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Evaluation and Management of Systemic Lupus Erythematosus, 2015
Michelle Petri, MD, MPH Professor of Medicine,
Johns Hopkins University School of Medicine Director, Hopkins Lupus Center
Baltimore, MD
February 20, 2016 CSRO
JW Marriott San Francisco, CA
• This CME activity is intended for practicing physicians, and other health care providers who may treat patients who have Systemic Lupus Erythematosus.
• There is no fee for participation in this CME activity.
This program is made possible through an
educational grant from UCB, Inc.
Accreditation
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of University Health Services Professional Education Programs (UHS-PEP) of Virginia Commonwealth University Health System and Miller Professional Group. UHS-PEP is accredited by the ACCME to provide continuing medical education for physicians.
UHS-PEP designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
CME Credit Statements
To receive continuing education credit, please complete the evaluation and Verification of Participation form and submit following the meeting. Credit Statements will be mailed within four weeks of activity completion.
IT IS ALSO A REQUIREMENT UPON EACH SPEAKER TO NOTIFY HIS/HER AUDIENCE
WHENEVER OFF-LABEL USE IS DISCUSSED.
Please Complete and Return
In the CME section of your meeting folders you will find the
• Program evaluation form
• Verification of participation form
These documents are used to evaluate the effectiveness of our programming, and to justify future educational programs of this quality.
Please be sure to return these completed forms to the speaker at the end of the program.
Please be aware you will receive (via e-mail) a follow-up questionnaire similar to the educational effectiveness survey you will complete for this program. It will come from the e-mail address [email protected]
Please be sure to return the completed follow up questionnaire.
Conflict of Interest Disclosures
Presenters
Michelle Petri, MD has reported participated in clinical trials for GSK, Medimmune, Pfizer and UCB; and is a Consultant for GSK, Pfizer, UCB and BMS.
The Planners of this activity report the following disclosure information:
John Boothby, Director, Continuing Medical Education, UHS-PEP has nothing to disclose.
Alan Epstein, MD is a member of the Speaker’s Bureau for Abbvie, Janssen, BMS, Celgene, Pfizer, Genentech and GSK.
Max Hamburger, MD is a member of the Speaker’s Bureau for UCB, BMS, Abbvie, Crescendo Bio and GSK; and is a Grant Recipient for UCB, BMS and Abbvie.
Objectives
Upon completion of this program, attendees will be able to:
• Evaluate the importance of the disease burden in SLE, consequences of inadequate disease control, and consequences of inflammatory burden on patients, their families, their communities and the healthcare system;
• Describe and discuss the impact of disease activity on patient outcomes, and the challenges of implementing treat to target concepts as applicable in the management of this highly pleomorphic disease;
• Apply current concepts of management including approaches to measurement of organ inflammation and/or involvement and disease activity;
• Collaborate with patients in the implementation of treatment goals; and
• Apply the principles of evidence based medicine to optimize SLE patient care by
1) Effectively using currently available tools for assessing disease activity in patients with lupus; evaluating the EULAR monitoring guidelines and applying them into the care of their lupus patients; and
2) Applying the treatment strategies from the EULAR and ACR guidelines and SLICC in their clinical practices and thereby optimizing patient care and functioning.
Treat to Target(s)
The Lupus 12 Step Program
Michelle Petri MD MPH
Johns Hopkins University School of Medicine
1. Classification Criteria Help in Everyday Practice (i.e. Diagnosis)
SLICC* Classification Criteria
At least 1 clinical + at least 1 immunologic criterion (for a total of 4)
OR
lupus nephritis by biopsy (in the presence of ANA or anti-DNA antibodies)
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
*Systemic Lupus International Collaborating Clinics
SLICC has recommended that BOTH the revised
ACR criteria AND the new SLICC classification criteria be used
SLICC Revision of ACR Classification Criteria
Clinical Criteria 1. Acute/subacute cutaneous lupus
2. Chronic cutaneous lupus
3. Oral/Nasal ulcers
4. Non-scarring alopecia
5. Inflammatory synovitis with physician-observed swelling of two or more joints OR tender joints with morning stiffness
6. Serositis
7. Renal: Urine protein/creatinine (or 24-hr urine protein) representing at least 500 mg of protein/24 hr or red blood cell casts
8. Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, cerebritis (acute confusional state)
9. Hemolytic anemia
10. Leukopenia (<4000/mm3 at least once) OR Lymphopenia (<1000/mm3 at least once)
11. Thrombocytopenia (<100,000/mm3) at least once
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
DERMATOLGIC
4 OTHER SYSTEMS
HEMATOLOGIC
SLICC Revision of ACR Classification Criteria
Immunologic Criteria 1. ANA above laboratory reference range
2. Anti-dsDNA above laboratory reference range (except ELISA: >2-fold laboratory reference range)
3. Anti-Sm
4. Antiphospholipid antibody lupus anticoagulant false-positive test for syphilis anticardiolipin — at least twice normal or medium-high titer anti-b2 glycoprotein 1
5. Low complement low C3 low C4 low CH50
6. Direct Coombs’ test in absence of hemolytic anemia
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
2. Understand Lupus Activity Indices Used in Clinical Trials
(Measure Activity That is Really Lupus)
Physician’s Global Assessment (PGA)
