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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.