Update on the treatment of lupus nephritis
2006; Elsevier BV; Volume: 70; Issue: 8 Linguagem: Inglês
10.1038/sj.ki.5001777
ISSN1523-1755
AutoresMeryl Waldman, Gerald B. Appel,
Tópico(s)Liver Diseases and Immunity
ResumoLupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Although the use of aggressive immunosuppression has improved both patient and renal survival over the past several decades, the optimal treatment of LN remains challenging. Improved outcomes have come at the expense of significant adverse effects owing to therapy. Moreover with long-term survival, the chronic adverse effects of effective therapies including risk of malignancy, atherosclerosis, infertility, and bone disease all become more important. Finally, some patients fail to achieve remission with standard cytotoxic therapy and others relapse when therapy is reduced. For these reasons, recent clinical trials have attempted to define alternate treatment protocols that appear to be efficacious in achieving and maintaining remission, but with less toxicity than standard regimens. This paper discusses established and newer treatment options for patients with proliferative and membranous LN, with an emphasis on the results of these recent clinical trials. We also review the experimental and human data regarding some of the novel targeted forms of therapy that are under investigation and in different phases of clinical trials. Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Although the use of aggressive immunosuppression has improved both patient and renal survival over the past several decades, the optimal treatment of LN remains challenging. Improved outcomes have come at the expense of significant adverse effects owing to therapy. Moreover with long-term survival, the chronic adverse effects of effective therapies including risk of malignancy, atherosclerosis, infertility, and bone disease all become more important. Finally, some patients fail to achieve remission with standard cytotoxic therapy and others relapse when therapy is reduced. For these reasons, recent clinical trials have attempted to define alternate treatment protocols that appear to be efficacious in achieving and maintaining remission, but with less toxicity than standard regimens. This paper discusses established and newer treatment options for patients with proliferative and membranous LN, with an emphasis on the results of these recent clinical trials. We also review the experimental and human data regarding some of the novel targeted forms of therapy that are under investigation and in different phases of clinical trials. Renal involvement is a frequent and serious complication of systemic lupus erythematosus (SLE). It contributes both directly to morbidity and mortality of the patients as well as indirectly through side effects of therapy directed at the renal lesions. Although survival has improved dramatically in patients with focal and diffuse proliferative lupus nephritis (LN), until recently 'standard' treatment for severe disease was associated with multiple potential adverse toxicities. Newer treatments for severe LN show promise of equivalent efficacy but less toxicity as well as the potential to treat resistant disease. Patient and renal survival of SLE patients has improved considerably over the past few decades, in part, due to earlier recognition of renal disease, aggressive immunosuppression, and prevention of complications of therapies.1.Fiehn C. Hajjar Y. Mueller K. et al.Improved clinical outcome of lupus nephritis during the past decade: importance of early diagnosis and treatment.Ann Rheum Dis. 2003; 62: 435-439Crossref PubMed Scopus (81) Google Scholar, 2.Bono L. Cameron J.S. Hicks J.A. The very long-term prognosis and complications of lupus nephritis and its treatment.QJM. 1999; 92: 211-218Crossref PubMed Google Scholar, 3.Uramoto K.M. Michet Jr, C.J. Thumboo J. et al.Trends in the incidence and mortality of systemic lupus erythematosus 1950–1992.Arthritis Rheum. 1999; 42: 46-50Crossref PubMed Scopus (274) Google Scholar The optimal immunosuppressive regimen for proliferative LN remains the subject of research, clinical trials, and intense debate. Until recently, the majority of nephrologists and rheumatologists relied on one 'standard' approach to the treatment of severe LN based upon a series of trials at the National Institutes of Health.4.Boumpas D.T. Austin III, H.A. Vaughn E.M. et al.Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis.Lancet. 1992; 340: 741-745Abstract PubMed Scopus (549) Google Scholar, 5.Gourley M.F. Austin III, H.A. Scott D. et al.Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis, A randomized, controlled trial.Ann Intern Med. 1996; 125: 549-557Crossref PubMed Google Scholar, 6.Illei G.G. Austin H.A. Crane M. et al.Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.Ann Intern Med. 2001; 135: 248-257Crossref PubMed Google Scholar, 7.Austin III, H.A. Klippel J.H. Balow J.E. et al.Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.N Engl J Med. 1986; 314: 614-619Crossref PubMed Google Scholar Recent well-performed, randomized controlled National Institutes of Health trials proved the efficacy of a regimen consisting of six monthly pulses of intravenous (i.v.) cyclophosphamide (CYC) (0.5–1 g/m2) followed by subsequent i.v. CYC pulses every 3 months for 2 years. This regimen was shown to have fewer flares and relapses and better renal survival than a shorter regimen of six monthly treatments without follow-up doses. Subsequent studies at the National Institutes of Health proved that concomitant i.v. methylprednisolone with monthly pulse i.v. CYC5.Gourley M.F. Austin III, H.A. Scott D. et al.Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis, A randomized, controlled trial.Ann Intern Med. 1996; 125: 549-557Crossref PubMed Google Scholar, 6.Illei G.G. Austin H.A. Crane M. et al.Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.Ann Intern Med. 2001; 135: 248-257Crossref PubMed Google Scholar was more effective in the short term than either therapy alone. In longer follow-up of the same population, the combination regimen had no greater toxicity than CYC alone, but far superior renal outcomes. Although clearly effective, this regimen is associated with both short-term and long-term adverse effects, including increased risk of severe infections, gonadal damage,5.Gourley M.F. Austin III, H.A. Scott D. et al.Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis, A randomized, controlled trial.Ann Intern Med. 1996; 125: 549-557Crossref PubMed Google Scholar, 8.Boumpas D.T. Austin III, H.A. Vaughan E.M. et al.Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy.Ann Intern Med. 1993; 119: 366-369Crossref PubMed Google Scholar, 9.Mok C.C. Lau C.S. Wong R.W. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy.Arthritis Rheum. 1998; 41: 831-837Crossref PubMed Scopus (194) Google Scholar and malignancy.10.Radis C.D. Kahl L.E. Baker G.L. et al.Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year follow-up study.Arthritis Rheum. 1995; 38: 1120-1127Crossref PubMed Scopus (190) Google Scholar A significant proportion of patients (up to 22%) fail to achieve remission with this regimen or relapse after treatment and some patients still progress to end-stage renal disease.11.Korbet S.M. Lewis E.J. Schwartz M.M. et al.Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group.Am J Kidney Dis. 2000; 35: 904-914Abstract Full Text Full Text PDF PubMed Google Scholar In view of this, there has been increasing attention on developing alternate therapies that promptly and effectively induce remission, prevent relapse, and maximize patient and renal survival while incurring the least toxicity. Akin to oncologists, nephrologists are now focusing on the concept of 'induction treatment' with vigorous initial therapies, followed by 'maintenance treatment' with lower doses of less toxic regimens. Such strategies include minimizing the use of CYC with lower dosages, use of sequential therapies with different immunosuppressive agents, and eliminating exposure to CYC entirely with use of alternative agents. Mycophenolate mofetil (MMF), rituximab, and newer biologics are all being studied in controlled, randomized trials. However, at present no single regimen has become the new standard of care for treatment of LN. Many physicians are cautious about using newer therapies until solid, long-term evidence shows that the alternate treatment is superior and/or less toxic. Furthermore, it has been difficult for many