Systemic Lupus Erythematosus – Internal Medicine Board Review Rina Mina MD, MS Division of Immunology, Allergy and Rheumatology Lupus Clinic, University of Cincinnati

ABIM Blueprint Systemic lupus erythematosus (SLE) <2% Drug-induced lupus-like syndromes Complications Discoid lupus Undifferentiated systemic lupus erythematosus

Systemic lupus erythematosus (SLE) Drug-induced lupus Question 1: In which of these autoimmune diseases is a patient presentation without antinuclear antibodies (ANAs) most likely? Systemic lupus erythematosus (SLE) Drug-induced lupus Mixed connective tissue disease Sjögren syndrome

Disease Associated with Positive ANA SLE Active 98 to 100 Remission 90 Scleroderma 95 Rheumatoid arthritis 45 Sjogren's syndrome 60 Mixed connective tissue disease 100 Drug-induced LE 80 to 95 Raynaud's phenomenon 40 Polymyositis/dermatomyositis 35 Juvenile idiopathic arthritis 15 to 40 Organ-specific autoimmune diseases Hashimotos thyroiditis 50 Graves' disease Autoimmune hepatitis 70 Primary biliary cirrhosis 50 to 70

Disease Associated with Positive ANA Malignancies Lymphoproliferative diseases Paraneoplastic syndromes Miscellaneous diseases Inflammatory bowel disease Interstitial pulmonary fibrosis

Autoantibodies: ANA Elisa and IF A negative Anti-nuclear antibody (ANA) - SLE unlikely High specificity: anti-Smith and anti-dsDNA Parallel disease activity: anti-dsDNA (along with complement levels) 27 of 195 children of mothers with lupus had a positive test for ANA

ANA pattern

Deposit pattern Specificity Clinical correlation Dense fine stippled nuclear Non-specific Healthy population (Most common pattern) Centromeric nuclear Anticentromere CREST, limited scleroderma Homogenous nuclear Anti-dsDNA antibody DNA-histones SLE Drug-induced LE Diffuse stippled nuclear Anti-Sm Anti-RNP MCTD, SLE Fine speckled nuclear Anti-Ro/SSA and La/SSB SLE Subacute cutaneous LE, Neonatal LE, Sjögren's Nucleolar Anti-nucleolus Systemic sclerosis Overlap syndrome Fine stippled cytoplasmic Anti-Jo1 Polymyositis/DM Mixed deposit patterns Anti-Scl-70 Systemic Sclerosis, Overlap syndrome

Forms of Lupus Systemic lupus erythematosus (SLE) Cutaneous Lupus Discoid lupus Subacute cutaneous lupus Drug-induced lupus Neonatal lupus

Question 2 A 23 year old woman presented with painful joints, rash on the face and back, as well as extremity color change and mouth sore. She has also complained chest pain on inspiration.

Raynaud’s phenomenon

Systemic lupus erythematosus (SLE) Sjögren syndrome Question 2 Labs showed positive ANA with titer of 1:640; anti-dsDNA and anti-Smith were elevated. Scleroderma Systemic lupus erythematosus (SLE) Sjögren syndrome Inflammatory myositis

Systemic Lupus Autoimmune multisystem disease Inflammation/involvement of most organ systems with remissions and exacerbations Variable course and prognosis Immunologic aberrations give rise to excessive autoantibody production

Classification Criteria

Classification Criteria The criteria are useful They were designed for classification and not for diagnosis For mild cases and patients with early disease the classification might not be sensitive for diagnosis

Epidemiology Prevalence in USA: 20-150/100,000 Incidence: 1.8-7.6/100,000/person years Most studies of SLE-90% women Age 14-64: 6-10-fold female In USA: three times more common in -African-Americans (>Asians > Caucasians) Twin concordance-24-50% monozygotic vs. 2-5% dizygotic

