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American Journal of Kidney Diseases

Ten Common Mistakes in the Management of Lupus Nephritis

Published:December 13, 2013DOI:https://doi.org/10.1053/j.ajkd.2013.10.056
      Management of patients with lupus nephritis can be complex and challenging. We suggest that there are some widely held misconceptions about lupus, and unfortunately, these underpin the treatment of many patients. There is little evidence to support the common assumption that intravenous pulse cyclophosphamide is the best treatment for lupus nephritis. Although there is much focus on which immunosuppressive agent to use, too little attention is paid to the proper dose and duration of corticosteroids and concomitant therapy with antimalarial agents. Many clinicians reflexively perform kidney biopsies when these biopsies may be high risk and not influence therapy. There is little emphasis on or awareness of nonadherence to therapy, which is an underappreciated cause of treatment resistance. Resolution of proteinuria and hematuria can take a long time, and immunotherapy should not be intensified based on urine sediment alone. Furthermore, the intensity of the immunosuppression must be considered in the context of lupus nephritis class and duration of kidney damage. Finally, clinicians are aware of the risks of pregnancy in the face of active lupus, but assume that their patients also are aware of this and forget to discuss this with them. With a combined experience of more than 50 years in managing children and adults with lupus, we offer our impression of recurrent mistakes in the management of lupus in general, with a focus on treatment of lupus nephritis.

      Index Words

      Joanne M. Bargman, MD, FRCPC, was the Donald W. Seldin Distinguished Award recipient at the 2013 National Kidney Foundation Spring Clinical Meetings. This award was established to recognize excellence in clinical nephrology in the tradition of one of the foremost teachers and researchers in the field, Dr Donald W. Seldin.
      Kidney involvement in systemic lupus erythematosus (SLE) can range from mild to severe and occurs in 50%-70% of patients with lupus.
      • Bastian H.M.
      • Roseman J.M.
      • McGwin Jr., G.
      • et al.
      Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis.
      • Petri M.
      • Perez-Gutthann S.
      • Longenecker J.C.
      • Hochberg M.
      Morbidity of systemic lupus erythematosus: role of race and socioeconomic status.
      • Pons-Estel B.A.
      • Catoggio L.J.
      • Cardiel M.H.
      • et al.
      The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among “Hispanics.”.
      Despite advances in therapy, morbidity and mortality remain high. In some studies, lupus nephritis leads to end-stage renal failure in 17%-25% of patients
      • Adler M.
      • Chambers S.
      • Edwards C.
      • Neild G.
      • Isenberg D.
      An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period.
      • Ward M.M.
      • Studenski S.
      Clinical prognostic factors in lupus nephritis. The importance of hypertension and smoking.
      • Williams W.
      • Sargeant L.A.
      • Smikle M.
      • Smith R.
      • Edwards H.
      • Shah D.
      The outcome of lupus nephritis in Jamaican patients.
      and also is associated with increased mortality.
      • Cervera R.
      • Khamashta M.A.
      • Font J.
      • et al.
      Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients.
      • Zonana-Nacach A.
      • Yanez P.
      • Jimenez-Balderas F.J.
      • Camargo-Coronel A.
      Disease activity, damage and survival in Mexican patients with acute severe systemic lupus erythematosus.
      There are some common misconceptions that are widely held and may compromise optimal therapy of these patients. If these misconception or myths are addressed, we believe the outcome of these patients might improve. These comments are based on our experience over the past quarter century dealing with a diverse ethnic lupus population in academically based multidisciplinary lupus clinics in Toronto.
      The following are the 10 most common mistakes we have observed surrounding the management of patients with lupus nephritis (Box 1).
      Ten Common Mistakes in the Management of Lupus Nephritis
      • 1.
        Assuming that intravenous cyclophosphamide is the gold-standard induction agent for lupus nephritis
      • 2.
        Improper dosing of corticosteroids
      • 3.
        Not using antimalarial agents routinely
      • 4.
        Using urinary sediment for response criteria
      • 5.
        Not scaling the intensity of immunosuppression to the different classes of lupus nephritis, especially class V membranous lupus
      • 6.
        Missing nonadherence to therapy as a cause of “treatment failure”
      • 7.
        Not reducing or minimizing immunosuppressive exposure in patients with advanced kidney disease
      • 8.
        Forgetting to monitor side effects of immunosuppression and to use prophylaxis
      • 9.
        Performing a biopsy on the kidney, especially in a high-risk patient, when it will not affect therapy
      • 10.
        Neglecting to address pregnancy

