Systemic Lupus Erythematosus: [Presenter Affiliation] What Providers Need to Know [Presenter Name] [Presenter Affiliation] Contributors: Irene Blanco, MD, Montefiore Medical Center; Al Denio, MD, Geisinger Medical Center; Sheetal Desai, MD, University of California at Irvine; Amanda Sammut, MD, Harlem Hospital Center

The Problem Lupus diagnosis may take 2-6 years1-5 and 3+ providers Delay may lead to organ damage and a 5 fold increased risk of death Patients go to primary care providers or emergency rooms at onset of illness, so detection of lupus by these providers is critical to early diagnosis These providers may have received only 45 minutes of training on lupus in medical school6 It is not a disease for just Rheumatologists or Nephrologists. Lupus is characterized by heterogeneous signs and symptoms, so most providers will encounter a lupus patient Providers in primary and emergency care are the gateway to treatment for most patients 1 Swaak et al. Systemic lupus erythematosus. I. Outcome and survival: Dutch experience with 110 patients studied prospectively. Ann Rheum Dis 1989;48:447-454 2 Pistiner et al. Lupus erthematosus in the 1980‘s. Semin Arthritis Rheum. 1991 Aug;21(1):55-64 3 Wallace et al. Systemic Lupus Erythematosus— survival patterns: Experience with 609 patients, JAMA 245: 934-938, 1981 4 Cervera et al. Systemic lupus erythematosus: Clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. Medicine 04/1993; 72(2):113-24. 5 Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. II. Predictor variables for mortality. J Rheumatol. 1995;22(7):1265-1270. 6 Survey data of program directors from ACR

The Consequence 46yo African American man presents to ER for a rash on his face and arms and a low grade fever. He was DC’d home with a cream. Months later he went to another ER with a recurrence of the rash and abnormal kidney function and creatinine of 3.0. He was told to follow up with his PCP. 3 months later, he was admitted with nausea, fevers and a malar rash. His BMP revealed ↑K and creatinine of 13.0 requiring dialysis. A kidney biopsy subsequently revealed class VI lupus nephritis.

Objectives After the presentation, participants should be able to: recognize the signs and symptoms of lupus perform a screening to aid diagnosis or management implement a process to appropriately refer patients to rheumatology

Assessment Thank you for taking our pre seminar assessment Data will be used solely to evaluate the content and delivery of the seminar

Systemic Lupus Erythematosus (SLE) Basics Inflammatory, multisystem, autoimmune disease of unknown etiology Can be a mild disease to a severe/life-threatening illness Diversity of clinical symptoms and all organ systems are vulnerable Onset may be abrupt or develop over time Characterized by periods of flare and remission (or low level activity) May culminate in irreversible end-organ damage 70% = Systemic lupus erythematosus 10% = Cutaneous lupus erythematosus (includes Discoid) 10% = Drug- induced lupus erythematosus 10% = Other overlap syndrome or mixed connective tissue disease (MCTD)

Epidemiology Prevalence: 2–140/100,000 worldwide but as high as 207/100,000 Incidence: 1–10/100,000 worldwide Health Disparities and At-Risk Populations: Women in their reproductive years Women are 9x more likely to develop lupus than men Non-Caucasians have the highest prevalence: Affects up to 1/250 Black women in US 2-3x higher risk than White women Asian and Hispanic Prevalence: More prevalent than AIDS, cerebral palsy, multiple sclerosis, sickle-cell anemia and cystic fibrosis combined. A health disparity is a particular type of health difference that is closely linked with social or economic disadvantage.  Health disparities adversely affect groups of people who have systematically experienced greater social and/or economic obstacles to health and/or a clean environment based on their racial or ethnic group; religion; socioeconomic status; gender; age; mental health; cognitive, sensory, or physical disability; sexual orientation or gender identity; geographic location; or other characteristics historically linked to discrimination or exclusion. Helmick CG, Felson DT, Lawrence RC, et al. Arthritis Rheum. 2008;58(1):15-25; Chakravarty EF, Bush TM, Manzi S, Clarke AE, Ward MM. Arthritis Rheum. 2007;56(6):2092-2094; Fessel WJ. Rheum Dis Clin North Am. 1988;14(1):15-23.