0 1 2 3
‘Severe’ means the worst in the universe of lupus,
not the worst for an individual patient
1. Furie, RA et al. Arthritis Rheum 61:1143-51.
2. Petri et al. J Rheumatol 1992;19:53-9.
• Used to assess the patient’s overall condition
• A visual analogue scale (10cm) ranging from 0–3 points
(no activity to severe life-threatening activity)
• ≥0.3-point increase (10%) = clinically-relevant worsening1
• Correlates with other disease activity indices2
Petri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8;
SELENA-SLEDAI
SELENA-SLEDAI Flare index
Petri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8;
9 Organ Systems are individually scored:
Constitutional, Mucocutaneous, Neuropsychiatric,
Musculoskeletal, Cardiorespiratory, Gastrointestinal,
Ophthalmic, Renal, Haematological
Each organ is scored for severity over the past month:
based on the net impact of individual symptoms
A=severe B=moderate C=mild D=inactive organ E=never active organ
Symptom Last Month Progress This Month Score Organ System
Severe Arthritis Same or Worse A Musculoskeletal
Severe Arthritis Significantly Improving B Musculoskeletal
No Rash New Severe Rash A Mucocutaneous
Severe Rash Significantly Improving B Mucocutaneous
Moderate Rash Significantly Improving C Mucocutaneous
BILAG 2004
SLE Responder Index (SRI) Used in Belimumab Phase III Trials
1. Petri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8; 2. Hay EM, et al. Q J Med.
1993;86(7):447-458; 3.Navarra SV, et al. Lancet 2011;377:721-31.
SRI
SELENA-SLEDAI ≥4-point reduction in
SELENA-SLEDAI
score1
Assesses 24 weighted variables to indicate
overall disease severity
BILAG No new BILAG A or
2 new BILAG B organ
domain scores2
Measures flare activity and severity across
8 organ domains
PGA No worsening in PGA
(<0.3-point increase)3
An overall assessment of changes in patient condition
and disease severity
SRI Responders Had to Meet All 3 Criteria
Landmark assessment All organs with moderate or severe activity at baseline (BILAG A) have improved: BILAG A (severe) improves to B (moderate) C (mild) or D (no activity) BILAG B (moderate) improves to C (mild) or D (no activity) and There is no worsening by BILAG, SLEDAI or Physician’s Global Assessment (PGA may not increase by more than 10% of the scale)
BILAG-based Composite Lupus Assessment: BICLA Used in Epratuzumab Phase II and III Trials
SLE Responder Index: Responders vs Nonresponders
Furie R et al. ACR 2011; Strand V et al. ACR 2011
Parameter SRI Resp (n=761)
SRI Nonresp (n=923)
> 7 point reduction 40.3% 1.3%
# organ domains improved (BILAG/SS) 1.45/2.00 0.40/0.39
% Change in PGA -58.3% -34.9%
Severe flare rate (SLE Flare Index) at wk 52 6.2% 29.1%
Reduction in prednisone to <7.5 mg/d 25.5% 16.4%
Increase in prednisone to >7.5 mg/d 4% 22%
Changes in DNA/C3/C4 -34%/14%/40% -26%/9%/29%
SF-36: PCS/MCS (MCID=2.5) 4.9/4.4 2.6/1.7
Fatigue (FACIT/SF-36 Vitality; MCID=4/5) 5.2/10.4 3/6.5
Furie et al. Lupus Sci Med. 2014 Jun 26;1:e000031. doi: 10.1136/lupus-2014
3. Avoid Maintenance Prednisone > 6 mg
Prednisone Is Directly or Indirectly Responsible for 80% of Organ Damage over 15 Years
Gladman DD, et al. J Rheum. 2003;30(9):1955-1959
CVS=cardiovascular system; GI=gastrointestinal; MSK=musculoskeletal
NP=neuropsychiatric
A Prednisone Dose of 6 mg or More Increases Organ Damage by 50%
Prednisone Average Dose
Hazard Ratio
>0-6 mg/day 1.16
>6-12 mg/day 1.50
>12-18 mg/day 1.64
>18 mg/day 2.51
Thamer M et al. J Rheumatol. 2009;36:560-564.
Adjusted for confounding by indication due to SLE disease activity
Prednisone Itself Increases the Risk of Cardiovascular Events
Prednisone use
Observed
Number of CVEs
Rate of Events/1000
Person-Years
Age-Adjusted Rate Ratios
(95% CI)
P Value
Never taken 22 13.3 1.0 (reference group)
Currently taking
1-9 mg/d 32 12.3 1.3 (0.8, 2.0) 0.31
10-19 mg/d 31 20.2 2.4 (1.5, 3.8) 0.0002
20+mg/d 25 35.4 5.1 (3.1,8.4) <0.0001
Magder LS, Petri M. Am J Epidemol. 2012;176:708-719.
4. Non-immunosuppressive Immunomodulators Can Control Mild-Moderate SLE, Helping to
Avoid Steroids
Immunomodulators
• Hydroxychloroquine1
• Vitamin D2
• Prasterone (synthetic dihydroepiandrosterone,
or DHEA)3
1. Petri M. Lupus. 1996;5(Suppl 1):S16-S22. 2. Petri M et al. Arthritis Rheum. 2013;65:1865-1871 . 3 Petri M et al. Arthritis Rheum. 2002;46:1820-1829.
Hydroxychloroquine as Background Therapy
Reduction in Flares Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991;324:150-154.
Reduction in organ damage Fessler BJ et al. Arthritis Rheum. 2005;52:1473-1480.
Reduction in lipids Petri M. Lupus. 1996;5(Suppl. 1):S16-S22. Wallace DJ et al. Am J Med. 1990;89:322-326.
Reduction in thrombosis Pierangeli SS, Harris EN. Lupus. 1996;5:451-455. Petri M. Scand J Rheumatol. 1996;25:191-193.
Improvement in survival Alarcon GS et al. Arthritis Rheum. 2005;52:S726. Ruiz-Irastorza G et al. Lupus. 2005;14:220.
Triples mycophenolate mofetil response
Kasitanon N et al. Lupus. 2006;15:366-370.
Prevents seizure Hanly JG et al. Ann Rheum Dis. 2012;71;1502-1509.
Hydroxychloroquine for Lupus Nephritis
Continuing hydroxychloroquine improves complete response rates with
mycophenolate mofetil
Kasitanon N et al. Lupus 2006;15:366-370.
