Therapeutic strategies for refractory systemic lupus erythematosus

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Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY

TODAY THERAPEUTIC

STRATEGIES

Immunological disorders

Therapeutic strategies for refractory systemic lupus erythematosus Prodromos I. Sidiropoulos, George K. Bertsias, Herakles D. Kritikos, Dimitrios T. Boumpas* Internal Medicine and Rheumatology, Clinical Immunology and Allergy, Medical School, University of Crete, Voutes 71500, Heraklion, Greece

Some patients with severe lupus erythematosus do not respond to conventional immunosuppression (usually a combination of corticosteroids with cyclophosphamide) or develop severe side-effects from such treatment,

necessitating

the

search

for

alternative

treatments. In this article, we discuss novel therapeutic strategies in experimental models of lupus that appear to be promising for the treatment of lupus in humans. We also analyze initial data from studies in lupus patients involving newer immunosuppressive agents (mycophenolate mofetil), hematopoietic stem-cell transplantation and antibodies against B lymphocytes (rituximab). These agents/approaches have been

Section Editors: Joachim Kalden – Medizinischen Klinik III, Erlangen, Germany Despite continuous progress in the management of systemic lupus there is an important subgroup of patients with severe SLE who do not respond to conventional immunosuppressive drugs or in whom immunosuppressive treatment has to be stopped because of severe side effects. Over the past decade new and in part promising treatment principles for SLE became available. In the field of immunosuppressive drugs it is mycophenolate mofetil (MMF) which has been proven as an effective alternative to other immunosuppressive agents. In addition, new biological therapies have been developed, however, most of these new treatment options are based on non-controlled clinical trials. Of special interest will be the future of B cell depleting medications and the blockade of antigen presentations to B cells by the infusion protein CTLA-4Ig. New lupus drug candidates are being presently tested in animal models for SLE. Professor Boumpas has a long-standing record in clinical and experimental work related to the etiopathogenesis and the development of new treatment principles for SLE.

tested so far in non-controlled trials conducted in patients with heterogeneous manifestations of lupus. Although the initial results are encouraging, long-term efficacy and safety of these agents have to be confirmed in randomized controlled trials.

Introduction Approximately half a million people in the United States have systemic lupus erythematosus (SLE), the great majority of whom are women in their childbearing years. Most patients present with arthritis, different types of rashes (sometimes scarring), serositis, cytopenias of various types, neurological *Corresponding author: (D.T. Boumpas) [email protected] 1740-6773/$ ß 2004 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ddstr.2004.11.011

symptoms with acute dramatic presentations (such as seizures, psychosis, strokes) or a subclinical, chronic course (such as loss of cognitive function), and nephritis. Although the clinical features are highly variable, the patients are unified by the invariable presence of multiple autoantibodies that seem to account for much of the tissue injury (Fig. 1).

Established treatments The treatment of severe lupus represents one of the most celebrated success stories in modern rheumatology. After the initial attempts of cytotoxic drug therapy at the Mayo Clinic that were met with only modest success, the introduction of pulse (see Glossary) cyclophosphamide (CY) in the www.drugdiscoverytoday.com

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Glossary Alloreactive T-cells: T cells that recognize foreign antigens presented by the antigen-presenting cells. Hematopoietic stem-cell therapy: transplantation of bone marrow derived hematopoietic stem-cell progenitors. High-dose immunoablative chemotherapy: high-dose chemotherapy that ablates lymphocytes whereas sparing hematopoietic stem-cells expressing high levels of aldehyde dehydrogenase. MRL-lpr/lpr mouse strains: the lpr gene is mutant allele of the Fas gene. The lpr/lpr strains produce autoantibodies, develop immune complex nephritis, and lymphadenopathy. The disease in more severe in an inbred strain called MRL (MRL-lpr/lpr). New Zealand Black (NZB), New Zealand White (NZW) mouse strains: the NZB and the (NZB  NZW)F1 hybdrid strain develop spontaneously lupus-like autoimmune disease with nephritis, hemolytic anemia, and production of anti-DNA antibodies. Pulse therapy: high-dose, intermittent therapy.

therapeutic armamentarium by researchers at the National Institutes of Health (NIH) resulted in a long-lasting remission off-therapy in up to 40% of patients with moderate to severe renal disease with approximately 85% of patients responding to immunosuppressive therapy [1]. Ovarian toxicity, flares (observed in approximately one-third of patients), incomplete response and, in rare cases, refractoriness to treatment have emerged from the lupus studies as a significant limitation of current cytotoxic therapy. The unmet clinical need for more effective therapies with a safer toxicity profile dictates the search for alternative treatment options.

