Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis

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1 Nephrol Dial Transplant (2013) 28: doi: /ndt/gfs285 Advance Access publication 3 July 2012 Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis Marc Weidenbusch, Christoph Römmele, Angelika Schröttle and Hans-Joachim Anders Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany Correspondence and offprint requests to: Hans-Joachim Anders; hjanders@med.uni-muenchen.de Equal contribution. Abstract Background. The treatment of lupus nephritis (LN) remains problematic because the current treatment regimen based on unspecific immunosuppressants such as steroids, cyclophosphamide and mycophenolate has significant side effects and is often inefficient. B-cell ablation with the chimeric anti-cd20 antibody rituximab (RTX) has been considered as an alternative treatment option but the randomized controlled LUNAR trial failed to show any additive effect of RTX beyond a steroid mycophenolate mofetil (MMF) combination for LN type III/IV/V in incident patients. At present, no such trial is available for the use of RTX in refractory LN. Methods. We analysed existing evidence on this topic by performing a systematic analysis of reports that document outcomes of RTX treatment for refractory LN. Results. Out of 233 reports, we selected 26 for analysis, which described 300 patients with a mean follow-up of 60 weeks. The complete or partial response criteria were met by 87% of patients with LN class III, 76% with class IV and 67% with class V, respectively. Mixed classes responded in 76% of patients. RTX induced complete responses in 60% (type III), 45% (type IV), 40% (type V) and 24% (mixed types), respectively. Conclusions. Our systematic review of existing evidence suggests that RTX effectively induces remission of LN in patients who have not achieved remission with standard therapies. Another randomized controlled trial should be conducted to test the efficacy of RTX in refractory LN. Keywords: systemic lupus erythematosus; glomerulonephritis; B-cell ablation; proteinuria; anti-cd20; B-cells; lupus nephritis; MabThera; remission; response; therapy Introduction Lupus nephritis (LN) often complicates systemic lupus erythematosus (SLE) determining morbidity and mortality of SLE patients [1, 2]. The management of LN is 4-fold: (i) identifying patients at risk of disease progression; (ii) treating patients at risk with intensive immunosuppressive therapy to control systemic as well as tissue inflammation; (iii) monitoring patients for remittent, persistent or flaring disease activity to tailor treatments to individual needs and also (iv) avoiding treatment-associated side effects. Patients at risk show urinary abnormalities and will undergo a renal biopsy to allow for further investigation. A sophisticated work-up by a renal pathologist of the renal cells collected is required to categorize renal lesions according to the current classification of LN [2]. When left untreated, proliferative (class III/IV) and membranous forms of LN (class V) often progress to renal failure and thus treatment with intensive immunosuppression immediately upon diagnosis is administered. Very few treatments have proven to be efficient in randomized controlled trials (RCT). One of the first RCT on LN documented that highdose steroids alone were not as effective as steroids plus cyclophosphamide (CYC) to maintain long-term renal function and flare-free intervals [4]. Recently, mycophenolate mofetil (MMF) was proven to be as efficient as highdose CYC in controlling class III/IV/V LN in Caucasian patients [5]. However, the use of both drugs is associated with severe side effects including fatal infections. Therefore, it remains an unmet medical need in the field of LN to develop novel drugs that are efficient but less toxic than current therapies. As the toxicities of CYC and MMF largely relate to their unspecific immunosuppressive activity, it is tempting to speculate that novel drugs that more specifically block any central disease pathomechanism of LN will meet this unmet medical need. The underlying pathomechanism that links SLE to LN is the same for all classes, i.e. immune complex disease [6, 7]. In fact, in SLE, systemic inflammation alone is unable to elicit LN in the absence of mature B-cells, lupus autoantibodies and renal immune complex deposition [8], even though mature B-cells appear to be more important than the autoantibodies themselves [9, 10]. For this reason, B-cell-directed therapies have raised great hope to more specifically target the immunopathology in SLE when compared with steroids, CYC or MMF. The lead compound in this area is rituximab (RTX), a chimeric anti-cd20 