Nephrol Dial Transplant (2011) 26: 3987–3992

doi: 10.1093/ndt/gfr109
Advance Access publication 8 March 2011

Intensive short-term treatment with rituximab, cyclophosphamide and

methylprednisolone pulses induces remission in severe cases of SLE
with nephritis and avoids further immunosuppressive maintenance
therapy

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Dario Roccatello, Savino Sciascia, Daniela Rossi, Mirella Alpa, Carla Naretto, Simone Baldovino,
Elisa Menegatti, Rita La Grotta and Vittorio Modena

Dipartimento di Malattie Rare, Immunologiche, Ematologiche ed Immunoematologiche, Centro di Ricerche di Immunopatologia e

Documentazione su Malattie Rare (CMID), Struttura Complessa a Direzione Universitaria di Immunologia Clinica, Ospedale Torino
Nord Emergenza San G. Bosco e Università di Torino, Torino, Italy
Correspondence and offprint requests to: Dario Roccatello; E-mail: [email protected]

Abstract Conclusions. Long-lasting remissions were obtained in

Background. B cells play a central role in systemic lupus patients with severe SLE and major organ involvement
erythematosus (SLE). Rituximab is expected to induce by this intensive administration of rituximab combined
apoptosis of all the CD20-positive B cells. A proportion of with low doses of intravenous cyclophosphamide and
patients are refractory or intolerant to standard immunosup- methylprednisolone pulses followed by a rapid tapering
pression. These are candidate to new therapeutic options. of prednisone to 5 mg/day as a sole maintenance therapy.
Methods. Eight patients [six women, two men, mean age 41-
year-old (27–51), with severe multiorgan involvement (kidney, Keywords: lupus nephritis; rituximab; systemic lupus erythematosus
skin, nervous system, polyarthritis, polyserositis, antiphospho-
lipid antibody syndrome)] were considered eligible for an in-
tensive combination therapy including rituximab. Rituximab Introduction
was administered (dose 375 mg/m2) on Days #2, 8, 15 and 22.
Two more doses were administered 1 and 2 months following Systemic lupus erythematosus (SLE) is a multisystem auto-
the last weekly infusion. This treatment was combined with immune disease characterized by the production of several
two pulses of 750 mg cyclophosphamide (Days #4 and 17) and autoantibodies against a variety of self-antigens. B cells
three pulses of 15 mg/kg (Days #1, 4 and 8) methylpredniso- play a central role in SLE. Targeting the B-cell compart-
lone followed by oral prednisone, 50 mg for 2 weeks rapidly ment is therefore an attractive alternative to current avail-
tapered until 5 mg in 2 months. Response was evaluated by able therapies. Rituximab is a human/mouse chimeric
assessing the changes in clinical signs and symptoms [Sys- monoclonal antibody that specifically reacts with the
temic Lupus Erythematosus Disease Activity Index (SLEDAI CD20 antigen, which is expressed on pre-B cells, imma-
score)] and laboratory parameters for at least 12 months. ture, mature naı̈ve and mature B cells but not plasma cells.
Results. Levels of erythrocyte sedimentation rate and anti- Rituximab is expected to induce apoptosis of all the CD20-
double-strand DNA antibodies significantly decreased (P < positive B cells. Rituximab has been investigated in SLE
0.01 at 12 months), whereas C3 and mainly C4 values because of the potentially serious toxicities of immunosup-
increased at 6 months (P < 0.01 for C4). Proteinuria im- pressive agents currently in use. Some trials in adults and
proved in the cases with renal involvement (P < 0.01 at 3, 6 children with SLE suggested that rituximab—although
and 12 months). SLEDAI score improved moving from the given in combination with other immunosuppressive
mean 17.3 (12–27) before therapy to 3.1 (1–5) after ritux- drugs—may improve several manifestations of SLE, in-
imab treatment. Constitutional symptoms including arthral- cluding skin rash, alopecia, arthritis, haemolytic anaemia
gia, weakness and fever disappeared in all the previously and thrombocytopenia [1–4]. The role of rituximab in the
affected patients; paresthesia improved in the four patients more severe forms of SLE is still being debated. Results of
with polyneuropathy and skin lesions gradually resolved in two randomized placebo-controlled studies [5, 6] devoted
the patients with necrotizing skin ulcers at presentation. to evaluate the efficacy and safety of rituximab were dis-
Drug side effects were negligible. appointing and are still object of debate [6, 7]. These trials
were conducted to test the superiority of rituximab

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3988 D. Roccatello et al.