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Novel therapies for refractory disease Mycophenolate mofetil Mycophenolate mofetil (MMF) is an immunosuppressive agent used in solid organ transplantation that has been evaluated in clinical studies of lupus nephritis both as an induction and as maintenance regimen. A study comparing MMF to CY as induction therapy, followed by azathioprine (AZA) as maintenance, showed comparable efficacy of MMF to CY for inducing remission and preserving renal function at two years [2]. However, longer follow-up (three years) of those patients revealed that patients treated with MMF relapsed more often than those treated initially with CY (46% versus 17%, respectively). More recently, Contreras et al. [3] compared pulse CY, AZA or MMF as maintenance therapy after inducing remission with pulse CY. Although the authors concluded that AZA and MMF might be superior to pulse CY for maintenance therapy, these studies were not powered to demonstrate superiority. There are case reports showing favorable effect of MMF in refractory immune thrombocytopenia and autoimmune hemolytic anemia (AIHA) in SLE patients. Although initial data suggest that MMF might be a useful drug as an induction or maintenance treatment in some cases of moderate to severe lupus, cyclophosphamide remains the most effective therapy for the initial treatment of aggressive lupus. Although it is true that some patients with disease refractory to cyclophosphamide might respond to MMF,

Figure 1. Pathogenesis of SLE. The aberrations in immune system function that characterize this disease cover almost the entire spectrum of cells, cytokines, and inflammatory mediators. Because so many immune abnormalities have been demonstrated, those crucial to disease pathogenesis have been difficult to determine. Among them, B-cell hyperactivity, due either to intrinsic abnormalities or to immunoregulatory defects in other cell types (especially T cells) and culminating in the production of pathogenic autoantibodies, is thought to represent a key event in the pathogenesis of the disease. Increased production of autoantigens because of increased rates of apoptotic cell death coupled with defects in their removal contributes to lymphocyte hyperactivity.

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Table 1. Comparison of therapeutic strategies under clinical investigation Strategy

Pros

Cons

Mycofenolate mofetil (MMF)

Controlled trials support efficacy in remission and maintenance, ease of administration

Equivalency to cyclophosphamide or superiority to azathioprine not proven, only partial responses in patients failing cyclophosphamide

Hematopoietic stem-cell transplantation (HSCT)

Expected to induce long-lasting remission

Considerable mortality rates

Controlled phase III clinical trial under development

[5,6]

USA, Europe

High-dose cyclophosphamide without stem-cell transplantation

Lower cost than HSCT

Single center experience

Ongoing randomized clinical trial (recruitment completed)

[7]

USA

Anti-CD20

Selectively targets B cells

Lack of controlled trials

Ongoing phase I/II trials

[11–13]

Anti-CD40L

Significant immunomodulatory effects

Thromboembolic episodes

Clinical trials have been halted

[19–21]

LJP 394

Selective tolerance induction

Modest clinical results

responses are usually only partial and long-term follow-up is not available from these patients (Table 1).

