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Pietro A Canetta

Treating Lupus in the Kidney: Where Are We Now, and Where Are We Going?

Abstract: Kidney involvement is a frequent and dreaded consequence of systemic lupus erythematosus. While historically this condition was devastatingly morbid, over the past thirty years an improved understanding of the disease's pathobiology has accompanied increasingly effective treatment regimens that have dramatically improved the prognosis for affected patients. Induction and maintenance of remission can now be obtained in the majority of patients, although at least 20-30% may be refractory to treatment. What's more, the standard drugs in use for lupus nephritis remain fairly broad immunosuppressants, and carry notable risks and side effects. Recent years have witnessed an explosion in the number of novel immunomodulatory drugs being developed, with increasingly specific targets of action in the immune system. These molecules hold promise for a range of autoimmune disorders, including lupus nephritis, and several are already being actively investigated for that purpose. Here we review the current state of the art in the treatment of lupus nephritis, highlight the limits of standard treatments, and discuss the most promising of the novel therapies coming down the pipeline.



Introduction

Systemic lupus erythematosus has often been described as the prototypic autoimmune disease (Klippel, 2008; Koffler et al., 1971). At its essence, it is a disorder of systemic dysregulated immune activation which may produce local inflammation and tissue damage in almost any organ system. From patient to patient, the actual clinical manifestations can vary tremendously, but one of the most frequently involved organs is the kidney, where the disease is known as lupus nephritis.

About one in six patients with systemic lupus erythematosus will have evidence of kidney involvement at the time of diagnosis, and at least 40-75% of all lupus patients will eventually develop overt nephritis (Huong et al., 1999; Seligman et al., 2002). Even when kidney disease is not clinically obvious, histopathological evidence of lupus is almost always present on biopsy (Appel et al., 1978).

Treatment of lupus nephritis has advanced remarkably in recent decades, but outcomes remain far from perfect. Even with aggressive regimens, treatment-refractory lupus nephritis occurs in a substantial proportion of patients (Illei et al., 2001; Korbet et al., 2000), and disease relapses are both common and associated with worse prognosis (El Hachmi et al., 2003; Moroni et al., 1996; Ponticelli and Moroni, 1998). Despite treatment, at least 10-15% of patients still progress to end-stage kidney disease requiring dialysis or kidney transplant (Cameron, 1999). The fact that affected patients tend to be young women of child-bearing age, facing the prospect of spending years of their adult lives buffeted between the opposite dangers of disease and immunosuppression, only increases the urgency of developing better tolerated and more effective therapy.

In response to this need, a large number of novel therapies are currently in various stages of development, driven by a wealth of research into the workings of the immune system and pharmacologic methods of modulating it. These drugs hold great promise for improving the health of many patients affected by lupus nephritis, and moving us closer to the day where effective therapy is available to every patient with the disease. In the rest of this review, we will summarize the current state of the art in the treatment of lupus nephritis and highlight the most promising of the emerging therapies. But before therapy can be discussed in detail, it is necessary to briefly outline the pathophysiology of the disease as it is currently understood.

Autoantibodies and Immune Complexes Play a Key Role in the Pathogenesis of Lupus Nephritis

The etiology and pathogenesis of lupus is complex and incompletely understood. Several etiologic factors have been implicated, including genetic, hormonal, and environmental factors. In brief, these factors interact to promote the development of autoantibodies, which then form immune complexes with their respective antigens, triggering complement fixation, inflammation, and tissue damage (Cameron, 1999; D’Cruz et al., 2007; Mortensen et al., 2008).

Early in the development of lupus, there appears to be dysregulation of apoptosis or impaired phagocytic clearance of apoptotic or necrotic cells. This permits prolonged or inappropriate exposure of self-antigens to the immune system, where they are eventually presented to autoreactive T and B lymphocytes, which may not have been properly silenced by the immune system. B cell activation induces these cells to produce antibodies to the self-antigens, characteristically against components of the nucleus (anti-nuclear antibodies, or ANA). High titers of autoantibodies against double-stranded DNA are nearly pathognomonic for lupus, and may be a useful marker of disease progression (Cameron, 1999). Other components of the nucleosome and ribosome commonly targeted include Sm, Ro (SS-A), La (SS-B), the complement component C1q, ribonucleoprotein (U1-RNP), and histones (Mortensen et al., 2008).