      1. Assuming that intravenous cyclophosphamide is the gold-standard induction agent for lupus nephritis

      Following the initial publication by Austin et al
      • Austin III, H.A.
      • Klippel J.H.
      • Balow J.E.
      • et al.
      Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs.
      in 1986, intravenous (IV) cyclophosphamide has been considered the gold standard for treatment of lupus nephritis. Based on this study, the National Institutes of Health (NIH) has promoted high-dose cyclophosphamide as a first-line induction agent for lupus nephritis, and this regimen is used by many rheumatologists and nephrologists. The cyclophosphamide dosage is 0.5-1.0 g/m2 monthly for 6 months, followed by repeat dosing every 3 months for 1 year, followed by an additional 2 doses 6 months apart. However, there are major concerns with this regimen, especially in young patients with lupus, due to the risks of gonadal toxicity and malignancy.
      In 2002, the Euro-Lupus Nephritis Trial compared low-dose IV cyclophosphamide (500 mg IV biweekly for 6 doses) versus the high-dose NIH regimen in 90 patients.
      • 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.
      Renal response and relapse rate were similar between the 2 groups. The long-term efficacy of the Euro-Lupus Nephritis Trial regimen also was shown in a 10-year follow-up study.
      • Houssiau F.A.
      • Vasconcelos C.
      • D'Cruz D.
      • et al.
      The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.
      However, there was no statistical difference in adverse events between groups. Limitations of the study are that most patients in the study were white, 78% had preserved kidney function (creatinine < 1.3 mg/dL), and the relatively small number (90) of patients treated. Interestingly, few have commented on the role of azathioprine, to which the low-dose IV cyclophosphamide group was transitioned after 3 months. Rather than being a comparison of high- versus low-dose IV cyclophosphamide, this study compared ongoing IV cyclophosphamide (high-dose group) therapy with low-dose IV cyclophosphamide followed by azathioprine past the 3-month point (low-dose group). Therefore, this study could be considered to be one comparing high-dose cyclophosphamide to azathioprine after the 3-month mark.
      More recently, mycophenolate mofetil (MMF) has been studied as alternative induction therapy to IV cyclophosphamide and may prove particularly effective in patients of African-Caribbean descent. Initially, MMF was compared to oral cyclophosphamide in 42 patients.
      • 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.
      • Chan T.M.
      • Tse K.C.
      • Tang C.S.
      • Mok M.Y.
      • Li F.K.
      Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis.
      Patients received either 12 months of MMF (2 g/d for 6 months and then 1 g/d for 6 months) or 6 months of oral cyclophosphamide (2.5 mg/kg/d) followed by 6 months of oral azathioprine (1.5 mg/kg/d). Both groups received corticosteroids. Complete remission, partial remission, relapse rates, and rate of chronic kidney disease (CKD) or end-stage renal failure were similar between groups. There was a trend for more infections in the cyclophosphamide group, but it was not statistically significant.
      This trial was followed by 3 randomized controlled trials comparing MMF versus IV cyclophosphamide.
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      • Ginzler E.M.
      • Dooley M.A.
      • Aranow C.
      • et al.
      Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.
      • Ong L.M.
      • Hooi L.S.
      • Lim T.O.
      • et al.
      Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
      One of the trials was an open-label crossover noninferiority trial and at 24 weeks showed significantly improved complete and partial remission rates in the MMF group (goal induction dose of 3 g/d) compared to the cyclophosphamide group.
      • Ong L.M.
      • Hooi L.S.
      • Lim T.O.
      • et al.
      Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
      There was an increased rate of pyogenic infection in the cyclophosphamide group. The ALMS (Aspreva Lupus Management Study) induction therapy study showed similar cumulative remission rates between both groups. The renal and nonrenal outcomes were equivalent at 6 months.
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      The 2 large trials comparing MMF versus IV cyclophosphamide are summarized in Table 1.
      Table 1Two Large Studies Comparing MMF Versus IV Cyclophosphamide for Induction Treatment of Lupus Nephritis
      StudyNTherapy (wk)Age (y)Race (%)Kidney Biopsy Class (%)Baseline SCr (mg/dL)24-h Urine Protein (g/d)Intervention (n)Outcome
      Ginzler
      • Ginzler E.M.
      • Dooley M.A.
      • Aranow C.
      • et al.
      Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.
      (2005)
      1402431.5 ± 9.5White, 17; black, 56.5; Asian, 5.5; Hispanic, 20; other, 1III, 15.5; IV, 54.5; V, 19.5; mixed membranoproliferative, 11.51.07 ± 0.504.25 ± 3.3MMF, mean maximal tolerated dose 2.6 g/d + prednisone (71); IV CYC, cumulative dose per patient 7,302 ± 1,695 mg + prednisone (69)MMF group: CR, 22.5%; PR, 29.6%; IV CYC group: CR, 5.8%; PR, 24.6%
      Appel
      • Appel G.B.
      • Contreras G.
      • Dooley M.A.
      • et al.
      Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.
      (2009; ALMS)
      3702431.9 ± 10.7White, 39.7; Asian, 33.2; other, 27III/III + V, 15.7; IV/IV + V, 68.1; V only, 16.21.13 ± 0.904.1 ± 3.7MMF, median dose 2.6 g/d + prednisone (185); IV CYC, median no. of doses, 6.0; median total dose per infusion, 0.75 g/m2 + prednisone (185)Primary efficacy end point achieved
      Primary efficacy end point: decrease in 24-hour urine protein to <3 in patients with baseline nephrotic-range proteinuria (≥3), or by ≥50% in patients with subnephrotic baseline proteinuria (<3), and stabilization (±25%) or improvement in SCr level at 24 weeks.
      in 56.2% of MMF group; 53% of IV CYC group
      Note: Conversion factor for SCr in mg/dL to μmol/L, ×88.4.
      Abbreviations and definitions: CR, complete remission defined as return to within 10% of normal serum creatinine levels, proteinuria, and urine sediment; CYC, cyclophosphamide; IV, intravenous; MMF, mycophenolate mofetil; PR, partial remission defined as 50% improvement in all abnormal renal measurements without worsening (within 10%) of any measurement; SCr, serum creatinine.
      a Primary efficacy end point: decrease in 24-hour urine protein to <3 in patients with baseline nephrotic-range proteinuria (≥3), or by ≥50% in patients with subnephrotic baseline proteinuria (<3), and stabilization (±25%) or improvement in SCr level at 24 weeks.
      These studies suggest that MMF is as effective as IV cyclophosphamide as an induction agent for lupus nephritis, with fewer adverse events such as gonadal toxicity and secondary malignancy. MMF should be considered as a first-line agent for induction, especially in young patients with lupus. Another consideration is that with only 6 months of follow-up, it is unclear how much of the effect is the result of high-dose corticosteroid therapy given in each arm. Going back to the pioneering study of Donadio et al
      • Donadio Jr., J.V.
      • Holley K.E.
      • Ferguson R.H.
      • Ilstrup D.M.
      Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide.
      published in 1978, corticosteroids alone led to the same early remission rate compared to corticosteroid in combination with a second immunosuppressive agent. Studies of different immunosuppressive regimens that have such a short follow-up (including trials up to 6 months) may have the same overarching effect of the corticosteroid, diluting or negating any potential difference among secondary agents.
      The other drug that is underused as an induction agent is azathioprine. A pooled analysis of 8 studies of lupus nephritis including 250 patients (including children) was published in 1984.
      • Felson D.T.
      • Anderson J.
      Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus nephritis. Results of a pooled analysis.
      In this analysis, 113 patients received only corticosteroids and the rest received corticosteroid with either azathioprine or cyclophosphamide. Analysis showed that patients who received azathioprine or cyclophosphamide with corticosteroid had less kidney deterioration, were less likely to have end-stage renal disease, and were less likely to die of kidney disease than patients receiving corticosteroid alone. There were approximately 60 patients in each group (prednisone vs cyclophosphamide/prednisone and prednisone vs azathioprine/prednisone), and hence results of the study did not reach statistical significance. The number of deaths in the azathioprine group was lower than that in the other 2 groups. Unfortunately, none of these studies was a head-to-head comparison of 2 immunosuppressive agents. However, within the limitations of this kind of analysis, azathioprine appeared to be a useful induction agent in the management of diffuse proliferative lupus nephritis.
      Another widely held belief is that if the biopsy shows very aggressive lupus nephritis, it mandates treatment with a more toxic agent (IV cyclophosphamide). There is no reason to believe that more aggressive disease requires therapy with a more toxic drug. The combination of the 2 may be a recipe for serious treatment-related side effects. When appropriate, less toxic drugs such as MMF or azathioprine should be considered for induction instead of cyclophosphamide. Furthermore, treatment with pulse IV cyclophosphamide leads to an unpredictable nadir in white blood cell count a week or 2 later. The leukopenia puts the patient at risk for infectious complications. This can be particularly fraught in the patient with diminished glomerular filtration rate, for whom even dose-adjusted IV cyclophosphamide can lead to severe prolonged leukopenia. At least with cyclophosphamide given as daily oral therapy, there is more control over therapy dose and consequent leukopenia.
      • McKinley A.
      • Park E.
      • Spetie D.
      • et al.
      Oral cyclophosphamide for lupus glomerulonephritis: an underused therapeutic option.
      However, these patients should be monitored closely for bladder toxicity secondary to daily exposure of oral cyclophosphamide.

