Systemic Lupus Erythematosus (SLE) Epidemiology of SLE (United States)

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1 1:10-2:25pm Closing the Loop on Lupus: Primary Care s Key Role in the Elusive Diagnosis and Management of Patients SPEAKER Richard Sadovsky, MD Richard Furie, MD Disclosures This session is supported by an independent educational grant from GlaxoSmithKline The following relationships exist related to this presentation: Richard Sadovsky, MD: No financial relationships to disclose. Richard Furie, MD: No financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Systemic Lupus Erythematosus (SLE) Epidemiology of SLE (United States) Chronic, multisystem, inflammatory autoimmune disease Characterized by flares, spontaneous remission, and relapses Disease mechanisms include autoantibody formation May affect any part of the body, but often results in damage to: Skin* Joints* Kidneys Heart Lungs Nervous system PREVALENCE 161,000 (definite SLE) 322,000 with definite or probable SLE BY RACE AND GENDER 11,000 white men 7,000 African American men 80,000 white women 56,000 African American women Female to male ratio: 9 to 1 Mean age at diagnosis: 31 years *Most commonly affected tissues Wallace DJ. Lupus: The Essential Clinician s Guide. New York, NY: Oxford University Press; Helmick CG, et al. Arthritis Rheum. 2008;58: Ferri FF. Ferri s Clinical Advisor Elselvier, Philadelphia, PA

2 Disease Mechanisms in SLE Disease Activity Predicts Organ Damage and Death Increased disease activity is associated with significantly increased risk of organ damage and death A 1 point increase in adjusted BILAG score is associated with: 8% increase in the risk of any new organ damage 11% increase in risk of CV, pulmonary, or musculoskeletal damage 15% increase in mortality Percent Survival Time to SDI Δ 1 by Disease Activity Level* (N=350) High Low Length of Follow up (years) *Low disease activity = BILAG score 0 to <2.59; high disease activity = BILAG score when how.com/rheumatology/systemic lupus erythematosus disorders of immune mediated injuryrheumatology part 1/. Accessed April 20, SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index. Lopez R, et al. Rheumatology. 2012;51: Early Organ Damage Is Associated With Reduced 10 Year Survival Rate Initial SDI assessment performed 6 months after study enrollment Early organ damage defined as initial SDI 1 25% of patients with early damage died within 10 years vs 7.3% with no early damage (P=0.0002) Survival Probability Survival Probability in Patients With and Without Early Organ Damage (N=263) a Initial SDI=0, n=190 Initial SDI >0, n= Disease Duration (years) Case 1: Whitney 36 year old African American woman presents with a facial rash that started one month ago Physical exam: Symmetrical malar non pruritic rash, sparing nasolabial folds 2 oral ulcers Diffuse alopecia Medical history Arthralgia affecting multiple finger joints in both hands, for 1 year; responsive to NSAIDs Rahman P, et al. Lupus. 2001;10:93 96.

3 SLE: Common Lab Findings ESR Anemia ANA+ (>90%) Anti DNA ab+ (50 90%) C3, C4 Leukocytopenia Thrombocytopenia Hypergammaglobulinemia Antiphospholipid ab+ Proteinuria Challenges with SLE Diagnosis Onset is insidious Many symptoms are nonspecific (fatigue, rash, joint pain) Misdiagnosis is common Note: A positive ANA is just one indicator for SLE Missed diagnoses are common Symptoms are often nonspecific (fatigue, rash, joint pain) Considerable variations in symptoms and lab findings, both between and within patients Biomarkers may be normal early in the course of disease Habif T. Clinical Dermatology, 6 th ed. New York, NY: Elsevier, Whitney s Lab Results ANA: 1:160 Urine: 2+ protein ACR Criteria for SLE Classification Malar rash Photosensitivity Discoid rash Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder ANA Immunologic disorder Diagnosis based on 4 of 11 criteria Tan EM, et al. Arthritis Rheum. 1982;25: Hochberg MC. Arthritis Rheum. 1997;40:1725.