Hematopoietic stem-cell transplantation The use of HIGH-DOSE IMMUNOABLATIVE CHEMOTHERAPY (see Glossary) with autologous hematopoietic stem-cell transplantation (HSCT) (see Glossary) to treat severe SLE manifestations was based on data from animal models of autoimmune diseases, showing reversal of autoimmunity after syngenic bone marrow transplantation and from reports of amelioration of concurrent autoimmune diseases after bone marrow transplantation performed mainly for life-threatening hematological diseases [4]. The rationale is to maximally suppress the immune system with a high-dose immunoablative regimen (most commonly high-dose CY combined with equine antithymocyte globulin and pulse methylprednisolone) and then rescue the patient from prolonged cytopenias by the infusion of mobilized CD34-enriched stem-cells. Thus far, the reported experience for HSCT originates mainly from one center in the United States (Northwestern University Medical School) and from a registry comprising 23 European centers [5,6]. Both groups treated patients with severe disease refractory to standard immunosuppressive treatment. Overall, there was improvement in disease activity in most patients (with some patients entering remission) but relapses were observed in approximately one-third of patients. The European groups reported deaths that were procedure-related. Difference in death rates between the two groups can be attributed to differences in patient population rather than differences in treatment protocols. Other common adverse events reported were neutropenic fever and infections. Taken together these data indicate that HSCT is expected to induce a long-lasting remission than a ‘cure’ in SLE patients. Initial data also suggest that HSCT might alter disease course

Latest developments

References

Group

[2,3]

[26]

to a more ‘benign’ one, requiring less immunosuppressive therapy. The higher mortality of the procedure (up to 12% in lupus patients) compared to lower rates in patients with rheumatoid arthritis is a significant obstacle but might relate to the involvement of vital organs in this disease. It is encouraging that with further refinements in the procedure the mortality decreases. One can question whether SLE represents the more appropriate disease for further study or whether diseases with higher mortality such as systemic sclerosis for which no available treatment options exist should first be targeted. Still the fundamental question is whether such an intense immunosuppressive treatment improves the long-term outcome. A phase III clinical trial is being developed to confirm the efficacy of HSCT, by comparison to continuing the standard NIH pulse cyclophosphamide regimen. Until more data are available, HSCT remains an experimental procedure that needs to be considered in critically ill lupus patients, ideally in centers with experience in both lupus and bone marrow transplantation in the context of formal protocols.

High-dose CY without stem-cell transplantation Potential advantages of this approach compared to HSCT is the elimination of the risk of reinfusing autoreactive cells (current CD34+ selection techniques deplete T cells by only 3–4 logs) and lower cost, whereas the duration of bone marrow aplasia seems to be comparable. In an open-label study comprising 14 SLE patients because of refractory renal, CNS or skin disease patients were treated with 200 mg/kg of CY (in four consecutive days) followed by 5 mg/kg of granulocyte colony stimulating factor (G-CSF) [7]. After a median follow-up of 32 months (range, 17–43 months), five patients were responders whereas six were partial responders. There were no reported deaths or fungal infections and interestingly no premature ovarian failure. A randomized trial comwww.drugdiscoverytoday.com

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paring this approach to the pulse cyclophosphamide regimen is under way.

Mesenchymal stem-cell therapy Bone marrow contains pluripotent mesenchymal stem-cells (MSC) that form bone, cartilage, adipose tissue, and muscle. These stem-cells are not immunogenic and escape recognition by alloreactive T-cells and natural killer cells. Adult bone marrow mesenchymal stem-cells given intravenously are immunosuppressive, inhibit the proliferation of ALLOREACTIVE T-CELLS (see Glossary) and prolong the rejection of mismatched skin grafts in animals. Mesenchymal stem-cells might also have a potent immunosuppressive effect in humans. Le Blanc et al. [8] has recently transplanted haploidentical mesenchymal stem-cells in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver with striking clinical response. MSC grafting could be used for the future treatment of organ-transplant rejection and autoimmune disorders [9].

Biologic therapies in humans B-cell depletion The implication of B cells in lupus pathogenesis goes further than precursors of antibody-secreting plasma cells and antigen-presenting cells (APCs), because they regulate APCs and T-cell function, produce cytokines and they have a central role in the development and maintenance of the organization of secondary lymphoid tissues. SLE patients demonstrate profound disturbances in B-cell homeostasis [10].

