CLINICAL TRIALS IN LN

02 January 2014 13:54

NIH TRIAL: compared three regimens in 65 patients with a mean serum creatinine of approximately 1.6 to 2.0 mg/dl. All received oral prednisolone beginning at a dose of 0.5 mg/kg per day and then tapering over a period of months to alternate-day maintenance therapy for control of extrarenal symptoms (minimum dose 0.25 mg/kg every other day). Parameters at 3 yrs Regimen A : IV CYC Monthly x 6 20 pts Regimen B: A + 3 monthly Iv CYC for total 24 months 20 pts Low 25% Low Regimen C: Iv methyl prednisolone 1 g/mt sq monthly X 6 dose without CYC 25 pts High 48%

Doubling of sr creatinine relpase

Low 25 % high

An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations.

patients with relatively mild disease (serum creatinine 1.3 mg/dL [115 micromol/L] and/or protein excretion 1.0 g/day) had a favorable prognosis.

2nd NIH trial : 82 pts with mainly Diffuse proliferative lupus nephritis. Mean baseline creatinine 1.1 mg/dl All received oral prednisolone as above, and were randomised to 3 groups PARAMETERS REGIMEN A STUDIED Monthly IV Median FU 5 yrs MP 1 g/m sq X 12 months REMISSION : Non censored censored Relpase Adverse events Osteonecrosis Infection Amenorrhea osteoporosis Ovarian failure 29% 26 % 36% = REGIMEN B REGIMEN C IV CYC .5-1 G/M sq X 6 MP + IV CYC mth--> 3 monthly IV CYC = 24 mths 62% 48% 7 High = High 25% High High High 52% 85 % 61% 0

less

High 52%

REMISSION defined as : <10 red blood cells per high power field, no cellular casts, and proteinuria <1 g/day TACROLIMUS in LN: 5 studies. A: comparision to IV CYC --> Chinese study -- 81 pts TAC + Steroids vs high dose IV CYC + Steroids ==> rate of CR, cumulative remission and adverse effect. 2nd trial : 60 pts: TAC+steroid vs MMF+ steroids vs high dose IV CYC + steroids. Similar CR and cumulative remission rate. Rapid improvement in Sr albumin and proteinuria in above trial with TAC. STUDIES MAINLY IN CHINESE. Efficacy in more diverse cohorts not known. MULTITARGET THERAPY : TAC+ MMF Bao H, Liu ZH, Xie HL, et al. Successful treatment of class V IV lupus nephritis with multitarget therapy. J Am Soc Nephrol 2008; 19:20012010. Cortes-Hernandez J, Torres-Salido MT, Medrano AS, et al. Long-term outcomes mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant 2010; 25:3939 3948.

Lanata CM, Mahmood T, Fine DM, et al. Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis. Lupus 2010; 19:935940.

EUROLUPUS NEOHRITIS TRIAL : ELNT 2002

Houssiau FA, Vasconcelos C, D'Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus highdose intravenous cyclophosphamide. Arthritis Rheum 2002; 46:21212131

90 pts enrolled. Multi centre prospective study == 19 european centres.. Sept 1996 to sept 2000. INCLUSION CRITERIA: >14 yrs age. LN class 3, 4, 5c,5d : WHO Proteinuria > 500 mg/d EXCLUSION CRITERIA : Previous Rx with CYC or AZA <1yr On > 15 mg/ d prednisolone. <1 month renal TMA pre existing CRF, pregnancy Previous malignancy: except Skin and Cervical IN DM, previous adverse events to immunosupression Anticipated poor compliance to Rx all patients received 3 daily pulses of 750 mg of IV methylprednisolone, followed by oral glucocorticoid therapy at an initial dosage of 0.5 mg/kg/day of prednisolone (or equivalent) for 4 weeks. A dosage of 1 mg/kg/day was allowed in critically ill patients (those with renal impairment or severe extrarenal disease). After 4 weeks, glucocorticoid dosages were tapered by 2.5 mg of prednisolone (or equivalent) every 2 weeks. Low-dose glucocorticoid therapy (5 7.5 mg of prednisolone per day) was maintained at least until month 30 after inclusion.

