopy and immunofluorescence, antinuclear antibody titers, anti-DNA binding, B,C component of
NYMAN ET AL
1130
complement, total hemolytic complement, and serum
immunoglobulin levels were followed serially t o d e m o n strate the pattern of clinical improvement and t o correlate various changes in laboratory p a r a m e t e r s and histologic studies. The sera was frozen and t h e assay for
antinuclear a n t i b o d y titers, a n t i - D N A binding, and serum immunoglobulin levels were done a t the same time.
A 21-year-old woman was first admitted to the UCLA
Center for the Health Sciences on April 4, 1972, with a history
of recent onset of myalgia, episodic fever, and tenderness of
her left pinna. She had painful ulcerated lesions in her nose
and mouth, an erythematous maculopapular eruption in the
malar distribution and over the trunk, and tender purpuric
lesions on the palmar surface of the hands. Laboratory examination revealed anemia, leukopenia, a positive direct
Coombs’ test, ANA 1:16 (normal 0). anti-DNA 17% (normal
0-20%), B,C 40 (normal 123-167), and normal renal function.
Skin biopsy revealed hyperkeratosis, parakeratosis, follicular
plugging, atrophy, liquefactive degeneration, and perivascular
degeneration consistent with SLE. Prednisone in a dosage of
60 mg every other day was begun at this time.
Over the next 2 years her clinical course included progressive cutaneous vasculitis, recurrent abdominal pain, fever,
arthralgia, arthritis, proteinuria with normal renal function,
and grand ma1 seizures. A percutaneous renal biopsy was done
in July 1973 and a careful review determined that the patient
had membraneous glomerulonephritis. Since September 1974
she manifested severe and incapacitating cutaneous vasculitis
involving her buccal mucosa, nasal mucosa, and the skin of
her face, forearms, and hands (Figure 1). Varying doses of
prednisone (up to 120 mg/day) and azathioprine (200
mg/day) were not successful in controlling her disease.
Azathioprine was discontinued on October 6, 1975, and the
patient was hospitalized on October 20 for baseline studies in
preparation for T D D . Because of failure to control the pa-
Fig 1A. The patient 2 months before the initiation of thoracic duct
drainage.
Fig 18. The patient l l weeks after the completion of thoracic duct
drainage.
CASE REPORT
THORACIC DUCT DRAINAGE IN SLE
Fig 1C. Serial photographs of patient's left middle, ring, and little fingers: 1219175-1 week a f e r ihe
initiation of thoracic duct drainage; 12/19/75-at ihe end of the second week of thoracic duct drainage;
2/26/76-in the eighth week of drainage; and 513176-11 weeks after the compleiion of thoracic duct
drainage.
Fig ID. Serial photographs of the patient's right hypothenar eminence; 12/9/75--1 week aJer the initiation
of thoracic duct drainage: 12/19/75-ai the end of the second week of thoracic duct drainage; 1/27/76-in
the seventh week of thoracic duct drainage: and 5/3/76--11 weeks a f e r the completion of thoracic duct
drainage.
1131
N Y M A N ET AL
1132
tient's disease activity and the recognized dangers and complications associated with long-term oral corticosteroid and
azathioprine administration, it was decided to initiate TDD.
On December 2, 1975, the thoracic duct was surgically
cannulated with a double-barreled cannula, through one lumen of which was administered a small volume of preservative-free heparin; through the other lumen the lymph was
collected in a sterile iced flask. Each morning the prior 24-hour
collection of lymph was removed and the sterile flask replaced.
The volume of lymph in any one 24-hour period ranged from
11 10 to 3460 ml. The number of lymphocytes drained per day
ranged from 200 X 108 to 33 X 108 cells. At the end of 10 weeks
of drainage, 277.8 X 108 lymphocytes had been removed from
the patient. The lymph was centrifuged in a sterile, continuous
flow centrifuge to remove the lymphocytes, and the cell-free
lymph was returned to the patient 24 hours later through
another cannula, which had been inserted into the left external
jugular vein.
After 1 week of TDD. there was obvious clinical improvement. During the remainder of the drainage procedure,
the cutaneous vasculitis continued to improve and it was possible to reduce steroid treatment to 60 mg every other day.
During the period of thoracic duct drainage, there was no
clinical evidence of change in the patient's lupus nephritis as
determined by serial 24-hour urinary protein, creatinine clearance, and pre- and postdrainage renal biopsies.
The patient has had three percutaneous renal biopsies.
The first biopsy was performed on July 6, 1973, and revealed a
generalized segmental proliferative glomerulonephritis. Immunofluorescence studies showed anti-IgG (2+-3+), diffuse,
linear; anti-lgA (2+) diffuse, fine, granular: anti-IgM (2+)
diffuse, fine, granular; anti-B,C (3+-4+) diffuse, linear to very
fine granular; antifibrinogen (1+-2+) diffuse, fine, granular.