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tory to conventional immunosuppressive treatments [12,13]. Different protocols were used, ranging from the usual fulldose regimen (375 mg/m2  4 weekly intervals) to various shorter and lower dosing schemes (500–1000 mg  2). The majority of the patients received simultaneously immunosuppressive therapy with cyclophosphamide and corticosteroids. Generally, rituximab was well tolerated and no major safety issues were reported. Infectious complications that appeared responded generally well to antibiotic treatment whereas to our knowledge opportunistic infections were not reported. As expected from the experience with rheumatoid arthritis and non-Hodgkin lymphoma, there were cases of disease relapse during the follow-up time (mean follow-up time ranging from 6 to 12 months). Differences in patient’s characteristics and outcome measures used, and the fact that the small studies were not controlled do not allow for an intergraded efficacy result to be extrapolated safely. However, in all these studies there was evidence of improvement in clinical as well as in serological and immunological parameters in a substantial proportion of the patients. Open issues with rituximab treatment are to define the efficient treatment dose, the need of adjuvant immunosuppressive agent, the safety of re-treating patients that relapse and the development of methods predicting responders. Because standard treatment for SLE patients with major organ involvement is cyclophosphamide, there is the need for a controlled trial to compare rituximab to the NIH cyclophosphamide regimen.

Co-stimulatory blockade Anti-CD20

Rituximab is a chimeric murine/human monoclonal antibody that binds specifically to the CD20 antigen, which is expressed on B-lymphocytes, from pre-B to activated B cells, but not on differentiated plasma cells. Although rituximab induces variable depletion of CD20-positive cells in the peripheral blood, antibody production is maintained through plasma cells and peripheral B cells reappear 4–12 months after therapy. There is evidence that rituximab treatment of SLE patients had immunological effects beyond autoantibody reduction, like the induction of T-cell deactivation and suppression of costimulatory molecules expression. Although several mechanism of B-cell depletion has been proposed, there is evidence suggesting the relative importance of the antibody-dependent cell-mediated cytotoxicity (ADCC) and that of B-cell apoptosis induction when cross-linked by Fcg receptor (FcgR) bearing cells [11]. In these studies, response to treatment does not seem to correlate consistently with the degree of B-cell depletion. To date, experience with rituximab treatment in SLE patients comes from uncontrolled trials and case reports. These were patients with various disease manifestations (renal, CNS involvement, cytopenias, serositis, etc.) refrac378

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Loss of tolerance to autoantigens is the hallmark of lupus. Tolerance is intimately linked to the process of co-stimulation. Thus, in addition to the antigen-specific stimulation of the T-cell receptor, a second (costimulatory) signal is required for optimal T-cell activation and effector function [14]. In most cases, the interaction between CD28 expressed on T cells and B7 molecules (B7.1 and B7.2) expressed on APCs and B cells appears to provide the major costimulatory signal to T cells [15] (Fig. 2). CTLA4Ig

This is a recombinant fusion protein consisting of the extracellular domain of CTLA-4 and the Fc portion of IgG1. CTLA-4 is a member of the CD28/B7 costimulatory molecules that is expressed on activated T-cells and serves as an alternative ligand of B7 on APCs and B cells, generating an inhibitory signal [15]. Of note, CTLA-4Ig has been used in humans and has demonstrated efficacy for psoriasis and rheumatoid arthritis. In the (NZB  NZW)F1 murine model of lupus (see Glossary), CTLA-4Ig prevents the progression of renal disease, prolongs survival, and has efficacy similar to that of CY (Table 2) [16,17]. In mice with advanced renal disease, the combination of CTLA-4Ig and CY was also shown to effec-

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Figure 2. T-cell activation. This requires two signals: signal 1, engagement of T-cell receptor (TCR) with major histocompatibility complex (MHC)–peptide complex and signal 2, ligation of costimulatory molecules on T cells with their respective ligands on APCs. Costimulatory molecules can deliver (a) positive Tcell signaling, thus promoting T-cell proliferation and cytokine production, and T helper or cytotoxic T lymphocyte differentiation, or (b) negative T-cell signaling, resulting in inhibition of proliferation and cytokine production, anergy, and induction of T regulatory cells.

