Latest in Lupus
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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.
Latest in 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
- 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?