Systemic Lupus Erythematosus

Systemic Lupus Erythematosus Catherine Van, PharmD, BCPS Assistant Professor, Pharmacy Practice West Coast University School of Pharmacy Learning Objectives •Identify risk factors associated with systemic lupus erythematosus (SLE) •Recognize SLE clinical presentations, diagnosis, and treatment goals •Examine management strategies for SLE and its manifestations •Formulate appropriate treatment plan for a patient diagnosed with SLE Readings DiPiro et al. (2020) Pharmacotherapy: A Pathophysiologic Approach, 11th Edition. McGraw-Hill. Chapter 103 (available through Access Pharmacy) DiPiro et al. (2023) Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw-Hill. Chapter 107 (available through Access Pharmacy) Introduction/Epidemiology •Systemic lupus erythematosus (SLE): autoimmune disease associated with autoantibody production •Occur most frequently in women of reproductive age (15–45 years old) •Rates are nine times higher in women than in men •Most common in those of African origin, but is also more common in people of Asian, Arab, Hispanic background, and Native Americans than in White people •Standardized mortality ratio 2 to 3 times higher than in the general population o Related to more CVD, renal disease, and infections •SLE survival is 95% at 5 years and 92% at 10 years after diagnosis •Most common and serious type of lupus o Other types: cutaneous lupus erythematosus, drug-induced lupus, neonatal lupus Dipiro 11th ed. Chapter 103.; Dipiro 12th ed. Chapter 107; CDC. Lupus. https://www.cdc.gov/lupus/index.html - * Drug-Induced Lupus Accounts for 10%-15% of cases of SLE TNF-α inhibitors Produce autoantibodies Infliximab (Remicade/Inflectra) Etanercept (Enbrel) Adalimumab (Humira) Dipiro 11th ed. Chapter 103. want lupus to D/ the drug affecting Drugs Procainamide (~20%) Hydralazine Isoniazid Quinidine Methyldopa Propylthiouracil Methimazole * Risk Factors •Gender (female): hormones play a role; presence of X chromosomes •Ethnicities Most common in those of African origin, but is also more common in people of Asian, Arab, Hispanic background, and Native Americans than in White people •Genetic influences o First-degree relatives of patients with SLE are 20 times more likely to develop the disease o 10% of patients with SLE have relatives with the disease o Major histocompatibility complex (MHC) class II alleles HLA-DR2 and HLA-DR3 known to be linked to SLE •Epigenetic regulation of gene expression (hypomethylation of DNA, histone modifications) Dipiro 11th ed. Chapter 103.; Dipiro 12th ed. Chapter 107 Risk Factors (Cont.) •Environmental factors o Cigarette smoking o UV light: cause DNA damage and keratinocyte apoptosis with the release of cytokines and stimulation of the immune system causing skin injury and possible systemic flares o Viruses (Epstein–Barr virus infection) o Others: air pollution; silica and asbestos; heavy metals such as uranium, cadmium, and lead; polycyclic aromatic hydrocarbons used to make dyes, plastics, and pesticides Dipiro 11th ed. Chapter 103.; Dipiro 12th ed. Chapter 107 Pathophysiology Fi Dipiro 12th ed. Chapter 107 Clinical Presentation/Diagnostic Tests •Symptoms Fatigue, depression, anxiety, photosensitivity, joint pain, headache, weight loss, nausea/abdominal pain •Signs Rash, alopecia, fever, oral and nasal ulcers, arthritis, renal dysfunction, seizure, psychosis, pleuritis, pleural effusion, cardiovascular disease, pericarditis/myocarditis, heart murmur, hypertension, anemia, leukopenia, thrombocytopenia, lymphadenopathy, Raynaud’s phenomenon, vasculitis •Diagnostic Tests Serology: autoantibodies, antiphospholipid antibodies, complement, inflammatory markers (CRP, ESR), blood chemistries, CBC, UA, LP, renal biopsy Dipiro 12th ed. Chapter 