Aim minimize SE of CYC. Randomized pts to low dose CYC (= 500 mg CYC biweekly X 6 months) vs NIH protocol. All pts received prednisolone and AZA for maintainance. 2 wk after last cyc dose. Dose 2 mg/kg/d NIH protocol : 6 motnhly pulse + 2 quarterly Dose adjusted to maintain nadir TLC Initial dose 0.5 g /m2, then increase by 250 mg to achieve nadir TLC MAX 1500 mg/ pulse Mesna : based on Rx physician decision. Benign renal flares (i.e., those not meeting the definition of severe flares [see below]) were treated with low-dose glucocorticoids (15 mg of prednisolone per day) for a 2-week period, hydroxychloroquine (6 mg/kg/day), and/or nonsteroidal antiinflammatory drugs (NSAIDs). A severe renal flare was defined as 1 of the following 3 features: renal impairment, increase in proteinuria, or severe systemic disease. Renal impairment was defined as an SLE-related increase of >33% in the serum creatinine level within a 1-month period.

An increase in proteinuria was defined as the recurrence or appearance of nephrotic syndrome (albuminemia <3.5 gm/dl and proteinuria 3 gm in a 24-hour sample). In patients with low-grade proteinuria at baseline (0.5 gm but <1 gm in 24 hours), a 3-fold increase in 24-hour urinary protein levels within a 3-month period was also considered a severe flare, provided that it was accompanied by microscopic hematuria and a >33% reduction of serum C3 levels within a 3-month period. Severe systemic disease was defined as any of the following events: central nervous system disease, thrombocytopenia (<100,000 platelets/l), hemolytic anemia, lupus pneumonitis, lupus myocarditis, extensive skin vasculitis, or serositis not responding to low-dose glucocorticoid and/or NSAID treatment. A severe flare was always treated by an increase in the glucocorticoid dosage (0.51.0 mg/kg/day of prednisolone) for 1 month, and then promptly tapered to the patient's preflare dosage. Up to 2 IV pulses of methylprednisolone (750 mg) were allowed within a 1-week period. Hypertension (diastolic blood pressure 90 mm Hg) was treated initially with angiotensin-converting enzyme inhibitors, unless contraindicated. Patients were evaluated monthly within the first year after study inclusion and quarterly thereafter. Median followup was 41 months (range 862 months). In addition to the primary end point, 3 secondary end points were examined. The primary end point was treatment failure, which was defined as 1 of the following 3 features: absence of a primary response after 6 months of therapy, occurrence of a glucocorticoid-resistant flare, or a doubling of the serum creatinine leve

The 3 secondary end points were as follows: 1) the kinetics of the response to therapy in the first year, based on serial measurements of serum creatinine, serum albumin, 24-hour urinary protein, and serum C3 levels, as well as the ECLAM score; 2) the rate of renal remission, defined as <10 red blood cells/high-power field and a 24-hour urinary protein level <1 gm, in the absence of a doubling of the serum creatinine level; and 3 the number of severe flares, as defined above.

FU 41 months Rx failure NO primary response Steroid resistant flair Cr X2 Cumulative dose

Low dose 44 16% 2 2 3

NIH protocol 46 PTS 20% 4 2 3

3g

8.5 g

Remission RENAL FLARE Adverse events

30 (71%) 12 (27%) 11 during AZA Rx =

22 ( 54%) 13 (29%) 7 during IV CYC Rx = but numerically higher infections 10 pts ( 17 episodes) 0

Infections ( SEVERE) Death

5 pts ( 7 episodes) 2 A : 14 yr wih SKI + nephrotic proteinuria + CHF. 28 th day of Rx : MOF B: 51 yr dropped o study @ 121 st week : Breast cancer--> sudden death week 194 : cause ?? 1 (wk 208)

ESRD Doubling of serum creatinine : Gonadal toxicity

2 (wk : 104 & 193)

LONG TERM =10 yr FU of EUROLUPUS Houssiau FA, Vasconcelos C, D'Cruz D, et al. The 10-year followup data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis 2010; 69: 6164 Limitations of the ELNT study: Mainly done in Caucasian population, Majority ( = 78% ) of patients had preserved renal function (creatinine <1.3 mg/dl), the small number of patients treated, and that care was delivered at specialized referral centers. Cyclosporine in LN : 3 RCTs. 1st : Fu LW, Yang LY, Chen WP, et al. Clinical efficacy of cyclosporin A neoral in the treatment of paediatric lupus nephritis with heavy proteinuria. Br J Rheumatol 1998; 37:217221. 40 children with SR proliferative LN. Randomised to receive cyclosporine (5 mg/kg/day) or oral cyclophosphamide (2 mg/kg/day) and prednisone (2 mg/kg/day). At 1 year, both groups achieved similar reductions in proteinuria 2nd : NIH in MN
Austin HA 3rd, Illei GG, Braun MJ, et al. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009; 20:901 911.

