CONCURRENT SYMPOSIUM : SLE - Defining treatment targets in lupus : need of the hour - Dr Vaidehi...

Defining Treatment Targets in Lupus: Need of the Hour

Vaidehi R Chowdhary26/11/16

Objectives

•Define treat-to-target (T2T) strategy•Applicability to Systemic lupus erythematous (SLE)

•Recommendations for T2T•Challenges

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)

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

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

Overarching Principle 1The management of SLE should be based on shared decisions between the informed patient and her/his physician(s)

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

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

Overarching Principle 4Patients with SLE need regular long-term monitoring and review and/or adjustment of therapy

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

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

Control of DA associated with lower damage

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Autoimmunity Reviews 13 (2014) 770–777

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

Recommendation 3GoR B

It is not recommended that the treatment in clinically asymptomatic patients be escalated based solely on stable or persistent serological activity

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.

Recommendation 4GoR A

Since damage predicts subsequent damage and death, prevention of damage accrual should be a major therapeutic goal in SLE

Number of patients with damage over 26 year period

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Rheumatology (Oxford). 2009 Jun;48(6):673-5

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

Recommendation 6GoR B

Early recognition and treatment of renal involvement in SLE patients is strongly recommended

Baseline Predictors of ESRD in LN

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Arthritis Care Res (Hoboken). 2010 Jun;62(6):873-80.

Recommendation 7GoR B

For lupus nephritis, following induction therapy, at least 3 years of immunosuppressive maintenance treatment is recommended to optimize outcomes

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

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

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

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

Recommendation 10GoR B

Irrespective of the use of other treatments, serious consideration should be given to the use of anti-malarials (AM)

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.

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

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

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.

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

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J. Rheumatol. 32, 1467–1472 (2005).

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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Target of Lupus Activity

Minimal disease activity, SLEDAI-2k ≤ 1

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)

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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

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Conclusions• Important step towards clinical care of SLE patients

•Should be studied across diverse populations

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Thank YouQuestions : chowdhary.vaidehi@mayo.edu

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