Insights into the epidemiology and management of lupus nephritis from the US rheumatologist's perspective
2016; Elsevier BV; Volume: 90; Issue: 3 Linguagem: Inglês
10.1016/j.kint.2016.03.042
ISSN1523-1755
AutoresPaul Hoover, Karen H. Costenbader,
Tópico(s)Liver Diseases and Immunity
ResumoLupus nephritis is a common and severe manifestation of systemic lupus erythematosus that disproportionately affects nonwhites and those in lower socioeconomic groups. This review discusses recent data on the incidence, prevalence, and outcomes of patients with lupus nephritis with a focus on low-income US Medicaid patients. We also review recent guidelines on diagnosis, treatment, and screening for new onset and relapses of lupus nephritis. Finally, we discuss the management of lupus nephritis from a rheumatologist’s perspective, including vigilance for the common adverse events related to disease and treatment, and we review prevention and new treatment strategies. Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus that disproportionately affects nonwhites and those in lower socioeconomic groups. This review discusses recent data on the incidence, prevalence, and outcomes of patients with lupus nephritis with a focus on low-income US Medicaid patients. We also review recent guidelines on diagnosis, treatment, and screening for new onset and relapses of lupus nephritis. Finally, we discuss the management of lupus nephritis from a rheumatologist’s perspective, including vigilance for the common adverse events related to disease and treatment, and we review prevention and new treatment strategies. Lupus nephritis (LN) affects approximately 40% of those with systemic lupus erythematous (SLE).1Ward M.M. Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third national health and nutrition examination survey.J Womens Health (Larchmt). 2004; 13: 713-718Crossref PubMed Scopus (90) Google Scholar, 2Helmick C.G. Felson D.T. Lawrence R.C. et al.Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I.Arthritis Rheum. 2008; 58: 15-25Crossref PubMed Scopus (1718) Google Scholar, 3Lawrence R.C. Felson D.T. Helmick C.G. et al.National Arthritis Data WorkgroupEstimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.Arthritis Rheum. 2008; 58: 26-35Crossref PubMed Scopus (3125) Google Scholar Over the past 5 decades, therapeutic advances, in particular immunosuppression, have significantly improved outcomes for patients with LN.4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar However, recent evidence indicates that improvement in LN outcomes plateaued in the 2000s, perhaps because we have reached the limitations of our current therapies.4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar With current induction and maintenance therapies, the risk of developing LN-related end-stage renal disease (ESRD) at 5, 10, and 15 years remains at 11%, 17%, and 22% (95% confidence intervals [CI]: 10%–12%, 16%–18%, 20%–23%) for the last decade.4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar The lack of sustained progress in LN outcomes may be due to poor health care access for some groups, limited efficacy of current therapies, and/or their adverse effects.4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar Here, we discuss recent epidemiological studies addressing which patients develop LN and LN-related ESRD with an emphasis on the US given its diverse population. We also discuss the role of the rheumatologist in the management of LN and review some recent management guidelines. We discuss patient- and medication-related obstacles that hinder progress, while highlighting several promising new ideas addressing these obstacles. SLE and LN both occur disproportionately among nonwhites, which is well demonstrated in the heterogeneous population of the US. In recent studies from the Centers for Disease Control, the overall prevalence of SLE was 72.2 and 74.4 per 100,000 persons in large patient cohorts from Georgia and Michigan, respectively.5Lim S.S. Bayakly A.R. Helmick C.G. et al.The incidence and prevalence of systemic lupus erythematosus, 2002–2004: the Georgia Lupus Registry.Arthritis Rheumatol. 2014; 66: 357-368Crossref PubMed Scopus (238) Google Scholar, 6Somers E.C. Marder W. Cagnoli P. et al.Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan Lupus Epidemiology and Surveillance program.Arthritis Rheumatol. 2014; 66: 369-378Crossref PubMed Scopus (293) Google Scholar However, the prevalence is several times greater in blacks than whites (116.1 vs. 34.8 per 100,000 persons), and a higher proportion of black SLE patients developed renal disease and ESRD (40.5% and 15.3%) compared with whites (18.8% and 4.5%).5Lim S.S. Bayakly A.R. Helmick C.G. et al.The incidence and prevalence of systemic lupus erythematosus, 2002–2004: the Georgia Lupus Registry.Arthritis Rheumatol. 