4 SLICC Criteria for SLE Classification Clinical Criteria Acute cutaneous lupus Chronic cutaneous lupus Nonscarring alopecia Oral or nasal ulcers Joint disease Serositis Renal Neurologic Hemolytic anemia Leukopenia or lymphopenia Thrombocytopenia SLICC = Systemic Lupus International Collaborating Clinics Petri M, et al. Arthrits Rheum. 2012;64: Immunologic Criteria ANA Anti dsdna Anti Sm Antiphospholipid antibodies Low C3, C4, CH50 Direct Coomb s test Diagnosis based on 4 of 17 criteria, including 1 clinical and 1 immunologic criterion OR biopsy proven lupus nephritis and positive ANA or anti dsdna Does Whitney Have Lupus? 36 year old African American presents with facial rash that started one month ago PHYSICAL EXAM # Criteria* Symmetrical malar non pruritic rash, sparing nasolabial folds 1 2 oral ulcers 2 Diffuse nonscarring alopecia 3 PAST MEDICAL HISTORY Arthralgias in both hands for 1 year; responsive to NSAIDs 4 LABS ANA: 1:160 5 Urine: 2+ protein 6 * Diagnosis based on 4 of 11 criteria Provisional Diagnosis of SLE Prompt Referral to Rheumatology for Confirmation and Initiation of Disease Modifying Treatment Roles of Primary and Specialty Care in SLE PCP Lupus Care Specialist Role of the Rheumatologist Primary Care SUSPECT SLE* Refer Mild Disease Increase in Disease Activity or Complications *Based on ACR or SLICC criteria. ACR Guideline Committee. Arthritis Rheum. 1999;42: Establish Diagnosis Assess Activity/Severity Establish Treatment Plan Monitor Disease Activity Frequently Management of Moderate/Severe Disease Management of Refractory/Serious Disease Confirmation of diagnosis Assessment of disease activity and severity General disease management Management of uncontrolled disease Management of organ involvement or life threatening disease Management/prevention of treatment toxicities Other specific circumstances Pregnancy Anti phospholipid antibody syndrome Surgery

5 Whitney s Rheumatology Visit Her diagnosis is confirmed; disease is assessed as mild She receives education about the disease and available treatments The rheumatologist works with her to establish an initial treatment plan SLE: Currently Available Treatment Options Establish diagnosis Determine likely prognosis Assess severity and organ involvement Lifestyle (eg, sun avoidance) Topical agents Symptomatic agents Manage comorbidities No Major Organ Involvement Antimalarials Low dose steroids Azathioprine/methotrexate Major Organ Involvement Cyclophosphamide (intravenous) Mycophenolate mofetil Calcineurin inhibitors (cyclosporine A or tacrolimus) Biologics (rituximab or belimumab) or Enroll in clinical trial *Only corticosteroids, hydroxychloroquine, and belimumab are FDA approved for treatment of SLE. Image adapted from Arthritis Research UK. professionals andstudents/reports/topical reviews/topical reviews spring 2013.aspx. Hydroxychloroquine* Corticosteroids* Azathioprine Methotrexate Leflunomide (lupus arthritis) Cyclophosphamide Mycophenolate mofetil Cyclosporine Tacrolimus Rituximab Belimumab* Medications for Treatment of SLE* Medication Uses Delivery Route Effects Hydroxychloroquine Long term protective effect for associated organ PO Multiple: immunomodulation without immunosuppression damage Glucocorticoids SLE without major organ damage (low dose) Lupus nephritis (higher doses) PO, IV (acute flare) Inflammation Immunosuppressants Azathioprine Cyclophosphamide Methotrexate Mycophenylate Tacrolimus Lupus nephritis Severe SLE PO Multiple effects NSAIDs Lupus joint pain PO Analgesic, anti inflammatory, antipyretic Belimumab SLE; Skin, mucosal, serositis IV, SC B cell activity (anti BLyS) Rituximab Refractory severe SLE IV B cell activity (anti CD20) *Only corticosteroids, hydroxychloroquine, and belimumab are FDA approved for the treatment of SLE Maidhof W, et al. PT. 2012;37: ; Lam NC, et al. Am Fam Physician. 2016;94: Glucocorticoid Treatment Hydrocortisone Prednisone Methylprednisolone Dexamethasone Betamethasone Multiple Agents Well Established Side Effects Well Established Benefits Anti inflammatory Immunosuppressive CV events Diabetes mellitus Osteoporosis, osteonecrosis Infections Glaucoma, cataracts Psychological disorders

6 Considerations for Starting HCQ Benefits Effective for early mild moderate disease Improvements noted in 70% within 12 weeks Associated with fewer thromboembolic events Decreases damage scores over time Decreased mortality rate Decreased disease activity during pregnancy without fetal harm Risks GI side effects Cardiac effects QT prolongation Retinal damage with long term use Rash Alopecia Myopathy/cardiomyopathy Cloroquine or hydroxychloroquine users Whitney starts: HCQ (200 mg/d) + prednisone (20 mg/d with a plan to taper, once her flare resolves) Broder A, et al. J Rheumatol. 2013J40(1):30 3. Shinjo K, et al. Arthr Rheum. 2010;62:pp SLE: General Management Education, counseling, support Exercise Diet Prevent sun exposure Avoid infection (vaccinate) General health maintenance: routine gynecologic visits, dental care, eye exams (especially for patients on HCQ or glucocorticoids) Ongoing Care and Monitoring of SLE All patients require ongoing education, counseling, support Lifelong monitoring is crucial for limiting flares and associated damage Complete ROS of potentially affected organs/systems Symptoms, eg: fever, weight change, fatigue Labwork: CBC, platelets, creatinine, urinalysis Adherence/side effects with medications Frequency of monitoring generally Q3 mo with active disease, Q6 mo with quiescent disease Frequency depends on SLE activity, severity, extent, response to treatment, type of treatment ACR Guideline Committee. Arthritis Rheum. 1999;42:

