The involvement of the central nervous system is 1of the major causes of morbidity and mortality inpatients with systemic lupus erythematosus
SLE), and it is the least understood aspect of the disease1). Indeed, its recognition and treatment continue toepresent a major diagnostic and therapeutic challenge.ue to the lack of controlled randomized trials, the cur-
ent therapeutic approach to the different manifestationsf neuropsychiatric SLE (NPSLE) remains empirical ands based on clinical experience (2,3). Various combina-
Department of Rheumatology, Hospital Universitario de Bellvitge—IDIBELL, Bar-celona, Spain.
The authors have no conflicts of interest to disclose.Address reprint requests to Javier Narváez, MD, PhD, Department of Rheumatol-
iogy (planta 10-2), Hospital Universitario de Bellvitge, Feixa Llarga s/n. 08907,L=Hospitalet de Llobregat, Barcelona, Spain. E-mail: [email protected].
ions of corticosteroids, immunosuppressants, anticoagu-ant therapy, and symptomatic drugs are used dependingn the presumptive main pathogenic mechanism, al-hough resistant cases have been described. At presenthere is no treatment strategy for patients with NPSLEho fail to respond to conventional therapies. There is
herefore a continuing need to identify new, more effec-ive therapies with fewer side effects for these complexituations.
The emergence of B-cell-depleting therapy with theonoclonal antibody rituximab (RTX), directed against
he B-cell-specific antigen CD20, could increase the ther-peutic armamentarium with respect to SLE (4). In recentears a considerable number of observational studies andase reports have demonstrated encouraging early resultsith RTX in cases of severe refractory SLE (5,6), although
We present a patient with persistently active NPSLE(seizure disorder and organic psychosis), despite conven-tional therapy, who responded dramatically to RTX. Cur-rent evidence on the therapeutic use of RTX in adultpatients with refractory NPSLE is also reviewed.
METHODS
In addition to describing our case, we analyzed currentevidence on the therapeutic use of RTX in adult patientswith refractory NPSLE by a systematic review of reportspublished in indexed international journals (not reviews,congress abstracts, or unpublished results) included in thePubMed database between January 1970 and February2011. The inclusion criteria in the analysis were (1) thepresence of a highly active NPSLE and (2) failure to re-sponse to standard therapy (including corticosteroids plusat least 1 immunosuppressive agent). Search terms in-cluded “systemic lupus erythematosus,” “neuropsychiat-ric,” “rituximab,” and “anti-CD20.” Only English-lan-guage reports were selected for review. Patients under 18years of age were excluded. The references of the studiesobtained were also examined to identify additional re-ports. We included only those cases that were sufficientlydetailed to be analyzed individually.
RESULTS
Case Report
A 38-year-old Hispanic woman had been diagnosed withSLE in April 2007 on the basis of arthritis, oral ulcers, leu-kolymphopenia, and positive antinuclear antibodies (ANA)and anti-dsDNA antibodies. She was treated with lowdoses of prednisone (10 mg daily), nonsteroidal anti-in-flammatory drugs, and hydroxychloroquine (200 mg/d).
One month later she was transferred to the emergencydepartment of our hospital because she had 3 generalizedtonic-clonic seizures. On questioning, her family revealeda 2-week history of cognitive dysfunction manifested byimpairments in mental activities (eg, memory, abstractthinking, and judgment), which had evolved into an or-ganic psychotic state over the previous 12 hours, withdisorientation, persecutory delusion, and visual and audi-tory hallucinations. On admission, the patient was afe-brile and normotensive, without neurologic focality. Lab-oratory results were as follows: erythrocyte sedimentationrate 57 mm/h, C-reactive protein 22 mg/L (normal �5),hemoglobin 9.5 g/dL, white blood cells 3.43 � 109/L520 lymphocytes/mm3), platelet count 326 � 109/L,amma-glutamyl transpeptidase 0.74 ukat/L (normal0.43), and ferritin 387 �g/L (normal range, 10-160).