2014; 66: 357-368Crossref PubMed Scopus (238) Google Scholar Similarly, in a national cohort of patients enrolled from 2000 to 2004 in Medicaid (the US government-administered health insurance for the poor), incidence rates of LN were 3.8 times higher in blacks, 3.7 in Asians, 2.3 in Native Americans, and 1.9 in Hispanics patients compared with white SLE patients.7Feldman C.H. Hiraki L.T. Liu J. et al.Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000–2004.Arthritis Rheum. 2013; 65: 753-763Crossref PubMed Scopus (300) Google Scholar Whereas the majority of new SLE cases occur in individuals between 15 and 40 years of age, approximately 15% of cases arise in patients 200 miles from the nearest rheumatologist, prohibiting timely access to medical care.11FitzGerald J.D. Battistone M. Brown Jr., C.R. et al.for the American College of Rheumatology Committee on Rheumatology Training and Workforce IssuesRegional distribution of adult rheumatologists.Arthritis Rheum. 2013; 65: 3017-3025Crossref PubMed Scopus (56) Google Scholar When a LN patient in a resource-poor area does find appropriate care, immunosuppressive medication may be prohibitively expensive or unavailable.12Oyoo G.O. Mody G.M. Report on the Fifth African League Against Rheumatism Congress in Nairobi, Kenya.Clin Rheumatol. 2007; 26: 1033-1035Crossref PubMed Scopus (9) Google Scholar Finally, new evidence suggests the care itself may be substandard in some medically underserved areas. In 1 study,13Yazdany J. Feldman C.H. Liu J. et al.Quality of care for incident lupus nephritis among Medicaid beneficiaries in the United States.Arthritis Care Res (Hoboken). 2014; 66: 617-624Crossref PubMed Scopus (38) Google Scholar less than one-half of Medicaid enrollees with new onset LN received standard antimalarial and renoprotective agents at 90 days, with little improvement at 1 year. These studies suggest high barriers to health care exist in resource-poor areas of the US, but barriers are probably higher in developing countries, which may contribute to increased rates of SLE-associated ESRD outside the US.4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar Systemic manifestations of SLE precede renal involvement in the majority of patients.14Balow J.E. Clinical presentation and monitoring of lupus nephritis.Lupus. 2005; 14: 25-30Crossref PubMed Scopus (95) Google Scholar The rheumatologist is therefore positioned to recognize new onset or recurrent LN and to refer to a nephrologist for kidney biopsy, initiation of appropriate therapy, and comanagement. The American College of Rheumatology (ACR) recommends regular screening for new onset and recurrent kidney involvement. Whereas the screening frequency depends on disease severity and prior history of LN, we are especially vigilant in the first 6 months of SLE diagnosis when new LN most often occurs.15Hanly J.G. O'Keeffe A.G. Su L. et al.The frequency and outcome of lupus nephritis: results from an international inception cohort study.Rheumatology (Oxford). 2016; 55: 252-262Crossref PubMed Scopus (259) Google Scholar Otherwise, screening should occur every 3 to 6 months in patients with no past history or stable LN. Specifically, blood pressure, body weight, anti–double stranded DNA, C3 and C4 complement levels should be followed.16Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines.Arthritis Rheum. 1999; 42: 1785-1796Crossref PubMed Scopus (217) Google Scholar, 17Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of RheumatologyAmerican College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (946) Google Scholar In addition, glomerular health should be regularly assessed with urinalysis and sediment analysis to identify new cellular casts (red cells, granular, tubular, or mixed casts), active urinary sediment (>5 red blood cells/high power field or >5 white blood cells/high power field in the absence of infection), or persistent proteinuria (>0.5 mg/day).17Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of RheumatologyAmerican College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (946) Google Scholar These biomarkers are not infallible, but increases in anti–double stranded DNA antibody titers and decreases in C3 and C4 track with disease activity and the risk of LN relapse. Other novel biomarkers, including urinary biomarkers, are being investigated but are not used for routine clinical care. SLE patients with evidence of new onset LN should undergo a renal biopsy (unless contraindicated) to evaluate for histopathologic lesions of glomerulonephritis, as well as other renal injury. As discussed in the accompanying review by Rovin et al.,18Anders H.