Systemic Lupus 1 Erythematosus (SLE) in Depth: From ... · Erythematosus (SLE) in Depth: From...

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Systemic Lupus Erythematosus (SLE) in Depth: From Practical to Clinical Considerations

Learning Modules 1-2

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Module

1Understanding SLE – Practical Tips in Managing Patients

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The Faces of SLE

What Is the Impact of SLE?

SLE in the Long Term for Patients

Optimizing Patient Care

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2The Clinical Impact of SLE – Defining and Achieving Success for your Patients

The Impact of Disease Activity in SLE

Treatment Considerations in SLE – Balancing Risk and Benefit

Treat-to-Target as an Approach to Improved Patient Outcomes

Key Practice Takeaways

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Please Select the Learning Module You Would Like to View:

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Module


Welcome to Module 1

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In this module, the following topics will be covered:

Whois a typical

SLE patient?

Howcan SLE impact a patient over the long term, and what can be done to mitigate the impact?

Whatis the impact of SLE on patients, from a health and QoL perspective?

Whatsteps – from monitoring to communication – can

be taken to optimize patient care?

Module 1 Learning Objectives

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Who Is the Typical Patient? More Often Than Not, She Is a Young Female

Prepubertal vs. postpubertal

Prepubertal onset is associated with a greater risk of organ damage1

15-4590% of individuals being diagnosed are women,

with most patients developing

SLE between the ages of 15 and 453

Age

Greater risk of mortality vs. adult SLE population2

< 19years of age

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2-4 times more frequent and more severe among non-white populations4

Also, more severe4 among:• Males• Pediatric

patients

SLE is...

But Certain Populations Are at Risk of More Severe Disease

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Certain Ethnic Populations Experience the Disease More Severely

Regardless of age or gender, Hispanic, African American and Asian patients with SLE tend to experience

greater disease activity and faster accrual of organ damage:

Hematological Serosal Neurological Renal

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Certain Ethnic Populations

Accrue more damage over time, at a faster pace4

Compared to white patients with SLE:

More frequently develop specific organ damage

(eg, renal and cutaneous)4

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mucosalmembranes

cardiovascular

hematological

respiratory

skin

gastrointestinal

kidneys

CNS

musculoskeletal

SLE: Various Symptoms, Various Patient Experiences

• SLE is a chronic, multi-symptom autoimmune disease5

• Symptoms are diverse, with inflammation affecting a wide variety of organ systems5,6

• The course of the disease varies from patient to patient. There are periods of disease inactivity followed by flares (waxing and waning disease)5

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For the Majority, Physical Manifestations Are Common

6 in 10 patients develop nephritis within 10 years of diagnosis9

Up to 8 in 10 patients experience cognitive impairment8

SLE patients are also over 2.5 times more likely to experience a cardiovascular event9

2.5X8 in 10 patients experience skin-related symptoms7

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Social, Mental, and Functional Wellbeing

SLE impacts patients’:

• Psychosocial wellbeing11-16

• Interpersonal relationships11-16

• Quality of life11-16

• Productivity11-16

• Healthcare utilization11-16

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Higher Mortality Rates

• Patients with SLE have a higher mortality rate compared to the general population17

• Younger patients with SLE (16-24) have much higher rates of mortality compared to their age cohort in the general population17

Most Common Causes of Death17 (N = 1 255)*

Per

cent

of C

ases

0

5

10

15

20

25

N = 291

23%

Lupus Heart Disease

N = 126

10%

Malignancy

N = 114

9%

Infection/Pneumonia

N = 64

5%

Renal

N = 34

3%

Stroke

N = 21

2%

Adapted from Bernatsky, et al.17

* Cause of death was acquired through probabilistic linkage to vital statistics registries. It is possible that the primary cause of death when identified as lupus was actually another condition (eg, cardiovascular disease or infection) but the patient’s pre-existing diagnosis of SLE may have led to this being listed as the cause of death.

Collaboration of the Systemic Lupus International Collaborating Clinics (SLICC) and the Canadian Network for Improved Outcomes In Systemic Lupus (CaNIOS) investigator groups (US, Canada, England, Scotland, Iceland, Sweden, South Korea). Mortality data were collected for 9 547 patients followed 1958-2001 (76 948 person-years). A total of 1 255 deaths occurred. Specific causes of death were not available from all cohorts. Durations of disease at time of enrolment was < 2 years for most patients and 90% of patients were female. Race/ethnicity was not reported for the entire cohort.

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Hospitalizations Are Common

Approximately

20%-25%of patients with SLE

are hospitalized annually17,18

1 in 6patients are

readmitted within 30 days15

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Quality of Life Is Affected Greatly

Nearly all patients (91%) reported a negative effect on their ability to perform at least one valued life activity, such as cooking, family care, and sleeping12

Per

cent

of P

atie

nts

Leisure

42%

100

80

60

40

20

0Walking

44%

Cooking

50%

Errands

61%

Working/School

73%

Sleeping

74%

VigorousActivity

83%

FamilyCare

58%

Adapted from Katz, et al.12

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SLE Impacts Patients’ Career Decisions*

44% 63% 67%

Changed their career paths due to the disease20

Retired or quit working earlier than planned20

Reduced their work hours20

44% 63% 67%

44% 63% 67%

* Data from the 2011 National Burden of Lupus survey funded and developed by GSK. This survey included 957 people in the lupus community—502 people who reported being diagnosed with SLE, 204 supporters (family members or friends) of people with lupus and 251 rheumatologists.