compared to conventional immunosuppressive treatment, score was separately assessed by two investigators (S.S. and M.A.) specif-
while the major target of uncontrolled studies was testing ically trained for activity score processing in rheumatology.
In order to prevent possible interferences in biological detection due
its role in refractory cases or in patients who were intolerant to complex formation of rituximab and antibody, serum samples were
to conventional treatments. collected 6 months after the last drug administration.
The present study focuses on the effects of an intensive Human anti-chimeric antibodies directed against rituximab were
course of therapy, using rituximab in combination with quantified using validated antigen-binding tests radio immuno assay
(RIA), while levels of therapeutic antibodies were assessed using validated
two intravenous pulses of cyclophosphamide and three enzyme-linked immunosorbent assay, both performed at Sanquin Diag-
pulses of methylprednisolone and followed by a short course nostic Services (Amsterdam, NH) on a routine base.
of prednisone, given prospectively to a selected cohort of Due to the low number of patients, mainly descriptive statistical anal-
severe patients. This intensive short-time treatment gave yses were performed. For comparing means between SLEDAI scores at
prolonged remissions even though maintenance therapy the beginning and at 12 months of study, the paired t-test was used. Differ-
ences among study groups were analyzed by multifactorial analysis of
consisted of only 5 mg prednisone since the second month. variance. Differences were considered statistically significant when two-
This represents the novelty of this open single-center study. sided P-values were <0.05. Statistical analyses were carried out using
StatView 5.0.1 for Macintosh (SAS Institute, Cary, NC).
This study was performed according to the local rules of off-label
Methods therapy in Piedmont Region (Northwest Italy).

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Baseline data are summarized in Table 1.
Eight patients, six women and two males, six white and two black
subjects, mean age 41 years (range 27–51 years), with severe multiorgan Results
involvement including kidney (five cases, including three patients with
Class IV and two with Class V International Society of Nephrology/Renal Treatment with rituximab resulted in complete depletion of
Pathology Society glomerulonephritis), skin lesions (six cases, with ne-
crotizing ulcers in four), involvement of central nervous system [2], poly- B cells in peripheral blood, as shown by the percentage of
neuropathy [4], severe polyarthralgias with arthritis [8], polyserositis [3], CD20-positive cells, diminishing from the pre-treatment
lymphadenopathy [4], secondary antiphospholipid antibody syndrome mean value of 18% (5.6–25%) to 0.1% 7 days after the
(APS) (two cases), were considered eligible for rituximab therapy due fourth infusion. No CD20-positive cells were found to be
to their resistance or intolerance to previous therapy (six cases) or as a
front line immunosuppressive treatment in two women with unsatisfactory
detectable at 12 months. A definite reappearance of CD20-
therapeutic compliance (#1) or as a specific request of a short-time im- positive cells was observed only after 18 months (mean
munosuppression for gestational perspectives (#7). value 14.2%, range 4.6–22%).
Previous immunosuppressive therapy included steroids in every case Rituximab blood levels were invariably undetectable
(three intravenous pulses of 15 mg/kg methylprednisolone followed by 6 months after the last drug administration.
prednisone 1 mg/kg/day for at least 4 weeks with subsequent tapering
according to clinical features), cyclophosphamide (given in a monthly intra- Anti-rituximab antibody levels were undetectable (i.e.
venous dose of 1 g for 6 months in Patient #4 and both intravenously and <12 AU/mL) in all cases but one (Patient #5) showing very
orally for a cumulative dose of 9 g in Patient #3) in two nephritis patients, high levels (1500 AU/mL).
azathioprine in three patients, mycophenolate mofetil in three patients, As shown in Figure 1, levels of erythrocyte sedimenta-
methotrexate in one non-nephritis patient, cyclosporine A in four cases,
hydroxychloroquine in six cases and thalidomide in one patient.
tion rate and anti-double-strand (ds) DNA antibodies sig-
Rituximab was administered intravenously at a dose of 375 mg/m2 on nificantly decreased (P < 0.01 at 12 months), whereas C3
Days #2, 8, 15 and 22. Two more doses were administered 1 and 2 months and mainly C4 values increased at 6 months (P < 0.01 for
following the last weekly infusion. This treatment was combined with two C4) and remained within the normal range at 12 months.
pulses of 750 mg cyclophosphamide (Days #4 and 17) and three intravenous Before treatment, only two patients had an increase in
pulses of 15 mg/kg (Days #1, 4 and 8) methylprednisolone followed by oral
prednisone, 50 mg for 2 weeks rapidly tapered until 5 mg in 2 months. serum creatinine [#3, serum creatinine 2.30 mg/dL, estimated
Response was evaluated by assessing the changes in clinical signs and glomerular filtration rate (eGFR)-Modification of Diet in Re-
symptoms and laboratory parameters for at least 12 months. SLEDAI nal Disease (MDRD) 33 mL/min; #4, serum creatinine 1.20