-J. Rovin B. A pathophysiology-based approach to the diagnosis and treatment of lupus nephritis.Kidney Int. 2016; 90: 493-501Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar lupus glomerulonephritis is categorized histologically into 6 classes by the International Society of Nephrology/Renal Pathology Society. Revised in 2003, this classification system has become the standard for renal biopsy interpretation because of interobserver reproducibility and improved correlation with prognostic and therapeutic outcomes.17Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of RheumatologyAmerican College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (946) Google Scholar, 19Markowitz G.S. D'Agati V.D. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years.Kidney Int. 2007; 71: 491-495Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar In addition to the International Society of Nephrology/Renal Pathology Society classes, other histological features affect treatment decisions and prognosis, although no guidelines exist for these.17Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of RheumatologyAmerican College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (946) Google Scholar, 19Markowitz G.S. D'Agati V.D. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years.Kidney Int. 2007; 71: 491-495Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar For example, patients with high “activity” lesions are usually treated with immunosuppression, whereas those with “chronic” lesions may not receive therapy because of a poorer response prognosis.19Markowitz G.S. D'Agati V.D. The ISN/RPS 2003 classification of lupus nephritis: an assessment at 3 years.Kidney Int. 2007; 71: 491-495Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 20Hiramatsu N. Kuroiwa T. Ikeuchi H. et al.Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions.Rheumatology (Oxford). 2008; 47: 702-707Crossref PubMed Scopus (98) Google Scholar Another concomitant biopsy finding, tubulointerstitial inflammation, confers more than 2-fold risk on the doubling of serum creatinine or ESRD in some ethnic populations (Figure 2).21Hsieh C. Chang A. Brandt D. et al.Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring.Arthritis Care Res (Hoboken). 2011; 63: 865-874Crossref PubMed Scopus (206) Google Scholar The significance of other biopsy findings, such as thrombotic microangiopathy, cryoglobulinemia, acute interstitial nephritis, and collapsing glomerulonephropathy, in treatment responsiveness and outcomes, is not yet well characterized. Six separate LN management guidelines from the US, Europe, and international sources were recently published and generally agree on major treatment strategies.22Wilhelmus S, Bajema IM, Bertsias GK, et al. Lupus nephritis management guidelines compared [e-pub ahead of print]. Nephrol Dial Transplant. pii: gfv102. Accessed February 1, 2016.Google Scholar Here, we highlight recommendations from the ACR and joint recommendations from the European League Against Rheumatism (EULAR) and European Renal Association-European Dialysis and Transplant Association (ERA-EDTA). The ACR and EULAR/ERA-EDTA recommend that all LN patients receive several adjunctive medications consisting of the following: (i) hydroxychloroquine (HCQ), (ii) a renoprotective agent, and (iii) a lipid-lowering statin. HCQ has many benefits and carries very low risk of side effects. HCQ reduces the rate of systemic relapses of SLE and may be associated with slowing renal damage, thromboses, hyperglycemia, and hyperlipidemia. Though rare, the most common and serious risk from HCQ is irreversible vision loss from retinal toxicity. Therefore, patients should have regular dilated retinal exams by a trained ophthalmologist. In cases of chronic renal insufficiency and ESRD, dosing guidelines for HCQ are not clear. Even reduced HCQ doses may increase the risk for retinal damage, as well as neurologic and muscle toxicities. Renin-angiotensin-aldosterone system inhibitors are recommended for patients with proteinuria >0.5 g/day. Patients with SLE, even more so with LN, have increased risk of cardiovascular events.23Schoenfeld S.R. Kasturi S. Costenbader K.H. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review.Semin Arthritis Rheum. 