Health Disparities Specific racial/ethnic minorities: are more likely to develop lupus at a younger age are more likely to have more severe symptoms at onset have mortality rates at least 3 times as high as White individuals with lupus Poverty, race, younger age associated with poor outcomes Healthcare disparities refer to differences in access to or availability of facilities and services. Poverty is associated with a variety of poor outcomes in lupus Higher mortality Greater disease activity More disease-related damage Poorer physical function Worse health-related quality-of-life Higher rates of depression after disease onset Duran S, Apte M, Alarcón GS. J Natl Med Assoc. 2007;99(10):1196-1198; Ward MM, Pyun E, Studenski S. Arthritis Rheum. 1995;38(2):274-283; Alarcón GS, McGwin G Jr, Bastian HM, et al. Arthritis Rheum. 2001;45(2):191-202. McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK. Arthritis Rheum. 1995;38(9):1260-1270; Cooper GS, Parks CG, Treadwell EL, et al. Lupus. 2002;11(3):161-167. CDC. MMWR Morb Mortal Wkly Rep. 2002;51:371-374.

Importance of Early Referral and Prognosis Year 5 yr survival 10 yr survival Prior 1948 50% 1949 Steroids widely accessible 1969 Dialysis widely accessible 1971 77% 60% 1980-present Increased use of immunosuppression 2000-2007 95% 90% Mortality is higher in lupus patients compared to the general population 5-year survival rate in 1953 was 50%, increased to 90% with better detection and treatment Currently 80 to 90% of lupus patients survive 10 years after diagnosis, but that drops to 60% with advanced stages of organ threatening disease Leading causes of mortality are preventable Appropriate therapeutic management, compliance with treatment and improved treatment of long-term consequences can prevent excess and premature deaths. This starts with clinical suspicion of the diagnosis and early recognition. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus. Guidelines for referral and management of systemic lupus erythematosus in adults. Arth Rheum 1999;42:1785--96

What Causes Lupus? Genetically susceptible individual Environmental factors Auto antibody production Inflammation Damage GENETIC SUSCEPTIBILITY Rate of SLE concordance in monozygotic twins is 24%–35%; in dizygotic twins is 2%–5% 10%–12% of SLE patients have 1st- or 2nd-degree relatives with SLE compared with <1% in healthy individuals SLE patients may have family members with other autoimmune diseases PATHOGENESIS OF LUPUS Autoimmunity is an altered immune homeostasis that leads to auto-reactivity, immunodeficiency, and malignancy. Immune dysregulation leading to autoreactivity and autoantibodies in SLE occurs in different phases and likely represents the untoward effects of environmental triggers on the genetically susceptible host.

Diagnosis is Difficult There is no gold standard diagnostic test for lupus. The Great Masquerader: can mimic viral syndromes, malignancies, allergic reactions, stress, etc. Symptoms might: Be nonspecific Vary widely Develop slowly or come on suddenly Hard to diagnose even for Rheumatologists.

Lupus Mimickers Rosacea, dermatitis Vasculitis Behçets disease Inflammatory bowel disease Sjӧgren’s syndrome Multiple Sclerosis Infections (HSV) Fibromyalgia

Which Case Is Lupus? Case A 28 year old woman presents with fatigue and diffuse joint pain. She has had joint pain for 10 years but it is much worse now. She has migraines but no other symptoms. Exam shows no inflammation of joints, but she has multiple tender points. Case B 28 year old woman presents with fatigue and diffuse joint pain. Her joint pain started about 4 months ago and has become worse. She has noted some new sores in her mouth and has had a rash with sun exposure recently. Exam shows swelling at PIP joints of hands. Case B

Antinuclear Antibodies (ANA) Autoantibodies against various components of the cell nucleus Higher the titer, higher the specificity Titer not a measure of disease activity ANA Titer Normal Population 1:40 30% 1:80 11% 1:160 5% 1:320 <1%

ANA: Sensitive, Not Specific for SLE Low specificity: ANA usefulness increases if the pretest probability for lupus is high; ie, the patient has symptoms and signs that can be attributed to SLE High sensitivity: a patient with negative ANA is unlikely to have lupus even when her/his clinical presentation is suggestive of lupus Interpret the ANA in context of clinical complaints +ANA ≠ SLE

ANA Associated Conditions Rheumatic Conditions Auto- Immune Misc Lupus Polymyositis Grave’s Aging Drug-induced Lupus Dermato- myositis Primary Biliary Cirrhosis Primary Pulmonary HTN Scleroderma RA Hashimoto Thyroiditis Sjogren’s Vasculitis Autoimmune Hepatitis MCTD MS What is the most common cause of a positive ANA in the primary care setting? Hashimoto’s Thyroiditis- 50% have a positive ANA! Present in autoimmune disorders and some healthy subjects: Non-lupus subjects 3%−4% SLE 95%−99% Scleroderma 95% Hashimoto’s thyroiditis 50%. Idiopathic pulmonary fibrosis 50% Incidence increases with age, chronic infections, and other chronic conditions