Criteria of Low and Higher Risk for Developing Retinopathy
Low Risk Higher Risk
Dosage < 6.5 mg/kg hydroxychloroquine < 3 mg/kg chloroquine
>6.5 mg/kg hydroxychloroquine > 3 mg/kg chloroquine
Duration of use < 5 years > 5 years
Habitus Lean or average fat High fat level (unless dosage is appropriately low)
Renal/liver disease None Present
Concomitant retinal disease
None Present
Age < 60 years > 60 years
Marmor MF et al. Ophthalmol 2002;109:1377-82.
Only SLE Patients with Visual Symptoms Need High Tech hsUHR-OCT (Optical Coherence Tomography) or mfERG (multifocal electroretinogram)
Rodriguez-Padilla JA, et al. Arch Ophthalmol 2007;125:775-80.
• Optical Coherence Tomography
• Serous retinopathy
• Multifocal Electroretinogram
• Cataracts
Common Causes of Abnormalities
Top: Normal Spectralis spectral domain optical coherence tomography (SD OCT) image with intact photoreceptor inner segment/outer segment junction (IS/OS). Bottom: Spectralis SD OCT from the left eye of patient 10 showing the “flying saucer” sign of hydroxychloroquine retinopathy, an ovoid appearance of the central fovea created by preservation of central foveal outer retinal structures (seen between the black arrows) surrounded by perifoveal loss of the photoreceptor IS/OS junction, and perifoveal outer retinal thinning. Abbreviations: ILM, internal limiting membrane; IPL, inner plexiform layer; OPL, outer plexiform layer; ELM, external limiting membrane; RPE, retinal pigment epithelium.
From: Chen E1, Brown DM, Benz MS, Fish RH, Wong TP, Kim RY, Major JC. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign). Clin Ophthalmol. 2010 Oct 21;4:1151-8. doi: 10.2147/OPTH.S14257.
High-Speed Ultra–High-Resolution Optical Coherence Tomography Findings in Hydroxychloroquine Retinopathy¹
Question: are early toxic effects from hydroxychloroquine (HCQ) detectable by hsUHR-OCT before clinical signs or symptoms
Fifteen patients referred for evaluation of HCQ maculopathy were studied.
Six age-matched patients with normal visual function were studied with hsUHR-OCT
hsUHR-OCT abnormality severity of maculopathy seemed to correlate with severity of mfERG and visual field testing
Unable to find an asymptomatic patient with evidence of definite damage on hsUHR-OCT
¹Julio A. Rodriguez-Padilla, et al, Arch Ophthalmol. 2007;125:775-78J0
Increasing 25-Hydroxy Vitamin D Modestly Helps Disease Activity and Urine Protein/CR
Disease Measure Slope over range
of 0-40 ng/mL (95% CI)
P-value Slope over range
of ≥40 ng/mL (95% CI)
P-value
Physician’s Global Assessment
–0.04 (–0.08, –0.01)
0.026 0.01
(–0.02, 0.04) 0.50
SELENA-SLEDAI –0.22
(–0.41, –0.02) 0.032
0.12 (–0.01, 0.24)
0.065
Log Urinary Protein/Creatinine
–0.03 (–0.05, –0.02)
0.0004 –0.01
(–0.01, 0.00) 0.24
Petri M et al. Arthritis Rheum. 2013;65:1865-1871.
SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index.
Model allowing slope to differ before and after 40 ng/mL
20-Unit Increase in 25-Hydroxy Vitamin D
• 13% decrease in odds of having a PGA score of 1 or more
• 21% decrease in odds of having a SLEDAI score of 5 or more
• 15% decrease in odds of having a urine pr/cr > 0.5
Petri, et al. Arthritis Rheum 2013;65:1865-71
Vitamin D May Have Cardiovascular and Hematologic Benefits
Targher G et al. Semin Thromb Hemostasis. 2012;38:114-124.
Vitamin D Reduced Thrombosis in Some Clinical Studies
• Cancer RCT: calcitriol+docetaxel vs. docetaxel (P=0.01)1
• General population lowest tertile of vitamin D:
• 37% (CI 15-64%) increased rate of VTE2
• Higher rates of VTE in African-Americans3
• VTE are seasonal: highest risk in winter; sunbathing reduces rise of VTE by 30%4
• Honolulu Heart Program: Low vitamin D predicted 34-year incident
stroke in Japanese-American men. HR 1.22 (CI 1.02-1.47), P=0.0385
• Asian Indian cohort: mean vitamin D lower in CAD P=0.0366
1. Beer TM et al. Br J Haematol. 2006;135:392-394. 2. Brøndum-Jacobsen P et al. J Thromb Haemost . 2013;11:423-431. 3. Grant WB. Am J Hematol. 2010;85:908. 4. Lindqvist PG et al. J Thromb Haemost . 2009;7:605-610. 5. Kojima G et al. Stroke. 2012;43:2163-2167. 6. Shanker J et al. Coron Artery Dis. 2011;22:324-332.
DHEA (Prasterone) 200 mg Daily
• NOT FDA-approved
• In women with disease activity, reduction in
prednisone to ≤7.5 mg/day achieved in 51% vs.
29% on placebo (P=0.03).1
• In women with disease activity, improvement or
stabilization achieved in 58.5% vs. 44.5% on
placebo (P=0.017)2
1. Petri M et al. Arthritis Rheum. 2002;46:1820-1829. 2. Petri M et al. Arthritis Rheum. 2004;50:2858-2868.
Prasterone Reduces SLE Flares
DHEA and Bone Density
• Prasterone provides mild protection against bone loss
• At month 18 with 200 mg vs. 100 mg: Dose-dependent increase in spine BMD (P=0.02)
Sanchez-Guerrero J et al. J Rheumatol. 2008;35:1567-1575.