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Title

Meet Christa

Patient Case Study

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The SELENA-SLEDAI, can be used to objectively assess a patient’s overall disease activity. It is included for the purpose of demonstrating how the variables you may already be evaluating in your clinical practice correlate with the SELENA-SLEDAI disease descriptors.

SELENA-SLEDAI SCORE: 12 pointsArthritis 4 points, Pleurisy 2 points, Rash 2 points, Elevated anti-dsDNA titer 2 points, Low complement 2 points

ChristaMother of two school-aged children who is mostly confined to home due to fatigue

Taking antimalarials plus low-dose glucocorticoids

Christa is a mother to two active children who often volunteers for school and sporting team events. She has had to reduce her activities and travel because of an increased need to rest.

History: • Diagnosed with SLE 8 years ago• Had 2 flares in the first year (joint pain in fingers),

resulting in higher glucocorticoid doses• Higher glucocorticoid dosage has led to side

effects (weight gain and swelling of the ankles)

• Feels her disease is getting worse

Clinical Profile:• Persistent pain in the proximal

interphalangeal joints• Pleurisy• Recurrent photosensitive discoid rash• Constantly tired and aching, and has rashes on

her face and ears

Patient Case Study

Note: This is a hypothetical patient; for illustrative purposes only.

Medication History:Antimalarial agent since diagnosis; low dose glucocorticoids daily since last flare; intramuscular glucocorticoid injections as needed to control joint pain and stiffness; immunosuppressive agents.

Lab Values:Hemoglobin (g/dL). . . . . . . . . . . . . . . . . . . . . . . 10.2

Platelets (x109/L) . . . . . . . . . . . . . . . . . . . . . . . . .170

WBCs (x109/L). . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2

Urinalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . Normal

Creatinine (mg/dL) . . . . . . . . . . . . . . . . . . . . . . . . 1.2

Anti-dsDNA (IU/mL) . . . . . . . . . . . . . . . . . . . . . . .150

Complement C3 and C4 (mg/dL). . . . . . . . .88 and 9

Lymphocytes (x109/L) . . . . . . . . . . . . . . . . . . . 1 100

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Christa: Mother of two school-aged children who is mostly confined to home due to fatigue

I’ve been able to manage my SLE pretty well for the first few years. The glucocorticoids are helpful but at the same time, the side effects have been more bothersome than I’d like to admit. At some point, I just want to know if I can get better…or if this is the beginning of a permanent downturn. I can’t picture myself watching the kids on the sidelines for good, when a year ago, I was coaching two soccer teams.

“”Note: This is a hypothetical patient; for illustrative purposes only.

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In Two Studies, Permanent Organ Damage Was Found in 33%-50% of Patients by Year 521,22

Adapted from Chambers, et al.21 Adapted from Urowitz, et al.22

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.”21 Cohort analysis of SLE patients followed for a minimum of 5 years by the Systemic Lupus International Collaborating Clinics International Research Network, comprising 27 centers from 11 countries. Year 0 represents time of enrollment. Mean age at enrollment was 35.3 years, 87% of patients were female, 55% were white, 12% were black, 14% were Asian, 16% were Hispanic and 2% were “other.”22

Per

cent

of P

atie

nts

with

SD

I* ≥ 1

100

80

60

40

20

01 Year

Chambers21

Urowitz22

1 Year

10%N = 232

11%N = 298

5 Years

33%

N = 232

10 Years

51%

N = 232

5 Years

50%

N = 298

15 Years

55%

N = 143

20 Years

65%

N = 75

100%

25 Years

0.11 0.770.420.91

Mean Damage Score1

Mean Damage Score2 1.341.01 1.26 2.17

N = 6

Percentage of Patients With Permanent Organ Damage

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1 Year 5 YearFollow-Up Year

10 Year

Musculoskeletal Damage21 (N = 232)

Renal Damage21 (N = 232)

Patients with SDI Scores > 0 22

(N = 298) (N = 298)

14.7%11.2%2.6%

32.2% 49.7%

0.4% 6.9% 12.9%

2.2% 5.6% 12.1%

Neuropsychiatric Damage21 (N = 232)

Patients With Damage In Selected Categories, And Overall SDI Scores

In the Same Two Studies, SDI Scores and Organ Damage Increased Year Over Year:

Patients with organ damage are at risk of more rapid progression to further damage21,22

Adapted from Chambers, et al.21 Urowitz, et al.22

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Did You Know…

The cost per patient* for a severe flare is approximately

$12 00023

*Patients with SLE were extracted from a large Medicaid database 2002-2009, n = 14 777 with 14 262 matched non-SLE patients.