clinicians to integrate the results of multiple prospective and retrospective studies recently performed in different populations into their general practice. The aim of this review is to update the reader on the results of several pivotal clinical trials, which lend strong support to the use of alternative induction and maintenance treatment regimens for proliferative LN. It will emphasize the potential benefits as well as the short comings of these studies. Recent data on treatment of membranous lupus nephropathy will be discussed. A brief overview of the promising novel biologic therapies currently under investigation will be included. The Euro-Lupus Nephritis Trial, a European-based multi-center prospective trial, was a head-to-head comparison of low-dose to 'conventional' high-dose i.v. CYC for severe active LN.12.Houssiau F.A. Vasconcelos C. D'Cruz D. et al.Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.Arthritis Rheum. 2002; 46: 2121-2131Crossref PubMed Scopus (481) Google Scholar Ninety patients were randomized to either high-dose CYC (six monthly i.v. pulses of 0.5–1 g/m2 followed by two quarterly pulses) or low-dose CYC (fixed i.v. pulses of 500 mg given every 2 weeks for a total of six doses). Following CYC, both groups received oral azathioprine (AZA) as maintenance therapy. The majority of patients was Whites and had class IV diffuse proliferative lupus nephritis (DPLN). At 41 months, there were no significant differences in the primary end point, cumulative probability of treatment failure, between the high- and low-dose treatment arms (20 vs 16%, respectively). There were also no differences in renal remissions (54 vs 71%, respectively) or renal flares (29 vs 27%, respectively). The shorter regimen had less toxicity with fewer and less severe infections. This study provides good support for a shorter duration and lower total dose of CYC for induction therapy for proliferative LN. Limitations of the Euro-Lupus trial include a population with relatively milder renal disease than in some other studies (mean creatinine 1–1.3 mg/dl; mean proteinuria 2.5–3.5 g/day for both groups). Moreover, almost 85% of the patients were Caucasian. In virtually every clinical study, African-Americans fare worse than non-Blacks and this racial factor is a strong independent risk for progressive renal disease.13.Dooley M.A. Hogan S. Jennette C. et al.Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network.Kidney Int. 1997; 51: 1188-1195Abstract Full Text PDF PubMed Google Scholar, 14.Austin III, H.A. Boumpas D.T. Vaughan E.M. et al.Predicting renal outcomes in severe lupus nephritis: contributions of clinical and histologic data.Kidney Int. 1994; 45: 544-550Abstract Full Text PDF PubMed Google Scholar, 15.Bakir A.A. Levy P.S. Dunea G. The prognosis of lupus nephritis in African-Americans: a retrospective analysis.Am J Kidney Dis. 1994; 24: 159-171Abstract Full Text PDF PubMed Google Scholar, 16.Austin III, H.A. Boumpas D.T. Vaughan E.M. et al.High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 patients.Nephrol Dial Transplant. 1995; 10: 1620-1628PubMed Google Scholar, 17.Barr R.G. Seliger S. Appel G.B. et al.Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity.Nephrol Dial Transplant. 2003; 18: 2039-2046Crossref PubMed Scopus (125) Google Scholar Nevertheless, the 'Euro-Lupus regimen' is an option for some patients with proliferative LN, in particular, Caucasians with less severe renal injury. In addition, the study confirms that the sequential use of CYC and AZA is a viable strategy to reduce toxicity without compromising overall efficacy. Recently, MMF has emerged as a promising alternative therapy for both induction and maintenance treatment for LN. Extensively used in organ transplantation, MMF has also been used in a variety of immune- and non-immune-mediated renal diseases. Mycophenolic acid (MPA), the active metabolite of MMF, is an inhibitor of the crucial enzyme involved in the de novo synthesis of guanosine nucleotides.18.Allison A.C. Eugui E.M. Mycophenolate mofetil and its mechanisms of action.Immunopharmacology. 2000; 47: 85-118Crossref PubMed Scopus (686) Google Scholar, 19.Eugui E.M. Almquist S.J. Muller C.D. et al.Lymphocyte-selective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion.Scand J Immunol. 