Lupus is an autoimmune disease that primarily affects women and can damage multiple organs in the body. While treatments have improved survival rates, people with lupus still have a higher risk of death than the general population, especially due to organ damage, cardiovascular events, infections, and certain cancers. Ongoing challenges in managing lupus include preventing organ damage, addressing comorbidities, and improving patients' quality of life. Recent research continues to explore new drug targets and non-pharmaceutical interventions to help achieve better outcomes for people living with lupus.

1. LATEST IN LUPUS
Swamy Venuturupalli, MD, F.A.C.R
Attending and former Clinical Chief - Rheumatology, Cedars Sinai
Medical Center.
Associate Clinical Professor of Medicine, UCLA.
8737 Beverly Blvd, Los Angeles, CA, 90048.
310-659-9959
www.drswamy.com

2. OVERVIEW
• What is Lupus?
• Who is at risk and for what?
• The promise of the biologic revolution -
what went wrong in lupus?
• Silver linings – select new data
• HOPE – The technological revolution is
coming to town!

3. Epidemiology of lupus
• 90% are females; 90% of whom develop it during their
reproductive years
• Ethnic groups in order of susceptibility: Native American >
African-American>Certain Asians (e.g., Chinese,
Filipino)>Hispanics and other Asians (e.g., Japanese,
Malay)>Caucasians
• Prevalence from 15–50 per 100,000 (ACR criteria)
• US estimates range from 200,000 (National Center for
Health Statistics) to 2,000,000 (Lupus Foundation of
America—includes self-reported cases)

4. Types of lupus
• Cutaneous (discoid) lupus erythematosus (10%)
• Systemic lupus erythematosus (70%)
• Nonorgan-threatening disease (35%)
• Organ-threatening disease (35%)
• Drug-induced lupus erythematosus (10%)
• Crossover or overlap syndrome and/or mixed
connective tissue disease (MCTD) (10%)

5. Classification criteria - NEW CLINICAL
CRITERIA
Lupus nephritis by renal biopsy OR 4 criteria including at least one clinical and
one immunologic criteria excluding HIV, hepatitis, malignancy or other causes
NEW CLINICAL CRITERIA
1. Acute cutaneous or subacute cutaneous lupus in absence of dermatomyositis
2. Chronic cutaneous lupus
3. Oral or nasal ulcers
4. Nonscarring alopecia
5. Nonerosive inflammatory arthritis in at least two joints
6. Serositis in the absence of other causes
7. >500mg proteinuria equivalent/24 hours or red cell urine casts
8. Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral
or cranial neuropathy or acute confusional state attributable to SLE
9. Hemolytic anemia
10. Leukopenia or lymphopenia (<4000 or <1000 respectively/ cu mm
11. Thrombocytopenia (<100,000/ cu mm)

6. Immunologic criteria
• 1. ANA above laboratory reference range
• 2. Anti ds DNA (if ELISA must be 2x ref range)
• 3. Antiphospholipid antibody (lupus anticoagulant,
biologic false positive syphilis, anticardiolipin 2x normal,
anti beta-2 glycoprotein)
• 4. anti Smith
• 5. Low C3, C4 or CH50
• 6. Positive direct Coombs in the absence of hemolytic
anemia
M Petri, Arthritis Rheum , 2009; v. 60, ACR Presentation

7. 7
Crow M. N Engl J Med 2008;358:956-961
A Model of the Pathogenesis of Systemic Lupus Erythematosus (SLE) That
Implicates the Products of Disease-Associated Polymorphic Genes
Figure 1. A Model of the Pathogenesis of Systemic Lupus Erythematosus (SLE)

8. Investigational Drugs
Mechanism Drug Current Phase
B Cell Targeting
B cell depletion (anti CD-20) Rituximab Phase 3
BLyS/APRIL inhibition Atacicept
Tabalumab
Blisibimod
Phase 2
Phase 3
Phase 3
B Cell modulator (anti CD22)
and interference with
trogocytosis
Epratuzumab Phase 3
Cytokine antagonists Tocilizumab
Sirukumab
Phase 1
Phase 2

9. Investigational Drugs (con’t)
Mechanism Drug Phase
T Cell Targeting
Toleragen Rigerimod/P140 peptide Phase 3
Selective co-stimulation
modulator
Abatacept Phase 3
Interferon antagonists Sifalimumab
Rontalizumab
Interferon α-kinoid
MEDI 546
Phase 2
Phase 2
Phase 1/2
Phase 2
Novel Mechanisms
Protein kinase inhibitors Sirolimus
GSK-2586184
Phase 2
Phase 2
Immunomodulating agent Laquinimod Phase 2

