ARTHRITIS & RHEUMATISM
Vol. 48, No. 4, April 2003, pp 1067–1070
© 2003, American College of Rheumatology
Treatment of Systemic Lupus Erythematosus–Associated
Type B Insulin Resistance Syndrome With
Cyclophosphamide and Mycophenolate Mofetil
Anil Gehi, Allison Webb, Martha Nolte, and John Davis, Jr.
Systemic lupus erythematosus (SLE) is an auto-
immune disease characterized by loss of immunologic
self-tolerance and the subsequent development of auto-
antibodies. These antibodies are thought to be impor-
tant in relation to the clinical manifestations of the
disease. One example is the development of multiple
cytopenias secondary to cytolytic or cytotoxic antibodies
directed toward red blood cells, platelets, and white
blood cells. Other antibodies may mediate abnormal
cellular mechanisms such as those seen with neuropsy-
chiatric manifestations of SLE. We report the occur-
rence of autoantibodies directed toward insulin recep-
tors and the subsequent development of type B insulin
resistance syndrome in a woman with SLE. This syn-
drome was treated successfully with cyclophosphamide
and mycophenolate mofetil.
The insulin resistance syndrome is a clinical state
in which there is a subnormal cellular and metabolic
response to insulin, characterized by elevated circulating
insulin levels (1). Most insulin resistance is cellular or
tissue based; common examples are obesity or type 2
diabetes mellitus. In these conditions, resistance results
from abnormalities in insulin receptor action or signal-
ing (1,2). The type A insulin resistance syndrome pre-
sents clinically as ovarian dysfunction and severe insulin
resistance accompanied by hyperglycemia. This syn-
drome is caused by genetic defects in the insulin signal-
ing system (2–5).
Serum-based insulin resistance is relatively un-
usual. Historically, the majority of such patients devel-
oped resistance due to insulin antibodies directed
against exogenously administered insulin, especially that
from bovine and porcine sources. After the introduction
of human insulin produced with recombinant DNA
technology, this form of resistance has declined dramat-
ically (6–11). It also occurs in conditions associated with
elevated circulating levels of autoantibodies, such as
autoimmune disorders and certain medications (12–17).
Insulin receptor autoantibody formation is espe-
cially rare. The type B insulin resistance syndrome is an
autoimmune phenomenon caused by polyclonal immu-
noglobulin G antibodies with antagonist activity directed
against the insulin receptor (1,2,4). This competition
results in hypersecretion of insulin to compensate, usu-
ally at insufficient levels to maintain normoglycemia
(1,2,18–20). Occasionally, the receptor autoantibodies
can have an insulin-like effect, which can cause hypogly-
cemia (21–24). The syndrome has been described in
patients with systemic lupus erythematosus (SLE) and
Sjo ¨gren’s syndrome as well as less clearly defined auto-
immune disorders (12,21,25–27). Acanthosis nigricans (a
marker of insulin resistance), amenorrhea in women,
and hyperandrogenism are usually present (4,12,28–30).
The patient, a 27-year-old African American
woman, was in good health until October 1999, when she
was in the fourth month of her second pregnancy. The
pregnancy became complicated by toxemia, pericarditis,
and pericardial and pleural effusions. She was treated
with aspirin, and the fetus was delivered prematurely by
cesarean section at 32 weeks. In April 2000, the patient
developed arthritis in both hands. SLE was diagnosed
based on antinuclear antibody (ANA) positivity (titer
?1:640) with an elevated double-stranded DNA
(dsDNA) antibody level (126 IU/ml) and Sm antibody
positivity. In January 2001, at a routine followup visit,
Anil Gehi, MD, Allison Webb, BS, Martha Nolte, MD, John
Davis, Jr., MD, MPH: University of California, San Francisco.
Address correspondence and reprint requests to John C.
Davis, Jr., MD, MPH, University of California San Francisco, 533
Parnassus Avenue, Room U383, San Francisco, CA 94143. E-mail:
Submitted for publication October 10, 2002; accepted in
revised form December 30, 2002.
the patient reported lower extremity edema and numb-
ness as well as weight loss. She was found to have
elevated plasma glucose levels. Euglycemic therapy was
initiated, but there was minimal response to multiple
oral medications given at high doses, including insulin
secretagogues, metformin, and a thiazolidinedione. In-
sulin therapy was added, but despite doses of U500
insulin of up to 1,200 units/day, she remained hypergly-
cemic. The patient’s medical history was unremarkable
except for the SLE. Her family history was notable for
hypertension and breast cancer, but no autoimmune
disease or diabetes.