      2. Improper dosing of corticosteroids

      The National Kidney Foundation’s KDIGO (Kidney Disease: Improving Global Outcomes) and other guidelines (American College of Rheumatology and the European League Against Rheumatism/European Dialysis and Transplantation Association) recommend an initial prednisone dosage of 1 mg/kg, with a slow taper over 6-12 months.
      Kidney Disease
      Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis.
      The guidelines also recommend using low-dose prednisone (≤10 mg/d) for maintenance therapy, and for relapse, the same dose of prednisone that was effective in inducing original remission. Although the dose and duration of oral corticosteroids have never been subject to evaluation by randomized controlled trials, these current recommendations seem to be effective in inducing and maintaining remission.
      However, it is our impression that most clinicians focus their attention more on the second agent than on the dose and duration of prednisone, and as a result, many patients are treated with lower dose prednisone that is tapered off quickly. This is due to concerns related to the multiple side effects of prednisone. Rapid tapering and/or discontinuation of prednisone put patients at high risk for relapse. Some patients, despite having a second agent, may need a prolonged or even life-long course of low-dose prednisone to maintain remission.
      Similarly, in refractory lupus nephritis, more attention is given to the second agent instead of the prednisone dose. There are patients who, despite changing their second agent, continue to be refractory to therapy. These patients potentially could benefit from increasing the dose of prednisone. (See also nonadherence, discussed later.)

