12/4) Chevalier Lecture: Systemic Lupus Erythematosus (SLE) Lupus (SLE): Chronic inflammatory autoimmune condition where Ab against “self” Ag are developed. Can be fatal!

- Risk Factors: Infection (EBV), UV light, Silica Dust, Drug-Induced (Vaccines/Biologics), Female (10x), Genetics - Cx/Pathogenesis: Susceptible individual (genetic or other risk factor) + Environmental Factor leads to immune

dysregulation in both B and T cells o B Cell Hyperactivity à antinuclear antibodies (ANA) directed against nuclear components of the cell o Formation of Immune Complexes (Ab+Ag) that accumulate in organs, leading to activation of

complement cascade, inflammation, and tissue injury - Sx/Clinical manifestations and presentation are varied as Lupus can fluctuate and change over time as a multi-

organ disease. As a result, therapy is specific to each patient’s condition o Constitutional Sx: Fatigue, Fever, Myalgia, Weight loss, Arthralgia, Skin stuff

§ Skin manifestations: Butterfly rash, Discoid lesions, Swelling (can’t fist) o Raynaud Phenomenon (20): Vasospasm of arteries in hands/feed leading to ßblood

flow, ulcers and gangrene may develop. Exacerbated by the cold and emotional stress § Tx: CCB (Nifedipine, Amlodipine)

o Hematologic: Anemia, Autoimmune Anemia (àHemolysis), Leukopenia, Thrombocytopenia o Renal: Lupus Nephritis (35%) o Cardiac: Pericarditis, Valvular disease, CADÝ o Thromboembolic Disease: Including the possibility of Antiphospholipid Ab Syndrome (APLS)

- Dx: First step is to test for ANA and find its titer (highest dilution level able to detect a response to Ag) o ANA titer > 1:80 is considered positive. Other diseases with ANA (Systemic Sclerosis, RA, Sjogren’s)

§ If patient is ANA positive, -OR- if they are Highly clinically presenting SLE Sx, then next step. o Anti-dsDNA: Highly specific for SLE and present in 70% of patients, it directly correlates with disease

activity so it can be monitored for disease progression, Affects the kidneys. Presence = Dx. o Antiphospholipid Ab (aPL): These are lupus anticoagulant, anticardioleptin, anti-b2-glycoprotein. If

these test positive à Very high risk of blood clots o Distinguishing from RA: Anti-CCP, if (-) points towards lupus, as in RA it is (+)

- Routine Labs: Complete Metabolic Panel (CMP), CBC w/ differential, Urinalysis (Kidney leaks) o Complements (C3/C4): Lowß, May indicate flare or increased risk of flare o ESR, CRP: If high, says inflammation is going on. o Anti-dsDNA: Correlates with disease activity, goal is undetectable levels

- Prognosis: Depends on how they present o Good Prognosis, 92% at 10 years: Skin or Musculo only, or Drug-Induced Lupus o Poor Prognosis: 88% at 10 years: CNS or Renal involvement

Goals of Treatment - Prevent disease flares and involvement of other organs (CONFINE LUPUS) - Achieve lowest possible disease activity to prevent organ damage - Minimize drug toxicity, minimize corticosteroid use - Improve QoL and Ensure long-term survival

Non-Pharmacologic Therapy: Avoid the Sun – Use Sunscreen (SPF>30). Have a balanced diet with hella VitD, Rest a lot, Exercise but avoid overexertion, Quit smoking now, Vaccinate early and treat your infections early Pharmacologic Therapy: Choose therapy based on organ system involved and activity/severity of the disease. Therapy is specific to each patient.

- FDA Approved Therapies: Limited to ASA, Pred, HCQ, and Belimumab… though these others are still “Standard of Care”. Why? Because insurance companies are a buncha assholes

- Defining a Flare: A measurable increase in disease activity in one or more organ systems, new or worsening S/Sx. Severity MILD Moderate Severe

Involves Skin, Joint, a little muscle. Some constitutional Sx.

