Clin Rheumatol (2005) 24: 178–181

DOI 10.1007/s10067-004-1024-2

CASE REPORT

Timothy B. Niewold Æ William I. Swedler

Systemic lupus erythematosus arising during interferon-alpha

therapy for cryoglobulinemic vasculitis associated with hepatitis C

Received: 10 November 2003 / Accepted: 23 August 2004 / Published online: 24 November 2004

Clinical Rheumatology 2004

Abstract We present the case of a 53-year-old woman

who developed systemic lupus erythematosus (SLE)
Introduction
after being treated with interferon-alpha (IFN-a) for
A variety of autoimmune phenomena have been re-
cryoglobulinemic vasculitis associated with hepatitis C
ported during therapy with interferon-a (IFN-a),
virus (HCV) infection. Her cryoglobulinemic vasculitis
including thyroid disease, systemic lupus erythematosus
resolved rapidly with IFN-a treatment. However, after
(SLE), rheumatoid arthritis, polymyositis, seronegative
10 months of IFN-a therapy, she developed a photo-
arthropathies, autoimmune thrombocytopenia, autoim-
sensitive malar rash, oral ulcers, arthralgias, lymphope-
mune hepatitis, and others [1, 2]. SLE is an infrequent
nia, and anti-SSA autoantibodies. She was diagnosed
complication of IFN-a therapy, and 13 cases [3–12] have
with SLE induced by IFN-a therapy. IFN-a was dis-
been previously described in detail. The development of
continued, she was treated with a short course of pred-
SLE has been reported in patients receiving IFN-a for a
nisone and hydroxychloroquine, and she improved
variety of indications, including chronic myelogenous
rapidly. This is the first report of IFN-a-induced SLE
leukemia [4, 5, 7, 9], hepatitis C [10, 12], malignant
complicating treatment of cryoglobulinemic vasculitis
carcinoid tumors [3], juvenile laryngeal papillomatosis
associated with HCV infection. The development of SLE
[6], malignant melanoma [8], and polyclonal gammop-
during therapy with IFN-a could be due to direct im-
athy associated with Sjögren’s syndrome [11]. Herein we
munomodulation by IFN-a, and review of experimental
describe the case of a woman who developed SLE during
data and prior case reports suggests a pathogenic role
therapy with IFN-a for cryoglobulinemic vasculitis
for IFN-a in SLE.
associated with chronic hepatitis C virus (HCV) infec-
tion and review prior case reports of SLE during IFN-a
Keywords Cryoglobulinemia Æ Hepatitis C Æ
therapy.
Interferon-alpha Æ Lupus erythematosus, systemic Æ
Vasculitis

Case report

A 53-year-old woman with chronic HCV infection pre-

No financial support or conflict of interest to declare
sented with an urticarial rash and palpable purpura. She
T. B. Niewold (&) had type 2 mixed cryoglobulinemia, and a skin biopsy
Department of Rheumatology, was consistent with leukocytoclastic vasculitis. She was
Hospital for Special Surgery, diagnosed with cryoglobulinemic vasculitis secondary to
535 East 70th Street, New York,
NY 10021, USA HCV infection, and began therapy with IFN-a at a dose
E-mail: niewoldt@hss.edu of 3·106 U three times per week and ribavirin. She had
Tel.: +1-212-7742788 undetectable levels of HCV RNA in her serum shortly
Fax: +1-212-6061519 after starting IFN-a. Her vasculitis resolved, and sub-
W. I. Swedler sequent testing for cryoglobulins was negative. She had
Section of Rheumatology, a positive antinuclear antibody (ANA) test prior to
University of Illinois at Chicago, initiating IFN-a therapy. Tests for specific autoanti-
900 S. Ashland Avenue, MBRB Suite 1158,
Chicago, IL 60607, USA bodies including anti-ssDNA, anti-dsDNA, anti-Sm,
Tel.: +1-312-9962385 anti-RNP, anti-SSA, anti-SSB, anti-histone, and anti-
Fax: +1-312-4139271 Scl70 were negative at that time.

