When to Stop Immunosuppression in LupusDAVID R. KARP, MD, PHD

PROFESSOR AND CHIEF, RHEUMATIC DISEASES

UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER

Competing Interests Research Grants

◦ GlaxoSmithKline◦ Bristol Meyers Squibb◦ National Institutes of Health

Drug

DamageActivity

Dise

ase

Activ

ity

Low Disease Activity?

Remission?Time

Treat to Target in Lupus

How Common is Remission?

2307 patients in Hopkins Lupus Cohort from 1987 to 2014

◦ Remission defined by clinical SLEDAI = 0; Provider Global

Assessment <0.5 (0-3), ± negative serology; ± prednisone

and immunosuppression

The BEST case – lack of clinical disease activity with treatment

allowed – reached remission in a median of 1.8 YEARS (0.8-

3.0)

Wilhelm, T. R., et al. (2016). Ann Rheum Dis.

Pro

babi

lity

of N

OT

bein

g in

rem

issi

on

Days of follow up

42% of patients with low disease activity

3% of patients with high disease activity

Wilhelm, T. R., et al. (2016). Ann Rheum Dis.

Length of Remission is Short

3 mo 8 mo 1 yr 2 yr 5 yr 10 yr05

101520253035404550

43.8

24.3

13.2

5.61.2 0.4

Perc

ent o

f pati

ents

in re

-m

issio

n

Wilhelm, T. R., et al. (2016). Ann Rheum Dis.

Never“HYDROXYCHLOROQUINE IS LUPUS HEALTH INSURANCE” – MICHELLE PETRI, MD

Hydroxychloroquine in SLE Concentrated in endosomes where it raises pH and inhibits TLR7/9 function

Shuts of IFN-a production by pDCs

Improves plasma glucose Improves lipid profile Anti-thrombotic

Wallace, DJ, et al, Nat Reviews Rheum, online ahead of print, 17 July 2012

Clinical Effects of Hydroxychloroquine in Systemic Lupus Erythematosus

Reduced Flares Increased Survival

Less Organ Damage Delayed Disease OnsetNEJM (1991), 324:150-154; Arth & Rheum (2005) 52:1473-1480Arth & Rheum (2010) 62:855-862; Lupus (2007) 16:401-409

Why Stop Anti-Malarials? HCQ rarely causes adverse effects:

◦ Blurry vision◦ Muscle weakness◦ Cardiomyopathy

HCQ is safe in pregnancy What about retinopathy?

◦ 2,361 patients in a 3.4 million HMO◦ 2% risk at 10 years; 20% at 20 years◦ Related to dose and tamoxifen use

Melles, R. B., et al. (2014). JAMA Ophthalmol 132(12): 1453-1460.

Current American Academy of Ophthalmology Recommendations

Limit HCQ dose to ≤ 5 mg/kg of real body weight (and CQ dose to ≤ 2.3 mg/kg)

Suggested screening tests:◦ Dilated fundus exam (rule out existing macular disease)◦ Automated visual fields (based on ethnicity)◦ Spectral Domain Ocular Coherence Tomography◦ (multifocal electroretinogram and fundus

autofluorescence)◦ NOT Amsler grid or color vision testing

Screen at baseline, 5 years, and then annually

Marmor, M. F., et al. (2016). Ophthalmology 123(6): 1386-1394.

AlwaysTHE MOST TOXIC DRUG WE PRESCRIBE IS THE ONE WE USE THE MOST!

Prednisone: The Major Cause of Organ Damage

2,199 patients followed in the Hopkins Lupus Cohort since 1987

SLICC-ACR Damage Index (SDI)

◦ 42 items track irreversible damage in 12 domains

SELENA-SLEDAI used to measure activity

Cox proportional hazard ratios calculated between mean prior

prednisone dose and new organ damage – cataracts, osteoporotic

fractures, cardiovascular damage, and renal damage.

Al Sawah, S., et al. (2015). Lupus Sci Med 2(1): e000066.

Prednisone and Organ Damage

Rate of cardiovascular disease 2.4 fold greater

in people taking 10-19 mg/d of prednisone and

5 fold greater in those taking 20 mg or more

Al Sawah, S., et al. (2015). Lupus Sci Med 2(1): e000066.Magder, L. S., et al. (2012). Am J Epidemiol 176(8): 708-719.

Disease Activity and Organ Damage

Al Sawah, S., et al. (2015). Lupus Sci Med 2(1): e000066.

Prednisone Dose has a Greater Effect on Damage than Lupus Activity

SLICC Multi-National Inception Cohort of 1,722 newly diagnosed SLE patients:

Corticosteroid users 64% more likely to

have any damage; 43% more likely worsen

vs. 17% and 10% of patients with higher

disease activity.

Al Sawah, S., et al. (2015). Lupus Sci Med 2(1): e000066.Bruce, I. N., et al. (2015). Ann Rheum Dis 74(9): 1706-1713.

SometimesCAN DRUGS LIKE AZATHIOPRINE OR MYCOPHENOLATE BE STOPPED?

Aspreva Lupus Management Study

MMF 1.5 g BID

IVC 0.5-1 g/m2 monthly

Response or Remission

MMF 1 g BID

AZA 2mg/kg/day

Exit study

YESRe-randomization

NO

24-wk induction phase 36-mo maintenance phase

370 pts 227 pts

Appel, G. B., et al. (2009). J Am Soc Nephrol 20(5): 1103-1112.Dooley, M. A., et al. (2011). N Engl J Med 365(20): 1886-1895.

ALMS induction: response to treatment

African-American

Appel, G. B., et al. (2009). J Am Soc Nephrol 20(5): 1103-1112.

ALMS Maintenance: Time to renal flare

Dooley, M. A., et al. (2011). N Engl J Med 365(20): 1886-1895.

Stopping Mycophenolate 44 patients from 2000-2010 Class III and IV LN Induction with either IV CYC or MMF Maintained on 2-3 g/d of MMF after 6 months MMF tapered per clinician discretion

◦ 2 gm/d 1.5 g/d 1 gm/d 0.5 gm/d➜ ➜ ➜◦ Patients in renal remission: reduction in proteinuria,

absence of hematuria/casts, improvement/stabilization of GFR; CR = no proteinuria & normal GFR

18 patients tapered; 26 stayed on original dose

Laskari, K., et al. (2011). J Rheumatol 38(7): 1304-1308.

Risk of Renal Flare After MMF ReductionVariable

Hazard Ratio 95% CI P Value

Tapering MMF 3.37 1.18-9.69 0.0240.5 g/d MMF increase 0.56 0.36-0.88 0.011< 18 mo from remission to reduction 6.85 2.21-21.22 0.001

< 18 mo from CR to reduction 6.29 1.52-26.07 0.011

Laskari, K., et al. (2011). J Rheumatol 38(7): 1304-1308.

73 of 161 with

LN

21 of 73 Flared

52/73 stopped therapy

32/73: No Flare

20/73: ≥ 1 Flare

Longer Treatment (98 vs 31 months)

Longer Complete Remission (53 vs 12 months)

More use of anti-malarials (52% vs 10%)Moroni, G., et al. (2013). Clin Exp Rheumatol 31(4 Suppl 78): S75-81.

Forced reduction in mycophenolate, azathioprine, and cyclosporine after 12 months of remission – 32% success initially but relapse in 12% over median follow up of 172 months

Conclusions High quality studies of stopping immunosuppression in lupus are lacking

Currently, the data support:

Never stopping hydroxychloroquine dosed according to weight

Always stopping prednisone if possible

Sometimes stopping azathioprine and mycophenolate after at least 18 months of remission.