Systemic Lupus Erythematosus (SLE) Heidi Roppelt, MD Assistant Professor of Medicine Associate Program Director Division of Rheumatology Director of the osteoporosis Center

History of Lupus 1200 AD: Term lupus is used for the first time to describe ulcerations on the face, literally means wolf. – Skin rash, like a wolf, seems to eat away the skin and destroy it – Skin looked like it had been bitten away by a wolf – Frightening appearance of lupus sufferers- thought to look like werewolves.

History of Lupus First described by a British dermatologist: – multiple cases of similar skin lesions on face 1890s- Sir William Osler noticed patients with distinct skin lesions also had internal organ involvement LE cell seen as commonality of patients with lupus at the Mayo Clinic proteins against one’s own tissue (antibodies) were discovered specific for lupus – Steroids used for first time in these patients 1970s: Lupus Foundation Organized

SLE: Chronic, inflammatory, autoimmune disease affecting multiple organs LUPUS LUNGS HEARTKIDNEY BLOOD SKIN BRAIN LIVER/ PANCREAS JOINTS

Incidence of Lupus Affects approx 1 million Americans More than 16,000 new cases each year First degree relatives have a 3% chance of developing the disease Identical Twins: second twin developing disease is between 25-65%

Incidence in Populations In America: – Incidence of lupus between years of age is 1 in 700 Caucasian women – In African American women, it is 1 in 265 women Different Populations are affected differently: – Caucasians- blood and skin involvement – Hispanics- kidney involvement – African Americans- generally more aggressive disease involving all organs

Criteria for Lupus (4 of 11) Malar Rash Kidney Disease Discoid Rash Neurologic Disorder Positive ANA Hematologic disorder Photosensitivity Positive Antibodies Oral Ulcers Arthritis Serositis

Malar rash – Fixed erythema, flat or raised, over the face- sparing the nasolabial folds Discoid rash – Raised patches, adherent keratotic scaling,follicular plugging; frequently causes scarring Photosensitivity – Skin rash induced by sunlight Oral or nasopharyngeal ulcers – Usually painless Arthritis – Nonerosive, inflammatory in two or more peripheral joints Serositis – Pleuritis or pericarditis

Renal disorder – Persistent proteinuria or cellular casts Neurologic disorder – Seizures or psychosis Hematologic – Hemolytic anemia, leukopenia (<4,000/mm 3 ), lymphopenia (<1,500/mm 3 ), or thrombocytopenia (<100,00/mm 3 ) Immunologic disorder – Antibodies to dsDNA or SM or positive antiphospholipid antibodies (IgG or IgM antibodies, lupus anticoagulant, or false-positive serologic test positive serologic test for syphilis) Antinuclear antibody test – Positive

Epidermal Lesions Malar (Butterfly Rash) – 50 % of patients with lupus develop this after UV exposure – May proceed overt SLE by months or occur as acute manifestation – May last for hours to days and often reoccurs – Biopsy: Immunoglobulins and complements at dermal-epidermal junction: “Lupus-Band Test” – DDx: Rosacea, facial flushing, seborrheic, atopic, contact dermatitis

Malar Rash

Systemic lupus erythematosus: malar rash, face

Epidermal Lesions Discoid Lupus – Seen in 25 % of patients with systemic lupus – Can occur independent of SLE Low titer ANA and low titer Anti-Ro antibodies 10 % of these will progress to systemic lupus erythematosus – Usually seen on face, neck, scalp, and upper torso – Discrete, erythematosus, infiltrated plaques extending into hair follicles – Leave depressed scars, hyper/hypo pigmentation – DDx: Psoriasis, Eczema, Lichen Planus, and Actinic Keratosis

Photosensitivity Occurs in % of patients with SLE Development of erythematous, sometimes raised/ puritic rash approximately hours after sun exposure – UV-B light most commonly responsible Sunlight, fluorescent lights Glass inhibits its penetration – UV-A (some patients)

Systemic lupus erythematosus: photosensitive erythematosus rash, upper back

Epidermal Lesions Subacute Cutaneous Lupus – 10 % of systemic lupus patients will develop this lesion – 50 % of patients with this lesion will develop systemic lupus – Associated with more photosensitivity than systemic lupus patients – Affected areas: shoulders, neck, forearms, and upper torso – Face is generally spared – Scarring does not occur

Alopecia Occurs in majority of SLE patients Scarring – Discoid Lupus Non-scarring – Lupus Hair Thinning and breakage of hair at times of increased disease activity. Returns to normal once disease is quiescent – Telogen Effluvium (Premature Hair Loss) 3 months after stressful event- hair loss Glucocorticoids, Emotional Stress, Pregnancy, etc. Will grow back to normal

Raynaud’s Phenomenon Triphasic color change in fingers: – White  Blue  Red Occurs upon exposure to cold or even to emotional stress If begins later in life, can be a clue to underlying autoimmune disease which may develop in months- years

Raynauds Picture

Systemic lupus erythematosis: vasculitis, hands

Musculoskeletal Manifestations and Lupus Arthralgias Arthritis Osteonecrosis Myalgia Osteoporosis

Systemic lupus erythematosus: Jaccoud’s arthropathy

Systemic lupus erythematosus: interarticular dermatitis, hands

Hematologic Manifestations of SLE Anemia – Autoimmune Leukopenia – WBC < 4,000 Autoimmune thrombocytopenia – Usually correlates with disease activity Increased risk of clotting – Anticardiolpin antibodies – Lupus Anticoagulant

Antiphospholipid antibody syndrome: clinical manifestations Arterial thrombosis Venous thrombosis Valvular abnormalities Pregnancy loss and infertility Livedo reticularis Neurologic complications – cerebrovascular thrombosis – Chorea Catastrophic APS syndrome Thrombocytopenia