107 2012 SLICC Classification Criteria for SLEs Clinical Criteria I criteria 1. Acute cutaneous lupus 2. Chronic cutaneous lupus 3. Oral or nasal ulcers 4. Non-scarring alopecia 5. Synovitis involving two or more joints 6. Serositis 7. Renal 8. Neurologic 9. Hemolytic anemia 10. Leukopenia (< (< 1000/mm3) 4000/mm3) or lymphopenia 11.Thrombocytopenia (<100,000/mm3) Immunologic Criteria Contend 1. Antinuclear antibody (ANA) above lab reference range 2. Anti-double-stranded DNA (dsDNA) above lab reference range 3. Anti-Sm 4. Antiphospholipid antibody 5. Low complement (low C3, C4, CH50) 6. Direct Coombs test (in the absence of hemolytic anemia) At least four criteria, including at least one clinical and one immunologic criterion OR biopsy-proven lupus nephritis with positive ANA or anti-dsDNA required for diagnosis Petra M, et al. Arthritis and Rheumatism. Aug 2012. ACR Revised Criteria for SLE Classification 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Nonerosive arthritis 6. Pleuritis or pericarditis At least 4 of the 11 ACR criteria required for diagnosis 7. Renal disorder 8. Neurologic disorder 9. Hematologic disorder 10. Immunologic disorder 11. Positive antinuclear antibody Hochberg, MC. ACR Revised Criteria for the Classification of SLE. Arthritis Rheum 1997; 40: 1725. Treatment Goals and Prognosis Treatment Goals Prevent disease flares and organ system involvement Decrease disease activity and prevent damage Achieve and maintain remission Reduce corticosteroid use Improve quality of life, while minimizing adverse effects and costs Prognosis Depends on disease severity and type/extent of organ involvement Disease limited to skin & musculoskeletal findings has better prognosis Worst seen with CNS or renal involvement Dipiro 11th ed. Chapter 103. General Approach Lifestyle Modifications Protection from the sun Smoking cessation Exercise Weight control Importance of immunizations Treat comorbidities Hypertension Hyperlipidemia Depression Dipiro 12th ed. Chapter 107 Immunizations •Patients with SLE at increased risk for infections because of immune dysfunction caused by the disease itself and immunosuppressive therapy the patients receive •Recommended that SLE patients receive: o Pneumococcal vaccine o Annual influenza vaccine o Hepatitis A and B vaccines (if at risk) •Live-attenuated virus vaccines are CONTRAINDICATED in patients receiving immunosuppressive therapy o MMR, varicella, intranasal influenza, yellow fever •Inactivated vaccines should preferably be given 2 weeks before starting immunosuppressive drugs •Live vaccines should be given at least 4 weeks before starting immunosuppressive drugs or 1 month after stopping them, depending on the duration of drug effects Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107 Pharmacologic Treatment Corticosteroids Biologics belimumab (BEL) rituximab (RTX) anifrolumab (ANI) Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107 Antimalarials hydroxychloroquine (HCQ) Immunosuppressants cyclophosphamide (CYC) mycophenolate mofetil (MMF) azathioprine (AZA) methotrexate (MTX) calcineurin inhibitors (CNI) (cyclosporine, tacrolimus, voclosporin) Hydroxychloroquine (Plaquenil) •Has anti-inflammatory, immunomodulatory, and antithrombotic effects •Primarily eliminated by the kidneys and has a long tissue half-life of about 40 to 50 days *•May take 2 to 8 weeks to see the therapeutic effects of hydroxychloroquine and up to 3 to 6 months for maximum clinical efficacy D •Has FDA approval for lupus erythematosus (including SLE) •Dose: 200 to 400 mg PO daily as a single daily dose or in 2 divided doses; administer with food or milk ⑮•ADR: retinal toxicity o Risk for retinal toxicity increased with doses >5 mg/kg/day actual body weight, more than 5 years