5. Treatment of Lupus Nephritis is NOT Just Immunosuppression!
ACR Guidelines for Kidney Biopsy
Indications for Kidney Biopsy*
Increasing serum creatinine without compelling alternative causes (eg, sepsis, hypovolemia, or medication)
Confirmed proteinuria of 1.0 gm/24 hours (either 24-hour urine specimens or spot protein-creatinine ratios)
Combinations of the following, assuming the findings are confirmed in at least 2 tests done within a short period of time and in the absence of alternative causes:
• Proteinuria 0.5 gm per 24 hours plus hematuria, defined as 5 RBCs per HPF
• Proteinuria 0.5 gm per 24 hours plus cellular casts
*All recommendations are level of evidence C. Hahn BH, et al. Arthritis Care Res. 2012;64:797-808.
EULAR Guidelines for Kidney Biopsy
Indications for Kidney Biopsy Level of
Evidence Statement Strength
Any sign of renal involvement; in particular, urinary findings including reproducible proteinuria ≥0.5 g/24 hours especially with glomerular haematuria and/or cellular casts
2 C
Clinical, serological or laboratory tests correlate modestly with renal biopsy findings. Proteinuria of ≥0.5 g/24 hours.
2 B
Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.
Adjunctive Therapy for Proteinuria
ACE-inhibitor
Angiotensin receptor blocker Duran-Barragan S, et al. Rheumatology 2008 47:1093-1096.
Spironolactone 25 mg or eplerenone 50 mg Epstein. Am J Med 2006;119:912-919.
ACR Guidelines: Adjunctive Therapies All SLE patients with nephritis should be treated with a background of
hydroxychloroquine unless there is a contraindication (level C evidence)
For patients with proteinuria 0.5 gm/24 hours (or equivalent by protein/creatinine ratios on spot urine samples), a blockade of the renin–angiotensin system, which drives intraglomerular pressure, is recommended (level A evidence for nondiabetic chronic renal disease)
Target blood pressure of 130/80 mm Hg (level A evidence for nondiabetic chronic renal disease)
Statin therapy should be introduced in patients with low-density lipoprotein cholesterol 100 mg/dL (level C evidence)
Women of child-bearing potential with active or prior lupus nephritis receive should counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence)
Hahn BH, et al. Arthritis Care Res. 2012;64:797-808.
EULAR Guidelines: Adjunctive Therapies Angiotensin-converting enzyme (ACE) inhibitors or angiotensin
receptor blockers (ARBs) for proteinuria or hypertension (level of evidence: 2; strength of statement: B)
Cholesterol lowering with statins for persistent dyslipidaemia (strength of statement: C)
Hydroxychloroquine (level of evidence: 3; strength of statement: C)
Acetyl-salicylic acid in patients with anti-phospholipid antibodies (strength of statement: C)
Calcium and vitamin D supplementation (strength of statement: C)
Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.
Initial Therapy: Class IV
ACR
– Mycophenolate mofetil (2-3 gm total daily orally) or IV cyclophosphamide along with glucocorticoids is recommended (level A evidence)
• Evidence suggestions that mycophenolate mofetil may be more likely to induce improvement in patients who are African American or Hispanic
EULAR
– Mycophenolic acid (mycophenolate mofetil target dose: 3 g.day for 6 months or mycophenolic acid sodium at equivalent dose) (level of evidence: 1; statement strength: A) or low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) in combination with glucocorticoids (level of evidence: 1; statement strength: B) are recommended as initial treatment as they have the best efficacy/toxicity ratio
Hahn BH, et al. Arthritis Care Res. 2012;64:797-808. Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.
Non-Caucasians Do Better with Mycophenolate
0
10
20
30
40
50
60
70
Asian Caucasion Combined Other* African American
Mycophenolate Mofetil IV Cyclophosphamide
P = 0.24
P = 0.83
P = .03
P = 0.39
Post Hoc Analysis
Re
spo
nd
ers
(%)
*Includes African Americans. Isenberg D, et al. Rheumatology (Oxford). 2010;49:128-140.
Initial Therapy: Class IV How Much Steroid? ACR
– Pulse IV glucocorticoids (500-1000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended, followed by daily oral glucocorticoids (0.5-1 mg/kg/ day), followed by a taper to the minimal amount necessary to control disease (level C evidence)
EULAR
– To increase efficacy and reduce cumulative glucocorticoid doses, treatment regimens should be combined initially with 3 consecutive pulses of IV methylprednisolone 500-750 mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to ≤10 mg/day by 4-6 months
Hahn BH, et al. Arthritis Care Res. 2012;64:797-808. Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.
There May Still Be a Role for Rituximab: Can We Avoid Steroids?
Condon MB, et al. Ann Rheum Dis. 2013;72:1280-6; Fischer-Betz et al. J Rheumatol. 2012;39:2111-7.
Multitarget Therapy for Induction Treatment of Lupus Nephritis
Multi-Target (Tacrolimus + MMF) IV Cytoxan
Complete Remission 45.9% 25.6%
Overall Response 83.5% 63.0%
Liu Z, et al. Ann Intern Med 2015;162:18-26.
Lupus Nephritis Maintenance Therapy : MMF is Superior to Azathioprine
Time to treatment failure Time to renal flare
N=227
Dooley MA, et al. N Engl J Med. 2011;365:1886-95. Not FDA-indicated for SLE
Lupus Nephritis: Other Options • Belimumab
• Not studied specifically in SLE patients with active nephritis1,2
• Leflunomide
• For mild-to-moderate SLE disease3
• Induction therapy for renal flare4,5
• Tacrolimus
• Consider in MMF-resistant or partial response patients, alone or in combination6-
9,12
• Approved for treatment of LN in Japan
• For severe nephritis (Class IV/V)6,10
• Rituximab
• LUNAR trial was negative11
1. Navarra S, et al. Lancet. 2011;377(9767):721-31; 2. Dooley MA, et al. ACR/AHCP annual meeting. November 4-9, 2011;Chicago, IL;
3. Tam LS, et al. Lupus. 2004;13:601-4; 4. Wang HY, et al. Lupus. 2008;17(638-44); 5. Tam LD, et al. Ann Rheum Dis. 2006;65:417-8;
6. Yap DY et al. Nephrology. 2012; 10.1111/j.1440-1797.2012.01574.x; 7. Li X, et al. Nephrol Dial Transplant. 2011; doi:
10.1093/ndt/gfr484; 8. Cortes-Hernandez J, et al; Nephrol Dial Transplant. 2010;25(12):3939-489. 9. Lanata CM, et al. Lupus.