      3. Not using antimalarial agents routinely

      Antimalarial agents such as hydroxychloroquine have been used to treat mucocutaneous, musculoskeletal, serosal, and constitutional manifestations of SLE. In randomized controlled trials and post hoc analyses, hydroxychloroquine has been shown to reduce the risk of damage accrual,
      • Fessler B.J.
      • Alarcon G.S.
      • McGwin Jr., G.
      • et al.
      Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual.
      improve survival,
      • Alarcon G.S.
      • McGwin G.
      • Bertoli A.M.
      • et al.
      Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L).
      • Ruiz-Irastorza G.
      • Egurbide M.V.
      • Pijoan J.I.
      • et al.
      Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus.
      and decrease the frequency of lupus flare.
      No authors listed. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group.
      • Tsakonas E.
      • Joseph L.
      • Esdaile J.M.
      • et al.
      A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group.
      It also has been shown to improve kidney outcomes. There is an increased probability of remission in patients with membranous nephritis treated with MMF when combined with hydroxychloroquine
      • Kasitanon N.
      • Fine D.M.
      • Haas M.
      • Magder L.S.
      • Petri M.
      Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis.
      and also a lowered probability of decrease in kidney function if used prior to the onset of lupus nephritis.
      • Siso A.
      • Ramos-Casals M.
      • Bove A.
      • et al.
      Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival.
      It retards the development of kidney damage in established lupus nephritis
      • Pons-Estel G.J.
      • Gonzalez L.A.
      • Zhang J.
      • et al.
      Predictors of cardiovascular damage in patients with systemic lupus erythematosus: data from LUMINA (LXVIII), a multiethnic US cohort.
      and is safe to continue during pregnancy.
      • Levy R.A.
      • Vilela V.S.
      • Cataldo M.J.
      • et al.
      Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study.
      Despite all this evidence, the role of antimalarial medications in the treatment of patients with SLE is underappreciated in the nephrology community. The probability of a patient with SLE receiving an antimalarial agent is substantially decreased (odds ratio, 0.51; 95% confidence interval [CI], 0.31-0.84) if their primary lupus physician is a nephrologist rather than a rheumatologist.
      • Lee S.J.
      • Silverman E.
      • Bargman J.M.
      The role of antimalarial agents in the treatment of SLE and lupus nephritis.
      Certainly in the nephrology community, there has been a great deal of discussion about what second agent to use, such that insufficient emphasis has been given to ancillary therapy, including long-term high-dose corticosteroid therapy and antimalarial agents.

      4. Using urinary sediment for response criteria

      The panel convened by the American College of Rheumatology to examine outcome markers in lupus nephritis recommends using urinary sediment for assessing response.
      • Liang M.H.
      • Schur P.H.
      • Fortin P.
      • et al.
      The American College of Rheumatology response criteria for proliferative and membranous renal disease in systemic lupus erythematosus clinical trials.
      According to the committee, improvement was defined as changing from active urinary sediment to inactive urinary sediment (eg, ≤5 red blood cells, ≤5 white blood cells, and no red blood cell or white blood cell casts). They defined worsening as active sediment in a patient who previously had inactive urinary sediment and for which there were no viable alternative explanations. The committee defined active urinary sediment as >5 red blood cells and >5 white blood cells per high-power field and/or cellular casts where none existed previously.
      However, in reality, the quantity of cells or casts observed can be influenced by the duration of centrifuge time and how vigorously the pellet at the bottom of the centrifuge tube is resuspended in the supernatant. We also know that some more benign processes such as mesangial proliferation (class II nephritis) can be associated with red blood cells and red blood cell casts in urine, and these lesions do not require immunosuppressive agents. Hence, using urinary sediment for response criteria can be misleading and can result in unnecessary use of potentially toxic therapies. In our experience, this is recognized more often by nephrologists than by rheumatologists. However, guideline panels setting criteria for kidney involvement in lupus unfortunately have a dearth of nephrologists.
      • Bargman J.M.
      Why are rheumatologists treating lupus nephritis?.

      5. Not scaling the intensity of immunosuppression to the different classes of lupus nephritis, especially class V membranous lupus

      Membranous lupus nephritis (MLN) accounts for approximately 10%-20% of cases of lupus nephritis.

      Lewis EJ, Schwartz MM, Korbet SM, eds. Membranous lupus glomerulonephritis. In: Lewis EJ SM, Korbet SM, eds. Lupus Nephritis. Oxford: Oxford University Press; 1999:219-240.