Significant Constitutional, Musculoskeletal, Hematological, but not life-threatening

Life-threatening, Renal or CNS involvement

Preferred Tx HCQ ± NSAIDs ± Pred-(Low/Short-term) “Low” means £ 7.5mg/Qdaily “Short-Term” for Rheumo means <3mo

HCQ ± Pred-(Med/Short-term) May require a steroid-sparing agent if resistance case. “Med” means 7.5-15mg/Qdaily

Induction: High IV Roids + MMF (6mo) Maintenance: Transition to PO MMF/AZA and ßRoids Failure? Rituximab

- NSAIDs: First-line (combo) for arthritis, musculoskeletal sx, fever, serositis (inflammation of organ lining) o Low Dose ASA. Especially in patients with aPL, will decrease risk of clots o Risks: ßRenal function, may increase cardiac events, risk of bleeding, ulcers, bronchospasms

- Corticosteroids: First-line (combo) for disease flares and to maintain low disease activity o I-say-‘Roids-you-think-Taper: use lowest effective dose to maintain low disease activity. If opportune,

use steroid-sparing medications to eliminate steroids, except for as needed for flares. o AE: Insomnia, HT, Dyslipidemia, Hyperglycemia/DM, Cataracts, Infection, Myopathy, Stroke

§ Avoid live vaccines in Pred > 20mg/Qdaily - Hydroxychloroquine (HCQ): All patients should take HCQ unless ContraX

o Function: Anti-inflammatory, Immunomodulatory, Antithrombotic effects o AE: Well-tolerated, some GI effects (N/V/D). Monitor Ocular toxicity, yearly eye exam.

- Methotrexate (MTX): Used primarily for Arthritis and Skin, May not come into play until late moderate. o Dose: Starting dose PO 10mg/Qweekly. Once you hit 25mg/Qweekly, this is the max absorbable, may

need to do SubQ if you want to bypass GI disturbances or dose higher. o AE: Hematologic (bone marrow suppression) – decreased CBC. Hepatotoxic: No boozing

§ N/V/D, Alopecia, - Add Folic Acid (1-3mg/Qdaily) to minimize. o Cautions: Renal/Hepatic: Monitor organ function, Renal impairment prolongs half-life, ßdose.

§ Avoid Live vaccines if dose is 0.4mg/kg - Azathioprine (AZA): Inhibits DNA synthesis, decreases immune cell proliferation. Check Enzyme activity

o TPMT Assay: Low enzyme activity increases the risk of myelosuppression and hepatotoxicity o Xanthine Oxidase: Avoid XO inhibitors (Allopurinol), otherwise risk myelosuppression/hepatotoxicity o AE: N/V/D, take with food or divide doses o Serious Caution:

§ Hepatotoxicity: Monitor LFTÝ, Bilirubin. May be sx of Hepatosplenic T cell lymphomas § Hematologic Toxicity: Dose-related, monitor CBC and Hg § PML, Pericarditis, Malignancy, Infections,,, yea this is bad § Avoid live vaccines when dose > 3mg/kg AZA

- Mycophenolate (MMF) - Considered to be not as effective for joints as AZA or MTX. Hella AE o MoA: Inhibits inosine monophosphate dehydrogenase (IMPDH), thereby inhibiting de novo synthesis of

guanosine nucleotides, ßproliferation/differentiation of T and B cells § Induces activated T cell apoptosis, Inhibits adhesion molecule expression

o Dosing: Depends on their tolerance o AE: Potentially severe N/V/D, Hematologic-Neutropenia, Hepatotoxic, Malignancies, Infections

§ Avoid live vaccines. - Belimumab (Benlysta): Anti-BLyS human mAb

o MoA: Binds to soluble BLyS (B-lymphocyte stimulatory) thus inhibiting its action at BCR. This will increase the apoptosis of B cells (especially auto-reactive B cells), decrease their differentiation, Ig production, and production of the autoantibodies.

o Place in Therapy: Treats active SLE Ab+ (ANA or Anti-dsDNA) on standard therapy (excluding cyclophosphamide and rituximab)

o Dosing: LD then once monthly IV infusion. § Prior to Initiation: Labs – CBC, TB, HepB+C

o AE: Most common are mood changes, depression, suicidal ideation. Must assess patient beforehand for predisposing conditions. Otherwise, N/D, Fever, Insomnia, HA

§ Severe: Infection, PML, Malignancy, Infusion Rxns o ContraX: CNS Lupus or Lupus Nephritis (Severe+Active) o Avoid Live vaccines

- Rituximab (Rituxan): Anti-CD20 Chimeric mAb o MoA: Target B cells by binding to CD20, depleting them. o AE: Common are fever, chills, weakness, N, HA, Rhinitis, Pharyngitis

§ Severe Infusion rxn, especially on 1st infusion – Urticaria, Hypotension, Hypoxia, Cardiogenic shock, Death. à Premedicate with [DPH, Medrol, APAP]