7 Labs Commonly Ordered for Lupus Monitoring In Primary Care CBC Leukopenia Anemia Thrombocytopenia CMP Renal function Liver function ESR and CRP Inflammation markers correlate with flares/disease activity dsdna, C3/C4 levels Levels correlate with flares, especially in lupus nephritis Spot urine protein/cr ratio in lupus nephritis ANA, anti Sm have limited utility for monitoring and can be expensive Whitney on Treatment At 6 weeks, rash has cleared, symptoms subsided Side effects: nausea, abdominal pain, improved by taking with food At 12 weeks: no SLE symptoms; begin steroid taper with input from the rheumatologist (or can refer) Now stable on HCQ Appears well, increased energy Whitney: 6 month Follow up Fatigue Right MCP joint pain, fullness Mild facial rash Labs CBC = WNL CRP = 15 mg/dl (N: <0.8 mg/dl) ESR = 75 mm/hr (NR: 0 20 mm/hr) CMP = WNL UACR = 25 mg/g (WNL) C3 = 66 mg/dl (NR: mg/dl) C4 = 13 mg/dl (NR: mg/dl) Whitney: Next Steps Referred back to the rheumatologist Switched to azathioprine (1 mg/kg/d); increased up to 1.5 mg/kg/d at 6 wk Restarted prednisone 20 mg/d Initially symptoms improved, but she s back in your office at 12 weeks with facial rash, fatigue, and shortness of breath

8 SLE: Currently Available Treatment Options Establish diagnosis Determine likely prognosis Assess severity and organ involvement Lifestyle (eg, sun avoidance) Topical agents Symptomatic agents Manage comorbidities No Major Organ Involvement Antimalarials Low dose steroids Azathioprine/methotrexate Major Organ Involvement Cyclophosphamide (intravenous) Mycophenolate mofetil Calcineurin inhibitors (cyclosporine A or tacrolimus) Biologics (rituximab or belimumab) or Enroll in clinical trial *Only corticosteroids, hydroxychloroquine, and belimumab are FDA approved for the treatment of SLE Image adapted from Arthritis Research UK. professionals andstudents/reports/topical reviews/topical reviews spring 2013.aspx. Hydroxychloroquine* Corticosteroids* Azathioprine Methotrexate Leflunomide (lupus arthritis) Cyclophosphamide Mycophenolate mofetil Cyclosporine Tacrolimus Rituximab Belimumab* Belimumab: BLISS 52 and BLISS 76 Trials: Primary Endpoint (SLE Responder Index) at Wk 52 BLISS 52 1 mg: P = mg: P = (n=287) 58% 51% 44% (n=288) (n=290) Navarra SV, et al; BLISS 52 Study Group. Lancet. 2011;377: Furie R, et al; BLISS 76 Study Group. Arthritis Rheum. 2011;63: n=288) BLISS 76 (n=290) 1 mg: P = mg: P = 0.02 (n=290) Efficacy of SC Belimumab in Reducing SLE Flares Role for Rituximab in SLE? Findings from the EXPLORER Trial Primary endpoint* not met; several proposed explanations Post hoc analyses Reduced risk of a subsequent first severe flare Lowered mean severe flare rates Efficacy signals in patient subsets, including African Americans and Hispanics Potential for use in steroid sparing treatment regimens and in patients with refractory disease Stohl W, et al. Arthritis Rheumatol. 2017;66: N=214 N=463 *P< 0.05; P < 0.01; P <0.001; P < *Achieving and maintaining clinical response at week 52, assessed using the BILAG index organ system scores Thanou A, Merrill JT: Nat Rev Rheumatol. 2014;10: Merrill JT, et al. Lupus. 2011;20: Merrill JT, et al. Arthritis Rheum. 2010;62:

9 More Treatments are Needed! What s on the horizon? Anti cytokines/anti interferons Anifrolumab Tocilizumab Cell activation inhibition Apremilast Baricitinib Evobrutinib Tofacitinib Anti Toll like receptor agents (target the innate immune system) Agents targeting mtor N acetylcysteine Rapamycin Toleragens Regirimod Costimulatory blockade Abatacept Case 2: Mindy 28 years old, Caucasian Diagnosed with lupus 9 months ago Has had mild disease responsive to HCQ + steroids; currently prescribed HCQ monotherapy Here for followup after an ED visit for a bad cold and pleuritic pain/shortness of breath ED CXR shows nothing specific; her cold is resolving, but the pain persists Labs: ESR = 35 mm/hr CRP 20 mg/dl C3 = 68 mg/dl C4 = 17 mg/dl Common Reasons Why Patients Stop Taking Their Medications Fear of potential side effects or becoming dependent on the medication Cost/lack of coverage Misunderstanding of what to expect (or not) Too many medications, too many pills, or too many doses/day Lack of symptoms Depression Medication Non adherence is a Problem in SLE US Medicaid data, New users of HCQ or immunosuppressive agents Non adherence rates 79% of HCQ users 83% of immunosuppressant users Nonadherence higher risks of ED visits, hospitalizations 2017 systematic review 2 11 studies Nonadherent patients: 43% 75% 33% discontinue treatment after 5 years 1. Feldman CH, et al. Arthritis Care Res ;67: Mehat P, et al. Arthr Care Res. 2017;69:

10 Improving Medication Adherence in SLE Patient education before starting treatment is key Convey benefits vs risks Emphasize the importance of achieving the best control possible to optimize short and long term outcomes Consider strategies known to improve adherence in chronic disease Motivational interviewing 1 Teach back method 2 Shared decision making 3 Motivational Interviewing Definition: A collaborative conversation between a practitioner and a patient that aims to strengthen the patient s motivation and commitment to change Four fundamental processes 1. Engaging 2. Focusing 3. Evoking 4. Planning 1. Zomahoun HTV, et al. International Journal of Epidemiology. 2017;46: Ha Dinh TT, et al. JBI Database System Rev Implement Rep ;14: Lofland JH, et al. Patient Prefer Adherence. 2017;11: Miller WR, Rollnick S. Motivational Interviewing: Helping People Change. 3rd ed. New York, NY: Guilford Press; Steps in Shared Decision Making Teach Back Method Intent: Increase understanding of disease information being communicated to patients by asking them to repeat back key points of the instruction Question examples Can you please tell me what we have discussed today? What can you tell your spouse/partner about changes in your medication? If patients respond with incorrect answers or seem to have difficulty understanding Identify what information needs to be repeated or clarified Continue until the patient answers correctly AHRQ. tools/shareddecisionmaking/index.html. Accessed April 18, Jager AJ, Wynia MK. J Health Commun. 2012; 17:

11 Other Interventions that Improve Adherence Technical (eg, simplifying dosage regimens and delivery) Behavioral (eg, reminders and incentives) Educational (eg, communications and technologies to improve knowledge and address concerns) Maintaining Treatment Adherence in SLE Once treatment is underway Don t assume patients are adherent Closely monitor response to treatment Continue to educate and communicate Interventions employing more than one approach are more effective Herriman E. IC Science Corp. 2007; 2(4). Available at Accessed April 15, Key Messages Lupus manifests in multiple ways Disease progression is heterogeneous Well coordinated multidisciplinary healthcare is essential All patients require lifelong monitoring Education/communication is needed to support adherence to medication and other interventions Goals of treatment are disease remission or low disease activity More treatments are needed Key Messages (con t) Most treatment and monitoring can take place in primary care, with input from the rheumatologist Patient communication is critical Discuss efficacy/safety Medications that are not taken will not work assess adherence Monitor (possible) side effects of medication Manage the whole patient

12 ACR Criteria for SLE Classification Malar rash Photosensitivity Discoid rash Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder ANA Immunologic disorder Tan EM, et al. Arthritis Rheum. 1982;25: Hochberg MC. Arthritis Rheum. 1997;40:1725. Diagnosis based on 4 of 11 criteria SLICC Criteria for SLE Classification Clinical Criteria Acute cutaneous lupus Chronic cutaneous lupus Nonscarring alopecia Oral or nasal ulcers Joint disease Serositis Renal Neurologic Hemolytic anemia Leukopenia or lymphopenia Thrombocytopenia SLICC = Systemic Lupus International Collaborating Clinics Petri M, et al. Arthrits Rheum. 2012;64: Immunologic Criteria ANA Anti dsdna Anti Sm Antiphospholipid antibodies Low C3, C4, CH50 Direct Coomb s test Diagnosis based on 4 of 17 criteria, including 1 clinical and 1 immunologic criterion OR biopsy proven lupus nephritis and positive ANA or anti dsdna