      Although the risk of decrease in kidney function is not as great as that with the endocapillary proliferative variants, up to 20% of patients with MLN require dialysis or kidney transplantation within 10 years of diagnosis.
      No authors listed. Lupus nephritis: prognostic factors and probability of maintaining life-supporting renal function 10 years after the diagnosis. Gruppo Italiano per lo Studio della Nefrite Lupica (GISNEL).
      • Appel G.B.
      • Cohen D.J.
      • Pirani C.L.
      • Meltzer J.I.
      • Estes D.
      Long-term follow-up of patients with lupus nephritis. A study based on the classification of the World Health Organization.
      • Mercadal L.
      • Montcel S.T.
      • Nochy D.
      • et al.
      Factors affecting outcome and prognosis in membranous lupus nephropathy.
      Kidney survival is only 50% in patients with MLN at 20 years,
      • Mercadal L.
      • Montcel S.T.
      • Nochy D.
      • et al.
      Factors affecting outcome and prognosis in membranous lupus nephropathy.
      but a recent study demonstrated kidney survival > 80% at 15 years.
      • Moroni G.
      • Quaglini S.
      • Gravellone L.
      • et al.
      Membranous nephropathy in systemic lupus erythematosus: long-term outcome and prognostic factors of 103 patients.
      Furthermore, there is a sizable incidence of thromboembolic events in patients with MLN.
      • Mercadal L.
      • Montcel S.T.
      • Nochy D.
      • et al.
      Factors affecting outcome and prognosis in membranous lupus nephropathy.
      • Pasquali S.
      • Banfi G.
      • Zucchelli A.
      • Moroni G.
      • Ponticelli C.
      • Zucchelli P.
      Lupus membranous nephropathy: long-term outcome.
      Thrombotic events are associated with antiphospholipid antibodies
      • Pasquali S.
      • Banfi G.
      • Zucchelli A.
      • Moroni G.
      • Ponticelli C.
      • Zucchelli P.
      Lupus membranous nephropathy: long-term outcome.
      and nephrotic syndrome.
      • Mercadal L.
      • Montcel S.T.
      • Nochy D.
      • et al.
      Factors affecting outcome and prognosis in membranous lupus nephropathy.
      High-dose alternate-day corticosteroid has been used widely as the first-line agent. However, this treatment regimen was derived from studies of idiopathic membranous nephropathy and there is little evidence that it works.
      No authors listed. A controlled study of short-term prednisone treatment in adults with membranous nephropathy.
      Still, that does not mean that daily corticosteroid therapy is not effective. A small (42-patient) randomized controlled trial compared adjunctive immunosuppressive drugs with prednisone alone.
      • Austin III, H.A.
      • Illei G.G.
      • Braun M.J.
      • Balow J.E.
      Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy.
      Adjunctive regimens included either cyclosporine for 11 months or alternate-month IV cyclophosphamide for 6 doses; the control group received alternate-day prednisone alone. The study showed that regimens containing cyclosporine or IV cyclophosphamide were each more effective than alternate-day prednisone alone in inducing remission of proteinuria in patients with MLN. At 1 year, the cumulative probability of remission of proteinuria was 27% with prednisone (4 of 15 patients), 60% with IV cyclophosphamide (9 of 15 patients), and 83% with cyclosporine (10 of 12 patients). Eight of the 10 patients who did not respond to prednisone or cyclosporine or who experienced a relapse after cyclosporine therapy was stopped subsequently achieved remission when treated with IV cyclophosphamide.
      It is well known that the antiproteinuric effect of calcineurin inhibitors tends to dissipate when the calcineurin-inhibitor treatment is stopped. In the aforementioned study, the agents were given for 11 months. Therefore, it is not surprising that there were relapses at the 1-year mark in the group receiving cyclosporine. Furthermore, although it is widely recognized that corticosteroids alone were not effective in this study, the steroid regimen was alternate day. We have observed many patients with membranous lupus enter remission on daily modest (0.5-mg/kg) doses of corticosteroid, obviating the need for more toxic therapy.
      A recent pooled analysis of 2 large, multicenter, randomized, controlled trials in pure class V MLN compared MMF versus IV cyclophosphamide for 24 weeks as induction therapy.
      • Radhakrishnan J.
      • Moutzouris D.A.
      • Ginzler E.M.
      • Solomons N.
      • Siempos II,
      • Appel G.B.
      Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis.
      Both groups received high-dose daily prednisone. Patients in both groups showed significant improvement in urinary protein excretion and stabilization of serum creatinine levels. Based on this finding, it was concluded that MMF was as effective as IV cyclophosphamide to induce remission in patients with class V MLN. However, it is conceivable that the remissions were obtained because of the sizable dose of corticosteroid, negating an effect of a second agent. The authors concluded that one second agent was as effective as the other, but it may be the case that the corticosteroid regimen was solely responsible for the remission. However, meta-analysis of 24 studies of class V lupus nephritis and nephrotic-range proteinuria showed that the addition of an immunosuppressive agent to prednisone resulted in a significantly higher complete or partial response rate than prednisone alone. However, there was no statistically significant difference in response rates among azathioprine, MMF, cyclophosphamide, or cyclosporine.
      • Swan J.T.
      • Riche D.M.
      • Riche K.D.
      • Majithia V.
      Systematic review and meta-analysis of immunosuppressant therapy clinical trials in membranous lupus nephritis.
      Class I and II lupus nephritis have minor abnormalities and excellent kidney outcomes and should not by themselves be an indication for immunosuppressive treatment. Similarly, “burnt-out” class IV lupus nephritis should be managed as in any patient with CKD, focusing on blood pressure control and other measures to delay progression.