After 10 months of IFN-a therapy, the patient
developed a photosensitive, erythematous malar rash
in a classic butterfly pattern over the bridge of her
nose sparing the nasolabial folds. The same rash was
present on her neck and upper chest in a V pattern,
and she had oral ulcers. She had arthralgias, but no
swollen joints. Laboratory studies revealed white
blood cell (WBC) count of 3800/mm3, absolute lym-
phocyte count of 1000/mm3, complement levels C3 of
26 mg/dl (reference range: 88–200 mg/dl), and C4 of
4 mg/dl (reference range: 10–40 mg/dl). She had been
hypocomplementemic over the last year secondary to
her cryoglobulinemic vasculitis; however, her hypo-
complementemia did not improve with the resolution
of her vasculitis. Repeat autoantibody testing showed
persistent positive ANA and elevated anti-SSA anti-
body titer to 411 lg/ml (0–91 lg/ml). Titers of all
other tested autoantibodies were normal. Urinalysis
and liver transaminases were in normal range. She had
no personal or family history of autoimmunity and
was not taking any drugs associated with drug-in-
duced lupus. The patient was diagnosed with SLE
arising during IFN-a therapy. IFN-a was discontin-
ued, and the patient was given prednisone and hy-
droxychloroquine.
Three months after discontinuing IFN-a, the patient
was doing well with resolution of her malar rash and
oral ulcers. Her cryoglobulinemic vasculitis had not re-
turned, and her liver transaminases remained normal.
Prednisone was gradually tapered due to the concern
that long-term glucocorticoid therapy would worsen the
prognosis of her hepatitis C. Laboratory studies at this
time showed WBC 11,000/mm3, absolute lymphocyte
count of 2300/mm3, and marked elevation of anti-SSA
titers to 6048 lg/ml. All other autoantibodies remained
within normal limits.
Discussion
There are eight prior case reports of SLE arising
during IFN-a therapy [3–5, 7, 9, 11, 12] which present
symptoms and laboratory data that fulfill 4 or more of
the 11 American College of Rheumatology (ACR)
1982 revised criteria for the diagnosis of SLE [13].
Three other case reports meet 3 of the 11 ACR cri-
teria and report a supportive renal [6, 10] or skin [8]
biopsy. The clinical data from these 11 case reports
are summarized in Table 1. These case reports reflect a
spectrum of disease that is not characteristic of drug-
induced lupus. Many common manifestations of SLE
such as malar or discoid rash, oral ulcers, photosen-
sitivity, and renal involvement are represented in these
reports, while the above-listed symptoms are rare in
drug-induced lupus. At least two additional patients
from two earlier cited reports [7, 9] were said to have
met four or more ACR criteria; however, sufficient
clinical data were not provided and these patients are
not included in Table 1.
179
The development of a ‘‘lupus-like’’ syndrome during
IFN-a therapy has also been reported in one series [7],
and the exacerbation of preexisting autoimmune disease
during IFN-a therapy has been described in another
series [14]. Both of these series describe a group of pa-
tients who developed autoimmune features during IFN-
a therapy that fulfilled three or fewer ACR criteria for
the diagnosis of SLE and did not fit easily into a diag-
nostic category.
Numerous investigations have addressed the rela-
tionship of IFN-a and interferon-gamma (IFN-c) with
SLE. IFN-a has many effects on the immune system,
including increased leukocyte bcl-2 expression, increased
MHC class I and II expression, as well as possible
concomitant immunosuppressive effects [1]. Levels of
IFN-a are elevated in SLE patients and correlate with
disease activity [15]. In a recent report, serum from SLE
patients was shown to induce differentiation of periph-
eral blood monocytes into antigen-presenting dendritic
cells capable of inducing a mixed lymphocyte reaction in
vitro. This activity was neutralized by an anti-IFN-a
antibody and was recreated by addition of IFN-a [16].
Presentation of autoantigens and activation of autore-
active lymphocytes by these dendritic cells could provide
a mechanism for IFN-a in the pathogenesis of SLE.
IFN-c activates macrophages, increases MHC class II
expression, and induces Th1 T-cell differentiation [2].
IFN-c is important in the pathogenesis of SLE in mouse
models [2], and serum IFN-c levels are elevated in SLE
patients, although serum levels do not correlate with
disease activity [15]. Two case reports describe the
development of SLE in patients with rheumatoid
arthritis who received IFN-c alone [2], and two of the
cases of IFN-a-induced SLE included in Table 1 were
treated with IFN-c concomitantly [6].
Antinuclear antibodies can be seen with both chronic
HCV infection and cryoglobulinemia. Our patient had a
positive ANA test, but all other autoantibodies were
negative prior to IFN-a therapy. Her anti-SSA titer rose
markedly during treatment with IFN-a and correlated
with the onset of her SLE. The high titer anti-SSA
antibody would not be expected with HCV infection or
cryoglobulinemia. Our patient’s SLE symptoms began
after successful treatment of her cryoglobulinemic vas-
culitis, and her course suggests a pathogenic role for
IFN-a.
Therapy for IFN-a-induced SLE has involved dis-
continuation of the IFN-a in 9 of the 11 cases that report
these data [3–8, 11, 12]. Corticosteroids were given in
seven of the above cases [3, 4, 6, 8, 9, 11, 12] and the use
hydroxychloroquine has been reported in one case pre-
viously [11]. Clinical improvement was typically seen
rapidly, within a few weeks to months in most reports,
and recurrence of SLE in the absence of IFN-a has not
been reported.
In conclusion, we present the case of a woman who
developed SLE during therapy with IFN-a for cryo-
globulinemic vasculitis associated with hepatitis C. A
pathogenic role for IFN-a in SLE is suggested by
 180