2010:19(8):935-40. 10. Szeto CC, et al. Rheumatology. 2008;47(11):1678-81; 11. Rovin BH, et al. Arth Rheum. 2012; doi:
10.1002/art.34359. 12. Chen W, et al. Lupus. 2012:21(7):944-952.
Leflunomide, tacrolimus, and rituximab are not FDA-indicated for SLE
6. Biologics in SLE
There are Many Potential Targets for
SLE Biologics
M. Ramanujam and A. Davidson. Arthritis Research and Therapy. 2004. 6:197-202.
Adapted from Ramanujam M, Davidson A. Arthritis Res Therapy. 2004;6:197-202.
X
TACI-Ig
BAFF-R-Ig
Anti-BLyS
X X CTLA4Ig
X
X
E-mab
CTX
Anti-CD40L Anti-CD40L X
X Sifalimumab
X Anti-IL-6
A Post-hoc Analysis Identifies SLE Patients
Likely to Respond to Belimumab
Characteristics associated with greater treatment effect (p<0.1)
SELENA SLEDAI score: ≥10 (vs ≤9)
Complement: low C3/C4 (vs normal)
Steroid use: greater (vs no/less)
Characteristics not associated with treatment effect (p>0.1)
Study
Region
Race
van Vollenhoven, et al. Ann Rheum Dis, 2012. [April Epub ahead of print, doi: 10.1136/annrheumdis-2011-200937].
The Subgroup with BOTH High Anti-dsDNA and Low Complement is About 20% More Likely to
Respond to Belimumab
van Vollenhoven RF, et al. Presented at EULAR 2011; May 25-28, 2011; London, UK
A Post-hoc Analysis Shows the Organ
Systems that Respond to Belimumab
Improvement = decrease in SS
score within an organ domain
Manzi S, et al. Ann Rheum Dis, 2012. [May Epub ahead of print, doi: 10.1136/annrheumdis-2011-200831].
Belimumab Reduced Severe Flares
Cervera R, et al. Presented at EULAR 2011: Annual European Congress of Rheumatology;
May 25–28, 2011; London, UK
Open label 296 patients
SLE Responder Index
Year 2 – 57%
Year 7 65%
Anti-dsDNA 40-60%↓
Prednisone 50-55%↓
Seven Year Followup on Belimumab
Ginzler EM, et al. J Rheumatol. 2014;41:300-7
1Tedder T F & Engel P. Immunol Today. 1994;15:450-454. 2Mok M Y. Int J Rheum Dis. 2010;13(1):3-11.
3Dörner T et al. Int Rev Immunol. 2012;31:363-378. 4Sieger N et al. Arth Rheum. 2013;65:770-779.
Epratuzumab (Anti-CD22) Mechanism of Action
2. CD22 negatively
regulates the BCR on B
cells3
Effector molecule recruitment3
CD22
1. Antigen binds to the
BCR and induces B cell
activation1,2
Cascade of downstream signalling
leading to calcium influx1
Gene transcription1
B cell activation2
BCR
CD79α/β
5Carnahan J et al. Clin Cancer Res. 2003;9:3982S-90S. 6Qu Z et al. Blood. 2008;111:2211-2219. 7Rossi E A et al. Blood. 2013;122:3020-3029. 8Jacobi A M et al. Ann Rheum Dis 2008;67:450–457.
3. Emab binds CD22 and acts
as a regulator of BCR-driven
activation of B cells3
Internalisation5 and
removal of BCR
proteins from the B cell
surface7
Reduced calcium flux4
Reduced BCR signalling4
B cell modulation8
Localisation4
CD22
phosphorylation5,6
Th
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t cu
rren
tly a
pp
rove
d fo
r the tre
atm
en
t of S
LE
Glossary
Epratuzumab Mechanism of Action
Epratuzumab induces the loss of BCR-related proteins from the B cell
surface in vitro
Adapted from Rossi, E. et al. Blood. 2013; 122(17):3020-29
% o
f untr
eate
d
Epratuzumab
Labetuzumab (isotype control)
CD22 internalised into B cells
CD19 trogocytosis on to monocytes
Experiments with Daudi B cell line and
primary human monocytes
Experiments with primary human B
cells
7. SLE Pregnancy is High Risk
•4,500/year U.S. SLE pregnancies
•20-fold increase mortality
•OR 1.7 C-section
•OR 2.4 Preterm labor
•OR 3.0 Pre-eclampsia
Ginzler EM, et al. Am J Obstet Gynecol. 2008;199:127.e1-6
Adverse Pregnancy Outcome
APO No APO
LAC 39% 3% (p < 0.0001)
Lockshin MD et al. Arthritis Rheum. 64:2311-8, 2012.
Comparison of Heparin/Aspirin vs Aspirin for Pregnancy-APS
Author Year Size Comparison
Arm 1
Comparison
Arm 2
Study Outcome
Kutteh 1996 50 Heparin initiated at
10,000 units
daily in 2
divided doses
Aspirin 81 mg/day
Aspirin 81 mg Heparin/aspirin
Rai 1997 90 UF Heparin 5000
units twice daily
Aspirin 75 mg
Aspirin 75 mg Heparin/aspirin
Farquharson 2002 98 LMW Heparin 5000
units
Aspirin 75 mg
Aspirin 75 mg No difference
8. Progress on Coronary Artery Disease
Coronary Artery Disease in SLE
• Substantial increased risk that cannot be completely
explained by traditional Framingham risk factors1
• Hospitalization for acute myocardial infarction (AMI) 2.3
times higher in SLE2
• Risk of cardiovascular events is 2.66 times higher in SLE
vs Framingham cohort3
1. Esdaile JM, et al. Arthritis Rheum 2001;44: 2331-7; 2. Ward MM. Arthritis Rheum. 1999;42(2):338-46; 3. Magder LS, Petri M. Am J Epidemiol. In press.