Autoantibodies may cause kidney damage through more than one mechanism. They may cross-react against glomerular antigens, causing either complement-dependent cytotoxicity or Fc-receptor mediated inflammation. Alternatively, circulating antigen-antibody immune complexes may deposit preferentially in different kidney structures (Cameron, 1999; Weening et al., 2004). The site of immune complex deposition or formation determines the pattern of injury, whether it be the mesangium (leading to mesangial hypercellularity and matrix deposition), subepithelium (leading to podocyte damage and membranous nephropathy), or subendothelium (leading to leukocyte recruitment, endocapillary proliferation, glomerular capillary destruction, and crescent formation of the classic proliferative lupus nephritis).

Treatment of Lupus Nephritis Is Guided by Histologic Disease Class

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis provides a standardized, reproducible classification of the disease. At present, the histologic pattern of the disease as classified by ISN/RPS broadly determines the therapeutic approach, placed in the appropriate context of an individual patient’s clinical parameters.

In general, immunosuppressive therapy directed at the kidney is not indicated in the setting of mild disease, represented by ISN/RPS class I nephritis (normal glomeruli by light microscopy with mesangial deposits on immunofluorescence or electron microscopy) and most class II nephritis (pure mesangial hypercellularity by light microscopy with mesangial immune deposits). Most patients with these forms of the disease will have good long-term kidney outcomes in the absence of progression to the other classes of lupus nephritis. The cornerstone of therapy is control of blood pressure and blockade of the renin-angiotensin-aldosterone system (RAAS) with either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). The rationale for this approach is based on extrapolation from human studies in other chronic, proteinuric kidney diseases (MacKinnon et al., 2006) as well as an abundance of animal studies (De Albuquerque et al., 2004; Monrad et al., 2008; Teplitsky et al., 2006). Additionally, in a large cohort study of lupus patients, ACEI use was associated with higher probability of survival without kidney involvement at 10 years (88.1% vs. 75.4% for non-users, p = 0.01), a delay in the development of kidney involvement [hazard ratio (HR) 0.27; 95% CI 0.09, 0.78], and a decreased risk of disease activity (HR 0.56; 95% CI 0.34, 0.94) (Duran-Barragan et al., 2008).

Focal or diffuse proliferative lupus nephritis is categorized in the ISN/RPS schema as class III or IV, respectively. They are each subclassified based on the presence of active lesions (A), chronic inactive or sclerosed lesions (C), or a combination of the two (A/C) (Weening et al., 2004). These proliferative forms of lupus nephritis, particularly with active lesions, confer the greatest risk of progressive kidney damage and loss of function, and they require aggressive immunosuppressive treatment. In this setting, it has become standard practice to separate treatment into two phases: induction, during which aggressive immunosuppression is used to induce complete or partial disease remission over a period of months, and maintenance, during which lower doses of immunosuppression are used to keep the immune system in check and prevent disease flares.

Conventional Induction Therapy Consists of Either Cyclophosphamide or Mycophenolate Based Regimens

Until the last decade, the standard agent of induction therapy for lupus nephritis was the cytotoxic agent cyclophosphamide (CYC) combined with high-dose corticosteroids. CYC is a nitrogen mustard alkylating agent, frequently used in chemotherapy regimens against hematologic and oncologic malignancies. It cross-links DNA leading to cell death, preferentially in rapidly dividing cells such as leukocytes (de Jonge et al., 2005), making it an effective nonspecific immunosuppressant.

Randomized, controlled trials performed at the NIH on patients with proliferative lupus nephritis showed that patients treated with corticosteroids plus monthly injections of CYC for six months followed by quarterly injections for at least two years were more likely to achieve clinical remission than patients treated with either corticosteroids or CYC alone, and were less likely to suffer relapses than patients treated with corticosteroids alone or shorter (6-month) courses of CYC (Boumpas et al., 1992; Gourley et al., 1996). A report providing extended follow-up on the larger of these trials (n = 82 subjects, median follow-up = 11 years) following the intention-to-treat principle demonstrated persistence of the superior outcomes in the combination CYC + corticosteroid group (Illei et al., 2001).