2013; 43: 77-95Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Therefore, lipid-lowering statin medications are also indicated for SLE and LN patients to maintain low-density lipoprotein 1 g/day or urinary acanthocytes. For patients with class III or IV proliferative glomerulonephritis, the guidelines uniformly agree on induction therapy with moderate oral glucocorticoid doses plus i.v. cyclophosphamide or mycophenolate mofetil (MMF), with or without initial pulses of i.v. methylprednisolone. One of 2 schedules of i.v. cyclophosphamide is administered according to ethnic background and disease severity: the “low-dose” Eurolupus regimen is usually administered to whites and consists of i.v. cyclophosphamide 500 mg every 2 weeks for 3 months; the “high-dose” National Institutes of Health regimen is usually administered to blacks and consists of 0.5 to 1 g/m2 monthly for 6 doses.22Wilhelmus S, Bajema IM, Bertsias GK, et al. Lupus nephritis management guidelines compared [e-pub ahead of print]. Nephrol Dial Transplant. pii: gfv102. Accessed February 1, 2016.Google Scholar Given cyclophosphamide’s risk of bladder and hematologic malignancies, ovarian failure in women, and mounting evidence that MMF is more effective in blacks, MMF may be the preferred induction therapy.25Muangchan C. van Vollenhoven R.F. Bernatsky S.R. et al.Treatment algorithms in systemic lupus erythematosus.Arthritis Care Res (Hoboken). 2015; 67: 1237-1245Crossref PubMed Scopus (77) Google Scholar Additionally, as both cyclophosphamide and MMF are potentially teratogenic, women of childbearing age should have negative pregnancy tests and receive contraceptive planning prior to starting therapy. The risk of ovarian failure associated with cyclophosphamide increases with age, and ovarian preserving regimens, such as gonadotropin-releasing hormone agonists, should be considered.26Clowse M.E. Behera M.A. Anders C.K. et al.Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis.J Womens Health (Larchmt). 2009; 18: 311-319Crossref PubMed Scopus (170) Google Scholar For maintenance therapy, both the ACR and EULAR/ERA-EDTA recommend MMF or azathioprine, with or without low-dose glucocorticoids. However, EULAR/ERA-EDTA recommends treatment only for “active lesions.” As is the case for induction therapy, MMF may be preferred in maintenance therapy given its superiority to azathioprine in preventing relapse.27Dooley M.A. Jayne D. Ginzler E.M. et al.Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.N Engl J Med. 2011; 365: 1886-1895Crossref PubMed Scopus (450) Google Scholar Whereas the duration of maintenance therapy is not agreed upon, EULAR/ERA-EDTA recommends continuation for 2 years after complete remission (proteinuria <0.5 mg/day, near normal glomerular filtration rate). The National Institutes of Health are currently sponsoring a randomized trial of MMF continuation versus withdrawal among LN patients who have been stable for 2 or more years to determine the ideal treatment duration and to identify those who could be tapered off earlier. For pure class V lupus glomerulonephritis, all guidelines endorse the use of renin-angiotensin-aldosterone system inhibitors to suppress proteinuria. In patients with nephrotic range proteinuria, both ACR and EULAR/ERA-EDTA recommend the addition of MMF. Patients should be seen initially every few weeks and monitored closely for therapeutic response and adverse side effects. Although a precise definition is not agreed upon, a “complete” renal response usually means significantly reduced proteinuria (<0.33 to 1.0 g/day), improved or stable glomerular filtration rate (15% to 25% of baseline), and/or normalization of urinary sediment (<5 to 10 red blood cells/high power field without casts).28Appel G.B. Contreras G. Dooley M.A. et al.for the Aspreva Lupus Management Study GroupMycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Crossref PubMed Scopus (781) Google Scholar, 29ACCESS Trial GroupTreatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study.Arthritis Rheumatol. 2014; 66: 3096-3104Crossref PubMed Scopus (184) Google Scholar, 30Rovin B.H. Furie R. Latinis K. et al.Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study.Arthritis Rheum. 2012; 64: 1215-1226Crossref PubMed Scopus (899) Google Scholar Complete-responders to induction therapy may thereafter be seen less frequently, whereas partial and nonresponders are seen more often. With current induction regimens, <60% of class III to V patients achieve a complete response.28Appel G.B. Contreras G. Dooley M.A. et al.for the Aspreva Lupus Management Study GroupMycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Crossref PubMed Scopus (781) Google Scholar Among those who attain a complete response, nearly one-half relapse at a rate of 5 to 15 per 100 patient-years.31Grootscholten C. Berden J.H. Discontinuation of immunosuppression in proliferative lupus nephritis: is it possible?.Nephrol Dial Transplant. 