[Downloaded free from http://www.sjkdt.org on Sunday, July 12, 2015, IP: 190.238.27.

12]

Saudi J Kidney Dis Transpl 2012;23(2):334-337

2012 Saudi Center for Organ Transplantation Saudi Journal
of Kidney Diseases
and Transplantation

Case Report

Rituximab in the Treatment of Refractory Lupus Nephritis with Vasculitis

Huseyin Kadikoy1, Waqar Haque1, Salman Ahmed1, Abdul Abdellatif1,2

Departments of Medicine1 and Division of Nephrology2, Baylor College of Medicine, Houston,

TX, 77030, USA

ABSTRACT. Dysfunction of the B lymphocyte, an important component of adaptive immunity,

is thought to be important in the pathogenesis of lupus nephritis (LN). There are several novel
strategies emerging including B-cell depletion by the monoclonal antibodies to B-cell markers,
rituximab. We describe an unusual clinical response of a 22-year-old Hispanic woman with class
IV LN with vasculitis while on dialysis to cyclophosphamide (CY) and adjunct rituximab. The
patient had a history of class III/V LN and was treated with nine months of CY and maintenance
therapy with mycophenolate mofetil (MMF) for three years. While on MMF, the patient deve-
loped class IV LN with vasculitis leading to end-stage renal disease (ESRD). While the patient
was on peritoneal dialysis, the patient was treated with two doses of rituximab and six doses of
intravenous CY. The patient responded to this regimen and recovered kidney function within four
months. The kidney function remained stable nine months after discontinuing peritoneal dialysis.

Introduction luated for LN and many more are under con-

While clinical outcomes for proliferative lupus
nephritis (LN) have improved since the 1990s
with widespread adoption of the National Ins-
titutes of Health treatment strategy using intra-
venous cyclophosphamide (CY) and cortico-
steroids,1 up to 25% of patients fail to respond
to this treatment.2 In recent years, many new
immunosuppressive therapies have been eva-
Correspondence to:
Dr. Abdul Abdellatif,
Assistant Professor of Medicine,
Division of Nephrology, Department of
Medicine, Baylor College of Medicine,
One Baylor Plaza, BCM 620,
Houston, TX 77030, USA.
Email: abdula@bcm.edu
sideration. Rituximab is a chimeric monoclonal
antibody that specifically binds to the CD20
molecule on the surface of pre- and mature B-
cells. It results in profound depletion of the B-
cell subsets through induction of cell lysis that
may be mediated by complement-dependent
cytotoxicity, antibody-dependent cell-mediated
cytotoxicity, or apoptosis. In a pilot open study
of five patients with refractory systemic lupus
erythematous (SLE), three of whom had neph-
ritis, a combination of rituximab and CY with
high-dose corticosteroid was well tolerated
and resulted in improvement of renal para-
meters in two patients.3
Case Report
A 22-year-old Hispanic woman presented to
[Downloaded free from http://www.sjkdt.org on Sunday, July 12, 2015, IP: 190.238.27.12]
Rituximab in the treatment of refractory lupus nephritis with vasculitis
Figure 1. Biopsy of the kidney showing glo-
merular changes consistent with lupus nephritis
class IV with vasculitis. There is global endo-
capillary proliferation in the glomerulus.
Figure 2. Small artery showing mononuclear infil-
tration in the vessel wall, limited to the intima.
Figure 3. Small vessel with mononuclear inflam-
matory cells in the media and fibrin deposition
within the lumen.
335
the emergency room with a 3-day history of
shortness of breath, swelling of the legs, and
headache. The patient had a history of class
III/V LN with interstitial fibrosis and tubular
atrophy diagnosed by biopsy two months prior
to presentation. She complained of sudden
onset of edema in her legs and shortness of
breath upon exertion. The patient denied double
vision, dizziness, nausea, vomiting, chest pain,
or orthopnea. The patient had no history of
smoking, drug or alcohol abuse. Family his-
tory was significant for a brother with type 1
Diabetes. Physical examination showed bila-
teral pitting edema. The chest, heart, and abdo-
minal examinations were unremarkable.
On admission, laboratory values included se-
rum creatinine of 4.1 mg/dL, urine protein of
320 mg/dL, albumin of 2.4 mg/dL, C3 of 32
mg/dL, and C4 of 3 mg/dL. Ultrasound guided
kidney biopsy was performed, which was con-
sistent with diffuse proliferative glomerulo-
nephpritis with some cellular crescents and
necrotizing vasculitis, consistent with class IV
LN with vasculitis (Figures 1, 2, and 3).
Initially, the patient received three days i.v.
methylprednisone, and was initiated on a six
month course of i.v. CY. Rituximab was added
as an adjunct therapy, at 350 mg/m2 for two
doses two weeks apart. During the first two
weeks of therapy, the patients kidney function
deteriorated and creatinine peaked at 6.0 mg/
dL prior to initiation of dialysis. The patient
was continued on hemodialysis and then trans-
ferred to peritoneal dialysis. At this point it
was decided to continue with aggressive the-
rapy of CY and steroids in the outpatient set-
ting. The patient was followed in clinic once
per month. Her creatinine improved from 6.0
mg/dL to 1.1 mg/dL within four months
(Table 1). She was taken off of peritoneal
dialysis after 16 weeks of follow-up due to
improvement in kidney function. Her renal
function remained stable at a creatinine of 1.1
mg/dL one year after the initial insult, and was
maintained on MMF and steroids.
Discussion
The prevalence of clinical renal involvement
[Downloaded free from http://www.sjkdt.org on Sunday, July 12, 2015, IP: 190.238.27.12]