How Can We Detect Cardiovascular Disease Early in SLE?
• Coronary calcium CT1
• Carotid duplex2
• In the FUTURE, techniques such as coronary CTA can
detect early noncalcified coronary plaques3
1. Kiani AN et al. J Rheumatol. 2008;35:1300-1306. 2. Maksimowicz-McKinnon K et al. J Rheumatol. 2006;33:2458-2463. 3. Kiani AN et al. J Rheumatol. 2010;37:579-584.
Prevention of CAD in SLE
Atorvastatin Did Not Change
1. Coronary calcium
2. Carotid intima media thickness
3. Carotid plaque
Petri M et al. Ann Rheum Dis 2010;70:760-765. Schanberg LE et al. Arthritis Rheum. 2012;64:285-296.
• Assess traditional cardiovascular risk factors and treat to target • Hypertension
• Obesity
• Hyperlipidemia (hydroxychloroquine)
• Smoking
• Sedentary Lifestyle
• Diabetes (hydroxychloroquine)
• Statin did NOT reduce progression in mice3 nor in two clinical trials:
• Adult1
• Pediatric2
• Mycophenolate: slowed progression in mice3 and transplant patients4
• Prednisone > 10 mg increases CV event risk5
Can We Reduce Cardiovascular Risk?
1. Petri MA, et al. Ann Rheum Dis. 2011;70(5):760-5; 2. Schanberg LE, et al. Arthtiris Rheum. 2012;64(1):285-96;
3. van Leuven SI, et al. Ann Rheum Dis. 2012 ;71(3):408-14; 4. Gibson WT, Hayden MR. Ann N Y Acad Sci. 2007
Sep;1110:209-21; 5. Magder L, et al. Am J Epidemiol. 2012; in press.
9. Prevention of Thrombosis in SLE: Are We There Yet?
Lupus Anticoagulant Is More Highly Associated With Thrombosis Risk
Petri M, et al. Ann Intern Med. 1987;106(4):524–531.
Derksen RH, et al. Ann Rheum Dis. 1988;47(5):364–371.
Ginsberg JS, et al. Blood. 1995;86(10):3685–3689.
Horbach DA, et al. Thromb Haemost. 1996;76(6):916–924.
Simioni P, et al. Thromb Haemost. 1996;76(2):187–189.
Wahl DG, et al. Lupus. 1997;6(5):467-73.
Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.
Time Since SLE Diagnosis (years)
Cum
ula
tive S
(t)
If Lupus Anticoagulant is Present, There is a 50% Chance of Thrombosis
Aspirin Insufficient for APS Prophylaxis
Aspirin has NOT been proven effective to reduce thrombosis from antiphospholipid antibodies
Ginsburg KS, et al. Ann Intern Med. 1992;117:997–1002; Erkan et al. Arthritis Rheum 2007;56:2382-2391.
Erkan et al. Arthritis Rheum. 2001;44:1466–1467.
Hydroxychloroquine Prevents Thrombosis in SLE
Study Study Design Outcome
Wallace et al, 1987 retrospective P < 0.05
Petri et al, 1994 prospective cohort OR 0.3
Ruiz-Irastorza et al, 2006 prospective cohort HR 0.28
Tektonidou et al, 2009 case-control HR 0.99
Jung et al, 2010 nested case-control OR 0.31
Petri M. Curr Rheumatol Reports 2010:13:77-80
10. Don’t Make Fibromyalgia WORSE (It’s Bad Enough as it is!)
Treating Pain: Tai Chi
12 weeks
79% of tai chi group vs 39% of control had clinically
meaningful improvement* (P=0.0001)
24 weeks
82% of tai chi vs 53% control had clinically
meaningful improvement (P=0.009)
FIQ=fibromyalgia impact questionnaire;
*”clinically meaningful” change in FIQ = 8.1 points
Wang C, et al. N Engl J Med.2010;363(8):743-754.
Fatigue
• Among most common complaints in lupus patients (50-80% of patients)1
• Chronic fatigue does not correlate with disease activity2
• Highly correlated with fibromyalgia, pain, depression, sleep abnormalities, poor quality of life2-5
• Associated with reduced physical fitness6
1. Tench CM et al. Rheumatology. 2000;39(11):1249–54; 2. Wang B, et al. J Rheumatol. 1998;25(5):892-5; 3. Gladman D, et al. J
Rheum. 1997;24:2145-9; 4. Bruce IN, et al. Arthritis Rheum. 1998; 41(suppl.9):S333; 5. Carr FN, et al. ACR/AHCP annual meeting.
November 4-9, 2011;Chicago, IL.
Exercise for SLE-related Fatigue
Clinical global impression change score
No (%) in exercise group (n=33)
No (%) in relaxation group (n=28)
No (%) in control group (n=32)
Very much better 3 (9) 4 (14) 1 (3)
Much better 13 (40) 4 (14) 4 (13)
A little better 5(15) 4(14) 3(9)
No change 6(18) 10(36) 14(41)
A little worse 4(12) 4(15) 10(31)
Much worse 2(6) 2(7) 1(3)
Very much worse 0 0 0
Tench CM, et al. Rheumatology. 2003;42:1050-54.
11. Don’t Forget New Information on Common Drugs
Cardiovascular Risk of NSAIDS
Salvo F, et al. Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies. Expert Opin Drug Saf. 2014;13:573-85.
Chinthapalli K. High dose NSAIDs may double the risk of heart attacks and heart failure, says new study. BMJ. 2013;346:f3533.