tively arrest the progression of lupus nephritis [18]. A controlled trial of CTLA-4Ig with and without CY for the treatment of lupus nephritis in humans is currently under consideration. Anti-CD40L

Anti-CD40L therapy ameliorates renal disease in animal models of SLE and improves survival even when used in animals with established disease [19]. In humans, a short course of

treatment with an anti-CD40L antibody in patients with proliferative lupus nephritis reduced anti-dsDNA antibodies, increased C3 levels, and decreased hematuria [20]. The aberrancies observed in the peripheral B-cell compartment at baseline normalized with treatment and there was a substantial reduction in the frequency of B cells secreting IgG and IgM anti-DNA antibodies. Another study using a different anti-CD40L antibody found no clinical benefit in patients with extrarenal lupus [21]. Although promising, the clinical

Table 2. Novel therapeutic approaches in experimental animal models of lupus Agent

Mechanism of action

References

CTLA4-Ig (CY)

Blockade of the CD28/B7 costimulation

[16–18]

CTLA4-Ig + anti-CD40L

Co-blockade of CD28/B7 and CD40/CD40L costimulation

[33,34]

Anti-B7h

Blockade of the ICOS/B7h costimulation

[31]

Anti-CD137

CD137 costimulatory T-cell receptor engagement

[32]

Anti-IL10

Blockade of the effect of a B-cell mediator

[29]

Anti-IL18

Inhibition of IFNg production

[35]

Anti-IFNg

Inhibition of B cells, reduction of autoantibody production

[36]

TGFb, TGFb-R

Inhibition of renal fibrosis

[38]

Anti-C5b

Blockade of complement complex attach

[39]

Crry-Ig

Regulation of C3 activity

[40]

MCP-1 analog

Blockade of MCP-1

[41]

Anti-CCR1

Blockade of CCR-1

[42]

ICOS, inducible costimulator; MCP-1, monocyte chemoattractant protein 1; IFNg, interferon g; CCR-1, chemokine receptor 1; TGFb, transforming growth factor b. www.drugdiscoverytoday.com

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potential of this approach is not clear yet, because all antiCD40L trials were halted due to an increased number of thromboembolic events in clinical studies using both antiCD40L antibodies.

B-cell deactivation

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significant reduction of peripheral B-cells. A phase II clinical trial with this anti-BLyS monoclonal antibody is currently under way.

Induction of tolerance LJP 394

BLyS

B lymphocyte stimulator (BlyS), also known as BAFF, TALL-1, THANK, TNFSF13B, is a protein of the tumor necrosis factor (TNF) ligand superfamily, that is expressed on myeloid lineage cells (monocytes, macrophages, dendritic cells) (Fig. 3). There is evidence that BLyS plays a role in autoimmune disease [22,23]. Recently, BLyS blockade through adenovirus mediated expression of soluble transmembrane activator and calcium-modulator and cyclophilin ligand-interactor (TACI)Fc fusion protein in the MRL-LPR/LPR model (see Glossary), reversed autoantibody production, reduced proteinuria and prolonged survival but failed to reduce T-cell expansion and interstitial kidney disease [24]. A fully human monoclonal antibody that neutralizes human BLyS bioactivity has been developed (LymphoStat-B) and has been evaluated in a randomized double-blind phase I clinical trial in 57 SLE patients [25]. LymphoStat-B was well tolerated and although there was not observed any change in disease activity, there was a

LJP 394 (abetimus sodium, riquent) is a synthetic toleragen molecule consisting of four double-stranded DNA epitopes attached to a pharmacologically inert triethylene glycol backbone. It is an immunomodulating agent that induces tolerance to B cells directed against double-stranded DNA (dsDNA), possibly by crosslinking anti-dsDNA surface immunoglobulin receptors on the B cells that lead to B-cell anergy or apoptosis. LJP 394 has been studied in 873 SLE patients participated in 13 randomized controlled trials (RCTs) with only modest clinical efficacy [26].

Anticytokine therapy There are data from animal models or small-scale clinical trials implementing a role for cytokines, like TNFa, interleukin (IL)-6, IL-10 in SLE pathogenesis, but clinical significance of these findings needs further confirmation [27–30] (Table 3).