Table 1 Summary of clinical characteristics of 11 prior case reports of SLE arising during IFN-a therapy. CML chronic myeloid leukemia, Raynaud’s Raynaud’s phenomenon,
hemolytic anemia Coomb’s positive autoimmune hemolytic anemia, + elevated above normal range, but not quantified, ANA titer of antinuclear antibodies, dsDNA titer of anti-double-
stranded DNA antibodies, anti-Sm titer of anti-Sm antibodies, SSA titer of anti-SSA antibodies, WBC white blood cell count given in thousands per mm3, LE cell lupus erythematosus
cell preparation, renal biopsy renal biopsy performed and results compatible with lupus nephritis, skin biopsy skin biopsy performed with positive lupus band test, proteinuria >0.5 g or
3+ protein if not quantified, MU million units

Reference Indication Symptoms Laboratory data IFN-a dose Months of

No./age/sex for therapy and signs therapy

[2]/23/F Malignant Arthritis, ANA >1/3200 6 MU/day 9

carcinoid tumor myalgias dsDNA 1/160
WBC 3.3
[3]/19/M CML Malar rash, ANA 1/9270 Not reported 39
arthralgias, fever dsDNA 1/9270
Proteinuria
Lymphopenia
[4]/35/F CML Malar rash, ANA 1/200 Not reported 29
arthritis, fever Anti-Sm+
[5]/10/M Juvenile Anasarca ANA 1/2500 3 MU/m2/day 84
laryngeal dsDNA 1/640
papillomatosis Proteinuria
Renal biopsy
[6]/26/M CML Arthritis, ANA 1/106 4 MU/day 6
discoid rash, Raynaud’s WBC 2.3 (+ IFN-c 50 lg/day)
[6]/40/F CML Arthritis ANA 1/256 3 MU/day 18
WBC 3.5 (+IFN-c 50 lg/day)
Hemolytic anemia
[7]/50/F Malignant melanoma Arthritis ANA 1/3200 9 MU 3·/week 7
dsDNA+ then 3 MU 3·/week
Skin biopsy
[8]/31/F CML Arthritis, ANA 1/640 10 MU/day 20
photosensitivity Hemolytic anemia
[9]/72/M Hepatitis C Not reported ANA+ Not reported Not reported
dsDNA+
LE cell+
Renal biopsy
[10]/59/F Sjögren’s and Arthritis, discoid rash, ANA >1/1280 7 MU 3·/week 1
polyclonal oral ulcers,
gammopathy photosensitivity
[11]/69/M Hepatitis C Arthritis, pleuritis ANA 1/2560 9 MU 3·/week 5
dsDNA 1/2560
LE cell+
Lymphopenia
Current report/53/F Hepatitis C with Malar rash, oral ulcers, ANA+ 3 MU 3·/week 10
cryoglobulinemic arthralgias Anti-SSA
vasculitis 1/6048
Lymphopenia