Trelle S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
New Data on PPIs
Proton Pump Inhibitors Increase Osteoporotic Fractures Yu EW, et al. Proton pump inhibitors and risk of fractures: a
meta-analysis of 11 international studies. Am J Med. 2011;124:519-26.
Maggio M, et al. Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. Bone. 2013;57:437-42.
Ding J, et al. The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int. 2014;94:597-607.
Moberg LM, et al. Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas. 2014;78:310-5
Proton-Pump Inhibitors Increase Risk of Cardiovascular Events Ghebremariam YT, et al. Unexpected effect of proton pump
inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013;128:845-53
Zou JJ, et al. Increased risk for developing major adverse cardiovascular events in stented Chinese patients treated with dual antiplatelet therapy after concomitant use of the proton pump inhibitor. PLoS One. 2014;9(1):e84985.
Shih CJ, et al. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. Int J Cardiol. 2014;177:292-7.
Leonard CE, Comparative Risk of Ischemic Stroke Among Users of Clopidogrel Together With Individual Proton Pump Inhibitors. Stroke. 2015 Feb 5. pii: STROKEAHA.114.006866. [Epub ahead of print]
12. Don’t Confuse Permanent Organ Damage with Active SLE or Co-
Morbidity
Percentage of Patients With Permanent Organ Damage
Chambers SA, et al. Rheumatology (Oxford). 2009;48:673-675.
One-Third of SLE Patients Accrue Permanent Organ Damage Within 5 Years of Diagnosis
Pe
rce
nt
of
Pat
ien
ts W
ith
SD
I ≥1
5 Years (N=232)
1 Year (N=232)
10 Years (N=232)
15 Years (N=143)
20 Years (N=75)
25 Years (N=6)
0.11 0.42 0.77 1.01 1.26 2.17 Mean
Damage Score
Retrospective analysis of records for patients with ≥10 years of consistent follow-up presenting at the University College London Hospital SLE clinic. Year 0 represents time of diagnosis. Mean age at diagnosis was 31.2 years, 95% of patients were female, 72% were white, 14% were black, 10% were Asian (Indian), and 4% were "other."
Percentage of Patients With Organ Damage Over 5 Years of Follow-up (N=298)
Disease Activity Over 5 Years of Follow-up (N=298)
Patients Still Accrue Organ Damage Even With Low Disease Activity
Urowitz MB, et al. Arthritis Care Res. 2012;64:132-137.
Me
an T
ota
l SLE
DA
I-2
K
Years in Registry
Pe
rce
nt
of
Pat
ien
ts W
ith
SD
I >0
Years in Registry
Prospective analysis of patients in the SLICC cohort recruited within 15 months of diagnosis and followed annually for ≥5 years. Mean age at enrolment: 35.3 years; 87% female; 55% white, 12% black, 14% Asian, 16% Hispanic, 2% “other.” At enrollment, mean disease duration=5.5 months; mean SLEDAI-2K score=5.9.
Myasthenia Gravis
0.2%
Headache
44.9%
Mood Disorders
15.4%
Myelopathy
1.1%
Pyschosis
2.0%
Polyneuropathy
3.3%
Mononeuropathy
2.2%
Acute Confusional State
3.6%
Cerebrovascular Disease
4.9%
Cognitive Dysfunction
5.3%
Anxiety Disorder
5.8%
Autonomic Disorder
0.2%
Demyelinating Syndrome
0.3%
Movement Disorder
0.9%Aseptic Meningitis
0.8%Neuropathy, Cranial
1.4%
Seizures and Seizure
Disorders
7.7%
NP Events at Enrollment (n=1404) (637 Events in 413 Patients)
Hanly JG, Urowitz MB, et al. Arthritis Rheum 56:265-73, 2007.
Headache Differential
SLE headache
Migraine headache: worsened by SSRIs Katsiari CG, et al. Headache 2011. Tjensvoll AB, etal. Cephalalgia 2010;31:401-408.
Cerebral venous sinus thrombosis (if LAC+)
Drug headache: NSAIDs, IVIG
Infection
Tumor
Heal Your Headache. D Buchholz and SG Reich. Workman Publishing Co., 1st ed., 2002
Headache in SLE
Headache is NOT increased in SLE compared to controls Mitsikostas DD, et al. Brain 127:1200-1209, 2004. Whitelaw DA, Spangenberg JJ. Lupus 18:613-617, 2009.
Mood Disorders
Depression very common: 20% Utset TO et al. J Rheumatol 21:2039-2045, 1994.
Depression correlates with cognitive impairment Petri M, et al. J Rheumatol 37:2032-2038, 2010..
Depression may be related to SLE Utset TO et al. J Rheumatol 21:2039-2045, 1994.
– Neuropsychiatric lupus OR 3.43 p=0.0005
– Secondary Sjogren’s OR 2.97 p=0.0006
Cognitive Impairment is Frequent at Baseline in an Inception Cohort
Scale Mean±SD (range)
SELENA SLEDAI 3.9±4.6 (0-28)
SLICC Damage Index 0.7±1.1 (0-4)
Krupp Fatigue Inventory 4.7±1.7 (1-7)
Calgary Depression Scale 5.0±4.6 (0-18)
Automated Neuronetics Assessments Matrix (ANAM):
1 SD below controls: 60%
2 SD or more below controls: 19%
Petri M, et al. J Rheumatol 37:2032-2038, 2010
Cognitive Impairment at Diagnosis of SLE Improves or is Stable Over Time
Cognitive impairment is common at baseline
It improves over time
Depression is the MOST important associate
Additional Slides
ETIOLOGY
Multifactorial
Predisposing genetic factors---2/3risk
Environmental factors---1/3 risk
Development of autoantibodies linked to pathologic manifestations
Preclinical phase with autoantibodies present years before clinical disease
Autoantibodies Precede the Diagnosis Of SLE By Years
Arbuckle MR, et al. N Engl J Med. 2003;349(16):1526-33.