Etiology Etiology is unknown and multifactorial Dietary factors Role for several factors: Genetic Hormonal Immunologic Environmental The mediators of SLE are autoantibodies and immune complexes they form with antigens Phagocytosis and clearing of immune complexes and of apoptotic cells are defective A decrease in cytotoxic T cells and in functions of suppressor T cells An increase in helper (CD4+) T cells Polyclonal activation of B cells and abnormal B cell receptor signaling Defects in B cell tolerance, perhaps related to defects in apoptosis, lead to prolonged lives of B cells Impaired clearance of dying cells  accumulation of cellular debris. DCs, rather than macrophages acquire autoantigens from these dying, late-apoptotic cells. These modified autoantigens activate autoreactive T cells, which provide help for B cells recognizing nuclear autoantigens and result in the B-cell secretion of autoantibodies. Immune complexes and/or autoantibodies deposit in various organs, causing immune-mediated organ damage. Dietary factors  Alfalfa sprouts and related sprouting foods containing  Canavanine Pristane and similar substance Infectious agents other than EBV Bacterial DNA Human retroviruses Endotoxins Bacterial lipopolysaccharides

Hormonal Factors Use of estrogen-containing contraceptive increases risk of SLE Early-onset menarche (age ≤10 years) or estrogen to postmenopausal women increases their risk of SLE SLE has been observed with higher frequency in Klinefelter's

Clinical Features Constitutional (fever, fatigue, weight loss) or result from inflammation of organ systems: skin, mucous membranes, joints, kidney, brain, serous membranes, lung, heart, and occasionally gastrointestinal Isolated or in combination Vital organs, particularly the kidney and CNS - significant morbidity or mortality

Renal Disease – Lupus Nephritis All studies of prognosis have identified lupus nephritis as predictor of poor outcome Renal disease is present in one-half to two-thirds of the patients Indications for biopsy: active urine sediment and > 500 mg/day proteinuria Renal biopsy: abnormal in patients, especially when tissue evaluated by EM and immunofluorescence

Lupus Nephritis in Biopsy 1. Minimal mesangial glomerulonephritis 2. Mesangial proliferative glomerulonephritis 3. Focal proliferative glomerulonephritis 4. Diffuse proliferative glomerulonephritis ESRD risk 10-20%, Immunosuppressives 5. Diffuse membranous glomerulonephritis ESRD risk < 10%, nephrotic syndrome, thrombosis, ACE inhibitors 6. Advanced sclerosing glomerulonephritis

Neurologic Manifestations Diffuse manifestations Organic brain syndromes Cognitive impairment Focal manifestations Cranial neuropathies CVA Transverse myelitis Seizures Other: headaches, aseptic meningitis (NSAIDS) Psychiatric manifestations

MSK Manifestations Arthritis: inflammatory non-erosive Myalgias – proximal muscle 40-80% Inflammatory myositis – 5-11% Differentiate from steroid-and antimalarial-induced myopathies EMG and muscle biopsy range from normal to pattern of inflammatory myopathy similar to Dermatomyositis/Polymyositis Jaccoud’s arthropathy

Avascular Necrosis of the Bone AVN – 5-12% of patients (Medstudy up to 30%) Risk factors: corticosteroids, Raynaud’s, small-vessel vasculitis, fat emboli, anti-phospholipid antibodies, ETOH MRI more sensitive

Other Manifestations Acute Pneumonitis “Shrinking lung syndrome” (decreased lung volumes without parenchymal disease) Pulmonary hemorrhage Valvular disease (Libman-Sacks endocarditis) CAD 50-fold increase in MI Liver disease –lupus hepatitis (vs. lupoid hepatitis) Cytopenia- thrombocytopenia consider TTP Cardiac abnormalities – over 50% Valvular disease – often mitral regurgitation, more in APL syndrome – 75% (Libman-Sacks endocarditis) Pericardial disease – pericarditis, silent effusion – up 55% Myocarditis, myocardial dysfunction – up to 78% Coronary artery disease – up to 16% Liver disease – lupoid hepatitis; autoantibodies to distinguish from autoimmune hepatitis; ANAs can be seen in both, anti–smooth muscle and antimitochondrial uncommon in SLE (<30%). histology rarely shows the periportal (interface) hepatitis with piecemeal necrosis characteristic of autoimmune hepatitis

SLE Treatment FDA approved drugs: Aspirin, glucocorticoids, hydroxychloroquine, belimumab Depends on extent of disease (minor or major manifestations) On the type of organ involvement

Major and Minor Manifestations Dermatologic Arthritis Serositis Leukopenia Fatigue Major Nephritis Cerebritis Thrombocytopenia Hemolytic anemia Infection

Antimalarials Constitutional symptoms Musculoskeletal involvement Serositis Cutaneous lesions