1991; 33: 161-173Crossref PubMed Google Scholar As lymphocytes do not possess a salvage pathway for the generation of these nucleotides, MMF results in selective blockade of B- and T-cell proliferation. Unlike CYC, MPA has little impact on other tissues with high proliferative activity (i.e. neutrophils, skin, intestine, bone marrow), which possess a salvage pathway for nucleotide synthesis. This accounts for its more favorable toxicity profile. In addition, MMF appears to have a variety of anti-inflammatory actions that are independent of its effect on cell-mediated immunity: (1) MPA may limit glomerular injury, progressive renal scarring, and fibrosis by inhibiting proliferation of mesangial cells and myofibroblast differentiation;20.Hauser I.A. Renders L. Radeke H.H. et al.Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion.Nephrol Dial Transplant. 1999; 14: 58-63Crossref PubMed Scopus (101) Google Scholar, 21.Badid C. Vincent M. McGregor B. et al.Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney.Kidney Int. 2000; 58: 51-61Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar (2) MPA may limit lymphocyte migration into renal tissue by inhibiting the glycosylation (and consequently the affinity) of adhesion molecules expressed by lymphocytes,22.Blaheta R.A. Leckel K. Wittig B. et al.Mycophenolate mofetil impairs transendothelial migration of allogeneic CD4 and CD8 T-cells.Transplant Proc. 1999; 31: 1250-1252Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 23.Heemann U. Azuma H. Schmid C. et al.Effects of mycophenolic acid mofetil on acute rejection of kidney allografts in rats.Clin Nephrol. 1996; 45: 355-357PubMed Google Scholar and (3) MPA appears to diminish renal cortical expression of the inducible isoform of nitric oxide synthase (iNOS),24.Lui S.L. Tsang R. Wong D. et al.Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice.Lupus. 2002; 11: 411-418Crossref PubMed Scopus (35) Google Scholar which has been implicated in the pathogenesis of renal injury in LN. Moreover, there is evidence to suggest that mycophenolate helps to retard the development of atherosclerosis. These properties and the potential to suppress both upstream and downstream inflammatory events make this medication an attractive therapy for treating LN. Murine studies,25.Corna D. Morigi M. Facchinetti D. et al.Mycophenolate mofetil limits renal damage and prolongs life in murine lupus autoimmune disease.Kidney Int. 1997; 51: 1583-1589Abstract Full Text PDF PubMed Google Scholar, 26.Van Bruggen M.C. Walgreen B. Rijke T.P. et al.Attenuation of murine lupus nephritis by mycophenolate mofetil.J Am Soc Nephrol. 1998; 9: 1407-1415PubMed Google Scholar numerous case reports, and small uncontrolled series all suggested potential therapeutic value of MMF in SLE.27.Buratti S. Szer I.S. Spencer C.H. et al.Mycophenolate mofetil treatment of severe renal disease in pediatric onset systemic lupus erythematosus.J Rheumatol. 2001; 28: 2103-2108PubMed Google Scholar, 28.Karim M.Y. Alba P. Cuadrado M.J. et al.Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents.Rheumatology (Oxford). 2002; 41: 876-882Crossref PubMed Google Scholar, 29.Kingdon E.J. McLean A.G. Psimenou E. et al.The safety and efficacy of MMF in lupus nephritis: a pilot study.Lupus. 2001; 10: 606-611Crossref PubMed Scopus (67) Google Scholar Recently, a number of major controlled trials have compared the efficacy of MMF to CYC in induction treatment for proliferative LN. The first of such trials by Chan et al.30.Chan T.M. Li F.K. Tang C.S. et al.Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.N Engl J Med. 2000; 343: 1156-1162Crossref PubMed Scopus (686) Google Scholar randomized 42 patients with DPLN to 6 months of induction with MMF (2 g/day) or oral CYC (2.5 mg/kg/day), both with concurrent oral prednisolone. During the maintenance phase, those in the MMF arm continued the drug at a reduced dose (1 g/day) and those in the CYC arm switched to AZA (1.5 mg/kg/day) for 6 months. At 12 months, there were no differences in complete remissions (CR), partial remissions (PRs), or relapses. There were also no significant differences in other parameters, including serum creatinine (Scr), complement, albumin, and 24 h urine protein. Adverse events were more common in the CYC group, although the rate of infectious complications was not statistically different. The study was extended to a period of over 5 years with enrollment of an additional 22 patients.31.Chan T.M. Tse K.C. Tang C.S. et al.Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis.J Am Soc Nephrol. 2005; 16: 1076-1084Crossref PubMed Scopus (322) Google Scholar After a median follow-up of 63 months, there was no difference in CR or PR. A total of 6.3% in the MMF group and 10.0% of CYC-AZA-treated patients showed doubling of baseline creatinine during follow-up (P=0.667). Four patients in the CYC-AZA group but none in the MMF group reached the composite end point of end-stage renal disease or death (P=0.06). At long-term follow-up, there was a similar rate of relapse and relapse-free survival in both groups. Significantly, fewer patients administered MMF developed infections requiring hospitalization. In addition, leukopenia was only observed with CYC, the only two deaths were in the CYC group, and amenorrhea was more frequent with cytotoxic therapy (36 vs 3.6%, respectively). The authors concluded that induction treatment with MMF was as effective as oral CYC, but with fewer side effects. This trial also suffers from limitations. It included only Chinese patients and, clearly, no African-Americans. Patients with some poor prognostic indicators including newly diagnosed DPLN, high Scr, and substantial glomerular and tubulointerstitial disease were also excluded from the study. Nevertheless, the study was well performed, randomized, and had long-term follow-up data. Certainly in the population studied, a strong argument can be made for use of MMF as induction therapy for many International Society of Nephrology class IV patients. In another trial from China, Hu et al.32.Hu W. Liu Z. Chen H. et al.Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis.Chin Med J (England). 2002; 115: 705-709PubMed Google Scholar compared the efficacy of 6 months of MMF to conventional i.v. CYC for induction therapy in 46 patients with DPLN. Patients randomized to MMF had greater reduction of proteinuria, lupus serologic activity, urinary sediment activity, and glomerular immune deposits on repeat biopsy while experiencing fewer side effects. A more recent study by Ginzler et al.33.Ginzler E.M. Dooley M.A. Aranow C. et al.Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.N Engl J Med. 2005; 353: 2219-2228Crossref PubMed Scopus (596) Google Scholar addressed the issue of efficacy of MMF induction in a high risk, multi-racial, American population in which 56% of the patients were African-American. This study was designed as an equivalency study. In this multi-center, prospective trial, 140 patients (the majority with class IV LN) were randomized to standard six monthly pulses of i.v. CYC or MMF (target dose 3 g/day) in conjunction with a tapering dose of corticosteroids. The study allowed crossover at 3 months for treatment failure or toxicity. No maintenance regimen was specified after the induction. The primary end point was CR at 24 weeks defined as normal values of Scr, absence of proteinuria, and normal urine sediment. PR was defined as >50% improvement in all renal parameters. At the 6-month end point, in an intention-to-treat analysis, there were fewer treatment failures, and more complete and complete plus PRs with MMF (22 and 52%, respectively) compared to CYC (4 and 30%, respectively). Crossover to the alternate arm was more common with CYC than with MMF (20 vs 8%, respectively). MMF was also associated with a lower incidence of severe infections, and in general fewer, milder side effects. At 3-year follow-up, there were no significant differences in time to first renal flare, renal failure, or death. However, all tended to be lower in the MMF group. The authors concluded that induction therapy with MMF was superior to i.v. CYC in inducing remissions of LN and was better tolerated. A major limitation of this study is the short duration of follow-up. Longer-term studies are needed to determine the relapse rate and long-term renal survival in this population. This study also did not compare MMF to CYC with steroid pulses, which many clinicians routinely use for severe LN. The