42 pts : 3 groups CsA + Pred 11 mth IV cyc 6 dose alternate month + Pred Alernate day prednisolone alone

1 yr cumulative remission rate

83% highest Quickest remission

60% Few relapse

27 % lowest

3rd : 2010
Zavada J, Pesickova S, Rysava R, et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus 2010; 19:12811289.

Jan 2002 - Dec 2006. Czech R + Slovakia

40 pts with proliferative GN: steroids + one of

CYC IV 10 mg/kg 8 boluses in 9 months Followed by oral CYC 10 mg/d 6 8 weeks interval CR in proteinuria Stable / improved creatinine 38% More 86%

Csa induction 9 months 4-5 mg/kg/d in divided dose Maintainence: gradual taper to 3.751.25 mg.kg.d 9 month More 69% 47% Increase BP, decrase GFr

RITUXIMAB IN LN: Off label use. Bhat P, Radhakrishnan J. B lymphocytes and lupus nephritis: new insights into pathogenesis and targeted therapies. Kidney Int 2008; 73:261268.==> role of B lymphocytes in LN. STUDY OF RITUXIMAB + IV CYC + prednisolone in refractory LN == rituximab + steroid. LUNAR. The Lupus Nephritis Assessment With Rituximab Study Trial ==> largest . 144 pts. OBJECTIVE : To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids.

MMF+steroid + Rituximab or placebo. Primary end point : renal response at 52 weeks. Rituximab given at dose of 1 g on day 1, 15, 168 and 182 MMF : 500 mg TDS --> by 4 week 3 g/d.--> continued for 52 weeks. MP IV 1000 mg D1 7 D3 Oral prednisolone : 0.75 mg/kg max 60 mg for 16 days, tapered to < 10 mg/d by 16 week. Any pt requiring rescue therapy --> labelled as non responder and withdrawn.

Overall response 57 vs 46%.

The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti doublestranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria.

Adverse events were equal, but RTX associated with more neutropenia, leucopenia and hypotension. LIMITAION: Not included refractory cases. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis : NDT 2012 A systematic review of use of Rituximab in refractory LN.

Maintenance therapy trials: First RCT on MMF: Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350:971980. 59 pts. Induction with high dose IV CYC+ Prednisolone Maintainance with : either MMF or AZA or Quarterly IV CYC. Primary endpoint was death / CRF.

RESULT: MMF & AZA > to CYC MMF with few relapse. Lower infection with MMF & AZA. SO IV CYC mainatinence was discarded TRIALS comparing MMF with AZA: MAINTAIN NEPHRITIS TRIAL :
Houssiau FA, D'Cruz D, Sangle S, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010; 69:20832089. EUROPEAN POPULATION, july 2002 - march 2006, 105 pts INDUCTION WAS ELNT.

MAINTAINANCE with MMF OR AZA : The primary end point of the trial was time to renal fl are RESULT--> no difference in renal flare over 4 yr period in both group. Result Renal flare MMF 10 of 53 19% 8 2 AZA 13 of 52 25% 6 4 3

Nephrotic Increase creat Increase proteinuria ADVERSE EVENTS Cr X2 DEATH

3 2 (Infection; disease activity)

4 PTS --

Cytopenia more in AZA group. ==> MMF == AZA, non superior Limitation: Caucasian Small sample size Non Blind Maintainence Rx started prior to achievement of significant renql response.

ALMS MAINTAINENCE TRIAL: 227 pts. Induction X 6 mths : IV CYC or MMF. Those who had attained renal response were ncluded. 116 : MMf 2 g/d mainatainence 111 AZA 2 mg/kg/d maintainence. The primary efficacy end point was the time to treatment failure, which was defined as death, endstage renal disease, doubling of the serum creatinine level, renal flare, or rescue therapy for lupus nephritis.

Secondary assessments included the time to the individual components of treatment failure and adverse events.

3 yr follow up Mmf : less treatment failure, and longer time to relapse. Adverse events similar in both Serious adverse events more in AZA group. Withdrawal due to SE more in AZA group. ==> favor MMF as mainatinance RX of choice irrespective of induction Rx, race, sex, geography. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011; 365:1886 1895. ** The ALMS maintenance trial is the largest RCT conducted in the maintenance treatment of lupus nephritis, and the results favored MMF use over AZA.

RECOMMENDATION IN LUPUS NEPHRITIS :

1. Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012; 71:17711782. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012; 64:797 808.

2.