2006; 21: 1465-1469Crossref PubMed Scopus (28) Google Scholar The risk of developing LN-related ESRD at 5, 10, and 15 years is 11%, 17%, and 22% (95% CIs: 10%–12%, 16%–18%, 20%–23%),4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar and patients with class IV LN are especially vulnerable: 44% develop ESRD at 15 years.4Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1970 to 2015: a systematic review and Bayesian meta-analysis [e-pub ahead of print]. Arthritis Rheumatol. http://dx.doi.org/10.1002/art.39594. Accessed February 1, 2016.Google Scholar The standardized incidence rate of LN-related ESRD in the US is higher among all nonwhites and 7-fold greater among blacks compared with whites.32Costenbader K.H. Desai A. Alarcon G.S. et al.Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006.Arthritis Rheum. 2011; 63: 1681-1688Crossref PubMed Scopus (174) Google Scholar Finally, survival rates at 10 years are 2- and 3-fold higher in complete responders than partial and nonresponders.33Korbet S.M. Lewis E.J. Schwartz M.M. et al.for the Lupus Nephritis Collaborative Study GroupFactors predictive of outcome in severe lupus nephritis.Am J Kidney Dis. 2000; 35: 904-914Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar Not surprisingly, nonresponders have the worst outcomes.34Chen Y.E. Korbet S.M. Katz R.S. et al.for the Collaborative Study GroupValue of a complete or partial remission in severe lupus nephritis.Clin J Am Soc Nephrol. 2008; 3: 46-53Crossref PubMed Scopus (206) Google Scholar Poor adherence to treatment regimens and appointments is not uncommon among SLE and LN patients and substantially negatively impacts outcomes. In a US publicly funded clinic, 80% over 2 years.35Marengo M.F. Waimann C.A. de Achaval S. et al.Measuring therapeutic adherence in systemic lupus erythematosus with electronic monitoring.Lupus. 2012; 21: 1158-1165Crossref PubMed Scopus (60) Google Scholar In a large multiethnic US Medicaid cohort from 2000 to 2006, poor adherence was associated with higher rates of systemic relapse, poor renal response, and increased hospitalizations.36Feldman C.H. Yazdany J. Guan H. et al.Medication nonadherence is associated with increased subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus.Arthritis Care Res (Hoboken). 2015; 67: 1712-1721Crossref PubMed Scopus (83) Google Scholar Assessing adherence is difficult in SLE and LN patients, but a recent study offers a possible solution. Serial serum measurements found that HCQ levels between 500 to 2000 ng/ml were associated with modestly improved SLE disease activity.37Durcan L. Clarke W.A. Magder L.S. Petri M. Hydroxychloroquine blood levels in systemic lupus erythematosus: clarifying dosing controversies and improving adherence.J Rheumatol. 2015; 42: 2092-2097Crossref PubMed Scopus (112) Google Scholar Whereas serum HCQ assays are not routine clinical practice, they may offer a quantitative method to assess adherence and/or adjust dosing to achieve a therapeutic range. In addition, patient education and behavioral support are potentially effective interventions to increase adherence in chronic diseases, although they have not yet been vigorously studied in LN. Recent work suggests that a genetic basis may partially account for poor renal outcomes. Genome-wide association studies over the past decade identified >50 SLE risk loci.38Mohan C. Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis.Nat Rev Nephrol. 2015; 11: 329-341Crossref PubMed Scopus (232) Google Scholar Although focused on SLE, a sizeable number of genome-wide association studies enrollees had LN, allowing for the identification of LN-associated risk loci such as BLK, STAT4, TNFS4, IKZF1, IRF5, TLR9, TNFAIP3, TNIP3, ACE, KLK, FCGR2A, FCGR3A, FCGR3B, and ITGAM.38Mohan C. Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis.Nat Rev Nephrol. 2015; 11: 329-341Crossref PubMed Scopus (232) Google Scholar Most participants were European and Asian, leaving open the questions of whether these or undiscovered risk alleles segregate along ethnicities, and to what extent they contribute to ethnic differences in disease severity and outcomes. For example, APOL1 risk alleles are associated with ESRD and are 60 times more frequent in blacks than whites. Among black SLE patients, this risk genotype more than doubles the risk of developing ESRD and shortens the time to ESRD by 2 years.39Freedman B.I. Langefeld C.D. Andringa K.K. et al.for the Lupus Nephritis—End-Stage Renal Disease ConsortiumEnd-stage renal disease in African Americans with lupus nephritis is associated with APOL1.Arthritis Rheumatol. 2014; 66: 390-396Crossref PubMed Scopus (197) Google Scholar The population attributable risk for SLE-ESRD due to the APOL1 risk genotype is estimated at 26% in blacks and <1% in whites.39Freedman B.I. Langefeld C.D. Andringa K.K. et al.for the Lupus Nephritis—End-Stage Renal Disease ConsortiumEnd-stage renal disease in African Americans with lupus nephritis is associated with APOL1.Arthritis Rheumatol. 