10. HOW DO WE TREAT LUPUS
• Establish the diagnosis
• Assess for the organ systems that are involved
• Assess for levels of inflammation
• Use anti-inflammatory medications
• Auxillary treatments: Diet, exercise, stress reduction
• Corticosteroids- extremely effective in reducing inflammation in lupus-
use as short a course as possible, and have a tapering plan.
• Anti-malarials- plaquenil, quinacrine for skin and joint disease and
fatigue
• Immunosuppresive treatments: mycophenalate, imuran,
cyclophosphamide etc. when organ involvement noted.
• Periodic monitoring of disease activity and reduction of non-
necessary medications
• Vigilant monitoring for infections, malignancies, cardiac and renal
disease

11. Who?
When?
What?

12. Uramoto KM, et al. Arthritis Rheum. 1999;42:46-50.
Cohort Diagnosed 1980-1992
0 1
100
40
80
60
20
2 3 5 6 7 8 9 10
Time (years)
4
Cohort Diagnosed 1950-1979PercentofPatients
Surviving
Expected Mortality in General Population
Expected Mortality in General Population
• Survival rates significantly
improved in patients
diagnosed 1980-1992 vs
patients diagnosed
1950-1979
• However, survival is
significantly worse than in
the general population
Despite Improvements in Survival Rates, SLE Remains a
Chronic Disease With Higher Than Expected Mortality Rate
SLE Patient Survival
The Rochester, Minnesota, Epidemiology Project
P<0.001*
P=0.02*
0
*Significance vs expected mortality rates in the general population

13. • A range of organ systems are
implicated in SLE mortality
– Mortality data from 9547
patients followed 1958-2001;
total of 1255 deaths occurred
– Patients followed for 76,948
person-years
• Mortality rates were significantly
higher for some of the most
common causes of death than
those seen in the general
population
– ~8x higher for renal causes
– ~5x higher for infections
– Almost 2x higher for heart
disease
Bernatsky S, et al. Arthritis Rheum. 2006;54:2550-2557.
Most Common Causes of Death (N=1255)*
Cardiovascular Events, Malignancies, and Infections
Are Among the Most Common Causes of Death in SLE
PercentofCases
40
20
0
n=21n=34n=64n=114n=126n=291
*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 (e.g., cardiovascular disease or infection), but the patient’s preexisting diagnosis of SLE may have led to this being
listed as the cause of death

14. Risk of Myocardial Infarction (MI) Is More Than
50 Times Greater for Women With SLEAged 35-44
Manzi S, et al. Am J Epidemiol. 1997;145:408-415.
• Cardiovascular disease is
an ongoing issue for
patients with SLE
• Compared to the
general population,
incidence rate of MI was
higher in women with
SLE overall
• Incidence of MI in
younger and
premenopausal women
was notably higher
versus the age-matched
general population
Incidence of MI in Women by Age
IncidenceRateofMI
per1000Person-Years
(n=2208)
(n=498)
Age (yrs)

15. • 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)
Work Loss Is a Common Consequence of SLE
Yelin E, et al. Arthritis Care Res (Hoboken). 2012;64:169-175.
Time to Work Loss by Incident SLE Manifestation (N=484)
PercentEmployed
Years Since SLE Manifestation
100
80
60
40
20
1 2 3 4 5 6 7 8
Musculoskeletal (n=170)
Neuropsychiatric (n=179)
Thrombosis (n=59)
0

16. Rahman P, et al. Lupus. 2001;10:93-96.
• Initial SDI assessment was
performed ≥6 months after
study enrollment
• Early organ damage was
defined as initial SDI ≥1
• 25% of patients with
early damage died within
10 years compared to 7.3%
with no early damage
(P=0.0002)
a
Survival Probability in Patients With
and Without Early Organ Damage
(N=263)
SurvivalProbability
Disease Duration (years)
1.0
0.9
0.8
0.7
0.6
2 4 6 8
Initial SDI=0, n=190
Initial SDI >0, n=73
Early Organ Damage IsAssociated With Reduced 10-Year Survival Rate
0 10

17. Percentage of Patients With Permanent Organ Damage
Chambers SA, et al. Rheumatology (Oxford). 2009;48:673-675.
One-Third of SLE PatientsAccrue Permanent Organ Damage
Within 5 Years of Diagnosis
PercentofPatientsWithSDI≥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

18. Principal Challenges Regarding the Management
of SLE
• Confirming a timely and correct diagnosis
• Treating inflammation without doing harm
• Addressing and screening for co-morbidities
(heart, cancer and infection)
• Establishing a medical home for patients with
lupus
• Establishing social support structures for
patients

19. The Biologic Revolution
HAVE WE CURED LUPUS?

20. “Drugs don’t work in patients who
don’t take them”
C Everett Koop, Surgeon General of the United States in Osterberg L, Blaschke T,
Adherence to medication. N Engl J Med. 2005;353:487.
•1/3 Canadian patients did not follow through with antimalarial mandated eye
exams.
•LUMINA cohort: 50% of patients were not compliant with medication!
•1/3 of renal failure patients in Toronto cohort resulted from failure to adhere to
follow up visits.