Table 1. Baseline characteristics of eight patients treated with rituximab under studya

Response duration
Pt/gender (age), SLE duration before (months) at last
ethnicity RTX (years) follow-up visit Manifestations

1/F (47) Bb 10 15 A, S, APS, CNS, K (LN IV)

2/F (27) W 10 59 A, S, H, PN, L
3/M (41) W 25 25 A, CNS, PN, S, H, K (LN IV)
4/M (35) W 12 12 A, H, K (LN V)
5/F (33) B 0.5 (1st cycle) 41 (1st cycle) A, H, S, Se, APS
3.5 (2nd cycle) 7 (2nd cycle)
6/F (46) W 12 54 A, S, L, PN, K (LN IV)
7/F (36) Wb 3 (1st cycle) 36 (1st cycle) A, S, Se, L, K (LN V)
3 (2nd cycle) 13 (2nd cycle)
8/F (55) W 12 48 A, S, L, PN
a
Pt, patient; F, female; M, male; B, black; W, white; A, arthritis; S, skin involvement; CNS, involvement of central nervous system; K, kidney; PN,
peripheral neurologic manifestations; L, lymphadenopathy; H, haematologic; Se, serositis.
b
First-line treatment.
Intensive treatment with rituximab of severe SLE 3989

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Fig. 1. Serologic profile of the SLE patients treated with rituximab. Anti-DNA antibodies (a DNA), erythrocytes sedimentation rate (ESR), eGFR,
evaluated by MDRD [8], and C4 were evaluated at 0, 3, 6 at 12 months.

mg/dL, eGFR-MDRD, 73 mL/min]. The general profile of

eGFR, evaluated by MDRD [8], is shown in Figure 1.
Proteinuria improved in all five cases with renal involve-
ment (P < 0.01 at 3, 6 and 12 months). SLEDAI score
ameliorated moving from the mean 17.3 (12–27) before
therapy to 3.1 (1–5) after rituximab treatment (Figure 2).
Constitutional symptoms including arthralgia, weakness
and fever disappeared in all the previously affected pa-
tients, paresthesia improved in the four patients with poly-
neuropathy and skin lesions gradually resolved in the four
patients with necrotizing skin ulcers at presentation.
No acute side effects were shown apart from mild bra-
dycardia solved by reducing infusion speed in Patient #8.
Asymptomatic urinary tract infections were detected in
Fig. 2. Proteinuria levels and clinical and serological response (evaluated
Patients #1, 5 weeks after the first infusion of rituximab. by SLEDAI) are shown. Proteinuria improved in all five cases with renal
At the beginning of the third month, every patient received involvement (at 3, 6 and 12 months). Values are shown as mean 6 SEM.
only 5 mg prednisone/day. The mean follow-up was 36.2 SLEDAI ameliorated after rituximab, with a statistical significance. SLE-
months (12–59 months). Two patients relapsed. Fourty-one DAI scores of Patients #6 and #7 and #1 and #3 coincide.
months after the last rituximab infusion, patient # 5 presented
with pericarditis, polyarthritis and diffuse myalgia. Her Because of the good results previously obtained, retreat-
serologic profile revealed haemolytic anaemia, leukopenia ment with the combined scheme of rituximab, cyclophos-
and decreased platelet count. She had a positive gravindex. phamide and methylprednisolone was proposed in both
She was given 50 mg prednisone, 400 mg hydroxicloro- cases. Both patients showed a complete clinical response.
quine, low doses of aspirin and low-molecular weight hep- Retreatment was safe also in Patient #5, who had been
arin because of her known antiphospholipid syndrome found to have anti-rituximab antibodies.
APS (Table 1). Nevertheless, she not only had a sponta- A representative case is shown in Figure 3. This is a
neous abortion at the 10th week but symptoms persisted 41-year-old male (Table 1, #3) with a 25-year duration of
despite continuous administration of 1 mg/kg/day predni- SLE and 25-year story of lupus nephritis with focal lesions
sone. She was the only patient of our cohort with high at the first biopsy when he was 17 years old, a III plus V
levels of anti-rituximab antibodies. lupus nephritis 16 years later. At the age of 39 years, he
A dramatic metrorrhagia due to the appearance of an presented acute nephritic syndrome with rapidly progres-
antibody-dependent factor VIII deficiency was observed sive renal deterioration. The renal biopsy (Figure 4)
36 months after rituximab in Patient #7. Proteinuria, pre- showed a diffuse extracapillary proliferation (Class IV)
viously undetectable, suddenly increased to 1.7 g. She also with 60% of florid crescents and focal necrosis. He also
complained of a severe polyarthritis. had four joints with pain and swelling, a recurrence of
3990 D. Roccatello et al.