antibody that efficiently and reliably depletes CD20-positive B-cells [11]. RTX was approved in 1997 for the treatment of various forms of B-cell lymphoma and later also for the treatment of rheumatoid arthritis The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Rituximab in lupus nephritis 107 [12]. In addition, its excellent toxicity profile renders RTX an attractive candidate drug for improving the treatment of LN. During the last decade, an increasing number of case reports and small case series have reported RTX treatment outcomes in LN patients which have led to a, so far, single RCT that compared high-dose steroids plus MMF with high-dose steroids plus MMF plus RTX [13]. Addon RTX treatment did not significantly increase the response rates which were selected as the primary end point, even though RTX doubled partial responses in black patients. There is an ongoing debate about the interpretation of these results which relates to dosing of the drugs, to the selection of end point parameters, and to patient selection. Furthermore, the intense background immunosuppressive regimen with repetitive infusion of 1 g methylprednisolone and high-dose oral MMF left little chance for RTX to prove additional benefits. In addition, it is a fact that the LUNAR trial included only incident LN patients, whereas most previous uncontrolled studies describe different patient cohorts. Here, we systematically reviewed reports about RTX treatment outcomes from patients with refractory LN only. Materials and methods We searched the PubMed database for studies and case reports including adult patients (>18 years old) with LN who were treated with anti-cd20/ RTX (MabThera). Our search for the terms lupus and rituximab (using a filter to select only studies in humans) in the MEDLINE indexed international journals between August 2001 and July 2011 resulted in 412 articles (Figure 1). We also searched the ISI Web of Knowledge database for non-indexed publications (using the same search terms) and thoroughly checked citations of included articles for additional data. In total, title/abstract information suggested clinical data on the use of RTX in SLE patients in 233 articles which, with minor limitations due to language and access barriers, we then studied in more detail. Clinical data were found in 70 articles. After evaluation of the full text, 44 articles were excluded because they either described paediatric patients, included non-relevant data or included information about patients who were already described in other publications (Figure 1). In the case of multiple published data, we chose the most recent paper. Finally, the remaining 26 articles were selected for systematic analysis as listed in Table 1 [12 39]. Reported data were screened for the following criteria: (i) established diagnosis of SLE in accordance with the American College of Rheumatology s revised criteria (ACR), (ii) the presence of active LN documented by renal biopsy and persistent clinical findings such as elevated serum creatinine or proteinuria and active urine sediment, despite (iii) previous therapy with one or more immunosuppressive agents. Unless otherwise indicated, responses were defined following the consensus of the American College of Rheumatology and the European League against Rheumatism [40, 41]. In brief, a complete patient response is defined as (i) the absence of all initial disease-related symptoms, (ii) the absence of an active sediment, (iii) proteinuria <0.5 g/g creatinine and (iv) return to normal or baseline serum creatinine. A partial patient response includes the absence of an active sediment, stable kidney function and a reduction of proteinuria by 75% or <1 g/g creatinine. Results Type of reports on RTX in refractory LN Among the 26 studies retrieved, 9 were prospective clinical trials, albeit non-randomized or blinded (Table 1). Another 9 were retrospective analyses studies, 4 case series and 4 single case reports. Together, at present treatment efficacy of RTX in LN is only reported by observational cohort studies and case reports. RCT on this topic are not currently available. Patient characteristics A total of 300 patients with a mean age of 35.1 years were reported in the 26 studies (Table 2). Eighty-seven percent of the patients were female. Ethnicity data were reported for 138 of the patients of which 59 (43%) were Caucasians, 31 (22%) were Afro-Caribbeans, 28 (20%) were Asians and 18 (13%) were Hispanics. While LN was present in all patients by definition, extrarenal lupus manifestations were reported only in 110 patients as listed in Table 2. The most frequent extrarenal manifestations Fig. 1. Selection of identified studies for analysis in this systematic review.