Electron microscopy revealed a segmental axial or mesangial
glomerular sclerosis with minimal increase in cells, particularly
mesangial. Most areas of glomeruli appeared unremarkable
with intact epithelial cells and endothelial cells as well as a thin
basement membrane. Only the localized sclerotic areas and
rarely a capillary loop contained dense deposits which were in
the mesangial and subepithelial regions.
The second (predrainage) renal biopsy was performed
on October 23, 1975. Light microscopy disclosed 14-21
glomeruli, none of which was completely hyalinized. There
was a diffuse uniform thickening in mesangial nuclei with a
minor increase in mesangial matrix in the same areas. Occasional synechial adhesions were present and there was a focal
mild increase in epithelial cells, but actual crescent formation
was not evident. Small localized areas of tubular atrophy were
associated with slightly increased amounts of interstitial fibrous tissue and a few mononuclear cells.
Immunofluorescent studies demonstrated diffuse,
granular glomerular basement membrane deposition of IgG in
2+ intensity, C, in 2+ intensity, and IgM in trace intensity.
Focal granular deposits of IgG were detected in tubular basement membranes. Focal linear deposits of C, were also detected on tubular basement membranes. Electron micrographs
revealed dense subepithelial deposits that appeared to extend
into and be incorporated within the basement membrane itself.
Irregular projections or spikes of basement membrane material extended outward among the deposits, sometimes lying
directly beneath the cytoplasm. In some instances the lamina
densa was evident. The lamina rara interna appeared intact.
Epithelial cells showed irregular loss of foot processes. Endothelial cells were somewhat swollen and frequently contained
vesicular and tubular virus-like particles.
The third (postdrainage) renal biopsy was performed
on February 24, 1976, and revealed changes essentially the
same as those found in the biopsy of October 23, 1975.
TDD was discontinued after 10 weeks because of positive cultures of lymph and blood for Cundidu vini. Although
asymptomatic, the patient was treated with 1 g of parenteral
amphotericin 9. Subsequently, she has been followed as an
outpatient with no clinical evidence of disease activity. A fullthickness skin graft from the patient's father (a D match)
remained viable for 13 weeks after drainage, but then was
rejected. Twenty-two weeks after the termination of thoracic
duct drainage and 14 weeks after the completion of administration of amphotericin 9, the patient has had no recurrence of
cutaneous vasculitis, although she has not been particularly
careful about avoiding sun exposure. She has been able to
return to work and resume horseback riding, while continuing
to take 60 mg of prednisone every other day.
Results of serial laboratory evaluations are presented
in Figures 2, 3, and 4.
DISCUSSION
The series of events leading to cutaneous vasculitis in SLE remains unexplained. Deposition of immune
complexes and complement in blood vessel walls and at
the dermal-epidermal junction may play a pathogenic
role in this process. With prolonged thoracic duct drainage, there was decreased immunoglobulin deposition in
involved and uninvolved skin. I n lesions, first there was
3+ continuous staining for both IgG and B,C. After 10
weeks there was no longer any lesion tissue to biopsy.
Uninvolved skin initially demonstrated 2+ continuous
staining for IgG and 1 focal deposition of B,C. At n o
time, either in involved or uninvolved skin, was there
immunofluorescence for IgM.
Recent reports (13,14) suggest that our patient
should have progressive renal disease because she had
IgG (rather than I g M ) staining a t the dermal-epidermal
junction. However she has membranous glomerulonephritis a n d has had a rather benign course with respect to renal disease. It may be that in our patient the
finding of predominantly IgG at the dermal-epidermal
junction is a n indicator of active dermatitis rather than
progressive nephritis. As Figure 2 shows, decreased deposition of IgG and B,C closely paralleled the clinical
course.
As expected in a patient with active lupus dermatitis, serum B,C was markedly depressed initially (Figure 3) and for 4 years had been in a range of 40-60
mg/dl. It rose immediately after initiation of drainage,
anticipating the observed clinical improvement. In con-
+
1133
THORACIC DUCT DRAINAGE IN SLE
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Fig 2. Clinical activity of cutaneous vasculitis and immunojluorescent
staining (for IgG and B,C) of tissue from cutaneous lesions, evaluated on
serial examinations before, during, and after thoracic duct drainage. The
severity index of cutaneous vasculitis is in arbitrary units from 0 to 4+ (0
= no activity. 4+ = marked activity). The intensity index ofjluorescence is in arbitrary units from 0 to 5 (0 = no jluorescence. 5 =
maximum fluorescence.)
,
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6
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WEEKS AFTER
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Fig 3. Serum concentration of B,C and A N A titer evaluated on serial
determinations before, during, and after thoracic duct drainage.
in serum total and B,C component of total complement.
At that time the patient was not immunosuppressed.
With further diversion of thoracic duct lymphocytes, a
decrease in the deposition of immune complexes in the
skin was associated with further clinical improvement
50.
d
2
40.
30.
trast, ANA titer did not parallel the clinical course; it
did not fall at all during the first 8 weeks of drainage and
became negative only at the end of drainage, when the
patient was markedly immunosuppressed (Figure 3).