CNIs In maintain therapy: Cyclosporine has been explored in two RCTs as maintenance therapy. The first trial compared cyclosporine plus steroids to AZA plus steroids after 3 months of induction therapy with oral cyclophosphamide and steroids.[43] The SLE relapse rates were the same in both groups, there was no difference in renal function, and more patients in the cyclosporine group achieved continued undetectable proteinuria at 4 years of follow-up. The second study prescribed 9 months of induction therapy with cyclosporine or intravenous cyclophosphamide (see above), then maintenance therapy with cyclosporine or oral cyclophosphamide.[20]At 9 months of maintenance therapy (18 months total therapy), remission rates were similar, but more patients in the cyclosporine group had complete remission in proteinuria. Tacrolimus has been studied as maintenance therapy in one pilot study in Japanese patients[44] and one recent RCT in Chinese patients.[45] The RCT was an extension of the tacrolimus induction therapy RCT described above[25] and randomized patients who achieved complete or partial remission to maintenance therapy with low-dose steroids plus either tacrolimus or AZA. At 6 months, relapses occurred in 0 of 33 patients in the tacrolimus group and 2 of 30 (7%) patients in the AZA group, and leucopenia was more common in the AZA group. Familiarity with the long-term use of the CNIs in transplant patients makes their use as maintenance therapy in lupus nephritis an attractive option. However, the limited data and concern for nephrotoxicity with prolonged use prevent their designation as the first-line maintenance therapies in lupus nephritis MMF as induction : How & why was it used?

 1.
2.

Safety and efficacy in renal Tx pts. Animal studies

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 1589. Van Bruggen MC, Walgreen B, Rijke TP, et al. Attenuation of murine lupus nephritis by mycophenolate mofetil. J Am Soc Nephrol 1998; 9:1407 1415) Trials in china : Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000; 343:11561162. 44 pts , non inferiority.infections = Chan TM, Tse KC, Tang CS, et al. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005; 16:10761084

3.

4.

1st RCT comparing MMF to CYC : 42 patients randomised to MMF or CYC: Both received steroids.

42 pts DOSE CR & PR Relapse Infections CKD/ESRD

MMF 2g/d X 6 mths 1g/d X 6 mths = =

CYC Oral 2.5 mg/kg/d X 6 mths AZA 1.5 mg/kg/d X 6 mths = = More, deaths seen only in this group

RCTs COMPARING MMF TO IV CYC. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005; 353:2219 2228.

a multicenter, open-label, noninferiority trial. DEC 1999 - OCT 2003

Exclusion criteria were creatinine clearance of less than 30 ml per minute, serum creatinine on repeated testing greater than 3.0 mg per deciliter (265.2 mol per liter), severe coexisting conditions precluding immunosuppressive therapy or conditions requiring intravenous antibiotic therapy, prior treatment with mycophenolate mofetil, treatment with intravenous cyclophosphamide within the past 12 months, monoclonal antibody therapy within the past 30 days, or pregnancy or lactation. MMF : Mycophenolate mofetil was initiated at a dose of 500 mg twice daily, and the dose was increased to 750 mg twice daily at week 2 and advanced weekly to a maximum dose of 1000 mg three times daily unless the white-cell count fell below 3000 per cubic millimeter. Iv cyc : NIH regimen, nadir TLC 2500 @ 10 days. Patients received prednisone at a dose of 1 mg per kilogram of body weight per day, with tapering by 10 to 20 percent at one-week or two-week intervals, on the basis of clinical improvement. Clinical deteriortion Rxed with increasing steroid.

140 pts included Oral MMF ( 3 g/d) vs IV CYC Black and hispanics represented ( race with severe disease) Primary endpoint CR @ 24 weeks . CR == defined as the return to within 10 percent of normal values of serum creatinine levels, proteinuria, and urine sediment. secondary endpoint PR. == defined as improvement of 50 percent in all abnormal renal measurements, without worsening (within 10 percent) of any measurement. Additional secondary end points included changes in renal function, complement components, antidouble-stranded DNA (dsDNA) antibody titers, and serum albumin levels. EARLY RESPONSE: defined as an improvement of 30 percent in at least two measures of renal function (serum creatinine, proteinuria, or urine sediment) if all three measures were abnormal at entry into the study, or an improvement of 30 percent in one measure if one or two others were abnormal, provided no measures that were normal at baseline became abnormal. RX FAILURE: a condition requiring higher doses of corticosteroids for disease control, failure to eet the criteria for an early response, or failure to reach complete or partial remission at 24 weeks.