Question? Which ANA result is most likely NOT a false positive: a. ≥1:1280, homogenous  in a 20 year old female with joint pain and 2+ proteinuria. b. 1:160, speckled in a 85 year old male with no other symptoms  c. 1:80, speckled in a 32 year old female with arthralgia/myalgia, sleep difficulty and fatigue.  d. 1:40, homogenous in a 35 year old female with low back pain Answer A

Clinical Associations Autoantibodies in SLE Antibodies Lupus Specificity Clinical Associations ANA Low Nonspecific Anti-dsDNA High Nephritis Anti-Sm Anti-RNP Arthritis, myositis, lung disease Anti-SSA Dry eyes/mouth, subacute cutaneous lupus erythematosus (SCLE), neonatal lupus, photosensitivity Anti-SSB Same as above Antiphospholipid Intermediate Clotting diathesis

Clinical Associations Autoantibodies in SLE Antibodies Lupus Specificity Clinical Associations ANA Low Nonspecific Anti-dsDNA High Nephritis Anti-Sm Anti-RNP Arthritis, myositis, lung disease Anti-SSA Dry eyes/mouth, subacute cutaneous lupus erythematosus (SCLE), neonatal lupus, photosensitivity Anti-SSB Same as above Antiphospholipid Intermediate Clotting diathesis

Is this a Case of Lupus? 23yo female who presents with fatigue and arthralgias. Feeling has been going on for several months. She is a college student and not sleeping very well trying to finish her senior project. ROS: + fatigue, + feeling “a bit feverish”, +joint aches in the back and neck, + occasional chest pain and shortness of breath, + redness over her face when she goes out into the sun PE: AVSS, exam is unremarkable Labs: wbc: 3.5 hgb: 9.0 plt: 150, ANA: 1:80, +SSA

Wide Variety of Organ Involvement Raynaud’s & vasculitis Eyes Skin Pleurisy Kidney disease Central nervous system Oral & nasal ulcers Pericarditis Blood disorders Joints & arthritis Muscle Medical Illustration Copyright © 2012. Nucleus Medical Media. All rights reserved.

Jaccoud’s arthropathy Lupus on the Outside Malar rash Synovitis Painless oral ulcer Discoid rash Alopecia Vasculitis Jaccoud’s arthropathy Raynaud’s Phenomenon

Classification Criteria Systemic Lupus International Collaborating Clinics (SLICC) SLE considered if: Biopsy proven lupus nephritis with + ANA or Anti- DNA OR > 4 criteria (at least 1 clinical and 1 laboratory) ACR Criteria At least 4/11 criteria met Stress that there are no diagnostic criteria for SLE- only classification criteria for research which can be used to make a clinical diagnosis.

Classification Criteria 1997 ACR criteria versus 2012 SLICC criteria Criteria Sensitivity Specificity Misclassified Cases ACR criteria 267/310 (86%) 365/392 (93%) 70 SLICC criteria 292/301 (94%) 361/392 (92%) 49 Petri M et al. Arthritis Rheum. 2012:64(8)2677

SLICC Clinical and Immunologic Criteria > 4 criteria (at least 1 clinical and 1 laboratory) Clinical Acute cutaneous lupus Chronic cutaneous lupus Oral or nasal ulcers Non scarring alopecia Arthritis Serositis Renal Neurologic Hemolytic anemia Leukopenia Thrombocytopenia (<100,000/mm3) Laboratory ANA above lab ref range Anti-dsDNA above lab ref range (or 2x ref range if tested by ELISA) Anti-SM Antiphospholipid antibody Low complement (C3,C4,CH50) Direct Coombs’ test (do not count in the presence of hemolytic anemia) Stress that there are no diagnostic criteria for SLE- only classification criteria for research which can be used to make a clinical diagnosis