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Even With Low Disease Activity, Organ Damage Occurs22

00

2

4

6

8

Mea

n To

tal o

f SLE

DA

I-2K

*

Years in Registry

1 2 3 4 5 0

Per

cent

age

of P

atie

nts

with

SD

I† >

0

Years in Registry

0

10

20

30

40

50

60

1 2 3 4 5

Adapted from Urowitz, et al.22

*The SLEDAI-2K (SLE Disease Activity Index 2000) is a validated measure of global SLE disease activity.†The SDA (SLICC/ADR Damage Index) is a validated measure of assessing damage in SLE.

Prospective analysis of patients in the SLICC cohort recruited within 15 months of diagnosis and followed annually for ≥ 5 years. Mean age at enrollment: 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.

Multiple factors may contribute to damage accrual, including the chronic use of corticosteroids.22

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Organ Damage in SLE as Assessed by the SLICC Damage Index Is Considered to Be Permanent19

…Control of disease activity in patients is thought to be important in reducing permanent organ damage and is likely to impact on the outcome of the patient.

“”– Lopez R, et al.24

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Organ Damage Can Go Unnoticed

Cardiovascular (CV) disease may be subclinical

• In patients with SLE vs. control group:

■ Prevalence of plaques in internal carotid artery is 3x higher26

■ Endothelial dysfunction, an early marker of atherosclerosis, is 2x as common27

• Osteonecrosis may be asymptomatic in patients with SLE25

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Risk of CV Event Is Much Greater for Patients With SLE

Risks of coronary heart disease and stroke are significantly higher for patients with SLE compared to general population

increased risk of CHD28

increased risk of stroke10

2-10X

6-8X 2.2

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Increased Risk of Myocardial Infarction

0 0.161.95 1.99

6.33

3.66

8.39

4.82

8.38

0

Inci

den

ce R

ate

of M

Ip

er 1

000

Per

son-

Yea

rs

15-240

2

4

6

8

10

Age (years)

Rate ratio95% CI

25-34 35-44 45-54 55-64

∞ ∞ 52.43 2.47 4.21NA NA 21.6, 98.5 0.8, 6.0 1.7, 7.9

■ General Population (N = 2 208)■ SLE Patients (N = 498)

Adapted from Manzi, et al.29

Prospective analysis of the incidence of MI in 498 women with SLE. Cardiovascular incidence rates were compared to 2 208 women of similar age participating in the Framingham Offspring Study, a prospective investigation of cardiovascular disease and the children of the 5 209 men and women who participated in the original Framingham Heart Study. A comparison of MI rates was made over the same time period (1980-1993).25

For women aged 35-44 the risk is greatest: 50x greater vs. general population29

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Monitoring for CV Health

• Refer to traditional Framingham risk factors and lupus-associated risk factors such as duration and level of disease activity and homocysteine levels29

• Even in young patients (35-44 years) with SLE, chest pain could be a warning sign of ischemic heart disease28,30

• Evaluate patients at least once yearly31

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5X 12X

Bone Health May Be Compromised

Patients with SLE: estimated 5x more likely to have bone fracture compared to age-matched controls

18 to 24 year-olds with SLE 12x more likely to have bone fracture vs. general population

• Risk of fracture is estimated to be significantly higher among patients with SLE32

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Monitoring for Bone Health

• Monitor regularly for the signs of osteoporosis early in disease course, since bone fracture risk associated with SLE disease activity may be independent of glucocorticoid use or menopausal status33

• Monitor more frequently if patient has additional risk factors (eg, menopause)34

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Nephritis: One of the Most Serious Complications

• Majority of patients will develop renal damage in the course of the disease7

• 60% of patients will develop renal abnormalities in the first 10 years after diagnosis9

• Renal damage is one of the most important predictors of mortality35

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Monitoring for Kidney Disease

• Assess patient’s history of renal disease ■ Urinalysis should be routinely

performed, even in the absence of previously diagnosed nephritis9

■ Evaluate associated risk factors and perform diagnostic assessments9

• The risk of end stage renal disease is:

5 years after diagnosis36

15 years after diagnosis36

• For patients with diagnosed nephritis, monitoring should be performed regularly9

11%

22%

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Cognitive Impairment Affects Up to 80% of Patients

• Cognitive impairment is the most frequent neurologic damage in SLE37

• Difficulties in concentration, attention, memory and visual perception are common38

• Headache, depression and anxiety are also common8

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Monitoring for Cognitive Impairment

• Refer to ACR nomenclature for neuropsychiatric syndromes to aid in diagnosis5

• For patients with symptoms of cognitive impairment, monitor their clinical history, and perform standardized neuropsychological testing39

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Treating SLE Is a Team Effort

Rheumatologists

Dermatologists

Neurologists

Psychiatrists

Ophthalmologists

Cardiologists

Nephrologists

Maternal-Fetal Specialists

Orthopedic

Musculoskeletal Specialists

Infectious Disease Specialists

Psychologists

Social Workers

Counsellors

As a multi-symptom disease, often unpredictable in its activity, SLE requires expertise from a multi-disciplinary team5:

Rheumatologists

Dermatologists

Neurologists/Psychiatrists

Ophthalmologists

Cardiologists

Nephrologists

Maternal-Fetal Specialists

Infectious Disease Specialists

Psychologists

Social Workers/Counselors

Orthopedic/Musculoskeletal Specialists

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Patient Care Is a Team Effort

In my clinical practice, I find the multidisciplinary team to be crucial for patient care…in addition to developing a strong partnership with the patient, good communication with other HCPs is critical in the management of SLE...