therapy, renal or macular disease, or concurrent tamoxifen use, kidney impairment o Daily dose should not exceed 5 mg/kg/day actual weight or 400 mg (whichever is lower) to minimize retinopathy risk I Dipiro 11th ed. Chapter 103.; Dipiro 12th ed. Chapter 107; Lexicomp Belimumab (Benlysta) IgG1-lambda monoclonal antibody Promote apoptosis of B-cells * Has FDA approval for lupus nephritis and SLE treatment Dose • 10 mg/kg IV Q2 weeks x 3 doses, then Q4 weeks o IV infusion over 1 hour; consider premedication to prevent infusion and hypersensitivity reactions • 200 mg SQ once weekly • Switching from IV therapy: Administer the first SubQ dose 1 to 4 weeks after the last IV dose Onset of action: 8 weeks to deplete B Cells, 16 weeks for clinical response Esi[ Volume of Distribution: 5 L, half-life 19.4 days (IV) Warnings Serious (sometimes fatal) infections, hypersensitivity reactions, malignancy, psychiatric events Dipiro 11th ed. Chapter 103.; Lexicomp Anifrolumab (Saphnelo) •Fully human IgG1κ monoclonal antibody that targets type I interferons through binding the type I interferon receptor subunit 1 D •Has FDA approval for treatment of moderate to severe SLE in adults who are receiving standard therapy •Dosing: 300 mg IV every 4 weeks Dipiro 12th ed. Chapter 107; Lexicomp Calcineurin Inhibitors (CNI) •Decrease inflammation and proteinuria •Voclosporin (Lupkynis): first oral drug approved by FDA for treatment I of active lupus nephritis o Analog of cyclosporine with much higher immunosuppressive effect o Used in combination with mycophenolate mofetil and corticosteroids; initial dose: 23.7 mg PO BID o Dose adjustment needed for renal or hepatic impairment o Do not use if baseline BP >165/105 mm Hg or baseline eGFR ≤45 mL/min/1.73 m2 o Administer on an empty stomach as close to every 12 hours as possible, but * with a minimum of 8 hours between doses ▪ Swallow capsules whole; do not crush, divide, or open ▪ Avoid grapefruit and grapefruit juice & Dipiro 12th ed. Chapter 107; Lexicomp Calcineurin Inhibitors (CNI) – Cont. • Tacrolimus: Fgi o Has different structure with higher immunosuppressive effects and less nephrotoxicity than cyclosporine o Most of the tacrolimus studies have been conducted in Asian populations o Has been used as monotherapy for induction and maintenance therapy o Also been used in combination with mycophenolate mofetil for induction therapy for patients with nephrotic range proteinuria Dipiro 12th ed. Chapter 107 Adverse Drug Reactions ABOLD Drug ADR Monitoring NSAIDs GI bleeding, hepatic toxicity, renal toxicity, HTN CBC, PLTS, SCr, UA, AST/ALT, BP Glucocorticoids, systemic Osteoporosis, cataracts, glaucoma, hyperglycemia, HTN, dyslipidemia, thinning of the skin, weight gain, sleep/mood disturbances BP, glucose, lipids, bone densitometry, ophthalmic exams Glucocorticoids, topical Skin atrophy, telangiectasias Skin appearance Hydroxychloroquine Retinal toxicity, nausea Fundoscopic and visual field exams, CBC, AST/ALT, albumin, SCr, Chem panel Belimumab Infusion reactions, hypersensitivity, nausea, diarrhea, fever, nasopharyngitis, bronchitis, insomnia, depression, migraine, pain in extremity Monitor for serious infections, hypersensitivity/ infusion reactions, worsening depression, mood changes, or suicidal thoughts Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107; Lexicomp Adverse Drug Reactions DBOLD Drug ADR Monitoring Anifrolumab Upper respiratory tract infections, infusion-related reaction, herpes zoster, malignant neoplasm, anaphylaxis, angioedema S/Sx’s of hypersensitivity and infection Voclosporin (>10%) Hypertension, diarrhea, UTI, anemia, headache, mean glomerular filtration rate decreased, cough; QT prolongation, hyperkalemia, neurotoxicity BP, eGFR, potassium, s/sx’s of