Coagulation profiles, renal function test results, alkalinephosphatase, aspartate aminotransferase, alanine amino-transferase, total bilirubin, creatine phosphokinase, se-rum lactate dehydrogenase, electrolytes, total proteins, al-bumin, cholesterol, triglycerides, serum calcium, serum
protein electrophoresis, thyroid hormones, and urinalysis
were all within normal limits. An immunological studyshowed ANA 1:320 (homogeneous pattern) and anti-ds-DNA 459 kint.u./L (normal �14.9). Anti-SS-A and anti-SS-B antibodies were positive, whereas anti-Sm, anti ri-bonucleoprotin antibodies, anticardiolipin antibodies,lupus anticoagulant, and beta-2-glycoprotein 1 antibod-ies were negative. Serum complement levels were reduced:C3 394 mg/L (normal range: 750-1400), C4 26.6 mg/L(normal: 100-340), and CH50 4 UH (normal: 51-136).
An electroencephalogram revealed signs of diffuse ce-rebral dysfunction (several brief bursts of generalizedspike and polyspike-and-wave complexes during hyper-ventilation and drowsiness). Cerebrospinal fluid (CSF)was normal (no cells, total protein 0.25 g/L, and glucose3.4 mmol/L). CSF and blood cultures were sterile. CSFpolymerase chain reaction assays for common viruses,Mycobacterium tuberculosis, and Neisseria meningitidiswere all negative, as was that for cryptococcal antigen.Brain magnetic resonance imaging (MRI) and cerebralmagnetic resonance angiography were normal.
She was initially treated with anticonvulsants (phenyt-oin and valproate), prednisone 1 mg/kg per day in divideddoses, and neuroleptics. However, despite this treatment,the organic psychosis rapidly worsened and seizures per-sisted even though different combinations of anticonvul-sants (phenytoin, valproate and clonazepam) were used.For this reason, 2 weeks after admission she was givenintravenous pulses of methylprednisolone (1 g/d for 3consecutive days), but showed no apparent clinical im-provement. In view of this lack or response, 20 days afteradmission she received an intravenous cyclophosphamide(IV-CYC) pulse (500 mg per square meter of body surfacearea) and 3 sessions of plasmapheresis, with only mildimprovement. We therefore decided, after obtaining in-formed consent, to add RTX to the IV-CYC. RTX wasadministered at a dose of 2 endovenous infusions of 1 gseparated by a 2-week interval (days 1 and 15); the firstdose of RTX was administered 51 days after admission(31 days after the first bolus of IV-CYC and 4 days beforethe second). The patient responded within a few weeks ofthe first dose of RTX, with disappearance of seizures andprogressive resolution of the psychiatric symptoms. Theinitial prednisone and IV-CYC therapy (6 monthly intra-venous pulses of 500 mg/m2) was followed by mainte-nance therapy with mycophenolate mofetil (at a dose of 2g/daily). The improvement was sustained and currently,41 months after the last dose of RTX, the patient remainsasymptomatic and has been able to resume work and per-form normal daily activities. The concomitant oral steroiddose has been reduced to 2.5 mg daily of prednisone,while mycophenolate and neuroleptics have been stoppedand hydroxychloroquine (200 mg/d) has been reinsti-tuted.
After the fourth round of CYC the patient developed aherpes zoster infection, but no other adverse effects wereobserved. Serum immunoglobulin levels remained within
normal limits.
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366 Rituximab therapy in refractory neuropsychiatric lupus
Literature Review
The MEDLINE search resulted in 139 articles (Fig. 1).Abstract information suggesting clinical data on the use ofRTX in refractory NPSLE was located in 34 articles. Afterevaluation of the full text, 13 articles were excluded: 5contained not relevant data, 3 were an editorial/review,and 1 contained duplicated data. The cases reported by Yeand coworkers (7) were excluded since they used RTX asa first-line therapy in 6 SLE patients with recent-onsetsevere myelopathy. We also excluded the cases reportedby Galarza and coworkers (11 patients) (8), Terrier andcoworkers (10 patients) (9), and Catapano and coworkers(13 patients) (10) because their clinical characteristicswere not sufficiently detailed to be analyzed individually.