Clinical criteria Vascular thrombosis Pregnancy morbidity (a) One or more unexplained deaths of a fetus at or beyond the 10th week of gestation, or (b) One or > premature births at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, or (c) Three or > unexplained consecutive spontaneous abortions before the 10th week of gestation

Laboratory criteria Anticardiolipin antibody (IgG and/or IgM) medium or high titer, on 2 or more occasions, at least 12 weeks apart Lupus anticoagulant present in plasma, on 2 or more occasions at least 12 weeks apart Anti-b2 glycoprotein-I antibody (IgG and/or IgM) present on two or more occasions, at least 12 weeks apart Definite APS if at least 1 clinical criteria and 1 laboratory criteria are met

Kidney Disease and SLE Abnormal urinalysis +/- proteinuria present in 50% at diagnosis, eventually 70% Most renal disease occurs within the first 6-36 months 6 Classes of renal disease: Class I Minimal mesangial LN Class II Mesangial proliferative LN Class III Focal LN* (50% of glomeruli) III (A): active lesions III (A/C): active and chronic lesions III (C): chronic lesions

Kidney Disease and SLE 6 Classes of renal disease cont: Class IV Diffuse LN – Diffuse segmental (IV-S) or global (IV- G) LN – IV (A): active lesions – IV (A/C): active and chronic lesions – IV (C): chronic lesions Class V Membranous LN Class VI Advanced sclerosing LN

Heart Disease and SLE Increased incidence of Myocardial Infarctions – Higher cholesterol- need to monitor! Target LDL<100 even <80 – Can get direct involvement of blood vessels Pericarditis Valvular disease

Lung Disease and SLE Pleuritis – Pleuritic Chest Pain Acute Pneumonitis Acute Lung Hemorrhage Interstitial lung disease

Systemic lupus erythematosus: nervous system manifestations Seizures Headache Stroke syndromes Transverse myelitis (may be associated with APS) Aseptic meningitis Peripheral neuropathy Cranial neuropathy Mononeuritis multiplex Ataxia Psychiatric disorders

Gastrointestinal Manifestations of SLE Abdominal Pain (30%) – Serositis/ Peritonitis – Mesenteric Ischemia Dyspepsia Pancreatitis Abnormal Liver Enzymes

Menstrual Function, Menopause in SLE Menstrual Function – Menorrhagia- heavy menstrual flow (15%) – Amennorhea- autoimmune activity against ovaries or from immunosuppressive agents Menopause – Symptoms of SLE seem to lessen – Higher risk of osteoporosis – Higher risk of heart disease Oral Contraceptive Use – No increased risk of disease flares – Avoid in those with antiphospholipid positivity

Pregnancy and SLE Pregnancy is NOT advised during active disease Patient should be in remission for at least 6 months Disease can become very aggressive during pregnancy – Renal involvement – Neurologic Premature birth

Neonatal Lupus Rash that occurs in newborns Mothers are positive for specific antibodies seen in lupus (and also in Sjogren’s syndrome) – Anti-Ro/ SSA and Anti-La/ SSB antibodies Resolves in 6-8 months Child does NOT have lupus

Subacute cutaneous lupus

Autoantibody-disease associations: SLE and drug-induced lupus AntigenSLEDrug-Induced LE dsDNA40%No Histone70%>95% Sm antigen30%No RNP30%No SS-A/Ro35%No SS-B/La15%No

Drug-induced lupus: definite drug associations Hydralazine Procainamide Minocycline Chlorpromazine Isoniazid Penicillamine Methyldopa Interferon-alpha

Laboratory Data Non-specific Tests – ANA – Complement C3/ C4 – ESR Specific Tests (Antibodies) – Anti-double stranded DNA – Anti- Smith – Anti-ENA Ab (Anti-Ro/ Anti-La/ Anti-RNP)

ANA (Anti-Nuclear antibody) Studies have shown that 10-25% of normal, healthy people have a positive ANA Other situations in which ANA is positive – Autoimmune Diseases Rheumatoid Arthritis Scleroderma Thyroid Disease Autoimmune Hepatitis Sjogren’s syndrome – Infections – Certain medications – Advanced age Can I have SLE without a positive ANA? – Yes, but extremely rare

Treatment General management – Fatigue – Support groups – Avoid sun exposure – Minimize risk factors for cardiovascular disease – osteoporosis

Treatment NSAIDS – May cause aseptic meningitis and cognitive dysfunction – Monitor for renal, hepatic, GI side effects – monitor CBC, LFT’s, BUN/CR, urinalysis

Treatment Corticosteroids – Relatively low doses for treatment of Constitutional sx, arthritis, cutaneous manifestations, serositis – High doses for treating nephritis, cerebritis, hematologic abnl, vasculitis – Mainstay of therapy during pregnancy – Side effects: osteonecrosis, hyperglycemia, HTN, hyperlipidemia, osteoporosis

Treatment Hydroxychloroquine (plaquenil) – Prevent flares – Effective for rx of mild skin disease, arthritis, mild serositis, constitutional sx – May have antithrombotic effects, lipid lowering effects – Monitor for macular damage; fundoscopic/ visual field checks q6months

Treatment Azathioprine (Imuran) – Purine analogue inhibiting nucleic acid synthesis; affects humoral and cellular immunity – Steroid sparing agent for rx of non- renal manifestations of SLE, or nephritis – Bone marrow and GI toxicity

Treatment Cyclophosphamide – Most commonly used for treatment for severe organ system disease, and nephritis – Hemmorrhagic cystitis, bladder ca, gonadal toxicity Use of GNRH agonists, Mesna to prevent – Most commonly given monthly IV for six months

Treatment Other: – Mycophenylate mofetil (Cellcept) – Methotrexate – IVIG