336 Beji S, Ben Fatma L, Chebbi A, et al

Table 1. Progression of patients serum creatinine.

Date Serum creatinine (mg/dL)
11/29/07 0.9
1/10/08 1.4
2/18/08 6.0
3/24/08 4.0
4/21/08 3.1
5/5/08 2.4
6/19/08 1.1
3/3/09 1.1

is between 30% and 90% of SLE patients, with
LN being more common in certain ethnic
groups and in children, and vasculitis is one of
the poorest prognostic factors in any patient.4
In LN, usually patients present with worse-
ning kidney function, hypertension, edema, and
nephritic/nephrotic syndrome. Patients with LN
usually also display characteristics of systemic
SLE including skin manifestations, synovitis,
and serositis. Upon presentation, our patient
had hypertension, worsening kidney function,
edema and nephritic range proteinuria with
hypoalbuminemia.
The etiology of autoimmunity in SLE may be
due to loss of self-tolerance as a result of
incomplete silencing or deletion of autoreac-
tive lymphocytes.5 Another possible mecha-
nism for autoimmunity is dysfunctional apop-
tosis characterized by incomplete removal of
nuclear remnants, which leads to increased
exposure to the immune system and subse-
quent recognition.6 In addition, there are cer-
tain genetic linkages in SLE that predispose
individuals to renal disease and influence the
severity of glomerular disease.7
B cells have a central role in the genesis of
SLE, as shown by the presence of pathogenic
autoantibodies such as anti-double stranded
DNA. However, the influence of B cells on
SLE is not limited to production of pathogenic
autoantibodies. A model of LN in mice showed
that a decreased number of B cells prevented
the development of SLE, but animals with
normal B cell count that were not able to
produce antibodies still had occurrence of SLE
and LN.8
The damage to the kidney in SLE is due to
either direct antibody-induced cytotoxicity,
immune complex lodging in the glomeruli, or
in situ immune complex formation.9-11 The
three criteria for clinical lupus nephritis are
30% decrease in creatinine clearance, protei-
nuria greater than 1000 mg/day, and renal
biopsy consistent with active lupus nephrititis.
The staging of LN was revised by the Inter-
national Society of Nephrology/Renal Pathology
Society in 2003, and is shown in Table 2.12
Several novel treatments for LN involve the
strategy of inhibiting B cell activity, other than
rituximab, such as LJP-394 (Abetimus so-
dium),13,14 which was shown in a retrospective
observation to improve renal function as it

Table 2. Abbreviated International Society of Nephrology/Renal Pathology Society (ISN/RPS)