Therefore, 21 articles were finally selected for review (3uncontrolled studies and 21 case series/case reports) (11-27).
In addition to our patient, 35 well-documentedcases of refractory NPSLE treated with RTX were iden-tified in the literature (11-27). Details of these patientsare summarized in Tables 1 and 2. There were 34(97%) women and 1 (%) man, with a mean age of 35 �11.6 years (mean � standard deviation; range, 18-64ears) and a median disease duration of 5 � 7.1 years
Figure 1 MEDLINE
range, 2 months-25 years). (
In all cases, neuropsychiatric involvement was the mainndication for RTX administration, although the majorityf patients (28 cases, 80%) had an active, multiorganicLE (with 2 or more clinical features) that was refractoryo corticosteroids and immunosuppressive drugs (Table). The mean number of previous immunosuppressantssed was 2.42 (range, 1-5). Only in 10 patients (29%) wasTX administered after the lack of response to a single
mmunosuppressant and corticosteroids (oral and/or in-ravenous). The proportion of patients who had previ-usly received CYC, azathioprine, cyclosporine, and my-ophenolate was 83% (29 patients), 43% (15 patients),9% (10 patients), and 23% (8 patients), respectively. Inddition to corticosteroids and immunosuppressive ther-py, plasma exchange was tested in 26% (9/34) of pa-ients, intravenous immunoglobulin in 9% (3/34), andmmunoadsorption in 9% (3/34).
With regard to neuropsychiatric manifestations, theeries included patients with acute confusional state11 cases), myelopathy (8), psychosis (7), seizures (6),eadache (4), mood disorder (4), central nervous sys-em vasculitis/cerebral vasculopathy (4), mononeu-opathy (2), cognitive dysfunction (2), anxiety disorder1), demyelinating syndrome (1), and polyneuropathy
: process selection.
1). Thirty-seven percent (13/34) of patients concur-
J. Narváez et al. 367
Table 1 Clinical Characteristics of 35 Reported Adult Cases of Refractory Neuropsychiatric Systemic Lupus ErythematosusTreated with Rituximab
MMF20 (21) F/48/NR Seizures Arthritis, skin rash CS, HCQ, AZA21 (22) F/64/6 yr Myelopathy CS, MP, CYC, IV
immunoglobulins22 (16) F/20/6 mo Acute confusional state Arthritis, cardiomyopathy CS, CYC, AZA23 (16) F/41/21 yr Acute confusional state Nephritis CS, MP, CYC, IA, PE24 (16) F/38/11 yr Mood disorder Nephritis, serositis,
arthritisCS, CYC, CsA, AZA
25 (16) F/29/5 yr Acute confusional state Nephritis, skin rash CS, CsA
368 Rituximab therapy in refractory neuropsychiatric lupus
rently presented more than 1 neuropsychiatric mani-festation.
The lack of standardization in the use of RTX with SLEpatients has resulted in different therapeutic regimens.The most frequently used RTX regimen was that recom-mended for the treatment of rheumatoid arthritis (two1000 mg doses separated by 15 days), which was used in34% (12/35) of cases. The recommended regimen for thetreatment of lymphoma (375 mg/m2 of RTX weekly for 4weeks) was administered in 26% (9/35) of cases. Theremaining patients were treated with other regimens (Ta-ble 2).