Because of difficulty with glycemia control, the
patient was referred to the University of California, San
Francisco Medical Center Diabetes Clinic. Medications
she was taking at the time of referral included glyburide
20 mg/day, metformin 2,000 mg/day, rosiglitazone 8
mg/day, hydroxychloroquine 400 mg/day, and pred-
nisone 12 mg/day. On physical examination, the patient
was noted to be 5 feet 8 inches tall, weighing 58 kg, with
a blood pressure of 136/78 and a heart rate 105 beats per
minute. There was evidence of thrush in the oropharynx.
Diffuse anterior and posterior cervical lymphadeno-
pathy was noted. There were areas of hyperpigmentation
on the back of the neck, consistent with acanthosis
nigricans. Trace edema was found in the extremities.
Joint examination results were notable for mild synovitis
of the metacarpophalangeal and proximal interphalan-
geal joints bilaterally. Abnormal laboratory findings
included ANA titer ?1:640, erythrocyte sedimentation
rate (ESR) 50 mm/hour, dsDNA antibody 126 IU/ml, C3
60 mg/dl, C4 ?10 mg/dl, Sm antibody positivity, RNP
antibody positivity, SSA antibody positivity, SSB anti-
body positivity, creatinine 0.9 mg/dl, hemoglobin AIc
15.3%, C-peptide 6.4 ng/ml, thyrotropin 1.36 mIU/liter,
white blood cell count 3.2 ? 109/liter with lymphopenia,
hematocrit 33%, platelet count 209 ? 109/liter, total
cholesterol 216 mg/dl, low-density lipoprotein choles-
terol 123 mg/dl, high-density lipoprotein cholesterol 85
mg/dl, insulin antibodies (porcine, bovine, human) neg-
The extreme difficulty in controlling the patient’s
blood sugar levels despite treatment with large doses of
insulin prompted consideration of the possibility that
she had an insulin resistance syndrome. Elevated
C-peptide and serum insulin levels and presence of
anti–insulin receptor antibodies at a high titer (1:100)
(tested in the laboratory of Dr. Ronald Kahn, Harvard
School of Medicine, Boston, MA) confirmed the pres-
ence of type B insulin resistance syndrome associated
The patient was referred to the University of
California, San Francisco Lupus Clinic for aggressive
treatment of the SLE, in the hope that this would lead to
ablation of the cellular clones responsible for formation
of the insulin receptor autoantibodies. Mycophenolate
mofetil treatment was initiated in May 2001. Prednisone
dosage during this period ranged between 8 and 15
mg/day. Despite a gradual increase of the dosage of
mycophenolate mofetil to 2.5 gm/day, the patient’s lupus
symptoms did not abate and the hyperglycemia contin-
ued to be unmanageable with oral euglycemics and
insulin. In September 2001, mycophenolate mofetil was
discontinued and therapy with cyclophosphamide
(CYC) was initiated. Two treatments with 750 mg CYC
were given, 1 month apart. With this therapy, the
patient’s synovitis, arthritis, and pleuritis improved and
the plasma glucose levels began to fall. She experienced
moderately severe reactive hypoglycemia, with plasma
glucose values between 27 and 60 mg/dl. In all instances,
hypoglycemia occurred within hours after she had eaten
high carbohydrate–containing foods.
Figure 1. Change in hemoglobin AIc(HgA1C) levels with mycophe-
nolate and cyclophosphamide (CYC) therapy. Mycophenolate was
given starting at week 0 and stopped during the time of CYC therapy.
(CYC at 750 mg was given in 2 infusions, 1 month apart.)
Figure 2. Change in C-peptide levels with mycophenolate and cyclo-
phosphamide (CYC) therapy. Mycophenolate was given starting at
week 0 and stopped during the time of CYC therapy. (CYC at 750 mg
was given in 2 infusions, 1 month apart.)