Despite their efficacy, these CYC-based induction regimens carried substantial side effects, including high rates of serious infection (26-32%) and premature amenorrhea (52-60%) (Illei et al., 2001). In response, several attempts were made to validate lower-dose regimens, one notable example being the Euro-Lupus Nephritis trial (Houssiau et al., 2002). In this study of 90 European patients with proliferative lupus nephritis, a low-dose regimen of 6 pulses of intravenous CYC 500 mg every 2 weeks achieved comparable remission rates to the higher dose NIH regimen described earlier. These results must be interpreted judiciously, however, since the patients treated in Euro-Lupus had several favorable prognostic factors compared to the NIH trials, including only mild kidney dysfunction (mean baseline serum creatinine 1.15 mg/dl) and a population that was largely Caucasian.

Clinical trials performed in the past ten years have firmly established mycophenolate mofetil (MMF) as a legitimate first-line alternative to CYC for induction therapy (Appel et al., 2009; Chan et al., 2000; 2005; Ginzler et al., 2005; Walsh et al., 2007). MMF acts by inhibiting inosine monophosphate dehydrogenase, the rate-limiting enzyme in guanosine nucleotide synthesis. B and T lymphocytes are particularly sensitive to MMF-induced guanosine synthesis inhibition, thus the drug exerts its immunosuppressive effect with less toxicity on bone marrow cells.

An early study randomized Chinese lupus patients to either MMF (2 g/day for 6 months then 1 g/day for 6 months) or oral CYC (2.5 mg/kg/day for 6 months) followed by azathioprine (AZA, 1.5 mg/kg/day for 6 months), with oral prednisolone used in both arms. Both the initial study and its 5-year follow-up report (Chan et al., 2005) showed statistically equivalent rates of complete remission, partial remission, and disease relapses between the two arms. However, at 5 years, rates of infection were significantly less in the MMF group (13% vs. 40%) and the only patients to reach end-stage renal disease or death were in the CYC group. A subsequent trial of 140 patients in the United States compared 6 months of oral MMF with a goal dose of 3 grams daily to monthly IV CYC pulses, with both regimens including tapering corticosteroids. The MMF arm experienced significantly higher rates of complete remission (22.5% vs. 5.8%), with lower rates of infections.

The Aspreva Lupus Management Study (ALMS) is the largest study comparing MMF to CYC for induction (Appel et al., 2009). This international, multi-center trial randomized 370 patients with class III, IV, or V nephritis to either MMF (3 g/day) or monthly IV CYC pulses and found virtually identical rates of complete and partial remission. Improvements in kidney function and mortality rates were also equivalent. These results appeared to hold even among those patients with severely reduced kidney function [defined as glomerular filtration rate (GFR) < 30 ml/min], although this group included only 32 patients.

In summary, the above studies indicate that either CYC or MMF-based regimens, combined with corticosteroids, are appropriate first-line choices for induction of lupus nephritis and generally equivalent for typical cases, with response rates in the range of 50-80%. Drug selection should be based on the respective side effect profiles and on careful consideration of an individual patient’s clinical status. For example, we strongly favor CYC in situations of rapidly progressive and crescentic lupus nephritis, especially in the presence of associated anti-neutrophil cytoplasmic antibodies (ANCA) (Nasr et al., 2008). We prefer MMF for most young females, and those for whom fertility issues, alopecia, or bladder problems related to CYC would be particularly problematic. Long term studies comparing outcomes of the two treatments are not available.

Conventional Maintenance Therapy Following Induction Is Best Provided by Mycophenolate or Azathioprine

Several agents have been studied for maintenance therapy in lupus nephritis, although the best available data supports AZA and MMF. Despite its value for induction, CYC appears to have an unacceptable safety profile for long-term use in maintenance therapy given the risks of impaired fertility, alopecia, and hemorrhagic cystitis (Contreras et al., 2004; Takada et al., 2001). A study by Contreras et al. (2004) randomized 59 patients to maintenance therapy with either quarterly CYC infusions, oral AZA, or oral MMF, continued for 1-3 years. AZA and MMF had higher event-free survival than CYC for the composite endpoint of death and chronic renal failure, and also lower risk of relapse. The safety profiles of AZA and MMF were also superior compared to that of CYC, with lower rates of hospitalization, amenorrhea, and infection.