3 108 M. Weidenbusch et al. Table 1. Reports on RTX use in refractory LN selected for analysis Type of study No. of patients Table 2. Classes of LN according to the ISN/RPA classification [3] Mean age Mean duration of disease (months) Class I or II 3 1% Class III 40 13% Class IV % Class V 25 8% Mixed type 25 8% Not classified 91 30% m:f ratio Albert et al. [14] Prospective :10 Boletis et al. [17] Prospective :10 Jönsdöttir et al. [24] Prospective :16 Li et al. [26] Prospective :12 Pepper et al. [31] Prospective :15 Sfikakis et al. [35] Prospective :9 Vigna-perez et al. Prospective :19 [39] Garcia-Carrasco Prospective :11 et al. [22] Arce-Salinas et al. Prospective :5 [15] Catapano et al. [19] Retrospective :28 Galarza et al. [21] Retrospective :40 Melander et al. [29] Retrospective :19 Terrier et al. [37] Retrospective :111 Gottenberg et al. Retrospective :1 [23] Lu et al. [27] Retrospective :30 Lateef et al. [25] Retrospective :6 Reynolds et al. [33] Retrospective :5 Ramos-Casals et al. [32] Retrospective n.a. 13:94 Camous et al. [18] Case series :3 Roccatello et al. Case series :1 [34] Moroni et al. [30] Case series :3 Chehab et al. [20] Case series :2 Tahir et al. [36] Case report :1 van den Bergh et al. Case report 1 43 n.a. 0:1 [38] Mardjuadi et al. Case report :1 [28] Bacconnier et al. [16] Case report :1 affected the skin (88%), musculoskeletal (82%) and haematological system (81%). Neuropsychiatric lupus was present in 13% of patients. The histopathological classes of LN included 1% of the International Society of nephrology/renal Pathology Association (ISN/RPA) classes I/II, 13% class III, 39% class IV, 8% class V and 8% with mixed classes III/V or IV/V. In 30% of cases, the class of the LN was not classified. Data on previous treatments were available for 289 patients (Table 3). Sixty percent had been pretreated with cyclophosphamide, and 47% with MMF. Another 47% were treated with azathioprine, and 30% with hydroxychloroquine prior to RTX treatment. Methotrexate was used in 19% of the patients, and cyclosporine A and tacrolimus in 8% and 0.3%, respectively. The definition of refractory disease varied among the reports and included the use of 1 to 3 immunosuppressant drugs in addition to corticosteroids before RTX was considered (Table 4). Thus, the reports represent a global patient cohort typical of severe SLE with mostly proliferative forms of LN that had been pretreated with multiple immunosuppressive drugs. RTX treatment regimen The use of RTX differs among the different reports and various dosing regimen have been also applied for the treatment of LN. In the reports selected for this systematic review, a dose of mg/m 2 was commonly used (49%) followed by mg per 2 weeks in 37% of patients (Table 5). RTX was not uniformly given as an alternative or add-on therapy. Thirty percent of cases received cyclophosphamide along with RTX, 25% received mycophenolate mofetil, 7% received azathioprine and 4% received methotrexate. Complete and partial responses of refractory LN to RTX therapy After a mean follow-up of 60 weeks (range weeks), RTX had induced a complete response in 40% of cases (Figure 2A) and a partial response in 34%. Twentysix percent of cases showed no response at all. In total, RTX induced some response ( partial or complete) in 74% of patients with refractory LN. Classes of LN and RTX efficacy The histopathological class of LN is a predictor of renal survival; hence, we examined the treatment efficacy of Table 3. Previous immunosuppressive therapies Data available a % Cyclophosphamide % MMF % Azathioprine % Hydroxychloroquine 87 30% Methotrexate 57 19% Cyclosporine A 23 8% Tacrolimus 1 0,3% a Remaining patients had on average two other previous immunosuppressive drugs. Table 4. Definition of refractory disease Active disease under steroids Immunosuppressant 96 32% 1, On average two immunosuppressants 51 17% 2 Immunosuppressants 52 17% 3 Immunosuppressants 11 4% Data not available 90 30%

4 Rituximab in lupus nephritis 109 Table 5. RTX dosing Dose/interval % mg/m 2 per week % mg/m 2 per 2 weeks 5 2% mg per 2 weeks 3 1% mg per 2 weeks 1 0% mg per 2 weeks 1 0% mg per 2 weeks % Other regimen 24 8% RTX in the different ISN/RPA classes of LN in those reports containing relevant data (Figure 2B). Complete responses were most frequent in type III (60%) and less frequent in type IV (45%) or type V (40%). Mixed types showed a complete response in only 24% of the reports. Any response (complete or partial) was also most frequent in type III (87%) and 76% (type IV), 67% (type V) and 74% (mixed type), respectively. As such, patients with type V membranous LN had the lowest responder rates with 1 out of 3 patients who did not respond at all to RTX within the mean follow-up period of 60 weeks. Fig. 2. Response rates upon RTX treatment. (A) The diagram illustrates the percentages of complete, partial or non-responders upon treatment with RTX in a mean follow-up period of 60 weeks. (B) The same type of graph illustrates the respective percentages for each of the types of LN as indicated.