infections, malignancy, neurotoxicity, ECG CI: concomitant use of CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin) BBW: Increased risk for developing malignancies and serious infections Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107. Lexicomp Adverse Drug Reactions D Drug BOLD ADR Cyclophosphamide Myelosuppression, opportunistic infections, hemorrhagic cystitis, bladder malignancy, (cancer agent) infertility CI: urinary outflow obstruction Monitoring CBC, PLTS, SCr, AST/ALT, urine cytology, urinalysis Mycophenolate mofetil Myelosuppression, nausea, vomiting, diarrhea CBC, PLTS, SCr, chem panel, BBW: embryofetal toxicity; women of reproductive AST/ALT, chest xray REMS drug potential must be counseled regarding pregnancy prevention and planning; malignancies; serious infections Azathioprine Myelosuppression, hepatoxicity BBW: increased risk of malignancy CBC, PLTS, SCr, AST/ALT, chem panel, albumin, TPMT assay Methotrexate Hepatic, hematologic, pulmonary toxicity, stomatitis, embryofetal toxicity CBC, PLTS, SCr, AST/ALT, albumin, Chem panel, Chest xray, Alk Phos, bilirubin Infusion reactions, infections, neutropenia, mucocutaneous reactions, fever, fatigue, PML, hepatitis B virus reactivation (Bold: BBW) CBC, PLTS, SCr, vital signs, HACA titers Has many BBW Rituximab Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107; Lexicomp Question Patients with SLE should be encouraged to stop smoking. Which of the following has been associated with smoking? A. Decreased effectiveness of hydroxychloroquine ↑ B. Decreased titers of anti-double-stranded DNA 4 C. Decreased incidence of hemorrhagic cystitis with cyclophosphamide ↑ D. Decreased cutaneous lupus disease activity Treatment of Non-Renal SLE Fis "Mild moderate , severe "given , •Mild: constitutional symptoms; mild arthritis; rash ≤9% BSA; PLTs 50-100 x 103/mm3; SLEDAI ≤ 6 •Moderate: moderate-severe (RA-like) arthritis; rash 9-18% BSA; PLTs 20-50 x 103/mm3; serositis; SLEDAI 7-12 •Severe: major organ threatening disease (cerebritis, myelitis, pneumonitis, mesenteric vasculitis); thrombocytopenia with platelets < 20 x 103/mm3; TTP-like disease or acute hemophagocytic syndrome; rash>18% BSA; SLEDAI > 12 Fanouriakis A, et al. Annals of the Rheumatic Diseases. 2024;83:15-29. Treatment of Non-Renal SLE Fanouriakis A, et al. Annals of the Rheumatic Diseases. 2024;83:15-29. Skin Lesions and Manifestations Cutaneous Malar or discoid rash Mouth/nasal sores Raynaud phenomena Cutaneous vasculitis Alopecia DBOLD Based on severity and extent Topical corticosteroids • May relieve itching, burning but may not provide adequate clearing of lesions when used alone • Low potency corticosteroid for use on thin skin such as face • Mid potency corticosteroid for trunk and extremities • High potency corticosteroid for thick-skin such as scalp, soles, palms • Creams and ointments for the body; foams or solutions for scalp Alternatives: topical calcineurin inhibitors – pimecrolimus or tacrolimus Antimalarials have photoprotective effects, commonly used as first-line systemic therapy for cutaneous lupus - hydroxychloroquine For refractory disease, may add: •Systemic immunosuppressants: corticosteroids, methotrexate, mycophenolate mofetil, or azathioprine •Immunomodulatory drugs (dapsone, thalidomide, or lenalidomide) •Biologics (rituximab, belimumab, or anifrolumab) •Oral retinoids Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107 Joint Pain Musculoskeletal Arthritis Arthralgia Myositis Dipiro 12th ed. Chapter 107 A BOLD Treatment can include low-dose glucocorticoids and antimalarials If inadequate, methotrexate can be added NSAIDs should be avoided or used with great caution because of adverse renal effects For refractory cases: leflunomide, azathioprine, mycophenolate