“”– Dr. Anca Askanase40

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Patients Underreport Their Symptoms

52% of patients report that they minimize their symptoms when talking to physicians*,21

72% of physicians are unaware that patients tend to underreport their symptoms*,21

* Data from the 2011 National Burden of Lupus survey was funded and developed by GSK. This survey included 957 people in the lupus community—502 people who reported being diagnosed with SLE, 204 supporters (family members or friends) of people with lupus and 251 rheumatologists.

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What Can We Do to Enhance Patient Interactions?

• Involve patient in SLE management plan

• Define clear goals

• Be an active listener

• Help patient understand disease

• Encourage patient to ask questions

5 Key Actions41:

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A Patient’s Perspective

...over the years, I’ve learned the importance of building a strong and open relationship with my doctors. It’s so extremely important.

“”– Rena, currently living with lupus

Rena is a paid spokesperson for GSK.

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In Patients With SLE, Cognitive Impairment May Impact Their Ability to Manage Their Condition

• Many patients exhibit some form of cognitive impairment42

“Sorry… I forgot what you told me.”

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A Chronic Disease That Should Be Monitored Regularly

are imperative for detecting signs and symptoms of new organ-system involvement and for monitoring response and adverse reactions to therapies5

Periodic follow-up and laboratory testing, including

What tests should be conducted?

Complete blood counts with differential Creatinine Urinalyses

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How Often Should Patients Be Monitored?

• For patients with very mild stable disease: every 3-6 months5

• Periodic assessment of complement levels and dsDNA titers may be used as adjuncts to clinical evaluation for predicting lupus flares43

Month

1Month

2Month

3Month

4Month

5Month

6Month

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8Month

9Month

10Month

11Month

12

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Lastly, Be Aware of Treatment-related Complications:

• Opportunistic infections and certain malignancies can develop, most often in patients receiving chronic immunosuppressive therapy43

• Chronic corticosteroid use is associated with cataracts, diabetes mellitus, atherosclerotic heart disease, osteoporosis and osteonecrosis, and fluid retention5

• Long-term use of NSAIDs is associated with GI bleeding and kidney damage5

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1. Cervera R, Khamashta MA, Font J, et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore). 1993;72(2):113-24.

2. Hersh AO, Trupin L, Yazdany J. et al. Childhood-onset disease predicts mortality in an adult cohort of patients with systemic lupus erythematosus. Arthritis Care Res. (Hoboken). 2010;62(8): 1152–1159.

3. Howard CH, Mayhew SL. The pharmacist’s role in the treatment of systemic lupus erythematosus. US Pharm. 2006;5:39-48.

4. Pons-Estel GJ, Alarcón GS, Scofield L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum. 2010;39(4):257.

5. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum. 1999;42(9):1785-1796.

6. Wallace DJ, Hahn B, eds. Dubois’ Lupus Erythematosus. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.

7. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, US Department of Health and Human Services. Lupus: A Patient Care Guide for Nurses and Other Health Professionals. 3rd ed. Bethesda, MD: National Institute of Arthritis and Musculoskeletal and Skin Diseases; 2006. NIH publication 06-4262.

8. Brey RL, Holliday SL, Saklad AR, et al. Neuropsychiatric syndromes in lupus: Prevalence using standardized definitions. Neurology. 2002;58:1214–1220.

9. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res. 2012;64(6):797-808.

10. Magder LS, Petri M. Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus. Am J Epidemiol. 2012;176(8):708-719.

11. Boomsma MM, Bijl M, Stegeman CA, et al. Patients’ perceptions of the effects of systemic lupus erythematosus on health, function, income, and interpersonal relationships: a comparison with Wegener’s granulomatosis. Arthritis Rheum. 2002;47(2):196-201.

12. Katz P, Morris A, Trupin L, et al. Disability in valued life activities among individuals with systemic lupus erythematosus. Arthritis Rheum. 2008;59(4):465-473.

13. Kiani AN, Strand V, Fang H, et al. Predictors of self-reported health- related quality of life in systemic lupus erythematosus. Rheumatology. 2013;52(9):1651-1657.

14. Panopalis P, Yazdany J, Gillis JZ, et al. Health care costs and costs associated with changes in work productivity among persons with systemic lupus erythematosus. Arthritis Rheum. 2008;59(12):1788-1795.

15. Chakravarty EF, Bush TM, Manzi S, et al. Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum. 2007;56(6):2092-2094.

16. Yazdany J, Marafino BJ, Dean ML, et al. Thirty-day hospital readmissions in systemic lupus erythematosus. Arthritis Rheum. 2014;66(10):2828-2836.

17. Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2550-2557.

18. Panopalis P, Yazdany J, Gillis JZ, et al. Health care costs and costs associated with changes in work productivity among persons with systemic lupus erythematosus. Arthritis Rheum. 2008;59(12):1788-95.

References

48

References

19. Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the systemic lupus international collaborating clinics/American college of rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39(3):363-369.