      6. Missing nonadherence to therapy as a cause of treatment failure

      A common concern in the medical field is whether patients adhere to the regimen of care recommended by the physician and the extent of their persistence over time. According to research, the highest estimate is that 50% of individuals with chronic disease comply with the recommendations of their physicians, irrespective of disease, treatment, or age.
      • Dunbar-Jacob J.
      • Erlen J.A.
      • Schlenk E.A.
      • Ryan C.M.
      • Sereika S.M.
      • Doswell W.M.
      Adherence in chronic disease.
      Adherence and persistence are low, even for patients who have diseases that carry a high or moderate risk of death.
      • Caro J.J.
      • Salas M.
      • Speckman J.L.
      • Raggio G.
      • Jackson J.D.
      Persistence with treatment for hypertension in actual practice.
      • Turner B.J.
      • Newschaffer C.J.
      • Zhang D.
      • Cosler L.
      • Hauck W.W.
      Antiretroviral use and pharmacy-based measurement of adherence in postpartum HIV-infected women.
      • Viller F.
      • Guillemin F.
      • Briancon S.
      • Moum T.
      • Suurmeijer T.
      • van den Heuvel W.
      Compliance with drug therapy in rheumatoid arthritis. A longitudinal European study.
      Similarly, in SLE, nonadherence has been a critical issue, especially when patients are exposed to medications such as corticosteroids that lead to cosmetic side effects. Nonadherence should be strongly explored before escalating therapy in patients when they are not responding to treatment. Suspicion should arise when patients do not develop visible side effects from steroids, such as cushingoid features, acne, and weight gain, or cannot immediately state how many pills they are taking every day. (As an example, if a patient is taking 40 mg of prednisone every day, he or she is counting out 8 tablets of 5 mg and therefore should be able to immediately recall how many prednisone tablets are taken). With the start of corticosteroid therapy, there is almost always a gratifying improvement in hemoglobin level and lupus-related serologic test results, much before improvements in urinary indexes. If there is no change in hemoglobin level early or in double-stranded DNA titers and complement levels within 3-4 months, nonadherence should be considered. The otherwise excellent KDIGO guidelines discuss switching therapies for “treatment failure” without addressing the possibility of nonadherence as the cause.
      Kidney Disease
      Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis.

      7. Not reducing or minimizing immunosuppressive exposure in patients with advanced kidney disease

      In a patient with stage 4 or 5 CKD secondary to lupus nephritis, a renal-limited flare might not warrant another course of aggressive immunosuppressive therapy. There will be significant scarring in the kidney and the patient will have very little or no benefit from another course of aggressive therapy. The intensity of immunotherapy should be guided by extrarenal manifestations.
      For patients who are on dialysis therapy, the immunosuppressive dose should be minimized, if possible, because they are at a high risk of infection. Immunosuppression is a risk factor for peritonitis in peritoneal dialysis patients
      • Golper T.A.
      • Brier M.E.
      • Bunke M.
      • et al.
      Risk factors for peritonitis in long-term peritoneal dialysis: the Network 9 peritonitis and catheter survival studies. Academic Subcommittee of the Steering Committee of the Network 9 Peritonitis and Catheter Survival Studies.
      and also in hemodialysis patients dialyzing through tunneled cuffed catheters.
      • Keane W.F.
      • Shapiro F.L.
      • Raij L.
      Incidence and type of infections occurring in 445 chronic hemodialysis patients.
      Although most patients with lupus have diminished clinical and serologic activity after starting dialysis therapy, some of them continue to have persistent disease activity.
      • Krane N.K.
      • Burjak K.
      • Archie M.
      • O'Donovan R.
      Persistent lupus activity in end-stage renal disease.
      • Mojcik C.F.
      • Klippel J.H.
      End-stage renal disease and systemic lupus erythematosus.
      Most flares in these patients are extrarenal. Immunosuppressive dose should be altered based on the clinical situation and, when possible, minimized.
      We strongly recommend that pulse cyclophosphamide therapy be avoided in patients with CKD because of the unpredictable risk of severe leukopenia, even with reduced dose.

      8. Forgetting to monitor side effects of immunosuppression and to use prophylaxis

      All the immunosuppressants used in managing lupus nephritis have side effects that need close monitoring and use of appropriate prophylaxis. Unfortunately, some of this recommended monitoring gets overlooked and patients end up with significant preventable health care problems.
      The following are the commonly missed side effects.

      Osteoporosis

      The prevalence of osteoporosis has been reported to range from 4%-24% in patients with SLE and 10%-20% in premenopausal patients. The reported prevalence of vertebral fractures in patients with SLE has been reported to be as low as 7.6% and as high as 37%.

      Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis. 2010 2010;69(7):1269-1274.