21. 18 SLE drugs in Phase II/III trials that
failed to meet their primary endpoint
➠Abetimus ➠Tabalumab
➠Edratide ➠R333 topical sykkinase
➠Abatacept ➠Sirukumab
➠Rituximab ➠Blisimibob
➠Atacicept ➠Laquinimod
➠Ocrelizumab ➠Lupuzor
➠Sifilumumab ➠Prasterone (DHEA)
➠Rontiluzumab ➠Mycophenolate
➠Pfizer anti IL-6 ➠Epratuzumab
Many of these agents are clearly effective

22. Why did 18 Phase II/III trials fail?
• The drug just did not work
• Trial design was flawed- too short, too few patients
• Inexperienced investigators
• We are terrible at measuring lupus- SLEDAI, BILAG etc
designed in the 1980s.
• Co-treatment with steroids and other drugs
• Need better biomarkers

23. Targeted Therapies in SLE
MOA Examples of Targets
T Cells
CTLA4-lg; modified CD40L mAb; ICOS, expand
CD4+CD25+ cells, CD8+CD28- cells
B Cells
mAbs to CD20, CD22, proteosome/plasma cells
antiBLyS, TACI-Ig, BAFF-RFc
Complement Anti-C5a
Cytokines
mAbs to sIL-6R, IL-6, IL-10, IL-17, IL-18, anti-
TNFs
Innate immune system Anti-IFNα and IFNy; blockade of TLR7 and/or 9
Toleragens
Peptides derived from nucleosomes, Sm Ag, Igs,
16/6 idiotype, spliceosomes
Cell surface receptor
activation inhibition
Syk-kinase inhibition; sirolimus
MOA=mechanism of action; Ig=immunoglobulin; mAb=monoclonal antibody; Sm Ag=Smith
antigen; ICOS=inducible costimulator; TACI=transmembrane activator and CML- interactor;
BAFF RFc=B cell activation factor-rosette-forming cells.
Wallace. BMC Med. 2010;8:77.

24. But we keep chugging on!

25. Lupus Clinical Investigators Network
• How LUCIN plans to overcome obstacles:
- Outstanding investigators
- Ongoing education for investigators and study personnel
- Financial support to trials sites to be enrollment ready
- Ongoing communication using social media (linkdn)
- Support by patient network
- Free access to data

26. High priority targets for LUCIN
• Biologics:
• Ustekinumab (Stelara)
• Rock2 inhibitor KD-025
• Complementary and alternative medicine
• Krill oil
• Kriya Kirtan meditation
• Small molecules
• Quinacrine, fingolimod, Baracitinib, ibrutinib

27. SLE Treatment Acceleration trials (STAT)
• Small focused biomarker rich studies- proof of concept
only
• Even if the trials do not meet full FDA approval, the data
should be robust to allow patients to have access to these
drugs and pharma to feel encouraged enough to do these
trials

28. Select Recent DATA

29. THE VITAMIN D STORY

30. Increased serum interferon α (IFNα) activity is associated with vitamin D
deficiency and increased number of autoantibody specificities.
Ritterhouse L L et al. Ann Rheum Dis 2011;70:1569-1574
©2011 by BMJ Publishing Group Ltd and European League Against Rheumatism

31. Vitamin D - conflicting data
• Patients were randomized either to a placebo or a low
dose group (daily 2000 IU) or a high dose treatment group
(daily 4000 IU) for 12 weeks.
• 16/33 on the Vitamin D supplement regime showed an
increase >=30ng/mL of Vitamin D.
• No difference in IFN signature response between
those who showed VitD repletion versus those who
were deficient
• No change in baseline in any of the measures within
treatment groups and compared to the control.
Ref: C Aranow et al. Arthritis Rheumatol. 2015 Jul;67(7):1848-57

32. Periodontal disease - high frequency
• Peridontal disease is a common chronic inflammatory
disease that has been associated with RA, limited data
exists in relation to SLE
(de Pablo, Dewan, Dietrich, Chapple, & Gordon, 2015)
• 105 individuals within a total group size of 484
participants were identified as having SLE.
• The age-controlled prevalence of periodontal disease
was 85% in SLE patients compared with 55% of
controls
• Individuals with SLE were more likely to develop periodontal
disease, and results held true for women with SLE compared to
female controls
• There was no disease prevalence difference for severe periodontal
disease in controls versus SLE patients.