5 110 M. Weidenbusch et al. Discussion The LUNAR trial failed to demonstrate any significant therapeutic effect of RTX as an add-on therapy on top of steroids and MMF in incident LN patients [13]. As such, the add-on-rtx-on-top-of-standard care concept which had been proven effective in B-cell lymphoma is no longer considered for incident LN. However, the intense background immunosuppressive regimen with repetitive infusion of 1 g methylprednisolone and high-dose oral MMF left little chance for RTX to prove additional benefits. Furthermore, the subgroup analysis of the LUNAR trial revealed that black patients with particularly poor prognosis had higher partial response rates with addon RTX [13]. These data indicate that RTX may be effective in patients who are not sufficiently controlled by standard treatments, an aspect that was not addressed by the study protocol of the LUNAR trial or by any other RCT. In fact, the LN community had instead considered RTX as an alternative than as an add-on drug on top-of-standard care which is documented by the fact that most reports on off-label RTX use in LN describe patients who had not achieved remission with standard treatments. This could represent an explanation for the apparent discrepancy of the data from LUNAR and other reports. So the question remains as to whether RTX is still a valuable therapeutic option for patients who cannot be controlled by either high-dose steroids and CYC or high-dose steroids and MMF. Our systematic review on this particular question revealed that RTX is effective in inducing partial and, to a lesser extent, also complete remission of LN in these patients. The response rates of 87% in refractory LN type III, 76% in type IV and at least 67% in type V are comparable with what can be achieved with highdose cyclophosphamide in incident patients [4]. Of course, this kind of meta-analysis is sensitive to a publication bias which favours reports on positive outcomes of RTX-treated patients. Thus, the real-life efficacy of RTX in refractory LN may be lower than our findings would suggest. There is also a considerable heterogeneity in co-medication, steroid use and the history of immunosuppressive drugs used in the patients reported here and the data quality does not allow to dissect this carefully. This, however, seems to represent the real life of lupus care, i.e. it may not really be a drawback to the interpretation of our findings. Also, RTX dosing and treatment intervals were heterogenous even though to date there have been no reports that provide clear evidence that one regime is more effective than others for B-cell depletion and response rates in LN. There is a general concern that nephrotic syndrome could affect the pharmacokinetics of RTX as the antibody may be more rapidly excreted along with albuminuria and other immunoglobulins. This could account for the lower response rates in class V LN and may argue for the use of more frequent dosing. Finally, not all reports adhere to the current definitions of partial and complete responses or report outcomes after different treatment periods. The rates of remission of LN, although commonly confined to a 6-month period after starting a cytotoxic agent, continue to increase over the first 1 to 2 years. Therefore, patients who improve with RTX after not having achieved a partial or complete response at 6 months may actually simply reflect the delay in achieving responses from the initial therapy and not really represent an RTX effect. These drawbacks on data quality must be taken into account. Other RCTs are clearly necessary to prospectively test the efficacy of RTX in refractory LN or even in incident LN as an alternative rather than an addon drug. RTX may be likely to show similar outcomes with less side effects. This strategic approach led to US Food and Drug Administration and European Medicines Agency approval of RTX for the treatment of rheumatoid arthritis at times where tumor necrosis factor blockers were already available. But until proven otherwise, current evidence currently supports the off-label use of RTX to induce remission of refractory LN. Acknowledgements. M.W., C.R. and H.J.A. were supported by the Deutsche Forschungsgemeinschaft Graduate College (See related article by Rovin. Targeting B-cells in lupus nephritis: should cautious optimism remain? Nephrol Dial Transplant 2013; 28: 7 9.) References 1. Manger K, Manger B, Repp R et al. 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