      The risk of fracture depends on the corticosteroid dosage and duration. The use of prednisone for 3 months or more with up to just 2.5 mg/d leads to a significantly increased fracture relative risk (RR) of 1.55. Similarly, significantly increased fracture risks for a dosage of 2.5-7.5 mg/d (RR, 2.59) and dosages > 7.5 mg/d (RR, 5.18) have been reported.
      • Van Staa T.P.
      • Laan R.F.
      • Barton I.P.
      • Cohen S.
      • Reid D.M.
      • Cooper C.
      Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy.
      One study reported that there was a 7-fold increase in hip fractures and 17-fold increase in vertebral fractures when 10 mg/d of prednisone was used for more than 90 days.
      • Kanis J.A.
      • Johansson H.
      • Oden A.
      • et al.
      A meta-analysis of prior corticosteroid use and fracture risk.
      Spinal bone mineral density is a significant predictor of new fractures in patients on corticosteroid treatment. Thus, for each reduction point in T score, the RR of fracture is 1.85 (95% CI, 1.06-3.21).
      • Van Staa T.P.
      • Laan R.F.
      • Barton I.P.
      • Cohen S.
      • Reid D.M.
      • Cooper C.
      Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy.
      New American College of Rheumatology recommendations have suggested performing densitometry in any patient who will use corticosteroids (prevention) and in patients already on corticosteroid (treatment) regardless of the dose and duration of corticosteroid use.
      • Grossman J.M.
      • Gordon R.
      • Ranganath V.K.
      • et al.
      American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.
      There currently are no guidelines for the frequency of follow-up dual-energy x-ray absorptiometry.
      When supplemented with vitamin D, calcium has been shown to significantly reduce the risk of vertebral fracture with no effect on nonvertebral fractures.
      • Ringe J.D.
      • Dorst A.
      • Faber H.
      • Schacht E.
      • Rahlfs V.W.
      Superiority of alfacalcidol over plain vitamin D in the treatment of glucocorticoid-induced osteoporosis.
      Although not currently in the American College of Rheumatology guidelines, use of bisphosphonates has been widely advocated in the first 1-2 years of prolonged corticosteroid therapy. However, after 2 years, there is a low-bone-turnover state and bisphosphonates are not likely to be helpful and may be harmful.
      • Teitelbaum S.L.
      • Seton M.P.
      • Saag K.G.
      Should bisphosphonates be used for long-term treatment of glucocorticoid-induced osteoporosis?.
      Relatively short-acting oral bisphosphonates such as alendronate and risedronate weekly are the drugs of choice for women of child-bearing age. However, due to lack of sufficient data, the safety of this drug is questionable in this age group. Long-acting IV medications, such as zolindronate, can be used in men or postmenopausal women.
      Patients with lupus using corticosteroids should have regular bone mineral density scans obtained and should be supplemented routinely with calcium and vitamin D (1,000 IU/d). Bisphosphonates should be added when appropriate. Other agents, such as teriparatide (recombinant parathyroid hormone), should be considered when bisphosphonates fail or are contraindicated.
      Patients with lupus with active disease may be at particularly high risk for osteoporosis because active SLE and corticosteroid therapy are important factors leading to the high incidence of osteoporosis and fractures in patients with SLE.

      Ocular toxicity of antimalarial agents

      Ocular side effects of antimalarial agents include keratopathy, ciliary body involvement, lens opacities, and retinopathy.
      • Bernstein H.N.
      Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy.
      There are a number of factors that may contribute to the development of antimalarial retinopathy, including daily and cumulative dosage, length of treatment, whether there also is kidney or liver disease, patient age, and concomitant retinal disease. Daily dosage and cumulative dose are the most important factors. The recommended dosage is <6.5 mg/kg/d, and this is in patients with normal kidney function.
      • Marmor M.F.
      • Carr R.E.
      • Easterbrook M.
      • Farjo A.A.
      • Mieler W.F.
      Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology.
      It has been suggested that a cumulative dosage > 100 g carries a significant risk of retinopathy.
      • Spalton D.J.
      Retinopathy and antimalarial drugs—the British experience.
      Patients using these medications should have an annual retinal examination. The only treatment for ocular toxicity is cessation of treatment with the drug.

      Pneumocystis jiroveci pneumonia prophylaxis

      Patients who are on high-dose steroid therapy are at higher risk of developing P jiroveci pneumonia (pneumocystis pneumonia) because of depletion of CD4+ T cells.
      • Godeau B.
      • Coutant-Perronne V.
      • Le Thi Huong D.
      • et al.
      Pneumocystis carinii pneumonia in the course of connective tissue disease: report of 34 cases.
      Human immunodeficiency virus (HIV)-positive patients with pneumocystis pneumonia (86%-92%) have better survival rates compared with HIV-negative patients with pneumocystis pneumonia with various underlying conditions (51%-80%).
      • Catherinot E.
      • Lanternier F.
      • Bougnoux M.E.
      • Lecuit M.
      • Couderc L.J.
      • Lortholary O.
      Pneumocystis jirovecii pneumonia.
      HIV-negative patients with pneumocystis pneumonia appear to rapidly develop fulminant pneumonia with severe oxygenation impairment, diffuse alveolar damage, and respiratory failure.
      Prophylaxis for pneumocystis pneumonia has been shown to decrease mortality and morbidity significantly. HIV-infected patients and kidney transplant recipients have clear guidelines about when to start prophylaxis and for how long. Unfortunately, there are no clear guidelines for pneumocystis pneumonia prophylaxis in patients with SLE on immunosuppression therapy. Hence, this easily can be missed, putting these patients at risk of developing pneumocystis pneumonia. We recommend following local health care guidelines with regard to the prophylactic agent of choice.