2014; 66: 390-396Crossref PubMed Scopus (197) Google Scholar Several clinical markers near the time of SLE diagnosis are also associated with renal outcomes. Among them, hypertension, elevated serum creatinine, proteinuria, and persistently elevated anti–double stranded DNA and low complements following immunosuppression all portend poor outcomes. However, early reduction in proteinuria is associated with renal preservation. In the 10-year follow-up of the Mycophenolate Mofetil versus Azathioprine for Maintenance Therapy of Lupus Nephritis (MAINTAIN) trial, the positive predictive value for preserving renal function was approximately 90% if proteinuria was reduced to 2-fold higher in LN than SLE patients (23.4 vs. 10.8 per 100,000 person-years).42Feldman C.H. Hiraki L.T. Winkelmayer W.C. et al.Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis.Arthritis Rheumatol. 2015; 67: 1577-1585Crossref PubMed Scopus (134) Google Scholar Among those with LN, the risk of serious infection was highest in those treated with glucocorticoids (hazard ratio: 1.51; 95% CI: 1.43–1.61) followed by immunosuppressive drugs (hazard ratio: 1.11; 95% CI: 1.03–1.20) compared with nonusers. To reduce infectious risks, we follow EULAR vaccination guidelines for patients with autoimmune rheumatic diseases.43van Assen S. Agmon-Levin N. Elkayam O. et al.EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.Ann Rheum Dis. 2011; 70: 414-422Crossref PubMed Scopus (476) Google Scholar Prior to starting immunosuppression, we screen all patients for tuberculosis mycobacterium, using a T-cell based blood test, and hepatitis B and C. We avoid live vaccinations in immunosuppressed patients, defined as those taking (i) prednisone >20 mg/day or the equivalent, (ii) azathioprine >3.0 mg/kg/day, or (iii) any dose of cyclophosphamide or MMF.43van Assen S. Agmon-Levin N. Elkayam O. et al.EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.Ann Rheum Dis. 2011; 70: 414-422Crossref PubMed Scopus (476) Google Scholar Killed vaccinations such as influenza, pneumococcus, hepatitis B, and human papillomavirus are also recommended during stable, quiescent periods. The EULAR guidelines do not recommend the Bacillus Calmette-Geurin vaccination, as its efficacy against tuberculosis is not proven in adults.43van Assen S. Agmon-Levin N. Elkayam O. et al.EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.Ann Rheum Dis. 2011; 70: 414-422Crossref PubMed Scopus (476) Google Scholar Prolonged use of glucocorticoids is a major challenge in the treatment of LN. There are many glucocorticoid-associated adverse effects, including osteoporotic fractures, avascular necrosis, diabetes mellitus, cataracts, glaucoma, and premature mortality.44Ruiz-Irastorza G. Danza A. Khamashta M. Glucocorticoid use and abuse in SLE.Rheumatology (Oxford). 2012; 51: 1145-1153Crossref PubMed Scopus (144) Google Scholar Unfortunately, mainly for their rapidity of action, glucocorticoids are still a mainstay therapy for LN induction and relapses. There is a current impetus to quickly taper the maintenance glucocorticoid dose, although the optimal taper rate is unknown. In addition, an ACR expert panel has made several recommendations to prevent bone-related complications.45Grossman J.M. Gordon R. Ranganath V.K. et al.American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.Arthritis Care Res (Hoboken). 2010; 62: 1515-1526Crossref PubMed Scopus (599) Google Scholar All patients starting glucocorticoids should be evaluated for fall risk and counseled on smoking cessation, reducing excessive alcohol, performing modest weight-bearing exercises, and consuming adequate amounts of calcium and vitamin D. Clinical testing should include a 25-hydroxy vitamin D level, and baseline and follow-up bone mineral density scans. The ACR recommends antiosteoporotic medication for patients who have a prior fragility fracture, are at high risk for fracture, or who will be on prolonged glucocorticoids. The choice of antiosteoporotic medications is not always straightforward. For example, bisphosphonates are contraindicated in patients with renal insufficiency or ESRD, and there is currently no consensus about use in women of childbearing age given bisphosphonates’ long half-life and potentially adverse effects on a developing fetal skeleton. Although glucocorticoid-sparing immunosuppressive agents (i.e., azathioprine, MMF, cyclosporine, and cyclophosphamide) have allowed for lower glucocorticoid doses and less toxicity, many LN patients still require prolonged low doses of glucocorticoid for remission maintenance. As a result, glucocorticoid-free maintenance therapy for LN is currently under investigation.46Lightstone L. Minimising steroids in lupus nephritis—will B cell depletion pave the way?.Lupus. 