AZA and MMF have been found to have similar efficacy in several randomized trials (Contreras et al., 2004; Sahin et al., 2008). Results from two good-quality trials comparing these two agents have recently become available. The trial of Azathioprine Versus Mycophenolate Mofetil for Maintenance Immunosuppression of Proliferative Lupus Nephritis (MAINTAIN) randomized 105 patients to either AZA or MMF for at least 3 years of maintenance (mean, 53 months) (Houssiau et al., 2010). No differences were noted in time to renal flare, to severe systemic flare, to benign flare, and to renal remission. Conversely, preliminary results from maintenance phase of the ALMS trial (thus far presented in abstract form), in which 227 patients were randomized, indicate that MMF was significantly superior to AZA with respect to the primary endpoint of time to treatment failure, defined as death, end stage kidney disease, doubling of serum creatinine, lupus nephritis flare, or requirement for rescue therapy with high dose corticosteroids (Ginzler et al., 2010). With the imminent publication and dissemination of the ALMS phase III data, we expect MMF will become the first choice for chronic maintenance immunosuppression in lupus nephritis. Caveats to this include that very long-term safety data is available for AZA but not MMF; AZA is currently a much less expensive drug; and unlike MMF, AZA has been used in pregnancy.

A Special Case: Membranous Lupus Nephritis

The treatment of pure membranous lupus nephritis, or class V in the ISN/RPS schema, is considered separately from proliferative nephritis. In mild forms, with stable kidney function, sub-nephrotic proteinuria, and the absence of proliferative lesions, RAAS blockade with ACEI or ARB may suffice. For more severe disease, several treatment options exist. A randomized controlled trial carried out by the NIH compared 42 patients with pure membranous lupus treated with one of three regimens: IV CYC with prednisone, the calcineurin inhibitor cyclosporine with prednisone, or prednisone alone (Austin et al., 2009). The groups combining IV CYC or cyclosporine with prednisone both significantly outperformed the group using prednisone alone in achieving remission. Several smaller, uncontrolled reports suggest good response of class V lupus nephritis to tacrolimus, another calcineurin inhibitor (Szeto et al., 2008; Tse et al., 2007). We recently published an analysis of 84 patients with pure membranous lupus pooled from two large trials of MMF versus IV CYC for lupus nephritis (Radhakrishnan et al., 2010). There were no differences between the groups in remission, relapses, or clinical outcomes. In summary, the best available evidence supports the use of either CYC, MMF, or a calcineurin inhibitor for membranous lupus nephritis.

Future Directions in Treatment Encompass a Variety of Immunomodulatory Approaches

At the time of this writing there were over 30 studies registered at ClinicalTrials.gov actively recruiting patients for the treatment of lupus nephritis. These include conventional immunosuppressants previously studied in lupus nephritis such as calcineurin inhibitors or mycophenolate, immunosuppressants that have shown success in other diseases, entirely novel immunomodulatory molecules, and non-drug therapies such as mesenchymal stem cell transplant. Below we review some of the more promising therapies that are reasonably close to potential clinical use.

Therapies Targeting B Cells

Rituximab

Rituximab is a chimeric monoclonal antibody targeting CD20 that depletes both mature B cells and their precursors, but not plasma cells. It was initially developed for use in non-Hodgkins lymphoma, but it has also had success in, and is FDA approved for, rheumatoid arthritis (Edwards et al., 2004) and more recently ANCA-associated glomerulonephritis (Jones et al., 2010; Stone et al., 2010). In lupus nephritis, rituximab has been used to treat over 300 patients with some success in patients with severe or refractory disease, albeit in small, uncontrolled, and predominantly retrospective studies (Lu et al., 2009; Melander et al., 2009; Vigna-Perez et al., 2006). Two recent randomized controlled trials have examined the use of rituximab in lupus. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial randomized 257 patients with moderately to severely active systemic lupus (but not nephritis) to receive rituximab x 4 infusions over 6 months or placebo (Merrill et al., 2010). No differences were noted between placebo and rituximab in the primary and secondary endpoints, which were mostly determined by disease activity scores. Subgroup analyses suggested a beneficial effect in the African American and Hispanic subgroups, but this result must be considered exploratory at best. The Lupus Nephritis Assessment with Rituximab (LUNAR) trial randomized 140 patients with severe lupus nephritis to rituximab or placebo in addition to an induction regimen of MMF (goal, 3 g/day) and tapering corticosteroids. While publication is still pending, results reported in 2009 indicate there was no statistically significant difference in the primary outcome of achieving remission of nephritis between treatment groups at one year (Furie et al., 2009). In light of these results, rituximab should not be used as an add-on to first line therapy with MMF/steroids for induction therapy of lupus nephritis. However, there may be a role for its use in patients who are resistant to conventional treatment, cannot tolerate conventional treatment, have concomitant ANCA vasculitis, or are in maintenance therapy (Vigna-Perez et al., 2006).