33. • 93 patients with lupus were randomly assigned to a
graded exercise program, relaxation program or usual
care
• 16/33 in the exercise group were “very much better”,
compared with 8/29 in relaxation group and 5/32 in the
usual care group.
• These results were statistically significant
Fatigue in systemic lupus erythematosus:
a randomized controlled trial of exercise
Tench, CM. Rheumatology, 2003 - 171.66.120.158

34. Cytokine and sTNFR responses to a single bout of acute moderate aerobic exercise in the
SLE group PRE and POST chronic exercise training program and in the HC group at baseline.
Luiz A. Perandini et al. J Appl Physiol 2014;117:639-647
©2014 by American Physiological Society

35. Diets
• Assessment of two different diets (a low glycemic index
(GI) and calorically restricted diet) have been evaluated to
reduce the fatigue in patients with SLE
(Ref: Davies et al., 2012)
• Low GI diet shows the carbohydrate intake was limited to
45g per day of low GI food, without restricting the
consumption of fat and protein.
• No caloric restriction – with estimated consumption of the diet being
10-15% from carbohydrates, 25% from protein, and 60% from
saturated and unsaturated fats.
• Control groups received a low calorie diet, being restricted to
2000kcal per day, with 50% coming from carbohydrates, 15% from
protein, and 30% from fat.
• Both diets showed a decrease in fatigue compared to baseline

36. ω-3-Polyunsaturated FattyAcids ↓SLE DiseaseActivity
(WrightSAetal,AnnRheumDis2008;67:841)
SLAM-R+
BILAG
statistically
significantly
different
from PBO

37. Psychological interventions
• Measurement of physiological function, life vitality,
depression, pain degree, disease activity, severity of
fatigue, and physical and mental outcomes.
• Psychological interventions employed – cognitive
behavioral treatment (CBT), theory-based educational,
self-management, or psychosocial interventions, and
biofeedback-CBT
• The duration of these interventions lasted from 6 weeks to 15
months.
• Psychological interventions significantly decreased
the level of depression and improved health status
• BUT there was no impact upon disease activity, level of pain, or
fatigue level
• CBT was shown to significantly reduce depression in SLE patients
Ref: International Journal of Nursing Sciences, 1(3), 298-305.

38.  Hard to define - major stress and minor stress.
 Psychological anxiety, high demand of self and job, poor
control of life, poor social support - these are surrogates that
are used to measure stress in scientific studies.
 There is a connection between stress and hormones - e.g.
cortisol
 Stress has not been shown to cause lupus in multiple
studies
 Stress can exacerbate lupus - shown in multiple studies
 Stress usually causes a worsening in the quality of life of
lupus patients
 Psychosocial factors can affect disease activity and quality of
life but not cause organ damage
 Coping with stress is associated with improvement in quality
of life.
Stress and Lupus
Neuroimmunomodulation 2006;13:283–293

39.  46 patients with lupus were followed for 6
months. They kept a daily diary of events and
had measurements of their lupus activity
through complement and DNA levels
 High intensity stressful events were not
associated with an increase in
symptomatology
 On the other hand, daily stress was
associated with worse symptoms and when
objective measures were performed, a
worsening of disease activity was noted.
The Effects of Daily Stress and Stressful Life Events on the
Clinical Symptomatology of Patients With Lupus Erythematosus
Psychosomatic Medicine 66:788-794 (2004)

40. Preventative strategies in SLE
• Patient education programs and support groups
• Involvement of patients in their own health
• Specialist access and interest from specialists (medical home)
• Aggressive vigilance for hypertension, hyperglycemia, hyperlipidemia,
obesity, smoking cessation
• Annual EKG, chest X-ray, duplex scanning, stress tests, 2-D echo for
pulmonary pressures in high-risk patients
• Prompt evaluation of all fevers
• Antiphospholipid antibody screening and prophylaxis
• Yearly bone densitometry and use of bisphosphonates
• Physical modalities: Exercise, PT, OT, ergonomic work stations
• Cognitive therapy (lupus fog), biofeedback (Raynaud’s)

41. AND DON’T FORGET
• Diet and exercise
• Diet and exercise
• Diet and exercise

42. What next?

61. Official Map of the Internet

65. Do you social network?