20. Lupus: A Survey Among SLE Patients, Physicians, and Supporters. New York, NY: GfK Roper Public Affairs & Corporate Communications; October 2011.

21. Chambers SA, Allen E, Rahman A, et al. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48(6):673-5.

22. Urowitz MB, Gladman DD, Ibañez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arthritis Care Res (Hoboken). 2012;64(1):132-7.

23. Kan HJ, Song X, Johnson BH, et al. Healthcare utilization and costs of systemic lupus erythematosus in Medicaid. Biomed Res Int. 2013;2013:80839.

24. Lopez R, Davidson JE, Beeby MD, et al. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford). 2012;51(3):491-8.

25. Houssiau FA, N’Zeusseu Toukap A, et al. Magnetic resonance imaging-detected avascular osteonecrosis in systemic lupus erythematosus: lack of correlation with antiphospholipid antibodies. Br J Rheumatol. 1998;37(4):448-53.

26. Ahmad Y, Shelmerdine J, Bodill H, et al. Subclinical atherosclerosis in systemic lupus erythematosus (SLE): the relative contribution of classic risk factors and the lupus phenotype. Rheumatology (Oxford). 2007;46(6):983-8.

27. El-Magadmi M, Bodill H, Ahmad Y, et al. Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women. Circulation. 2004;110(4):399-404.

28. Schoenfield S, Kasturi S, Costenbader K. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Seminars Arthritis Rheum. 2013;43:77-95.

29. Manzi S, Meilahn EN, Rairie JE, et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997;145(5):408-15.

30. Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus. Arthritis Rheum. 1999;42(2):338-346.

31. Mosca M, Tani C, Aringer M, et al. European league against rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis. 2010;69(7):1269-1274.

32. Ramsey-Goldman R, Dunn JE, Huang CF, et al. Frequency of fractures in women with systemic lupus erythematosus: comparison with United States population data. Arthritis Rheum.1999;42(5):882-90.

33. Grossman J, Gordon R, Ranganath V, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res 2010;62:1515-1526.

34. Bultink IE, Harvey NC, Lalmohamed A, et al. Elevated risk of clinical fractures and associated risk factors in patients with systemic lupus erythematosus versus matched controls: a population-based study in the United Kingdom. Osteoporos Int. 2014;25(4):1275-83.

49

References

35. Danila MI, Pons-Estel GJ, Zhang J, et al. Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic US cohort. Rheumatology (Oxford). 2009;48(5):542-5.

36. Tektonidou MG, Dasgupta A, Ward MM. Risk of End-stage Renal Disease in Patients with Lupus Nephritis, 1970 to 2015: A systematic review and Bayesian meta-analysis. Arthritis Rheumatol. 2016 Jan 27.

37. Petri M. Monitoring systemic lupus erythematosus in standard clinical care. Best Pract Res Clin Rheumatol. 2007;21(4):687-697.

38. Kajs-Wyllie M. Lupus cerebritis: a case study. J Neurosci Nurs. 2002 Aug;34(4):176-83.

39. Carlomagno S, Migliaresi S, Ambrosone L, et al. Cognitive impairment in systemic lupus erythematosus: a follow-up study. J Neurol. 2000;247(4):273-279.

40. Askanase A. Systemic Lupus Erythematosus (SLE): Understanding and Addressing Patient Needs. Patient Care Insights. http://www.talksle.com/assets/patient_care_insights_newsletter.pdf. Accessed April 1, 2016.

41. Beusterien K, Bell JA, Grinspan J, et al. Physician-patient interactions and outcomes in systemic lupus erythematosus (SLE): a conceptual model. Lupus. 2013;22(10):1038-1045.

42. Petri M, Naqibuddin M, Carson KA, et al. Cognitive function in a systemic lupus erythematosus inception cohort. J Rheumatol. 2008;35(9):1776-81.

43. Bartels CM. Systemic Lupus Erythematosus (SLE) Treatment & Management. Medscape. http://emedicine.medscape.com/article/332244-treatment. Updated Sept 25, 2015. Accessed Jan 29, 2016.

©2016 GSK group of companies.All rights reserved. Produced in the USA. 630501R0 June 2016

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Welcome to Module 2

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Module 2 Learning Objectives

In this module, we’ll cover the following topics:

Howdoes disease activity

affect long-term outlook?

Whatis Treat-to-Target and can

it help improve patient outcomes? Some current

thinking on achieving meaningful targets

Whatconsiderations should be taken in balancing risk/benefit in treating SLE?

Howcan we help manage

patients to optimize care in the face of an unpredictable,

chronic condition?

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Survival rates of SLE patients have improved over the past 5 decades1

However, SLE patients

still have a 2.6x higher mortality rate

vs. general population1

SLE Patients’Survival

Rates

Progress in SLE – But Room For Improvement Exists

Time

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• Causes of death vary, but majority of deaths are due to CV events, infections or cancer2

• Persistent disease activity is linked to increased organ damage, which in turn is predictive of increased damage and mortality2

Mortality Rates Remain High

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Adapted from Doria, et al.2

CAD = chronic active disease; CQD = clinically quiescent disease; MDA = minimal disease activity; RRD = relapsing-remitting disease; SLICC DI = Systematic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.