Figure 3. Role of BlyS. BlyS (B lymphocyte stimulator), also known as BAFF, TALL-1, THANK, TNFSF13B, is a protein of the TNF ligand superfamily, that is expressed on myeloid lineage cells (monocytes, macrophages, dendritic cells). BCMA (B-cell maturation antigen), TACI (transmembrane activator and calcium-modulator and cyclophilin ligand-interactor), and BAFF-R (BAFF receptor) serve as receptors of BlyS. mRNA expression of each of these receptors is restricted to B cells although activated T-cells might express TACI mRNA. BAFF-R is probably the key BLyS receptor for B-cell function, whereas TACI under normal conditions inhibits B-cell activation. (a) BLys protein is engaged to BAFF-R promotes B-cell activation and immune responses. (b) In the presence of BLys analog proteins which cannot activate BAFF-R, or (c) BLys antagonists (e.g. TACI-Ig, anti-BLys blocking antibodies), or (d) BAFF receptor blockers, BLys cannot bind to BAFF-R and B-cell activation is inhibited.

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Table 3. Anticytokine therapy Target cytokine

Strategy

References

Tumor necrosis factor a (TNFa)

Anti-TNFa chimeric monoclonal antibody

[27]

Interleukin-6 (IL-6)

Anti-IL-6 receptor monoclonal antibody

[28]

IL-10

Anti-IL-10 murine monoclonal antibody

[29,30]

Novel therapeutic approaches in experimental animal models of lupus (Table 2) Costimulation blockade Inducible costimulator (ICOS) and its ligand B7 homologous protein (B7h) (also known as ICOS-ligand (ICOS-L) or B7related protein-1) is another pair of costimulatory molecules that regulates T-cell-dependent humoral immune responses. Administration of anti-B7h antibody before the onset of renal disease in (NZB  NZW)F1 mice significantly delayed the onset of proteinuria and prolonged survival [31]. CD137 costimulatory T-cell receptor engagement by anti-CD137 monoclonal antibodies in (NZB  NZW)F1 mice between 26 and 35 weeks of age reversed acute disease, blocked chronic disease development and significantly prolonged mice’s lifespan [32]. Simultaneous blockade of more than one costimulatory pathways might result in more efficient treatment of murine lupus nephritis [33,34]. Cytokines and complement components have also served as therapeutic targets in experimental models of lupus. MRL/lpr lupus-prone mice vaccinated against autologous IL-18 had a significant reduction in spontaneous lymphoproliferation, interferon-g (IFN-g) production, and glomerulonephritis [35]. Depletion of IFN-g receptor was shown to prevent autoantibody production and renal damage in lupus-prone mice [36]. Intramuscular administration of plasmids with cDNA encoding IFN-gR/Fc in MRLlpr mice reduced serum levels of IFN-g and disease manifestations (autoantibodies, lymphoid hyperplasia, glomerulonephritis, mortality) [37]. Delivery of transforming growth factor b (TGFb) or TGFb receptor fusion molecules by both viral and nonviral vectors has also been used to attenuate renal injury [38]. Complement proteins play important roles in both amplifying immune complexinitiated inflammatory reactions and in immune tolerance, and are, therefore, good candidates for manipulation [39,40]. Other possible therapeutic targets include antagonists of chemokines, which are implicated in the pathogenesis of lupus glomerular injury. Experimental approaches include expression of a monocyte chemoattractant protein 1 (MCP1/ CCL2) analog [41] and blockade of the chemokine receptor CCR1 [42].