1068 GEHI ET AL
Because of concern that she could be developing
antibodies with agonist activity, the patient was briefly
hospitalized for observation and consideration of plas-
mapheresis. In the hospital, she was able to maintain
fasting glycemic control, but would exhibit early post-
prandial hyperglycemia, followed by late postprandial
hypoglycemia. This phenomenon was reduced when she
ate meals with a more limited amount of complex
carbohydrates. Her insulin, hemoglobin AIc, and
C-peptide levels subsequently improved and returned to
baseline values (Figures 1–3). Mycophenolate was re-
started as maintenance therapy. The insulin receptor
autoantibody titers began to decline within 10 weeks
after initiation of CYC therapy. By January 2002, no
insulin receptor antibody could be detected, although
other serologic findings remained abnormal (ESR 38
mm/hour, dsDNA antibody 191 IU/ml, C3 85 mg/dl, C4
13 mg/dl). At present, the patient’s SLE is under good
control, with minimal synovitis and arthritis and occa-
sional pleuritic chest pain. Fasting blood glucose and
hemoglobin AIclevels are normal. She still has occa-
sional postprandial glucose elevation, and although her
insulin levels are higher than normal, they are continu-
ing to decrease toward the normal range.
We have described a novel approach to the
treatment of the type B insulin resistance syndrome
associated with SLE. Specifically, we advocate using
pulse CYC, guided by plasma glucose and insulin levels,
to accelerate the immunosuppressive response, with
subsequent oral mycophenolate for maintenance sup-
pression. Kawanishi et al described a 45-year-old woman
with Sjo ¨gren’s syndrome–associated type B insulin resis-
tance syndrome that was successfully treated with pred-
nisone and CYC. With immunosuppressive therapy for 8
months, the insulin resistance resolved and the patient
became normoglycemic. However, with temporary ter-
mination of CYC treatment, glucose intolerance re-
curred (31). Bloise and colleagues reported the case of a
23-year-old woman with type B insulin resistance syn-
drome associated with scleroderma. With immunosup-
pressive therapy consisting of prednisone and CYC, the
insulin resistance remitted and the patient became hy-
poglycemic (26). Eriksson et al described a 41-year-old
woman with type B insulin resistance associated with
SLE. The patient was initially treated with plasmaphere-
sis and CYC. Cyclosporin A and azathioprine were used
as maintenance therapy. There was a rapid improvement
in insulin resistance, with response to therapy sustained
at followup of ?4 years (32).
The patient described herein, a 27-year-old
woman, was diagnosed with type B insulin resistance
syndrome associated with SLE. Despite SLE therapy
with prednisone and hydroxychloroquine supplemented
by aggressive treatment with oral euglycemic agents and
insulin, glycemic control was inadequate. We initially
attempted therapy with substantial doses of mycopheno-
late mofetil (up to 2.5 gm/day) with limited success: it
took 10 weeks of therapy to effect a drop in the antibody
titer, and there was no discernible change in the patient’s
glycemic control. Potent immunosuppression was
achieved with CYC at a dose of 750 mg given on 2
occasions 1 month apart. As evidenced by the develop-
ment of frank hypoglycemia and declining C-peptide,
serum insulin, and hemoglobin AIclevels, the CYC
rapidly ameliorated the insulin resistance. Anti–insulin
receptor antibodies could not be detected following
CYC therapy. Mycophenolate was resumed as mainte-
nance therapy, and no recurrence of significant insulin
resistance was observed during 10 months of followup.
It is possible that the disappearance of the recep-
tor autoantibody could be part of a spontaneous remis-
sion. Even if this were the case, we believe the remission
was accelerated by the CYC because of the dramatic
decrease in the patient’s plasma glucose level within 1–3
weeks after the first CYC treatment and definitive
resolution of hyperglycemia following the second dose.
We thus recommend that the possibility of insulin
resistance be considered in any at-risk patients, such as
those with autoimmune disorders, who exhibit excessive
insulin requirements. Assuming poor compliance with
insulin therapy, improper injection technique, and inad-
equate insulin potency have been ruled out, such pa-
tients should be evaluated for the presence of circulating
Figure 3. Change in serum insulin levels with mycophenolate and
cyclophosphamide (CYC) therapy. Mycophenolate was given starting
at week 0 and stopped during the time of CYC therapy. (CYC at 750
mg was given in 2 infusions, 1 month apart.)
CYC AND MYCOPHENOLATE MOFETIL IN SLE-ASSOCIATED TYPE B INSULIN RESISTANCE SYNDROME1069
insulin autoantibodies. In individuals with marked resis-
tance and the absence of insulin antibodies, the possible
presence of insulin receptor autoantibodies should be
explored. In such patients, elimination of receptor auto-
antibodies with aggressive immunosuppression may be a
successful therapeutic strategy. We suggest a regimen of
pulse CYC and maintenance mycophenolate mofetil
with close monitoring of serum insulin, hemoglobin AIc,
and anti–insulin receptor autoantibody levels when
treating patients with severe SLE-associated type B
insulin resistance syndrome.
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