2004

Mea

n SL

ICC

DI

Follow-up, Years

0

0.5

1.0

1.5

p > 0.001

p = 0.003

2.0

2005 2006 2007 2008 2009 2010

CQD

MDA

RRD

CAD

Disease Activity Is Linked To Organ Damage Accrual2

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Possible predictor of flares, which

impacts morbidity and mortality3,4

Lower probability of remission4,5

Higher use of glucocorticoids6,7

Persistent disease activity has long-term consequences for patients:

Persistent Disease Activity: Predictor of Negative Outcomes

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Up to 24XHospitalizations for serious infections in patients with SLE

Hospitalization rates for serious infections in SLE patients were as much as 24 times higher than in the general public.8

* Retrospective analysis using data of the Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project, of the Agency for Healthcare Research and Quality from 1996-2011.

Did You Know…

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Antimalarials

NSAIDs

Low doses of corticosteroids

Corticosteroids

Cytotoxic and immunosuppressive

agents** In addition to medications for less severe disease.

Helpful in treatment of mild symptoms such as arthralgias

and musculoskeletal cutaneous

manifestations

Used in patients with significant

organ involvement and severe cutaneous

manifestations

SLELess Severe Disease

More Severe Disease

Overview of Mainstay Treatments in SLE9

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All drugs have potential side effects, so the balance of risk versus benefit is always at the forefront of a [SLE] treatment regimen.“

”– Levy, et al.10

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QoL

DA

MA

GE

Persistent Disease Activity

Drug-related Side Effects

Further Damage

Decreased Quality of Life

Mood Disorders

Reduced Work Productivity


In Addition To Disease Activity, Drug-related Side Effects Can Result In Accrual of Organ Damage

Death

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• Antimalarials have been associated with reduced disease activity, reduced risk of flares and organ damage, and reduced mortality11-15

• Improved ophthalmology screening tools and new knowledge on prevalence of toxicity can help clinicians minimize vision loss16

Antimalarials

In the treatment of SLE, the mechanism of action of antimalarials is not fully understood; their anti-inflammatory and immunosuppressive properties may help explain their effectiveness9

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Antimalarials – Toxicity, Monitoring

• Most common side effects: gastrointestinal upset, dermatologic reactions, headache, and lightheadedness9

• Rare but serious side effects include psychosis, convulsions, toxic neuropathy, skeletal myopathy, cardiac myopathy, and ophthalmologic toxicity, including vision loss9

• American College of Rheumatology recommends a baseline examination (funduscopy and visual field) prior to initiating antimalarial treatment9,17

■ Follow up ophthalmologic assessments every 6-12 months9,17

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Immunosuppressants

• Used in induction and maintenance of remission and reduction of flares or relapses13

• Can be given in combination with glucocorticoids to control flares, or to lower the dose of each medication; or to reduce incidence of adverse events17

• Some immunosuppressant agents may be used to treat neuropsychiatric symptoms and severe cutaneous manifestations9

Immunosuppressant agents are typically reserved for more severe disease, as well as for patients who have active disease despite antimalarials and/or glucocorticoids9

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Immunosuppressants – Toxicity, Monitoring

Potential adverse events include (varies with specific medications in this class):• Myelosuppression17

• Hepatotoxicity17

• Renal dysfunction17

• Infertility17

• Increased risk of infection and/or cancer17

Common monitoring parameters:• Baseline and routine CBC, platelet count,

SCr, LFTs, and urinalysis (depending on individual drug)17

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Owing to their potent anti-inflammatory effects, glucocorticoids are used to treat a wide number of rheumatic diseases, including SLE:

• Low-to-moderate doses used for mucocutaneous and vasculitic skin lesions (with no organ involvement)18

• Useful for moderate-to-severe polyarthritis18

• High doses used for major organ involvement18

Glucocorticoids are potent, inexpensive, and rapid in onset.19 They can be used to treat a range of manifestations at various dosage ranges.18

Glucocorticoids* Remain a Mainstay of Treatment for SLE

*In this module, the term ‘glucocorticoids’ also refers to prednisone equivalents.

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– Luijten, et al.20

…Our clinical decision making concerning the use of glucocorticoids in SLE patients is often based on clinical experience, making it more an art than science.

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Adverse effects of glucocorticoids —time and dose relationship21

Adverse effect Time-dependent Dose-dependent

Osteoporosis Yes (early) Yes (maximum 6 months)

Hyperglycemia Yes (early) Yes

Cushing Syndrome Yes (at least 1 month) Yes

Cardiovascular disease Yes Yes

Increased risk of infections Yes Yes

Dermatologic Yes Yes

Glaucoma Yes Yes

Cataracts Yes (delayed) Yes

Psychological and behavioral Yes (early) Yes

Adapted from Ruiz-Irastorra, et al.21

Consider the Time and Dose Relationship

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Years Years Years0 2 4 6 0 2 4 6 0 2 4 6

Relapsing- Remitting (RR)

Disease Activity

Remission

Chronically Active (CA)

Long- Quiescent

Time Time Time

Adapted from Barr, et al.22

*Data from prospective observational studies of SLE patients with follow-up times of at least 5-year period.5,22-24

60-85% of SLE patients fall under RR or CA patterns5,22

Disease Activity in SLE May Appear in Different Patterns*,5,22-24

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Prevention of flares may be a realistic goal25

What Is Considered a Realistic Goal In SLE?