mofetil, or tacrolimus may be tried D Lupus Nephritis Renal Proteinuria Hematuria RBC casts Nephrotic syndrome Elevated SCr All patients with nephritis should receive hydroxychloroquine to reduce damage and flares ACE-I or ARB can reduce proteinuria and delay progression of renal disease BP maintained < 130/80 Statin if LDL > 100 Immunotherapy based on histological findings of renal biopsy Histological Findings Induction therapy (6months) Class I and II No immunotherapy Class III and IV, Class V mixed with III/IV MMF or cyclophosphamide + glucocorticoids Class V (pure membranous) MMF + glucocorticoids Dipiro 12th ed. Chapter 107 Maintenance therapy: MMF or azathioprine Lupus Nephritis (Class III/IV) Fyi Classification of SLE Nephritis Fyi Class Class I Classification Minimal mesangial Class II Mesangial proliferative Features Normal light microscopy findings, abnormal electron microscopy findings Hypercellular on light microscopy Class III Focal proliferative Class IV Diffuse proliferative Class V Membranous <50% of glomeruli involved =50% of glomeruli involved Class VI Advanced sclerosing Predominantly nephrotic disease [may occur with class III or IV] =90% of glomeruli involved without residual activity Musa R, Brent LH, Qurie A. Lupus Nephritis. https://www.ncbi.nlm.nih.gov/books/NBK499817/ Neuropsychiatric Lupus Neurologic Seizure Psychosis Stroke Peripheral neuropathy ABOLD Antimalarials may decrease the risk for seizures and brain atrophy through their anti-inflammatory and antithrombotic effects Symptomatic treatment – antidepressants, anticonvulsants, antipsychotics as needed Underlying cause Inflammation or neurotoxic damage glucocorticoids +/- immunosuppressant (azathioprine or cyclophosphamide) Moderate-high titers of antiphospholipid antibodies and/or thrombosis Dipiro 11th ed. Chapter 103; Dipiro 12th ed. Chapter 107 Anticoagulants and/or antiplatelet SLE Medications and Pregnancy YBOLD •Hydroxychloroquine: can be continued throughout the pregnancy and may decrease the risk of flares, disease activity, and heart block in atrisk pregnancies •Potentially teratogenic drugs (methotrexate, mycophenolate, cyclophosphamide, and thalidomide) should be stopped before attempting pregnancy o Time before conception ▪ 1 to 3 months for methotrexate and thalidomide ▪ More than 6 weeks for mycophenolate ▪ 3 months for cyclophosphamide Dipiro 12th ed. Chapter 107 SLE Medications and Pregnancy – Cont. p •If flare occurs and immunosuppressive drug required during the pregnancy: o Azathioprine may be considered because limited placental transfer occurs, and the fetal liver is unable to metabolize to its active form ▪ Dose should not exceed 2 mg/kg/day o Calcineurin inhibitors (cyclosporine, tacrolimus) are alternative choices o If corticosteroids needed, maintenance doses should be kept as low as * possible (preferably 7.5 mg or less) o Fluorinated corticosteroids (such as dexamethasone or betamethasone) * cross the placenta and should be avoided o Cyclophosphamide should only be used during the second or third Fri trimester of pregnancy if alternatives failed and the mother’s life is in danger Dipiro 12th ed. Chapter 107 Question A patient has cutaneous lupus on her face and treatment is needed. She is very concerned about her appearance. Which of the following is most associated with causing skin atrophy and telangiectasias? A. Hydroxychloroquine steroids B. Methotrexate particularly C. Topical pimecrolimus D. Topical triamcinolone acetonide in Question Which of the following drugs used to treat SLE could be started before pregnancy and continued throughout pregnancy with the least potential for harm to a fetus? A. Cyclophosphamide B. Dexamethasone C. Hydroxychloroquine D. Mycophenolate mofetil