classification of lupus nephritis (2003).
Class I: Minimal mesangial lupus nephritis
Class II: Mesangial proliferative lupus nephritis
Class III: Focal lupus nephritisa
Class IV: Diffuse segmental (IV-S) or global (IV-G) lupus nephritisb
Class V: Membranous lupus nephritisc
Class VI: Advanced sclerosing lupus nephritis
Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity
of arteriosclerosis and other vascular lesions
a
Indicate the proportion of glomeruli with active and with sclerotic lesions
b
Indicate the proportion of glomerli with fibrinoid necrosis and cellular crescents
c
Class V may occur in combination with class III or IV, in which case both will be diagnosed
[Downloaded free from http://www.sjkdt.org on Sunday, July 12, 2015, IP: 190.238.27.12]
Rituximab in the treatment of refractory lupus nephritis with vasculitis
reduced proteinuria.15 Another anti-B cell drug,
Belimumab (LymphoStat-B), 16 showed im-
proved disease activity and quality of life
scores in patients with moderate disease,17 and
is currently in phase III trials for treatment of
SLE.18 The use of the renal biopsy enables
more patient-directed therapy based on histo-
logic examination.19
Our case supports the aggressive treatment of
LN with vasculitis, even if renal replacement
therapy is initiated. We aggressively treated
our patient to salvage any remaining kidney
function. Fortunately, our patient showed im-
pressive recovery of kidney function to a
creatinine near her baseline. Rituximab may be
a beneficial adjunct therapy in class IV LN
with vasculitis even though recent trials have
been negative for rituximab role in therapy for
lupus nephritis with vasculopathy but without
vasculitis. Further studies are required to
verify the use of aggressive pharmacologic
therapy in patients who are dialysis dependent
secondary to LN with vasculitis.
References
1. Fiehn C, Hajjar Y, Mueller K, et al. Improved
clinical outcome of lupus nephritis during the
past decade: importance of early diagnosis and
treatment. Ann Rheum Dis 2003;62:4359.
2. Illei GG, Austin HA, Crane M, et al.
Combination therapy with pulse CY plus pulse
methylprednisolone improves long-term renal
outcome without adding toxicity in patients
with lupus nephritis. Ann Intern Med
2001;135:24857.
3. Leandro MJ, Edwards JC, Cambridge G,
Ehrenstein MR, Isenberg DA. An open study
of B lymphocyte depletion in systemic lupus
erythematosus. Arthritis Rheum 2002;46:2673-
7.
4. Pasquali S, Banfi G, Zucchelli A, Moroni G,
Ponticelli C, Zucchelli P. Lupus membranous
nephropathy: long-term outcome. Clin Nephrol
1993;39:175-82.
5. Mecklenbrauker I, Saijo K, Zheng NY, et al.
Protein kinase C delta controls self- antigen-
induced B-cell tolerance. Nature 2002;416:
860-5.
337
6. Stuart L, Hughes J. Apoptosis and autoimmunity.
Nephrol Dial Transpl 2002;17:697-700.
7. Lea, J. Lupus Nephritis in African Americans.
Am J Med Sci 2002;323:85-9.
8. Grammer AC, Lipsky PE. B cell abnormalities
in systemic lupus erythematosus. Arthritis Res
Ther 2003;5:S22-7.
9. Clynes R, Dumitru C, Ravetch JV. Uncoupling
of immune complex formation and kidney
damage in autoimmune glomerulonephritis.
Science 1998;279:1052-4.
10. Berden JH. Lupus Nephritis. Kidney Int 1997;
52:538-58.
11. Daugas E, Nocy D, Huong du LT, et al. Anti-
phospholipid syndrome nephropathy in sys-
temic lupus erythematosus. Am J Kidney Dis
1997;29:119-24.
12. Yokoyama H, Wada T, Hara A, et al. The
outcome and a new ISN/ RPS 2003 classi-
fication of lupus nephritis in Japanese. Kidney
Int 2004;66:2382-8.
13. Cordeiro AC, Isenberg DA. Novel therapies in
lupus-focus on nephritis. Acta Rheumatol
Portuguesa 2008;33:157-69.
14. Alarcon-Segovia D, Tumlin JA, Furie RA, et
al. LJP394 for the Prevention of Renal Flare in
Patients with Systemic Lupus Erythematosus.
Arthritis Rheum 2003;48:442-54.
15. Cardie MH, Tumlin JA, Furie RA, et al.
Abetimus sodium for renal flare in systemic
lupus erythematosus: results of a randomized,
controlled phase III trial. Arthritis Rheum
2008;58:2470-80.
16. Bhat P, Radhakrishnan J. B lymphocytes and
lupus nephritis: New insights into pathogenesis
and targeted therapies. Kidney Int 2008;73:
261-8.
17. Furie RLJ, Merrill JT, Petri M, et al. Multiple
SLE disease activity measures in a multicenter
phase 2 SLE trial demonstrate belimumab
(fully human monoclonal antibody to B-
lymphocyte stimulator [BLYS]) improves or
stabilizes SLE activity. Ann Rheum Dis
2006;65:63.
18. Belimumab: anti-BLyS human monoclonal anti-
body, anti-BLyS monoclonal antibody, BmAb,
human monoclonal antibody to B-lymphocyte
stimulator. Drugs R D 2008;9: 197-202.
19. Tumlin, JA. Lupus Nephritis: Histology,
Diagnosis, and Treatment. Bull NYU Hosp Jt
Dis 2008;66:188-94.