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EULAR has made defining remission in SLE a priority focus, with the establishment of the DORIS (Definition of Remission in SLE) task force26

It is remarkable that while remission has been used to describe a favorable clinical state for [SLE]…there has not yet been an agreed-upon definition of remission in SLE.

“”– van Vollenhoven, et al.26

Lack of Consensus on What Remission Means

Ann Rheum Dis, December 2015.26

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• SLEDAI-2K ≤ 4

• No new signs/ symptoms of disease activity since previous assessment

• PGA ≤ 1

• Current glucocorticoid dose ≤ 7.5 mg/day

• Well-tolerated immunosuppressants/biologics

• ≥ 2 years without clinical disease activity

• Persistent serologic activity (anti-dsDNA and/or low complement)

• Antimalarials permitted

• No corticosteroids or immunosuppressives

• Complete: 5 years without clinical or serologic disease activity (only antimalarials permitted)

• Clinical remission off glucocorticoids: SACQ (antimalarials/immunosuppressants permitted)

• Clinical remission on glucocorticoids: SACQ (glucocorticoids ≤ 5 mg/day, antimalarials, immunosuppressants permitted)

Lupus Low-disease Activity State27

Serologically Active Clinically Quiescent

(SACQ)28 Remission29

Examples of Proposed Stages of SLE Disease

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• Systemic rheumatic diseases such as SLE do not have a single measurement that accurately depicts disease course and patient outcome30

• Knowing this, the idea of broadening treatment goals and success may prove to be more useful and achievable30

• Treat-to-Target is a therapeutic strategy with the view to improve disease outcomes30

CompleteRemission

Low

-dis

ease

Activi

ty with or without Low-dose Glucocorticoid

Treat-to-Target Is One Approach to Improving Patient Outcomes

Glu

coco

rticoid-free Clinical Rem

ission


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Recommendations for improving SLE management using a Treat-to-Target approach were developed by a multidisciplinary, multinational task force25

A selection of the recommendations are as follows…

CompleteRemission

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Implementing Treat-to-Target in Practice

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ission


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The treatment target of SLE should be remission of systemic symptoms, organ manifestations or, where remission cannot be reached, the lowest possible disease activity, measured by a validated lupus activity index and/or organ-specific monitors25

In Absence of Remission, Aim for Lowest Possible Disease Activity25

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luco

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ission


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Preventing Flares Is a Realistic Goal25

Prevention of flares (especially severe flares) is a realistic target in SLE and should be a therapeutic goal25

Time

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Preventing Damage Accrual Is a Major Goal25

Since damage predicts subsequent damage and death, prevention of the damage accrual should be a major therapeutic goal in SLE252.2

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Treat Factors Linked to Poor HRQoL25

QoLFactors negatively influencing HRQoL such as fatigue, pain, and depression should be addressed in addition to control of disease activity and prevention of damage252.2

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Aim For Lowest Glucocorticoid Dosage For Disease Control25

SLE maintenance treatment should aim for the lowest glucocorticoid dosage needed to control disease, and if possible, glucocorticoids should be withdrawn completely252.2

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Treat-to-Target Can Be Successful if…

The appropriate target(s) can be identified25

Measuring the target is possible25

Appropriate interventions exist to (attempt to) achieve the target25

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Patient Case Study

Meet Alicia

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SELENA-SLEDAI SCORE: 6 pointsRash 2 points, Arthritis 4 points

83

Signs of low disease activity but is taking glucocorticoids to prevent flares

Alicia is a stay-at-home mom; she finds that her SLE interferes with her ability to take care of her kids:• She is frequently tired • Arthritis flares make doing chores

around the house difficult and painful

History:• Diagnosed 5 years ago• Received an antimalarial until

intolerable GI upset• Has occasional pain in her wrists

and rashes on the face

Clinical Profile:Chronic fatigue with flares of malar rash and polyarthritis in the wrists.

AliciaStay-at-home parent with mobility and fatigue issues

Patient Case Study

Medication History:• Moderate dosage of glucocorticoid daily • Reducing doses of glucocorticoids results

in flares

Lab Values:Hemoglobin (g/dL). . . . . . . . . . . . . . . . . . . 12.2

Platelets (x109/L) . . . . . . . . . . . . . . . . . . . . . 210

WBCs (x109/L). . . . . . . . . . . . . . . . . . . . . . . 3.9

Urinalysis . . . . . . . . . . . . . . . . . . . . . . . . Normal

Creatinine (mg/dL) . . . . . . . . . . . . . . . . . . . . . 0.9

Proteinuria (g/day) . . . . . . . . . . . . . . . . . . . . . 0.1

Anti-dsDNA (IU/mL) . . . . . . . . . . . . . . . . . . . . . 5

Complement C3 and C4 (mg/dL). . . . 90 and 30

Lymphocytes (x109/L) . . . . . . . . . . . . . . . . 1 100


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Alicia: Stay-at-home parent with mobility and fatigue issues

Getting up in the morning is hard because this is when my arthritis feels the worst. At this age, I should have enough energy to keep up with my children, but I don’t. If there was something I could do to get my energy levels up and the flares down, I’d definitely consider it.


