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xAzathioprine therapy for patients with systemic lupus erythematosus

M Abu-Shakra and Y Shoenfeld
Lupus 2001 10: 152
DOI: 10.1191/096120301676669495

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 Lupus (2001) 10, 152±153
ß 2001 Arnold All rights reserved 0961±2033
www.arnoldpublishers.com/journals

REVIEW

Azathioprine therapy for patients with systemic lupus

erythematosus
M Abu-Shakra1 and Y Shoenfeld2*
1
Rheumatic Diseases Unit and Department of Medicine D, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel; and 2Department of
Medicine B, and Research Unit of Autoimmune Diseases, Tel-Hashomer Medical Center and Tel-Aviv University, Tel-Aviv, Israel

Azathioprine is the only purine analog that is widely used for the management of systemic lupus
erythematosus (SLE). For SLE patients without renal involvement, it is given to those patients who
require a maintenance dose of 15 mg or higher of prednisone and for those who experience
recurrent ¯ares. Azathioprine in combination with steroids may be given to a large number of
patients with lupus nephritis. It is also effective for patients with skin lesions, pneumonitis,
thrombocytopenia or hemolytic anemia. Azathioprine may be used during pregnancy but not during
lactation. It has not been shown to increase the risk for the development of malignancies among
patients with SLE. Lupus (2001) 10, 152±153.

Keywords: azathioprine; SLE; Immunosuppression

Azathioprine belongs to the purine analogs which also
include 6-mercaptopurine and 6-thioguanine. It is
generated by attaching an imidazole group to 6-
mercaptopurine, an analog of hypoxanthine in which
the 6-OH radical is replaced by a thiol group. In vivo,
azathioprine is converted to 6-mercaptopurine.
Although the main mechanism by which azathio-
prine induces a state of immunosuppression is not
clear, most likely it is associated with suppression of
DNA synthesis by the nucleoprotein metabolites of
6-mercaptopurine which inhibit the enzymatic con-
version of inosinic acid to xanthylic acid and of
adenylosuccinic acid to adenylic acid.1
Currently azathioprine is the only purine analogue
that is widely used for the management of systemic
lupus erythematosus (SLE). The drug is given for
various clinical manifestations of SLE, usually in
combination with corticosteroids. For SLE patients
without renal or central nervous system (CNS) invol-
vement, azathioprine is given to those patients who
require a maintenance dose of 15 mg or higher and for
those who experience recurrent ¯ares. This regimen is
associated with a lower rate of development of severe
forms of SLE compared with patients who did not
*Correspondence: Y Shoenfeld, Department of Medicine B, Sheba
Medical Center, Tel-Hashomer 52621, Israel.
E-mail: Shoenfel@post.tau.ac.il
receive azathioprine.2 Furthermore, reduction in the
dosage of azathioprine is a strong predictor of lupus
¯are.3
The role of azathioprine in the treatment of patients
with severe lupus nephritis is not clear. Two short-
term studies have indicated that azathioprine plus
steroids is not better than steroids alone for the
treatment of patients with severe lupus nephritis.4
Based on these data, it has been suggested that
azathioprine should be used only for mild cases of
lupus nephritis and only as an alternative agent for
cyclophosphamide when patients refuse to take cyclo-
phosphamide. However, a large study published in
19752 showed that azathioprine therapy of 54 patients
with severe renal or CNS involvement was associated
with improved long-term survival. Similarly, subse-
quent long-term studies have shown that a protocol of
steroids and azathioprine is associated with better
clinical and histological renal outcome compared
with those who received only prednisone for diffuse
proliferative lupus nephritis.5 Furthermore, the mor-
tality and morbidity of lupus patients followed by a
major lupus clinic that rarely uses cyclophosphamide
for lupus nephritis are similar to those of other centers
where cyclophosphamide is used more frequently.6
Although cyclophosphamide and prednisone are
considered the primary treatment for severe lupus neph-
ritis, more recently this has become a controversial
issue. It has been suggested that cyclophosphamide be

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used only for a short-term period for initial control of
the nephritis and then therapy be maintained with
prednisone and azathioprine. This period ranges from
only three pulses given over 3 weeks up to 6 months
given either by monthly or daily pulses.5,7 This pro-
tocol was found to also be effective for patients with
pure membranous nephritis with severe proteinuria.
Of 20 SLE patients with pure membranous nephritis
who were given this protocol, 11 patients had com-
plete remission and seven patients achieved signi®-
cant improvement within 12 months of therapy.8
Others have indicated that the use of cyclophospha-
mide for a short period of time results in a higher rate
of ¯ares after discontinuing the cyclophosphamide
compared with those who maintain cyclophosphamide
for a long period of time.9
Taken together, the data suggest that azathioprine is
effective for patients with lupus nephritis. While those
cases of severe and refractory nephritis require cyclo-
phosphamide, azathioprine and prednisone may be
given to a large number of patients with nephritis.
The role of azathioprine therapy in the treatment of
the other clinical manifestations of SLE is not clear.
Azathioprine is not indicated for the management of
the constitutional symptoms, arthritis and the serositis
of patients with SLE. A literature review has failed to
identify even a single controlled clinical trial studying
the role of azathioprine in the neurological features of
SLE. Similarly, the effects of azathioprine on the non-
renal features have not been studied in a well-
designed controlled study and most of the available
data is based on case reports or case series.
Case reports have indicated that azathioprine may be
used in refractory cases of discoid and subacute cuta-
neous lupus and for the control of cutaneous vasculitic
lesions. Three out of six patients with chronic cutaneous
lesions and ®ve out of six patients with vasculitic lesions
had improved following treatment with azathioprine.10
Several case reports reported mainly by Matthay et al11
suggested that azathioprine may control lupus pneumo-
nitis. Seven out of 12 patients with pneumonitis also
received azathioprine; this series was associated with a
high mortality rate (50%) and permanent pulmonary
damage in 25%.
Azathioprine may be given to SLE patients with
autoimmune hemolytic anemia or autoimmune throm-
bocytopenia. This is based on the data from studies of
patients with idiopathic autoimmune hemolytic anemia
and thrombocytopenia where azathioprine was found to
be effective in selected cases of anemia and thrombo-
cytopenia not responding to steroids or splenectomy.
A single case report of an infant born with preaxial
polydactyly to a mother taking azathioprine has
suggested that azathioprine may be teratogenic.12
However, large series of pregnancy among patients
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Azathioprine therapy for SLE patients
M Abu-Shakra and Y Shoenfeld
153
with SLE, renal transplant patients or in¯ammatory
bowel diseases have failed to con®rm this observation.
It is widely accepted that pregnant women with SLE
can maintain the azathioprine therapy during preg-
nancy. However, azathioprine is contraindicated
during lactation.13
Case reports have indicated that azathioprine may
trigger the development of malignancies. In a study of
a large number of SLE patients, an increased risk for
the occurrence of hematological malignancies was
observed among patients with SLE. However, none
of the patients with hematologic malignancies
received azathioprine or other immunosuppressive
agents.14
In summary, azathioprine has been used in the
management of various clinical manifestation of
SLE for more than four decades, however its role in
SLE has not been studied in well-designed controlled
clinical trials.
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Lupus