In all cases, RTX was administered together withcorticosteroids, while 12 patients (34%) received intra-venous methylprednisolone as induction therapy. In34% (12/35) of patients, treatment with RTX was ad-ministered concomitantly with intravenous CYC. In23% (8/35) of cases, induction therapy included RTX,CYC, and intravenous methylprednisolone. Althoughnot all reports specify the maintenance regimen afterRTX therapy, it mainly consisted of oral antimalarial
Due to the heterogeneous definitions of treatment re-sponse, it is difficult to obtain consistent results based onuncontrolled data from longitudinal studies and case re-ports. However, the majority of these reports defined clin-ical response as the disappearance of the symptoms thatmotivated the use of RTX (complete response) or signif-icant improvement of the disease manifestations (partialresponse). A clinical response using these criteria was ob-served in 85% (29/34) of patients (patient number 15 waslost to follow-up at 3 months and was therefore excludedfrom the analysis), it being classified as complete in 50%of cases (17/34) and partial in 35% (12/34). The 5 pa-tients with NPSLE who did not respond to RTX hadeither an acute confusional state (2 cases), myelopathy (1patient with 17 episodes of recurrent myelitis), major de-pression (1 case), or mood disorder with cognitive impair-
sOther Organ/Systems
Concomitantly Affected Previous Therapies
Nephritis, arthritis CS, HCQ, MTX, AZA,CYC
AC, CS, MP, AZA, HCQ,CsA, CYC, MTX
IV immunoglobulins
Arthritis CS, AZA, CYC, CsA,MTX, MMF
Skin rash, arthritis CS, CYC, MMF, CsA
Arthritis, skin rash CS, CYC, MMF, CsA
Antiphospholipidsyndrome, arthritis, skinrash
AC, CS, CYC and other2 immunosuppressiveagents not specified
Arthritis, skin rash,nephritis
CS, MP, PE, IVimmunoglobulins
Autoimmune hemolyticanemia
concomitantly affectedAntiphospholipid
syndrome, arthritis,serositis, nephritis
AC, CS, MP, CYC, AZA,MMF
HCQ, CS, MP, CYC
Arthritis, oral ulcers,lymphopenia
CS, MP, CYC, PE
female; CS, oral corticosteroids; CsA, cyclosporine; CNS, centralmmunoadsorption; M, male; MMF, mycophenolate mofetil; MTX,yelitis optica; NR: data not reported; PE, plasma exchange; VCR,
station
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ment (1 case) (12,19,27). In 2 of these patients, neuro-
d; PC,
J. Narváez et al. 369
psychiatric involvement accompanied other severemanifestations, including nephritis, which also failed torespond to RTX (12,19). In addition, 1 of the patientswith an initial partial response to RTX (patient number
Table 2 Treatment and Outcome of 35 Adult Cases of Refrwith Rituximab (RTX)
and died due to fatalpancarditis related toactive SLE 5 mo post-RTXtreatment)
Complete response At least 6 mo/NoPartial response At least 6 mo/NoComplete response At least 6 mo/NoComplete response 1.5 mo/NoPartial response 6.5 mo/NoNonresponder No clinical response at 2 mo
after treatmentNonresponder No clinical response at 6 mo
after treatmentNonresponder No clinical response at 6 mo
after treatmentNonresponder No clinical response at 6 mo
after treatmentComplete response 28 mo/Yes (9 mo)Complete response 10 mo/Yes (NR)Complete response 34 mo/Yes (33 mo)Complete response 28 mo/Yes (6 mo)Partial response 28 mo/NoComplete response 15 mo/NoPartial response 12 mo/NoNonresponder No clinical response at 5 mo
ported 10 patients with persistently active NPSLE, de-
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370 Rituximab therapy in refractory neuropsychiatric lupus
spite conventional therapy (including corticosteroids,immunosuppressants, plasma exchange, and/or immuno-adsorption therapy), with an overall clinical response toRTX of 100%, with remissions lasting 4 to 29 months.The systemic lupus erythematosus disease activity index(SLEDAI) scores improved significantly during treatmentin all cases, from 19.9 (mean range, 49-2), before treat-ment to 6.2 (range, 15-0), after treatment (P � 0.013).