The expected decrease in immunoglobulin concentration during TDD, with a rise at the cessation of
drainage, was seen with IgG and IgM (Figure 4).The
results for IgA are surprising; it was undetectable prior
to and early in drainage, but became detectable late in
drainage and has remained so since. Although the reasons for this behavior are unknown, one can speculate
that T D D may have depleted a subpopulation of "suppressor" T cells that were inhibiting "IgA-committed" B
cells. A similar explanation may be postulated to explain
the change from a positive to a negative ANA-i.e.,
with drainage there was either loss of a subpopulation of
B cells committed to ANA production, or a loss of a
population of helper T cells that were essential to the
production of ANA by B cells.
Initially during thoracic duct drainage there was
clinical improvement that was associated with increases
20.
10.
0'
,
1Wl
muiw
m
c
mm
I
I
YEEKscf
DRAINAGE
!
MTLR
DRAINAGE
WE*,
ORIIM6E
Fig 4. Serum concentrations of IgA, IgG, and IgM evaluated on serial
determinations before, during, and after thoracic duct drainage.
NYMAN ET AL
I I34
b u t little, if any, immunosuppression. With prolonged
drainage there w a s m a r k e d immunosuppression, which
was demonstrated by prolonged skin graft survival a n d
was associated with decreasing titers of A N A , which
eventually become negative.
We conclude t h a t s o m e of t h e lymphocytes circulating in t h e thoracic d u c t m a y b e i m p o r t a n t particip a n t s in processes leading t o cutaneous vasculitis in
SLE, and t h a t mechanical removal o f these cells may be
associated with t e m p o r a r y clinical improvement.
ACKNOWLEDGMENTS
The authors thank E. Robert Harris, M.D., who referred and continues to care for the patient; Lillian Rosenthal
for the immunofluorescent studies of the skin biopsies; and
Pauline Tu, Betty Elliott, and the nurses of the UCLA Clinical
Research Center for their conscientious management of the
cannulas and lymph.
REFERENCES
Olhagen B, Franksson C: Immediate effects of lymph
drainage in systemic lupus erythematosus. Xlth International Congress of Rheumatology, Mar del Plata, 1965.
pp 265-266 (abstr)
Dubois EL: Lupus Erythematosus. Second edition. Los
Angeles, University of Southern California Press, 1974,
pp 228-230
Shulman LE, Harvey AM: Systemic lupus erythematosus,
Arthritis and Allied Conditions. Eighth edition. Edited by
J L Hollander, DJ McCarty. Philadelphia, Lea & Febiger,
1972, pp 893-917
Gilliam J N , Hurd ER, Ziff M: Immunoglobulin i n clinically uninvolved skin in systemic lupus erythematosus:
Effect of immunosuppressive therapy. J Rheumatol 1: 4,
1974 (suppl 1 )
5. Paulus HE, Machleder HI, Bangert R, et al: A case report:
thoracic duct lymphocyte drainage in rheumatoid arthritis. Clin Immunol lmmunopathol 1:173-181, 1973
6. Shellam GR: Mechanism of induction of immunological
tolerance. VI. Tolerance induction following thoracic duct
drainage or treatment with anti-lymphocyte serum. Immunology 17:267-280, 1969
7. Dumont AE, Mayer DJ, Mulholland JG: Thesuppression
of immunologic activity by diversion of thoracic duct
lymph. Ann Surg 160:373-383, 1964
8. Tihey NL, Atkinson JC, Murray JE: The immunosuppressive effect of thoracic duct drainage in human kidney
transplantation. Ann Intern Med 12559-64, 1970
9. Graber DC, Fitts CT, Williams AV, et al: Immunocompetence in the lymph-dialyzed patient. Surg Gynecol Obstet
128:1-7, 1969
10. Wegelius 0, Laine V, Linstrom B, et al: Fistula of the
thoracic duct as immunosuppressive treatment in rheumatoid arthritis. Acta Med Scand 187:539-544, 1970
1 1 . Y u DTY, Peter JB, Stratton JA, et al: Lymphocyte dynamics: change in density profiles and response to phytohemagglutinin of human lymphocytes during prolonged
thoracic duct drainage. Clin lmmunol lmmunopathol
11456-462, 1973
12. Yu DTY, Paulus HE, Peter JB, et al: Long-term thoracic
duct drainage in a rheumatoid arthritis patient: a study of
the clinical response and of lymphocyte and immunoglobulin dynamics, Neuromuscular Diseases. Edited by K
Kunze, J E Desmedt. Basel, S Karger, 1973, p p 231-235
13. Roubinian JR, Papoian R, Pillarisetty R, et al: Regulation
of IgM t o IgG switching in the antibody response to DNA
and RNA in NZB/NZW F, mice. Arthritis Rheum
l9:8 19. I976 ,(abstr)
14. Pennebaker J, Gilliam JN, Ziff M: Significance of anti-ND N A classeb in serum and skin in prognosis of SLE.
Arthritis Rheum 19:815, 1976 (abstr)
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