Clinical SLE Preceded by Complicated Autoimmune Changes
ANA, Anti-Ro, Anti-La, Antiphospholipid antibodies appear first
Anti-dsDNA antibodies appear next
Anti-Sm and Anti-RNP antibodies appear just before disease onset
The number of autoantibody types continues to increase until the time of diagnosis
Immunopathogenesis
Induction of Surface Blebs during Apoptosis
Rahman A, Isenberg DA. N Engl J Med 2008;358:929-939.
Mechanism Summary-I In SLE patients there is defective clearance of apoptotic cells
Leads to exposure of intracellular immunogenic components
Taken up by DC and presented to autoreactive B cells
In the right genetic environment, these
B cells may become activated to produce
autoantibodies
Mechanism Summary-II
Once autoantibodies (particularly anti-DS DNA) are present, they can complex with DNA exposed on dying cells
Results in high levels of IFN-a production
IFN-a encourages a feed-forward mechanism of continued plasma cell activation to produce increased amounts of autoantibodies and encourage further disease progression and tissue destruction
The interferon signature and its regulation in SLE More than half of patients with SLE show a dysregulation in the expression of genes in the IFN pathway The type I IFNs are potent cytokines (IFNα and IFNβ) and also mediate the Th1 response, sustain activated T cells, sustain B cell survival, and lower the B cell activation threshold These responses propagate proinflammatory cytokines, contributing to chronic inflammation and tissue damage IFN also acts as a bridging mechanism between the innate and adaptive immune systems
One of the mechanisms of action of Plaquenil is to inhibit interferon alpha production by pDC’s (also inhibits TLR signaling)
Complement Split Products Bound to RBCs May Help in Diagnosis of SLE
SLE Other
Diseases
Normal
Healthy
EC4d Net MFI (CI 95%) 17.6 (15.2-20.0) 6.3 (5.7-6.8) 5.3 (4.6-6.1)
BC4d Net MFI (CI 95%) 110.4 (96.3–124.5) 34.9 (26.1–41.6) 23.5 (21.4–25.6)
PC4d Net MFI (CI 95%) 16.2 (12.0–20.5) 3.6 (3.0–4.2) 2.0 (1.2–2.8)
ECR1 Net MFI (CI 95%) 13.3 (12.4–14.1) 16.1 (15.1–17.1) 20.7 (19.6–21.7)
Kalunian KC. Abstract 597. Presented at: American College of Rheumatology, 2011.
ANA=antinuclear antibodies; BC4d=complement C4d levels on B cells; ds=double-stranded;
EC4d=complement C4d levels on erythrocytes; ECR1=complement receptor 1 levels on erythrocytes;
MFI=mean fluorescence intensity; MVC=mutated citrullinated vimentin antibodies; PC4d=complement C4d
levels on platelets;SLE=systemic lupus erythematous
Detection of New Clinical Activity in SLE
Variable Detected Number of visits with
new variable (N=173)
Number of patients with
≥1 visit with new
variable (N=127)
Cast 16 16
Hematuria 10 9
Proteinuria 15 15
Pyuria 42 35
Low complement 55 45
DNA antibodies 36 32
Thrombocytopenia 8 7
Leukopenia 7 7
Serum creatinine 9 8
Hemoglobin 6 6
Frequency of New Isolated Variables of Interest in 515
Patients, ≥3 Visits, ≥18 months Follow Up
Key point: Patients should be followed with
clinical and laboratory measures every 3 months Gladman DD, et al. Abstract 2301. Presented at American College of Rheumatology Annual Meeting. 2011.
Hormone Replacemant Therapy
The largest study of 351 postmenopausal women with SLE suggested only a small increase in the risk of flares
Buyon et al, Ann Int Med 2005;142:953
Oral Contraceptive Therapy Double blind, randomized, noninferiority trial.
183 women with inactive(76%) or stable active(24%).
Severe flares occurred in 7.7%receiving OC’s and 7.6%receiving placebo.
Rates of mild-moderate flares were 1.40 flares per person-year in patients on OC’s and 1.44 flares per patient-year for subjects receiving placebo.
Conclusion: oral contraceptives do not increase the risk of flare in women with SLE whose disease is stable.
Petri et al. NEJM 353;24:2550, 2005.
Rate of SLE Mortality Remains High Relative to the General Population Age 16-24---19.2X
Age 25-39---8X
Age 40-59---3.7X
Age >60------1.4X
Bernatsky S, et al. Arthritis Rheum. 2006;54:2550-2557.
Work Loss Is a Common Consequence of SLE • At baseline, 26% were aged 18-34 years and 60% were
35-55 years
– Individuals who reached age 65 without work loss were censored
• Overall, 33% (160/484) of patients stopped working during the 4-year follow-up period
• Work loss associated with incident SLE manifestations by Year 4:
– Musculoskeletal: 34% (58/170)
– Neuropsychiatric: 38% (68/179)
– Thrombotic: 58% (34/59)
Yelin E, et al. Arthritis Care Res (Hoboken). 2012;64:169-175.
ORGAN DAMAGE
Despite Improvements in Survival Rates, SLE Remains a Chronic Disease With Higher Than Expected Mortality Rate
• Survival rates significantly improved in patients diagnosed 1980-1992 vs patients diagnosed 1950-1979
• However, survival is significantly worse than in the general population
Uramoto KM, et al. Arthritis Rheum. 1999;42:46-50.
CONCLUSIONS 1) SLE is a complex disease with predisposing genetic and environmental factors.
2) SLE is difficult to diagnose.
3) SLE is not a pain disease.
4) Limit the use of Prednisone.
5) Selecting treatment can be difficult, but data are emerging that can help.
6) Follow renal disease with urine protein/creatinine ratio.
7) Risk of coronary heart disease greatly increased in patients with SLE.
8) Hydroxychloroquine
9) We have a lot of work to do: pt dx’ed at age 20 has 1/6 chance of dying by age 35