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Fig. 3. Renal function valuated by serum creatinine, proteinuria and serum proteins of a representative case treated with rituximab (Table 1, #3). Notably,
proteinuria decreased from 10 to 2 g/24 h and creatinine from 2.8 to 1.5 within 1 month, dropping to normal range in 9 weeks.

proportion shows haematologic intolerance or cannot be

satisfactorily treated because of elevated cumulative doses
of cyclophosphamide. All these patients are candidate to
new therapeutic options.
Results of an intensive scheme using rituximab combined
with low doses of intravenous cyclophosphamide and pulses
of methylprednisolone are presented in this open uncontrolled
study in a few severe cases. The main interest of these data
resides in the relatively short time of standard immunosup-
pression, which strongly limits the possible adverse effects of
steroids and cyclophosphamide assuring a long-lasting remis-
sion without immunosuppressive maintenance therapy. Be-
Fig. 4. Renal biopsy of a patient (Table 1, #3) who showed a Class IV sides, this scheme might also be useful in low-compliance
lupus nephritis with diffuse extracapillary proliferation (60% of florid patients and avoid prolonged hospitalization. All patients, in-
crescents) and focal necrosis. cluding a case with rapidly progressive glomerulonephritis,
were allowed to restart their own work within 2 weeks.
inflammatory type rash, fever, decreased platelet count, Biochemical parameters, symptoms and SLEDAI score
hypocomplementaemia and high levels of anti-dsDNA proved that patients reached long-lasting remission. The
with a total SLEDAI score of 28. By that time, he had complete reversal of urinary abnormalities and functional
reached a cumulative dose of cyclophosphamide (9 g), improvement convinced us not to perform a second renal
which imposed the search of a rescue therapy which re- biopsy. Some other aspects need to be discussed.
duced further administration. Figure 3 shows the profiles of A decrease in anti-dsDNA antibody levels was observed in
serum creatinine, proteinuria and serum proteins. Notably, this sample of patients in the long run. In patients with SLE,
proteinuria decreased from 10 to 2 g/24 h and creatinine treatment with rituximab was associated with decline in anti-
from 2.8 to 1.5 in 1 month, dropping to normal range in 9 dsDNA antibody levels in most [2, 3, 9–13] but not all studies
weeks (not shown). This patient, a night-working taxi- [1, 4, 14], implying that self-reactive B cells do play patho-
driver, interrupted his activity just for 5 days following genetic roles beyond the production of autoantibodies [15].
renal biopsy. Rituximab-induced improvements may be related to effects
on antigen presentation [16], cytokine production [17] and
cell-to-cell interactions with T cells [18]. Of interest, a small
Discussion population of CD20-expressing T cells was depleted after
rituximab [19]. Moreover, a rituximab-induced increase in
A few SLE patients prove to be refractory to standard ther- numbers of peripheral T-regulatory cells, known to be low
apy with steroids and immunosuppressive drugs. A greater in active SLE patients, was reported too [12]. Finally, Anolik
Intensive treatment with rituximab of severe SLE 3991

et al. [11] found that peripheral blood B-cell abnormalities in ing and avoid prolonged administration of conventional
patients with SLE, including naive B-cell lymphopenia and immunosuppressant drugs, obtained long-lasting responses
increased memory B cells and plasmoblasts, were corrected without relapse in patients with cryoglobulinaemic vasculitis
by rituximab treatment. because of a more extensive tissue depletion of CD20-
Our patients did neither show significant mild-to- positive cells [27–29]. Accordingly, reappearance of
moderate infusion reactions nor clinically relevant infec- CD20-positive cells in circulation was found in our SLE
tion sequelas. Rituximab has proven to be generally well patients only after 18 months.
tolerated. However, it has been rarely associated with se- This is an uncontrolled single-center study in severe SLE
rum sickness, agranulocytosis, fatal infections especially patients showing promising results similar to those obtained in
progressive multifocal leukoencephalopathy [20–24]. The Lu’s large series in comparably difficult patients [34]. These
incidence of serious infections could be quantified in a results are in contrast with two recently concluded controlled
representative cohort of 1053 rheumatoid arthritis patients trials. Both ‘Explorer’ [5] and ‘Lunar’ [6] were randomized,
as 5.4 events per 100 patient-year [25]. Fatal infections double-blind placebo-controlled studies addressed to deter-
were invariably associated to the combination of rituximab mine the additional efficacy of rituximab added to standard
with conventional immunosuppressants, especially gluco- immunosuppressive therapy in moderate or severe SLE with
corticoids in moderate to high doses, azathioprine, myco- [6] or without nephritis [5]. Despite a significant improvement