ACR Criteria 4/11 needed to suspect lupus 7. Proteinuria Malar rash Discoid Rash Photosensitivity Oral ulcers Arthritis Serositis 7. Proteinuria 8. Seizures or Psychosis 9. Hemolytic anemia, or cytopenias 10. Antinuclear antibodies (ANA) 11. Anti-dsDNA, anti-Smith ab, or antiphosphoplipid antibodies OLD ACR criteria: 1997 Serositis: Pleuritis/Pericarditis > 1 day on exam or ECG Oral ulcers: non vasculitis or infection, usually painless Arthritis: > 2 joints swelling or tender with AM stiffness for > 30 minutes Photosensitivity: Unusual reaction to sun exposure Blood disorder: Immune-mediated hemolytic anemia, leukopenia (< 4 × 103 cells/µL on >1 occasion), lymphopenia (< 1500 cells/µL on >1 occasion), thrombocytopenia (< 100 × 103cells/µL in the absence of offending medications)   Renal involvement: Proteinuria (>0.5 g/day or 3+ positive on dipstick testing) or cellular casts (including red blood cells [RBCs], hemoglobin, granular, tubular, or mixed) Antinuclear antibodies (ANA): Higher titers generally more specific (>1:160) in absence of medications associated with drug-induced lupus. Immunologic disorder: anti-DNA antibody, anti-Sm antibody, or antiphospholipid antibodies, low complements, biologic false-positive serologic test results for syphilis Neurologic disorder: Seizures, psychosis, mononeuritis, myelitis, acute confusional state in absence of other causes Malar rash: Fixed, flat or raised, erythema over cheeks and nose Discoid rash: Raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring Tan EM, Cohen AS, Fries JF, et al. Arthritis Rheum. 1982;25:1271-1277. Hochberg MC. Arthritis Rheum. 1997;40:1725. [Letter].

When to Suspect SLE Symptoms Malar rash, rash with sun exposure (acute cutaneous lupus) Discoid rash (chronic cutaneous lupus) Oral or nasal ulcers Non scarring alopecia Synovitis (>2 joints) Raynaud’s phenomenon Serositis Proteinuria (Renal) Neurological problems (unexplained) Hemolytic anemia (low blood counts) Leukopenia/lymphopenia Low platelets ANA Gender Age Race History

Case Presentation A History: A 23-year-old Hispanic woman with no past medical history presented to a primary care physician (PCP) with an 8-week history of: Fever Myalgias Weight loss Facial rash She was treated for “cellulitis” with oral Keflex. Two days later, she was seen in the emergency department (ED) with a temperature of 103F, proteinuria, and anemia. She was told it was a “viral syndrome” and discharged home. Putting it all together… a typical patient journey Issue: Many times we overlook these “nonspecific” symptoms – these symptoms may have been overlooked because she is a young girl who “wants to look good” so the physician thought nothing of it.

Case Presentation A (cont.) She went back to the local clinic with pleuritic chest pain and exam revealed: T 100.2 F BP 130/90 Ulceration on the palate Malar rash Diffuse lymphadenopathy What exam findings are concerning for lupus? What symptoms of lupus did this patient present with?

Case Presentation A (cont.) Labs: WBC 2.5x109/L Total protein 9 g/dL Albumin 3 g/dL Hgb 10g/dL Hct 32% BUN 11 mg/dL Cr 0.6 mg/dL UA: 100 mg/dL protein RBC 20–40/hpf WBC 0–1/hpf ANA+ What is concerning for lupus in labs? What do you do next?

Case Presentation B 23 year old woman from Western Africa with recently diagnosed anemia (presumed but not confirmed to be iron- deficiency anemia), presents with swelling of her feet and a non-specific rash on her face and arms. She also reports generalized body aches, joint swelling, and noticed “bumps” on her neck, which on exam was confirmed to be lymphadenopathy. What is concerning for lupus? Discussion of case Notes from Amanda Sammut: This was a patient who actually was seen in a primary care clinic but was not seen by a rheumatologist. She had Class IV lupus nephritis but her symptoms were not taken as seriously as they should have been – a young woman with swelling, lymphadenopathy, etc. I ask the audience to think about what in the case makes them think of lupus. I try make sure that this is a patient they would urgently refer or call me about. Then I tell them about how she had active class IV LN and those are the symptoms she had.

Case Presentation B Chart review reveals: ANA of 1:1280 4.2 WBC with normal differential Hb/Hct is 9.6/30.4 MCV 77.3 Plt 307 What is concerning for lupus? What do you do next? Discussion of case Notes from Amanda Sammut: This was a patient who actually was seen in a primary care clinic but was not seen by a rheumatologist. She had Class IV lupus nephritis but her symptoms were not taken as seriously as they should have been – a young woman with swelling, lymphadenopathy, etc. I ask the audience to think about what in the case makes them think of lupus. I try make sure that this is a patient they would urgently refer or call me about. Then I tell them about how she had active class IV LN and those are the symptoms she had.

Screening and Referral Procedure

Contact Rheumatology

Assessment Thank you for taking our post seminar assessment and evaluation Data will be used solely to evaluate the content and delivery of the seminar Stay tuned for a 6 week post seminar assessment and evaluation