early crossover design may have resulted in premature designation of treatment failures. In addition, patients with rapidly progressive renal failure, ARF, and Scr >3 mg/dl or CrCl 5. After induction therapy with 4–7 monthly pulses of i.v. CYC, 83% of the patients achieved remission and were then randomized to one of three maintenance regimens: i.v. CYC pulses (every third month) or AZA (1–3 mg/kg/day) or MMF (0.5–3 gm/day) for approximately 2 years. Fewer patients treated with AZA and MMF group reached the primary end points of death and CRF compared to the CYC group. Relapse-free survival was higher with MMF (78%) and AZA (58%) compared to i.v. CYC (43%). Mortality was increased with i.v. CYC compared to both oral agents. Complications of therapy including hospitalizations, amenorrhea, infections, and gastrointestinal problems were significantly lower with MMF and AZA. The authors concluded that maintenance therapy with either MMF or AZA was superior to i.v. CYC. There are several limitations with this study. Some patients did not achieve remission at the end of the induction phase with i.v. CYC, which may be attributable to the large percentage of Hispanics and Blacks in the study. Patients with rapidly progressive and crescentic disease were excluded. Nevertheless, the favorable response to AZA and MMF compared to continued every third month i.v. CYC strongly suggests a role for the less toxic oral agents in maintenance therapy. In light of these results and the Euro-Lupus trial, a randomized multi-center trial (MAINTAIN Nephritis Trial) conducted by The European Working Party on Systemic Lupus Erythematosus is currently underway to compare the efficacy and toxicity of MMF and AZA as remission-maintaining treatment for proliferative LN following induction with a short course of i.v. CYC. Over the last two decades, increasing understanding of the complex pathologic mechanisms underlying SLE in combination with accelerating advances in molecular and cellular immunology have paved the way for development of biologic therapies for LN. In contrast to the global effects of conventional immunosuppressants, these novel agents interfere with specific pathways responsible for the pathologic autoimmune responses. Although the pathophysiology of SLE is complex, B-cell hyperactivity and autoantibody production have been a consistent feature.38.Jacobi A.M. Diamond B. Balancing diversity and tolerance: lessons from patients with systemic lupus erythematosus.J Exp Med. 2005; 202: 341-344Crossref PubMed Scopus (35) Google Scholar, 39.Lipsky P.E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity.Nat Immunol. 2001; 2: 764-766Crossref PubMed Scopus (354) Google Scholar, 40.Waldman M. Madaio M.P. Pathogenic autoantibodies in lupus nephritis.Lupus. 2005; 14: 19-24Crossref PubMed Scopus (84) Google Scholar In addition to the production of antibodies, B cells lead to the activation of the immune system through antigen presentation, activation of autoreactive T cells, dendritic cell regulation, and production of cytokine and chemokines. Thus, B cells represent a rational therapeutic target in SLE. More than one therapeutic approach to impair or delete B-lymphocytes has been explored including the use of LJP 394 and rituximab. LJP 394 (riquent, abetimus sodium) was the first of such agents designed to selectively modulate autoantibody producing B cells and reduce pathologic antibodies directed against dsDNA.41.Abetimus: Abetimus sodium LJP 394 BioDrugs. 2003; 17: 212-215Crossref PubMed Google Scholar This agent, consisting of four dsDNA helices conjugated to an inert polyethylene scaffold, is believed to reduce circulating autoantibodies by two mechanisms: (1) crosslinking anti-dsDNA surface immunoglobulin receptors on B cells leading to tolerance via anergy or apoptosis, and (2) binding to circulating antibodies, forming small soluble complexes that are subsequently cleared.42.Jones D.S. Barstad P.A. Feild M.J. et al.Immunospecific reduction of antioligonucleotide antibody-forming cells with a tetrakis-oligonucleotide conjugate (LJP 394), a therapeutic candidate for the treatment of lupus nephritis.J Med Chem. 1995; 38: 2138-2144Crossref PubMed Google Scholar In a m
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