Ocrelizumab

Ocrelizumab is another monoclonal antibody targeting CD20, but unlike rituximab it is fully humanized. This carries the theoretical advantages of avoiding first dose transfusion reactions and the development of human anti-chimeric antibodies (HACA) seen in approximately 10% of patients treated with rituximab (Albert et al., 2008; Vincenti et al., 2010). While the clinical significance of HACA is unclear, they may block the efficacy of repeated doses of rituximab. However, the Study to Evaluate Ocrelizumab in Patients with Nephritis Due to Systemic Lupus Erythematosus (BELONG) was suspended prematurely due to an increased incidence of serious and opportunistic infections in the treatment group. The role of humanized anti-CD19/CD20 antibodies in lupus nephritis remains to be defined.

Epratuzumab

Epratuzumab is a humanized monoclonal antibody against CD22, a marker of mature B cells but not plasma cells (Bhat and Radhakrishnan, 2008). This drug has been studied in phase II trials of moderate to severe lupus (but not nephritis), including a 12-week, double-blind trial of 227 patients presented at the American College of Rheumatology 2010 Annual Meeting. It appears to be well tolerated, it successfully depletes B- ells, and it was associated with improvements in disease activity as measured by severity scores (Dorner et al., 2006). A phase III trial is underway (ClinicalTrials.gov Identifier: NCT01262365).

Belimumab

Belimumab made headlines in 2011 when it became the first drug to become FDA-approved for the treatment of lupus since hyrdoxychloroquine in 1955. Instead of targeting B cells directly, belimumab is a humanized monoclonal antibody that targets the B cell growth factor B lymphocyte stimulator protein (BLyS), also known as B cell activating factor (BAFF). Two phase III, placebo-controlled trials of belimumab vs. placebo showed that the drug was significantly associated with improvement in disease activity by various scoring systems (Navarra et al., 2011). Neither trial examined either lupus nephritis or kidney-related outcomes. We expect such a trial to be forthcoming.

Therapies Targeting Plasma Cells

Bortezomib

Bortezomib is a proteasome inhibitor approved in the U.S. for the treatment of multiple myeloma. It acts by preferentially depleting antibody-producing plasma cells. This unique action has generated interest in using the drug for a variety of diseases driven by pathogenic antibody production, including antibody-mediated rejection in organ transplant where case-reports have documented its success (Mai et al., 2009; Walsh et al., 2010). A set of experiments in a mouse model of lupus demonstrated that bortezomib depleted plasma cells producing anti-dsDNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival (Neubert et al., 2008). We are not aware of any convincing reports of its efficacy in human lupus (Frohlich et al., 2011); however, a clinical trial to test its efficacy in lupus nephritis is seeking to enroll patients (ClinicalTrials.gov Identifier: NCT01169857).

Therapies Targeting Co-stimulatory Molecules

Abatacept

When a T lymphocyte recognizes an antigen-MHC complex on an antigen-presenting cell (APC), a co-stimulatory signal produced by the binding of B7 receptors on the APC to CD28 or CTLA4 on the T cell is required for T cell activation. Abatacept, or CTLA4-Ig, consists of the extracellular domain of CTLA4 fused to an immunoglobulin domain. This molecule binds to B7 on the APC, blocking the co-stimulatory signal needed for T cell activation. It is an approved drug for the treatment of rheumatoid arthritis (Genovese et al., 2005), and is being actively investigated in several other autoimmune disorders including ulcerative colitis and type I diabetes mellitus. A randomized trial of abatacept versus placebo added to induction therapy with CYC (Euro-lupus regimen) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) is currently enrolling patients with lupus nephritis (ClinicalTrials.gov Identifier: NCT00774852). Another large randomized blinded controlled trial of abatacept in lupus nephritis sponsored by Bristol-Myers Squibb is no longer enrolling patients, but it is unclear when results will be available (ClinicalTrials.gov Identifier: NCT00430677).

Belatacept

Differing from abatacept by only two amino acid groups, belatacept employs the same mechanism of action but binds B7 much more potently (Martin et al., 2011). It is primarily being marketed for use in organ transplant, and we know of no trials active involving lupus. If trials of abatacept show promise in lupus nephritis, we expect belatacept to follow suit. Even if abatacept produces negative results, it is reasonable to hypothesize that belatacept’s potency might give it a competitive advantage and that it may still be worth studying in lupus.