experimental evidence showing activation of antigen-
presenting cells by IFN-a and supported by clinical data
from reports of IFN-a-induced SLE. Given the
increasing use of IFN-a for a variety of indications,
clinicians should be aware of the potential for autoim-
munity.
Take home message
Interferon-alpha therapy has been associated with the de
novo development of SLE in a number of patients, and
discontinuation of IFN-a resulted in resolution of SLE
symptoms for most patients. Basic science data support
a potential pathogenic role for IFN-a in SLE, and cli-
nicians should be aware of potential autoimmune side
effects of IFN-a therapy.
References
1. Ioannou Y, Isenberg DA (2000) Current evidence for the
induction of autoimmune rheumatic manifestations by cytokine
therapy. Arthritis Rheum 43:1431–1442
2. Krause I, Valesini G, Scrivo R, Shoenfeld Y (2003) Autoim-
mune aspects of cytokine and anticytokine therapies. Am J
Med 115:390–397
3. Ronnblom LE, Alm GV, Oberg KE (1990) Possible induction
of systemic lupus erythematosus by interferon-a treatment in a
patient with a malignant carcinoid tumour. J Intern Med
227:207–210
4. Schilling PJ, Kurzrock R, Kantarjian H, Gutterman JU, Tal-
paz M (1991) Development of systemic lupus erythematosus
after interferon therapy for chronic myelogenous leukemia.
Cancer 68:1536–1537
181
5. Mehta ND, Hooberman AL, Vokes EE, Neeley S, Cotler S
(1992) 35-year-old patient with chronic myelogenous leukemia
developing systemic lupus erythematosus after a-interferon
therapy. Am J Hematol 41:141
6. Tolymat A, Leventhal B, Sakarcan A, Kashima H, Monteiro C
(1992) Systemic lupus erythematosus in a child receiving long-
term interferon therapy. J Pediatr 120:429–432
7. Wandl UB, Nagel-Hiemke M, May D, Kreuzfelder E, Kloke O,
Kranzhoff M et al (1992) Lupus-like autoimmune disease in-
duced by interferon therapy for myeloproliferative disorders.
Clin Immunol Immunopathol 65:70–74
8. Hory B, Blanc D, Saint-Hiller Y (1992) Systemic lupus eryth-
ematosus-like syndrome induced by alpha-interferon therapy.
Eur J Med 1:379
9. Flores A, Olive A, Feliu E, Tena X (1994) Systemic lupus
erythematosus following interferon therapy. Br J Rheumatol
33:787
10. Yoshida A, Takeda A, Koyama K, Morozumi K, Oikawa T
(1994) Systemic lupus erythematosus with nephropathy after
interferon-a 2A therapy. Clin Rheumatol 13:382
11. Morris LF, Lemak NA, Arnett FC, Jordon RE, Duvic M
(1996) Systemic lupus erythematosus diagnosed during inter-
feron alfa therapy. South Med J 89:810–814
12. Fukuyama S, Kajiwara E, Suzuki N, Miyazaki N, Sadoshima
S, Onoyama K (2000) Systemic lupus erythematosus after a-
interferon therapy for chronic hepatitis C: a case report and
review of the literature. Am J Gastroenterol 95:310
13. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Roth-
field NF et al (1982) The 1982 revised criteria for the classifi-
cation of systemic lupus erythematosus. Arthritis Rheum
25:1271–1277
14. Conlon KC, Urba WJ, Smith JW, Steis RG, Longo DL, Clark
JW (1990) Exacerbation of symptoms of autoimmune disease in
patients receiving alpha-interferon therapy. Cancer 65:2237–
2242
15. Kim T, Kanayama Y, Negoro N, Okamura M, Takeda T,
Inoue T (1987) Serum levels of interferons in patients with
systemic lupus erythematosus. Clin Exp Immunol 70:562–569
16. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J (2001)
Induction of dendritic cell differentiation by IFN-a in systemic
lupus erythematosus. Science 294:1540–1543