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phenolate mofetil and cyclophosphamide, rather than in anti-dsDNA and complement levels in rituximab-treated
rituximab alone [26]. patients of both studies, and a definite trend toward a greater
A steroid and immunosuppressant-sparing strategy is control of disease activity of the rituximab arm in the ‘Lunar’
probably mandatory to avoid the rare but fatal complica- study, both trials failed to demonstrate statistically significant
tions of combination therapy. A combination of rituximab differences between rituximab and placebo groups with re-
with a short-term intensive steroid treatment and low doses gard to efficacy on clinical activity. Background treatment,
of intravenous cyclophosphamide was used in this open concomitant therapies and ethnic factors have been empha-
study in order to offer the patients an effective therapy sized as relevant factors in explaining the different outcomes
limiting the effects of a prolonged immunosuppression vir- of patients examined in controlled and uncontrolled studies [8,
tually abolishing immunosuppressive maintenance treat- 31, 35]. As recently emphasized [7], the possible synergistic
ment. This scheme was adapted from Leandro’s effect of rituximab in combination with cyclophosphamide,
experience [2] with some modifications, mainly consisting which has been suggested by some authors to have significant
of a four plus two infusion protocol of rituximab, which advantages in complicated, refractory SLE cases [34, 36], was
was associated with a delayed occurrence of relapses in our not evaluated in randomized controlled trials.
own experience in other immune-mediated diseases [27– Moreover, open uncontrolled studies focussed on pa-
30]. Since the beginning of the third month of therapy, tients either refractory or intolerant to standard immuno-
patients were given 5 mg prednisone. The mean post-in- suppressive drugs who are not exceptionally observed in
duction follow-up was as long as 36 months (range 12–59 clinical practice. Actually, it is unlikely that these patients
months). Two patients needed a reinduction after 36 and 41 may be included in randomized controlled studies.
months and had a complete remission. Although patients treated with rituximab are B-cell de-
Our results are similar to Gunnarsson’s experience in pleted and definitely immunosuppressed, drug safety pro-
seven cyclophosphamide-resistant female patients treated file seems to be better than standard immunosuppression.
with a combination of rituximab and cyclophosphamide In conclusion, although this prospective study had major
[13]. SLEDAI score and anti-dsDNA significantly drop- limits (especially in the absence of control patient group), it
ped, while on repeat renal biopsy, improvement in the his- brings additional evidence of a role of rituximab as an off-
topatologic class of nephritis with a decrease in the renal label drug in severe cases of SLE (with or without neph-
activity index occurred in the majority of patients. ritis) who are intolerant to conventional therapy and need
It is generally accepted that there is a relationship between alternative therapeutic options. Used in an intensive short-
serum rituximab concentration and degree of B-cell deple- term course in combination with intravenous cyclophos-
tion in patients with SLE and between B-cell depletion and phamide and methylprednisolone, rituximab obtained a
reduction in disease activity score, i.e., only SLE patients long-lasting remission, which was maintained with mini-
with B-cell depletion equal or greater than <5 cells/lL did mal doses of prednisone by the beginning of the third
experience significant reduction in disease activity scores month of therapy, avoiding the need of prolonged immu-
[13]. Our patients experienced a complete B-cell depletion nosuppression and minimizing the devastating effects of
within 5 weeks following the first injection. This is expected steroids. This scheme could have a place in the context
in rheumatoid arthritis [31] but is not the rule in SLE [32]. of the acknowledged opportunity to offer patient treatments
An early CD20-positive cell depletion has been found to tailored to the individual needs based on the severity of the
affect long-term clinical outcome [32]. Moreover, patients disease but also ethnicity, or desire to have children [37].
who had the shortest duration of B-cell depletion showed a
trend toward a less favourable outcome [13]. Besides, at least
in mice, despite depletion of B cells from the circulation,
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wild-type hosts: implications for the generation of architectural Received for publication: 2.1.11; Accepted in revised form: 8.2.11