oreover, SLEDAI decreased to 0 in 9 of the 10 patientst 1 to 6 months after RTX treatment. These authorseported a rapid improvement in patients with an alteredevel of consciousness after RTX administration, with the
ean Glasgow coma score rising from 3 to 6 to 14 to 15etween the second and fifth day. They also assessed theffects of RTX on MRI and single-photon emission com-uted tomography results before and after treatment. In 4atients, RTX improved cerebral flow as determined byingle-photon emission computed tomography, whereaspatients showed significant improvement in high-inten-
ity lesions observed in T2-weighted MRI images.Other reported positive effects of RTX on SLE features
ere a significant reduction in SLEDAI and British Islesupus Assessment Group Index scores (12,16-21) (Table), a significant reduction in anti-dsDNA levels (17-21), aignificant reduction in anti-C1q levels (18), a significantmprovement in C3 and/or C4 levels (17-21), and a re-uction in the mean dose of daily corticosteroid therapy
Table 3 Reported Positive Effects of Rituximab onSLEDAI or BILAG
Patient SLEDAI(Reference) Baseline/Post RTX
2-11 (12,16) [meanand range]*
19.9 (49-2)/6.2 (15-0)†
12 (17) 9/2*13 (18) 8/414 (18) 40/10*
BILAG (nervous system)Baseline/post RTX
7 (12,16) A/C8 (12,16) A/C
15 (19,20) B/D16 (19,20) B/D17 (19,20) Died 5 mo post-RTX
*SLEDAI mean and range for the total population (10 patients).†P � 0.05.
16-20).
ollow-Upfter Rituximab Therapy and Safety
lthough the reported data support a potential role forTX as induction therapy in refractory NPSLE, long-
erm information is scarce. As already commented, 1 pa-ient was lost to follow-up at 3 months and 5 patients wereonresponders. Data on follow-up of at least 4 monthsere available in 27 of the remaining 29 patients. Our
nalysis shows that after a median follow-up of 17 monthsrange, 4-46 months), 45% (13/29) of patients relapsedreappearance or worsening of neuropsychiatric symp-oms) despite the maintenance regimen after RTX ther-py. Relapses occurred at a mean of 14 months after RTXdministration (median, 9.5 months; range, 4-33onths), with only 2 (15%) occurring within the first 6onths. This suggests that the majority of relapses in
hese patients could be related to the severity of refractoryLE, since B-cell levels usually return to normal after 6onths.Information about the response to RTX retreatment
as not detailed in the majority of these cases, with thexception of the 2 patients reported by Weide and co-orkers (24): both patients received maintenance therapyith 375 mg/m2 of RTX every 3 months without serious
adverse events after a follow-up of 28 and 10 months,respectively.
The most frequent adverse event reported was infec-tions, with 11 episodes being described in 10 patients(29%). These included pneumonia (4 cases), herpes zos-ter (2 cases), urinary tract infection (2 cases), infection ofdecubitus ulceration (1 case), chickenpox (1 case), andenteritis infection (1 case). No cases of severe infusionreactions or hematologic abnormalities were reported.Only 1 patient died due to SLE progression (fatal pancar-ditis), in this case 5 months after RTX treatment.
DISCUSSION
RTX is increasingly being used off-label in SLE. Numer-ous reports, including several open-label studies, a largenumber of case reports, and the French registry data witha relatively large sample size (including “real-life” patientsseen in regular clinical practice), have shown promisingearly results for RTX in treating patients with active SLEwho are nonresponsive to standard immunosuppressivetherapy (3-5,9). However, 2 randomized controlled trials(RCTs), the EXPLORER and LUNAR studies, failed tofind a difference between RTX and placebo when targetedat extrarenal and renal SLE (28,29).
When interpreting the incongruence of the 2 RCTswith respect to the rest of the published data, it is impor-tant to note that while both studies failed to show thesuperiority of RTX over standard treatments (corticoste-roids, CYC, and mycophenolate), especially in patientswith mild-to-moderate disease, this does not rule out thepossible benefits of using RTX in patients with severe
refractory SLE. In fact, the greatest difficulty in interpret-
J. Narváez et al. 371
ing these 2 studies is that the patients involved were si-multaneously receiving conventional therapy. The inter-ference of standard therapy is clearly a confounding factorhere, since one would expect a high proportion of patientsto respond to treatment with corticosteroids and immu-nosuppressants, thereby obscuring the potential effect ofRTX or of any other superimposed therapy. Another im-portant aspect that should be taken into account is thatsevere and/or refractory patients were not included in the2 RCTs (for example, in the EXPLORER trial patientswere specifically excluded for severe central nervous sys-tem or organ-threatening lupus or any other active con-ditions requiring significant use of steroids or recenttreatment with a cyclophosphamide or a calcineurin in-hibitor), although these patients constitute the majorityin open-label studies and case reports. For these reasons,the observational studies of “real-life” patients who arerefractory to conventional therapy are more informativeas regards the potential effect of RTX. By contrast, the 2RCTs conducted with nonrefractory patients, who weretreated with conventional therapy with or without RTX,leave only a narrow margin of action for RTX. Therefore,the results of these studies should be considered as non-informative or inconclusive rather than as negative, andthey do not preclude the usefulness of RTX in selectedclinical contexts, such as in severe refractory NPSLE.