§ Cardiac Risk – Cardiac Arrhthmias § Nephrotoic, Cytopenic, PML, SJS, TEN Basically everything

o Monitoring: Check HepB+C before starting therapy o Special: No need to monitor TB, this is the therapy of choice for patients treated for cancer < 5y

- Cyclophosphamide (Cytoxan, CYC) Cytotoxic Alkylating Agent – Inhibits DNA synthesis o Dosing: IV is preferred (PO available). Must prophylactically dose

with Zofran for severe Nausea § Prior to Dosing, Check: Renal function, CBC, UA

o AE: Hemorrhagic Cystitis (Stay hydrated), Sterility (harvest them eggs!), Malignancy, Cardiac toxicity, Leukopenia, Thrombocytopenia

o I see no reason why we would give this medication. Treatment Considerations

- Immunizations: Lupus patients are more susceptible to HPV, they do not clear the virus well à So we should vaccinate, though it will raise the risk of Thromboembolic events - especially when aPL

- Treat Comorbidities: Such as HT, Depression - Treat SLE Sequelae: Raynaud’s, APLS

Cutaneous Lupus (CL): 3 types, of which they are most often found on the head/neck, upper trunk, arms. - Treatment: If lifestyle modifications or topical therapies are ineffective, change to prescription

o Lifestyle Modifications: Avoid the sun, use sunscreen (SPF >30) o Topical Therapies: Corticosteroids, CNI

CNS Lupus: To properly treat this condition, must identify the source and nature of the problem. Treatment will be based on neurologic manifestations, often requiring symptomatic therapy (anticonvulsants, antidepressants)

- If it is Inflammatory: roids ± immunosuppression - Find Thrombosis or titers of aPL: Use anticoags ± inhibitors of platelet aggregation

Lupus Nephritis (LN): Must biopsy all patients with evidence of active LN, and all patients will receive HCQ - ACR Treatment Guidelines: Classifies LN, where I, II are not bad, VI means game over, your kidneys are fucked

o I,II: No immunosuppression required. This is called minimal mesangial LN o III,IV: Induction therapy (for 6mo) using MMF, then low dose maintenance o V: MMF + Pred

§ Improve? Switch Pred to AZA- § Not improve? Switch CYC to MMF, keep Pred, add GC pulse

- If LDL > 100mg/dL à Add statin therapy Managing Pregnancy in SLE: Major goal of this lecture. Pregnant women have a much higher rate of developing lupus.

- Mortality Risk: There is a high risk of developing Lupus and increased maternal morality. - Flares: SLE often flares during pregnancy/post-partum, though it is less likely if SLE is in remission at the time of

conception, moreso if stable for ³6mo. o APLS: Clot off plascenta and lose baby.

- Want to get pregnant? o Wait until it is ³6mo from a severe flare. o d/c teratogenic drugs at least 3mo prior to conception (MTX, MMF, CYC) o d/c biologics 3-6mo prior to pregnancy o Use low dose ASA to decrease the risk of preeclampsia and feta loss [Consider low MW Heparin] o May continue to use HCQ as it reduces the incidence of flares o If needed, roids can be used, use the lowest effective dose otherwise predisposing self to DM o If immunosuppression is needed, use AZA

Antiphospholipid Ab Syndrome (APLS): 40% of SLE pt have aPL, though not all will have APLS. - Dx: Must meet 1 lab criteria and experience at least 1 clinical event. Secondly, the lab criteria and clinical event

must be >12w apart but <5years. The guys who made these guidelines smoked crack, but I bet there’s some logic o Lab Criteria: Lupus anticoag, anticardiolipin Ab, Anti-b2glycoprotein (x2, q12w) o Clinical Events: Arterial or Venous Thrombosis, CVA, PE, Pregnancy complications (fetal death)

- Tx: Give low dose ASA for pt without hx of arterial or venous thrombosis o Have a TE event: Give warfarin with an INR goal of 2-3, they’ll be long-term anticoags.

Drug-Induced Lupus: ~common, presents as constitutional symptoms (rash, myalgia, arthralgia, weightß, fever) - Dx: Antibody to histones is an excellent indicator (>96%), though oddly, low incidence of anti-dsDNA. - Pathogenesis: Drug triggers immune response in a pt w/o hx of SLE

o Implicated drugs: Isoniazid, Penicllamine - Tx: d/c offending med, Sx usually resolve.