concurrent symposium : sle - defining treatment targets in lupus : need of the hour - dr vaidehi...
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Defining Treatment Targets in Lupus: Need of the Hour
Vaidehi R Chowdhary26/11/16
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Objectives
•Define treat-to-target (T2T) strategy•Applicability to Systemic lupus erythematous (SLE)
•Recommendations for T2T•Challenges
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Question: My biggest challenge in management of SLE patients is- 1. Treatment related mortality and morbidity2. Achieving remission or low disease activity3. Measures, clinical and biologic, to assess
disease activity4. Management of fibromyalgia, pain and
depression
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Treat-to-target (T2T): Definition
•Therapeutic strategy aimed to treat patients to a goal which is capable of improving disease outcome
•T2T used for management of diabetes, hypertension tailored to a specific measurable goal (A1C or blood pressure)
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T2T Strategy in Rheumatology•Clinical course, long-term damage and functional status of rheumatoid arthritis, improves remarkably when disease activity is low and treatment is tailored to a specific measurable goal
Ann Rheum Dis 2010;69:631–7
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What is treat-to-target in SLE (T2T/SLE)
• European lupus experts panel met May 08, 2012 to discuss T2T approach in SLE
• Systematic literature review (SLR) performed and results graded for the level of evidence (LoE) on a scale of 1–5, and grade of the recommendation (GoR) on a scale from A (highest) to D (lowest)
• 4 overarching principles, 11 recommendations Ann Rheum Dis. 2014 Jun;73(6):958-67
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Overarching Principle 1The management of SLE should be based on shared decisions between the informed patient and her/his physician(s)
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Overarching Principle 2Treatment of SLE should aim at ensuring long-term survival, preventing organ damage, and optimizing health-related quality-of-life, by controlling disease activity and minimizing comorbidities and drug toxicity
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Overarching Principle 3The management of SLE requires an understanding of its many aspects and manifestations, which may have to be targeted in a multidisciplinary manner
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Overarching Principle 4Patients with SLE need regular long-term monitoring and review and/or adjustment of therapy
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Recommendation 1 GoR C (SLE)/A (LN)The treatment target of SLE should be remission of systemic symptoms and organ manifestations or, where remission cannot be reached, the lowest possible disease activity, measured by a validated lupus activity index and/or by organ-specific markers
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Persistence of disease activity causes damage and mortality
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Rheumatology 2012;51:491498
Mortality, HR 1.15New Organ Damage HR 1.08
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Control of DA associated with lower damage
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Autoimmunity Reviews 13 (2014) 770–777
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Recommendation 2 GoR B (SLE)/A (LN)
Prevention of flares (especially severe flares) is a realistic target in SLE, and should be a therapeutic goal
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Recommendation 3GoR B
It is not recommended that the treatment in clinically asymptomatic patients be escalated based solely on stable or persistent serological activity
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Treatment of serologically active clinically Quiescent lupus (SACQ)• N=41, DBRCT, Prednisone 30 mg X 2 weeks, 20 X 1
week and 10 mg X 1 week versus placeboFlares in placebo 6 versus 0 in the prednisone group (P 0.007)• Toronto cohortPatient with SACQ accrued less damage over 10 years
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Arthritis Rheum. 2006 Nov;54(11):3623-32
Arthritis Care Res (Hoboken). 2012 Apr;64(4):511-8.
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Recommendation 4GoR A
Since damage predicts subsequent damage and death, prevention of damage accrual should be a major therapeutic goal in SLE
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Number of patients with damage over 26 year period
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Rheumatology (Oxford). 2009 Jun;48(6):673-5
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Recommendation 5GoR B
Factors negatively influencing health-related quality of life (HRQoL), such as fatigue, pain and depression should be addressed in addition to control of disease activity and prevention of damage
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Recommendation 6GoR B
Early recognition and treatment of renal involvement in SLE patients is strongly recommended
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Baseline Predictors of ESRD in LN
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Arthritis Care Res (Hoboken). 2010 Jun;62(6):873-80.