As regards the effectiveness of B-cell depletion therapyin refractory NPSLE, this global analysis of all cases re-ported to date suggests a potential benefit for the off-labeluse of RTX in these complex situations. In this heteroge-neous group of patients we found high efficacy (a com-plete or partial therapeutic response was achieved in 85%of the patients) and an acceptable rate of adverse events(infections in 29% of the cases), which was not muchhigher than that observed for other biological agents orimmunosuppressive drugs. The clinical outcome after B-cell depletion therapy suggests that substantial disease re-mission is achievable after 1 cycle of treatment in morethan half the cases. A positive correlation between sero-logical markers of disease activity and clinical outcomehas also been demonstrated (14,16-21), and clinical im-provement was accompanied by significant reduction inthe daily dose of oral corticosteroids (16-20). However,recurrence after RTX treatment was noted in 45% ofcases. This suggests that long-term remission of neuropsy-chiatric involvement probably requires maintenance ther-apy with RTX in some of these patients, in a similarregimen to that proposed for rheumatoid arthritis.
The appropriate dosing schedule of RTX for the treat-ment of NPSLE remains uncertain, since the dosing regi-mens used in these open-label trials and case reports vary asregards drug dose, scheduling, and concomitant or condi-tioning regimens. Despite this variety of dosing regimens,there appeared to be no significant differences between pa-tients as regards side effects, tolerability, or response.
The mechanism through which RTX acts on SLE re-
mains unclear. It substantially reduces levels of CD20� B
cells in human peripheral blood within days to weeks.This effect may be sustained for up to 6 months (13,30)and subsequent immune reconstitution improved periph-eral B-cell abnormalities, including lymphopenia and ex-pansion of autoreactive cells (31). This suggests that treat-ment with RTX might alter the pathology of the diseaseonce B-cell repletion occurs. However, it does not appearto work solely via the diminution of autoantibodies.Mechanisms of action that have been proposed in theliterature include complement-mediated cellular lysis, B-cell-triggered apoptosis, and antibody-dependent cellulartoxicity (32). In addition, it has been found that SLEpatients receiving this biological agent show a reducedexpression of the costimulatory molecules CD40 andCD80 on B cells, and of CD40L, CD69, and induciblecostimulator on CD4� T cells. These findings suggestthat RTX modulates the interaction of activated B and Tcells through costimulatory molecules (32).
In summary, the evidence for the effectiveness of RTXas induction therapy in NPSLE is based solely on severalcase reports and noncontrolled trials. Although it is notyet possible to make definite recommendations, theglobal analysis of these cases supports the off-label use ofRTX as a second-line therapy in patients with severe re-fractory NPSLE. The safety profile of B cell depletiontherapy is favorable, although ongoing vigilance for ad-verse reactions is required.
In interpreting the results of our study, one needs toconsider the pitfalls inherent in any systematic review.These include the relatively small number of patients, theretrospective design, and incomplete follow-up data insome cases. In addition, the high rate of efficacy foundmay be partially explained by the fact that most reportsinclude cases with a favorable response, whereas caseswithout such a response are often not reported. Random-ized clinical trials are clearly needed to confirm open-labeldata and to establish the correct dose, the length of ther-apy, and the appropriate use of concomitant medications.However, as noted above, it must be remembered thatinadequately designed trials may yield confounding re-sults. Therefore, when designing future studies it is im-portant that these include patients with high disease ac-tivity and who are refractory to conventional therapy or,alternatively, that they analyze the effect of RTX in com-parison to conventional immunosuppressive treatment.
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