2013; 22: 390-399Crossref PubMed Scopus (25) Google Scholar Rituximab, a monoclonal antibody targeting the B-cell surface protein CD20, was initially examined in the Lupus Nephritis Assessment with Rituximab (LUNAR) trial, which included 144 patients with class III or IV LN. In that trial, rituximab did not statistically affect the outcomes in patients who also received MMF and glucocorticoids. However, in a more recent prospective observational study, 50 LN patients, 44% with pure class V, were treated without any oral glucocorticoids.47Condon M.B. Ashby D. Pepper R.J. et al.Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids.Ann Rheum Dis. 2013; 72: 1280-1286Crossref PubMed Scopus (305) Google Scholar Subjects received only 2 pulses of methylprednisolone, and 2 1-g doses of rituximab separated by 2 weeks, plus daily MMF. At 1 year, 52% of patients achieved complete renal remission (urine protein–creatinine <50 mg/mmol, creatinine <15% above baseline) with low rates of adverse events. Although small and unblinded, this study laid the foundation for a larger ongoing trial, Trial of Rituximab and MMF without Oral Steroids for Lupus Nephritis (RITUXILUP). In this randomized noninferiority multicenter trial, both arms of LN patients are receiving 2 pulses of methylprednisolone and daily MMF. In addition, the experimental arm receives 2 1-g doses of rituximab, and the control group receives daily weight-based oral glucocorticoids. Comparing renal response rates and glucocorticoid toxicities between the 2 arms over time will address the question of whether combining rituximab and MMF can replace oral glucocorticoids for maintenance therapy. LN affects approximately 40% of SLE patients over their lifetime and disproportionately burdens nonwhite women from lower socioeconomic groups.1Ward M.M. Prevalence of physician-diagnosed systemic lupus erythematosus in the United States: results from the third national health and nutrition examination survey.J Womens Health (Larchmt). 2004; 13: 713-718Crossref PubMed Scopus (90) Google Scholar, 2Helmick C.G. Felson D.T. Lawrence R.C. et al.Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I.Arthritis Rheum. 2008; 58: 15-25Crossref PubMed Scopus (1718) Google Scholar, 3Lawrence R.C. Felson D.T. Helmick C.G. et al.National Arthritis Data WorkgroupEstimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.Arthritis Rheum. 2008; 58: 26-35Crossref PubMed Scopus (3125) Google Scholar The ACR and EULAR/ERA-EDTA recommend close monitoring for new onset or recurrent LN in SLE patients by routinely screening for kidney involvement at least every 3 to 6 months and obtaining a kidney biopsy for persistent evidence of LN barring any contraindication.17Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of RheumatologyAmerican College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (946) Google Scholar They also recommend high doses of glucocorticoid plus cyclophosphamide or MMF to induce a complete renal response within 6 months. After remission, maintenance therapy with either MMF or azathioprine should be continued for some time, although the duration of therapy is not agreed upon. Of these medications, MMF may be preferred due fewer associated toxicities compared with cyclophosphamide and superiority over azathioprine in preventing relapse.25Muangchan C. van Vollenhoven R.F. Bernatsky S.R. et al.Treatment algorithms in systemic lupus erythematosus.Arthritis Care Res (Hoboken). 2015; 67: 1237-1245Crossref PubMed Scopus (77) Google Scholar, 27Dooley M.A. Jayne D. Ginzler E.M. et al.Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.N Engl J Med. 2011; 365: 1886-1895Crossref PubMed Scopus (450) Google Scholar All LN patients should receive additional medications that include HCQ, a renin-angiotensin-aldosterone system inhibitor for proteinuria, a statin for goal low-density lipoprotein <100 mg/dl, and antihypertensives to maintain blood pressure <130/80 mm Hg. Women planning or anticipating pregnancy should be counseled regarding potential complications related to LN and medications, as many are toxic to the developing fetus. Finally, glucocorticoid-induced osteoporosis and other complications are ongoing challenges.45Grossman J.M. Gordon R. Ranganath V.K. et al.American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.Arthritis Care Res (Hoboken). 2010; 62: 1515-1526Crossref PubMed Scopus (599) Google Scholar
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