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How Can Current Perspectives Change Current Practices?

A selection of recommendations from various peer-reviewed sources and task forces are presented here…2.2

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When Remission Is Not Possible, Consider Alternate Targets

• Complete remission is the goal for patients with SLE 25

• Clinical remission (complete or partial) can be an effective target as well25

• Low-disease activity would be a subsequent goal if clinical remission is not achievable25

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Minimize Disease Activity

• Persistent disease activity can result in ongoing organ damage31

• Disease activity and immunologic factors can predict flares

• Assess disease activity regularly; patient history, physical assessment, and labs can help detect and define disease activity32-35

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Monitor For Subclinical Activity

• Regular monitoring should be undertaken to detect “silent variables”36

• Data support following patients with mild or inactive disease at 3-4 month intervals36

In a retrospective analysis, 1 in 4 patients seen over 2 years had at least one “solitary silent variable,” detectable only through routine laboratory assessments (N = 515)36:

Variable DetectedNumber of Visits with New Variable

(N = 173)

Number of Patients with ≥ 1 Visit with

New Variable (N = 126)

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

Elevated serum creatinine 9 8

Low hemoglobin 6 6

Laboratory parameters were the sole manifestation of SLE in 24.7% of patients.

Frequency of New Silent Variables of Interest in 515 Patients, ≥ 3 Visits, ≥ 18 Months’ Follow-up

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Greater Riskof developingany new organ

damage

1.7X≥ 7.5 mg/dayGlucocorticoids

Reduce – As Much As Possible – Glucocorticoid Dosage

• Glucocorticoids are invaluable in the treatment of SLE; however, their chronic use has consistently shown to increase irreversible damage in lupus patients, a major predictor of morbidity and mortality21

• Use of the lowest effective dose of glucocorticoids can reduce the risk of glucocorticoid-related damage accrual25,37

• In general, the risk of organ damage increases at a dose of 7.5 mg/day38

Adapted from Al Sawah, et al.38

*At the time of this analysis, the cohort included 2 265 patients with SLE who were followed over the course of 26 years between 1987 and October 2012, with the average duration of follow-up from cohort entry until lost to follow-up being 6.2 years. Cox proportional hazards models were used to estimate the impact of different levels of exposure to [glucocorticoids] (as defined by [glucocorticoid] cut-off points endorsed in some SLE clinical trials) on the risk of developing any new organ damage or any new organ damage at the individual organ systems over time. Organ damage was measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) or by components of the SDI at the individual organ systems level.

Analysis* of data from the Hopkins Lupus Cohort study of 2 265 patients over 26 years, investigating impact of [glucocorticoid] doses on risk of organ damage development.38

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Patient Case Study

Meet Brianne

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SELENA-SLEDAI SCORE: 12 pointsArthritis 4 points, Mucosal ulcers 2 points, Alopecia 2 points, Elevated anti-dsDNA 2 points, Low complement 2 points

Medication History:• Antimalarial for 2 years; moderate dosage of

glucocorticoid daily for flares

Lab Values:Hemoglobin (g/dL). . . . . . . . . . . . . . . . . . . . . 12.2

Platelets (x109/L) . . . . . . . . . . . . . . . . . . . . . . . 260

WBCs (x109/L). . . . . . . . . . . . . . . . . . . . . . . . . 3.9

Urinalysis . . . . . . . . . . . . . . . . . . . . . . . . . . Normal

Creatinine (mg/dL) . . . . . . . . . . . . . . . . . . . . . . 1.2

Proteinuria (g/day) . . . . . . . . . . . . . . . . . . . Normal

Anti-dsDNA (IU/mL) . . . . . . . . . . . . . . . . . . . . . . 40

Complement C3 and C4 (mg/dL). . . . . . . 60 and 5

Lymphocytes (x109/L) . . . . . . . . . . . . . . . . . 1 200

Taking an antimalarial agent alone but is having flares requiring short-term glucocorticoids

Brianne is a certified accountant working full-time. Over the past 6 months, she’s experienced increasing difficulty in completing tasks on time due to:

• Increased fatigue • Joint pain in her hands, which are crucial for

her ability to do computer work for extended periods of time

History:

• Diagnosed with SLE 2 years ago • For past 6 months, has experienced:

– Fatigue – Hair loss – Increasing pain in her hands and fingers – Ulcers on her palate

BrianneFull-time professional with worsening symptoms affecting her work life

Patient Case Study


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Brianne: Full-time professional with worsening symptoms affecting her work life

I started working at a new accounting firm last year and was really keen on taking on bigger projects and clients. But lately it’s been challenging to keep up – and it scares me to think I’ll have to scale back. I’ve worked so hard to get where I am – I just wish to get back to some kind of normal.


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1. Lee YH, Choi SJ, Ji JD, Song GG. Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis. Lupus. January 24, 2016.

2. Doria A. et al. Optimizing outcome in SLE: treating-to-target and definition of treatment goals. Autoimmun Rev. 2014;13(7):770-7.

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