@ 6months CR PR RELAPSE ON FU INFECTIONS GI SE Upper Lower Death

MMF 22.5% 29.6% =

IV CYC 5.8% 24.6% = MORE

= More. 0

= but required admission in 7 pts 2 a: cerebral bleed, only 1 doseiv cyc b: sepsis+active LN, 2 dose iv cyc

==> MMF noninferior even safer.

LIMITATIONS: Not blinded. IV CYC dose was adjusted based on GI SE, so less CR rate ?? Short duration Not studied the flare rate with MMF induction, and appropriate mainatainance regimen.

ALMS INDUCTION TRIAL : Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20:1103 1112. JASN Above studies were in CHINA & US. Hence the following study was done globally. Also 2 phase trial : Induction and maintenance

Randomised 370 pts. 88 centre, 20 countries. 12-75 yr age. July 2005 - oct 2006 enrollment period. Multinational MMF : 0.5 g BD= 1 wk; --> 1 g BD wk 2; --> 1.5 g BD wk 3 onwards. Those with SE, dose decreased to 2 g/d IV CYC : NIH protocol Both : Prednisolone oral 60 mg/d starting dose. Induction phase : till 24 weeks. Patients were withdrawn at week 12 when their serum creatinine was30% above baseline on two successive measurements separated by at least 4 wk or when they required other immunosuppressive treatment. Patients could be withdrawn if the MMF dosage fell below 2 g/d for 14 d or was stopped for 7 d. AIM : to see is MMF superior to IV CYC?

MMF Cumulative remission Outcomes @ 6mths Deaths 56% = 9 7 due to infection None due to SLE 68.5 61.4 13%

IV CYC 53% = 5 2 infection 2 SLE 61.7 66.7 7.2%

Infections GI SE Withdrawal due to SE

CONCLUSION: MMF no superiority over IV CYC. High risk population responded better with MMF. BLACK RACE, LATINS, hispanics: responded poorly to IV CYC. Complete remission rates were low for both treatments in comparison with other studies.

Persistent urine protein is common after 6mo of treatment for severe LN, regardless of treatment regimen, and usually decreases further with continued follow-up

So is Induction of 6 months enough?? IS MMF effective in : a: DPGN & MN : Radhakrishnan J, Moutzouris DA, Ginzler EM, et al. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int 2010; 77:152160. Karim MY, Pisoni CN, Ferro L, et al. Reduction of proteinuria with mycophenolate mofetil in predominantly membranous lupus nephropathy. Rheumatology (Oxford) 2005; 44:13171321. Spetie DN, Tang Y, Rovin BH, et al. Mycophenolate therapy of SLE membranous nephropathy. Kidney Int 2004; 66:24112415. b: crescentic LN : Tang Z, Yang G, Yu C, et al. Effects of mycophenolate mofetil for patients with crescentic lupus nephritis. c: black & hispanics : Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 2010; 49:128140. Mohan S, Radhakrishnan J. Geographical variation in the response of lupus nephritis to mycophenolate mofetil induction therapy. Clin Nephrol 2011; 75:233241. * This study analyzed the lupus nephritis outcomes for MMF vs. other induction therapies in the context of geographic factors, and found that MMF led to more complete remissions in patients outside of Asia ADJUNCTIVES IN LN Rx: HCQS : The Canadian Hydroxychloroquine Study Group demonstrated via a small randomized withdrawal trial that stable SLE patients who continued HCQ experienced less disease flares over a 24-week period compared with those who took placebo.[46] At 3 years of follow-up, there was a nonsignificant trend toward less renal flares (relative risk 0.26, 95% confidence interval 0.032.54, P = 0.25) with continuing HCQ. 6% pts retinopathy =--> therefore regular opthalmological examination must.

RAAS blockade : The Lupus in Minorities: Nature vs. Nurture study demonstrated an association between ACEI use and less development of lupus nephritis in those who did not have renal disease, and an improvement in proteinuria and decreased risk of disease activity in those with established lupus nephritis. Special Clinical Considerations Women with SLE are 58 times more likely to have coronary heart disease than those in the general population.[58,59] Although optimum cholesterol levels in lupus nephritis patients have not been

established, it is appropriate to use statins in lupus nephritis similarly to other causes of chronic kidney disease. Osteopenia and osteoporosis are common in SLE, perhaps linked to excess glucocorticoid use, and lead to a five-fold increased risk of symptomatic fracture in SLE patients compared with the general population.[60] Management of bone disease with calcium and vitamin D supplementation should be considered in all patients with lupus nephritis. Finally, approximately 30% of patients with SLE will also develop the antiphospholipid antibody syndrome (APLS) and are at risk for thromboembolic events, renal thrombotic microangiography, and catastrophic APLS.