      9. Performing a biopsy on the kidney, especially in a high-risk patient, when it will not affect therapy

      Diagnosis of lupus nephritis based on only clinical features is not very reliable, emphasizing the need for kidney biopsy. Histopathologic findings in lupus nephritis can be very diverse and kidney biopsy not only determines the diagnosis and prognosis, but guides the management. Kidney biopsy also helps rule out other kidney disease that may affect patients of similar age and sex. These include renal thrombotic microangiopathy, acute tubular necrosis, drug-induced interstitial nephritis, focal segmental glomerulosclerosis, and immunoglobulin A kidney disease.
      However, kidney biopsy has its own risk and bleeding remains of foremost concern following a kidney biopsy. Major complications, those requiring blood transfusion or invasive intervention, have been reported in 0%-6.4% of biopsies. Low hematocrit and high creatinine values are predictors of complications. Patients with SLE have additional risks of bleeding due to platelet dysfunction, hypertension, and decrease in kidney function, although this has not been proved in studies. Hence, biopsy should be deferred if it is not going to change the present management and also in situations in which the risk of bleeding is very high (eg, in patients with elevated serum creatinine levels or receiving anticoagulation). A common scenario is the patient with lupus, either at first presentation or with a major flare, presenting with hypertension, pancytopenia (including thrombocytopenia), elevated serum creatinine level, hematuria, and nephrotic-range proteinuria in the context of positive lupus serologic test results. Many clinicians feel compelled to perform a kidney biopsy, although the comorbid conditions may render the procedure high risk. It is obvious that the diagnosis is lupus nephritis and mandates aggressive immunosuppression (measurement of serum antiphospholipid antibody can help rule out renal thrombotic microangiopathy). The kidney biopsy therefore is not going to change the initial approach to therapy. Similarly, if the patient presents with some extrarenal manifestation that mandates aggressive immunotherapy, such as pulmonary hemorrhage, there is little to gain and a lot to risk by performing a kidney biopsy when the patient is going to receive aggressive therapy in any case.
      We do not see the value of repeat kidney biopsy in patients with no significant change in clinical parameters. A study by Arends et al
      • Arends S.
      • Grootscholten C.
      • Derksen R.H.
      • et al.
      Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis.
      confirmed that a protocol repeat kidney biopsy does not offer much additional information regarding long-term kidney outcome after immunosuppressive treatment in patients with proliferative lupus nephritis. Not surprisingly, a decrease in activity index from baseline to biopsy at 2 years was associated inversely with time to occurrence of renal relapse after 2 years, but the chronicity index and activity index from repeat kidney biopsies could not predict long-term renal outcome. Therefore, repeat biopsy added very little to clinical observation.

      10. Neglecting to address pregnancy

      Approximately 90% of patients with lupus are women. When given the diagnosis of lupus, many are concerned about becoming pregnant. Advising these patients about pregnancy and managing them during pregnancy can be challenging. It is important to involve a high-risk obstetrician and a rheumatologist who have experience in managing pregnant patients with lupus.
      Many patients with active lupus have no idea that pregnancy at this time is fraught with risk for both mother and fetus. It is incumbent upon the physicians caring for the patient to counsel strongly against conception during a lupus flare or persistently active disease. Relatedly, practical advice about contraception also should be offered. Patients should be screened for the presence of lupus anticoagulant prior to the use of estrogen-containing birth control pills because this combination is associated with a significant risk of thrombosis.
      Many patients with lupus are able to have a successful pregnancy. However, patients with lupus are more likely to develop pregnancy complications compared to the general population. The disease needs to be in remission before the patient becomes pregnant. A general recommendation is to avoid pregnancy until at least 6 months after the lupus disease activity, especially kidney disease, has been completely brought under control.
      • Petri M.
      • Howard D.
      • Repke J.
      Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience.
      Appropriate contraceptive advice should be given to patients when their disease is not under control and while they are receiving teratogenic medications such as MMF. A switch from MMF to azathioprine should be made well in advance, and then the go-ahead for pregnancy should be given only if the patient still continues to be in remission after the switch. Patients also should come off treatment with medications that are not safe in pregnancy, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Corticosteroids, hydroxychloroquine, azathioprine, and cyclosporine are acceptably safe to use during pregnancy, and their use must be weighed against the risk of relapse during the pregnancy. It is recommended that hydroxychloroquine treatment be continued during pregnancy because there is a risk of flare upon its cessation.
      Patients also need be counseled about the potential risk of stillbirth, fetal loss, intrauterine growth restriction, and prematurity. Women of child-bearing age with lupus also should be screened for antiphospholipid antibody because it is associated with fetal loss. We suggest referring these patients to experts who manage high-risk pregnant patients with SLE.

      Acknowledgements

      Support: None.
      Financial Disclosure: Dr Silverman is a consultant for Eli Lilly and Glaxo Smith Kline. The remaining authors declare that they have no relevant financial interests.

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