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Recommendation 7GoR B
For lupus nephritis, following induction therapy, at least 3 years of immunosuppressive maintenance treatment is recommended to optimize outcomes
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Duration of maintenance treatment• Chinese study, predictors of a composite outcome of doubling
of serum creatinine, ESRD and Mortality Maintenance immunosuppresion < 3 years , HR 4.62(1.35-15.8)
• Patient reducing MMF ≤ 18 months after remission
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Am J Med. 2006 Apr;119(4):355.e25-33J Rheumatol. 2011 Jul;38(7):1304-8
6.8-fold higher risk of relapse compared to those taking a stable dose
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Recommendation 8GoR B
SLE maintenance treatment should aim for the lowest glucocorticoid dosage needed to control disease, and if possible, glucocorticoids should be withdrawn completely
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Glucocorticoid dose and damage
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J Rheumatol. 2009 Mar;36(3):560-4
Hazard Ratio for organ damage Cumulative steroid dose
1.16 (95% CI 0.54, 2.50) > 0-180 mg/month
1.50 (95% CI 0.58, 3.88) > 180-360 mg/month
1.64 (95% CI 0.58, 4.69) > 360-540 mg/month
2.51 (95% CI 0.87, 7.27) > 540 mg/month
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Recommendation 9GoR C*Prevention and treatment of antiphospholipid syndrome-related morbidity should be a therapeutic goal in SLE; therapeutic recommendations do not differ from those in primary antiphospholipid syndrome* Based on low-quality randomized controlled trials and non-randomized controlled cohort studies
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Recommendation 10GoR B
Irrespective of the use of other treatments, serious consideration should be given to the use of anti-malarials (AM)
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Effect of AM in SLE graded according to quality of evidence –Systematic Review
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Ann Rheum Dis. 2010 Jan;69(1):20-8.
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Effect of AM in SLE graded according to quality of evidence
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Recommendation 11, GoR C*Relevant therapies adjunctive to any immunomodulation should be considered to control comorbidity in SLE patients
* Mechanism based reasoning
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Treat-to-target (T2T): Is it effective? • Proof of concept, Asia Pacific lupus collaboration• Lupus low disease activity state (LLDAS)- SLE Disease Activity Index (SLEDAI)-2K ≤4 - no new lupus disease activity compared with the previous assessment- (SELENA)-SLEDAI physician global assessment (scale 0-3)
≤1- use of glucocorticoids at a dose ≤7.5 mg/ day prednisone
equivalent; and- well-tolerated standard maintenance doses of
immunosuppressive or biologic agents
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Treat-to-target (T2T): Is it effective?
• 191 pts, average FU 3.9 years• Patients who spent greater than 50% of their
observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and
• significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005).
Ann Rheum Dis. 2016 Sep;75(9):1615-21.
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Challenges in T2T/SLE
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Challenge 1 –Assessment of DA• Clinical heterogeneity of SLE makes a unique
disease activity assessment instrument difficult- Should target be a composite lupus activity index or
a separate one for each organ?- best index to use in clinical practice?- cut off threshold for the index?- weighted score e.g. proteinuria or arthritis both give
a SLEDAI of 4- Most indices do not include patient reported
measures
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Challenge 2 –Definition of Remission• Urowitz: Complete absence of clinical and
serological disease activity for at least 5 years in patients with SLE who no longer require immunosuppressive drugs (other than chloroquine-based drugs)
• Achieved in only 1.7% of patients in the Canadian cohort
©2010 MFMER | slide-40
J. Rheumatol. 32, 1467–1472 (2005).
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Challenge 2 –Definition of Remission• Complete remission• - clinical serological healing in patients who
are free of any treatment• Clinical remission -absence of signs, symptoms, urinary and hematological abnormalities in patients who are at least corticosteroid free
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©2010 MFMER | slide-42
Target of Lupus Activity
Minimal disease activity, SLEDAI-2k ≤ 1
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Challenge 2 –Definition of Remission
• Definition of treatment targets for individual organs have to be defined (e.g. platelet count)
• Time constituent? e.g. Stable disease for 6 months?
• Need for biomarker correlating with disease outcomes (serologically active, clinically quiescent lupus SACQ)
©2010 MFMER | slide-43
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Challenge 3•Lack of many effective therapeutic options for SLE
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Summary- T2T/SLE• Promising concept but treatment targets
need definition• Composite index versus organ based
definition of outcomes• Concept of remission, disease activity
and continuation of therapy needs to be defined
©2010 MFMER | slide-45
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Conclusions• Important step towards clinical care of SLE patients
•Should be studied across diverse populations
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