Concluding remarks There are few diseases for which the etiology, natural history, and response to treatment have been as complex or

difficult to define as those of SLE. Given the remarkable heterogeneity in pathogenesis and clinical expression of the disease, it is unrealistic to expect that any particular treatment modality will be consistently effective in all subgroups of patients. Similar to other complex diseases, we need to better define for each patient the key pathogenetic mechanism operant and use strategies that specifically target them. To this end, novel molecular tools such as gene arrays or proteomics might facilitate prediction of response to treatment. Until such tools become available, we need to further expand our armamentarium with pilot, proof-ofconcept trials confirmed with appropriate RCTs with longterm follow-up. Lupus is a life-long disease and ideally, therapy should induce long-lasting remission with the potential to retreat – should the disease flare. To this end, the ability of newer therapies to induce long-lasting remissions comparable to cyclophosphamide has not been adequately documented. Relapses are common with mycophenolate mofetil and have also been reported with rituximab. Because rituximab is not fully humanized, repeat infusions might give rise to neutralizing antibodies limiting its efficacy. This should be circumvented with new fully humanized monoclonal antibodies. Still, this antibody is considered today as a debulking agent – at best – rather than as a curative treatment. Thus remission with current therapies has, in most cases, an end. Whether more specific immunosuppression, inhibiting co-stimulatory molecules such as the CTLA4-Ig, induces tolerance and remission remains to be seen. Induction of long-term remission seems unrealistic at present without combining old with new therapeutic agents.

Outstanding issues  Are new treatments under clinical investigation as effective as pulse CY in the long-term?  Can surrogate markers such as change in anti-DNA antibody titers, complement levels or proteinuria – used in more recent trials – predict clinical outcomes such as preservation of renal function?  Can any of the new agents be safely combined with pulse CY in the induction phase?  What is the efficacy and safety of the new treatments as long-term maintenance therapy?  Is there a synergistic effect in combining immunosuppressive agents with the new biologics?  Can new technologies in genomics or proteomics identify subsets of patients requiring variations in standard therapy or predict response to therapy?

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References 1 Illei, G.G. et al. (2001) Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann. Intern. Med. 135, 248–257 2 Chan, T.M. et al. Hong Kong-Guangzhou Nephrology Study Group (2000) Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N. Engl. J. Med. 343, 1156–1162 3 Contreras, G. et al. (2004) Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 4 Ikehara, S. et al. (1985) Rationale for bone marrow transplantation in the treatment of autoimmune diseases. Proc. Natl. Acad. Sci. USA 82, 2483– 2487 5 Traynor, A.E. et al. (2002) Hematopoietic stem cell transplantation for severe and refractory lupus. Analysis after five years and fifteen patients. Arthritis Rheum. 46, 2917–2923 6 Jayne, D. et al. (2004) Autologous stem cell transplantation for systemic lupus erythematosus. Lupus 13, 168–176 7 Petri, M. et al. (2003) High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus. Arthritis Rheum. 48, 166– 173 8 Le Blanc, K. et al. (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 9 Frank, M.H. et al. (2004) Immunomodulatory functions of mesenchymal stem cells. Lancet 363, 1411–1412 10 Lipsky, P.E. (2001) Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat. Immunol. 2, 764–766 11 Anolik, J.H. et al. (2003) The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48, 455–459 12 Leandro, M.J. et al. (2002) An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 46, 2673–2677 13 Looney, R.J. et al. (2004) B lymphocytes in systemic lupus erythematosus: lessons from therapy targeting B cells. Lupus 13, 381–390 14 Bugeon, L. et al. (2000) Costimulation of T cells. Am. J. Respir. Crit. Care Med. 162, S164–S168 15 Carreno, B.M. et al. (2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu. Rev. Immunol. 20, 29–53 16 Daikh, D.I. et al. (2001) Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide. J. Immunol. 166, 2913–2916 17 Finck, B.K. et al. (1994) Treatment of murine lupus with CTLA4Ig. Science 265, 1225–1227 18 Cunnane, G. et al. (2004) Prevention of renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide. Arthritis Rheum. 50, 1539– 1548 19 Sidiropoulos, P.I. et al. (2004) Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391–397 20 Boumpas, D.T. et al. (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 21 Kalunian, K.C. et al. (2002) Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, doubleblind, placebo-controlled trial. Arthritis Rheum. 46, 3251–3258 22 Stohl, W. et al. (2003) B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 48, 3475–3486

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Vol. 1, No. 3 2004

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