Miscellaneous Agents

Laquinimod

Also known as TV-5600 or ABR-215062, laquinimod is an oral immunomodulator with an uncertain mechanism of action. In animal studies, the drug appears to reduce leukocyte infiltration into target tissues, alters the balance of Th1/Th2 lymphocytes, and modulates cytokine balance (Jonsson et al., 2004; Yang et al., 2004; Zou et al., 2002). It has been best studied thus far as therapy for multiple sclerosis (Weiner, 2008). An ongoing trial randomizes patients with lupus nephritis to laquinimod vs. placebo in addition to induction therapy with MMF (2 g/day) and corticosteroids (ClinicalTrials.gov Identifier: NCT01085097).

ACTH

Adrenocorticotropic hormone (ACTH) has been used in Europe for patients with the nephrotic syndrome of various etiologies (Berg and Arnadottir, 2004), and is FDA approved for the treatment of the nephrotic syndrome in the U.S. In a randomized trial, ACTH was equivalent to CYC for inducing remission of idiopathic membranous nephropathy (Ponticelli et al., 2006). Several small clinical trials are underway in the United States to formally evaluate ACTH in the setting of a variety of nephrotic and proteinuric states, including diabetic nephropathy. Because of its success in membranous nephropathy, a clinical trial of ACTH in class V lupus nephritis (lupus membranous) is expected to begin seeking enrollment in the near future.

Other therapies

Several other approaches to lupus nephritis are worth mentioning. Calcineurin inhibitors, discussed above in relation to membranous lupus nephritis, have been studied in proliferative lupus nephritis with good success in combination with corticosteroids and MMF as part of a “multitargeted” approach (Bao et al., 2008). Agents directed against tumor-necrosis factor alpha (TNFα) have raised interest for their success against rheumatoid arthritis, but their potential in SLE remains uncertain, especially in light of their documented ability to induce or unmask an SLE-like syndrome (Ramos-Casals et al., 2007). A Japanese group has reported two patients with class IV lupus nephritis resistant to corticosteroids that experience remarkable clinical and biochemical amelioration after treatment with all-trans retinoic acid, although in neither case had therapy been attempted with immunosuppression that would be considered standard of care in the U.S., i.e., CYC or MMF (Kinoshita et al., 2010). Nevertheless, the same group has undertaken to study a synthetic retinoid for lupus nephritis in the context of a clinical trial (ClinicalTrials.gov Identifier: NCT01226147).

Hematopoietic Stem Cells

Finally, a non-pharmacologic approach worth noting is the use of mesenchymal stem cell transplants for severe and refractory lupus. Registry data indicates relatively high remission rates, but also high rates of relapse and mortality, as might be expected from disease aggressive enough to merit such treatment (Tyndall, 2009). Generally speaking, such a risky therapy seems difficult to justify for kidney-threatening disease alone, given the relatively lower-risk alternative of dialysis and eventual kidney transplantation. With more extensive disease and proper patient selection, however, it may be a valuable option of last resort. There are trials registered for both allogeneic and autologous stem cell transplant (ClinicalTrials.gov Identifiers: NCT00659217, NCT00698191).

Conclusion

The treatment of lupus nephritis has evolved dramatically in the past several decades. Physicians today can rely on well-validated induction and maintenance immunosuppression regimens that will bring improvement to the majority of their patients, with reasonable side-effect profiles. However, a substantial minority of patients will be left with uncontrolled or only partially controlled disease despite first-line treatments, and for these patients there is a pressing need to develop tolerable and effective alternatives. An increasingly sophisticated understanding of immune system regulation, a devotion to pharmacological creativity, and the willingness of patients and clinicians to test new therapies within the bounds of clinical trials are the necessary ingredients to ensure that we continue towards the goal of providing all patients with a painless reprieve from this insidious disease.

Disclosure

Dr. Pietro Canetta has no conflicts to declare. Dr. Andrew Bomback has received research support from Novartis, Teva, Alexion, and Questcor. Dr. Bomback has served as a consultant for Questcor. Dr. Jai Radhakrishnan has no conflicts to declare.

Corresponding Author

Jai Radhakrishnan, M.D., Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, 622 West 168th Street, PH4-124, New York, New York 10032, USA.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(65):341-349, October 2011. Copyright © Discovery Medicine. All rights reserved.]

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