THE BIG DILEMMAS IN LUPUS - When to stop immunosuppression in lupus - Dr David R Karp
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Transcript of THE BIG DILEMMAS IN LUPUS - When to stop immunosuppression in lupus - Dr David R Karp
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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
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Competing Interests Research Grants
◦ GlaxoSmithKline◦ Bristol Meyers Squibb◦ National Institutes of Health
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Drug
DamageActivity
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Dise
ase
Activ
ity
Low Disease Activity?
Remission?Time
Treat to Target in Lupus
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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.
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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.
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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.
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Never“HYDROXYCHLOROQUINE IS LUPUS HEALTH INSURANCE” – MICHELLE PETRI, MD
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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
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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
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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.
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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.
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AlwaysTHE MOST TOXIC DRUG WE PRESCRIBE IS THE ONE WE USE THE MOST!
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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.
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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.
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Disease Activity and Organ Damage
Al Sawah, S., et al. (2015). Lupus Sci Med 2(1): e000066.
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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.
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SometimesCAN DRUGS LIKE AZATHIOPRINE OR MYCOPHENOLATE BE STOPPED?
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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.
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ALMS induction: response to treatment
African-American
Appel, G. B., et al. (2009). J Am Soc Nephrol 20(5): 1103-1112.
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ALMS Maintenance: Time to renal flare
Dooley, M. A., et al. (2011). N Engl J Med 365(20): 1886-1895.
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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.
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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.
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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
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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.