Corticosteroids in Lupus Indication Corticosteroid regimen Rashes Topical Intralesional Minor disease activity Oral prednisone (or equivalent) <0.5 mg/kg Major disease activity Oral prednisone (or equivalent) 1 mg/kg Intravenous methylprednisolone 1g or 15 mg/kg often repeated 3 consecutive days

Indications for High-Dose Steroids Severe lupus nephritis (combined with immunosuppressive) CNS lupus with severe manifestations Autoimmune thrombocytopenia with very low platelet counts Autoimmune hemolytic anemia Acute pneumonitis Other severe manifestations

Immunosuppressives Methotrexate and Belimumab: Musculoskeletal Cutaneous Serositis Azathioprine and Mycophenolate mofetil: Cyclophosphamide and Rituximab: Major organ (kidney, CNS, severe hematologic, vasculitis)

Indication for Cyclophosphamide Drug Use in SLE Hematologic Severe Thrombocytopenia – Platelet count < 20.000 TTP-like syndrome Severe hemolytic or immune neutropenia not responding to steroids Pulmonary – lupus pneumonitis or alveolar hemorrhage Cardiac – myocarditis or pericarditis with impending tamponade Gastrointestinal – abdominal vasculitis Nervous system – transverse myelitis, cerebritis, mononeuritis multiplex

Outcomes and Survival The 5-year survival has increased from 40% in the 1950s to more than 90% in studies after 1980. Causes of death: In the first years - activity of disease or infections Later death – illness complications (end-stage renal disease) or treatment complications (infections) or both (coronary artery disease)

SLE and Pregnancy Inactive or mild disease at conception- 81% of subjects had uncomplicated pregnancies High disease activity in 1st and 2nd trimesters showed a threefold increase in pregnancy loss Higher rate of SLE flares-25-60%

SLE and Pregnancy Labs: aPLs, anti-Ro/SSA and anti-La/SSB, anti-dsDNA, renal function (creatinine, urinalysis with urine sediment, spot urine protein/creatinine ratio), Complete blood count (CBC), Liver function tests, Complement (CH50, or C3 and C4), Uric acid Continue: hydroxychloroquine Contraindicated: cyclophosphamide, mycophenolate mofetil, methotrexate, leflunomide

Forms of Lupus Systemic lupus erythematosus (SLE) Cutaneous Lupus Discoid lupus Subacute cutaneous lupus Drug-induced lupus Neonatal lupus

Butterfly Rash Acute cutaneous spares nasolabial folds interface dermatitis and include apoptotic keratinocytes, vacuolization of the basal cell layer of the epidermis, a lymphohistiocytic infiltrate in the superficial dermis, and dermal mucin deposition [16]. The findings can be subtle. Topical and intralesional corticosteroids, oral glucocorticoids, oral antimalarial drugs, and glucocorticoid-sparing immunomodulatory agents have all been utilized depending on extent of disease and response to first- and second-line therapies. Acute cutaneous spares nasolabial folds

Discoid LE – Scarring Alopecia Discoid lupus 5% chance of developing SLE Higher in disseminated DLE

Discoid LE The association with SLE varies among the subtypes of cutaneous LE and mainly has been estimated from cross-sectional studies and retrospective studies ACLE – >90 [3] ●SCLE – 48 to 50 [9] arcuate erythematous plaques that resolve without scarring strong association between SCLE, human leukocyte antigen (HLA)-DR3, antibodies to Ro/SSA, 80% Photosensitivity including antihypertensive drugs, lipid-lowering agents, proton pump inhibitors, antifungal agents, TNF-alpha inhibitors improvement in the clinical manifestations of SCLE within eight weeks of drug withdrawal and a decrease in anti-Ro/SSA antibodies within eight months following drug withdrawal ●Localized DLE – 5 to 10 [10] ●Generalized DLE – 15 to 28 [10]

Subacute Cutaneous Lupus The association with SLE varies among the subtypes of cutaneous LE and mainly has been estimated from cross-sectional studies and retrospective studies ACLE – >90 [3] ●SCLE – 48 to 50 [9] arcuate erythematous plaques that resolve without scarring strong association between SCLE, human leukocyte antigen (HLA)-DR3, antibodies to Ro/SSA, 80% Photosensitivity including antihypertensive drugs, lipid-lowering agents, proton pump inhibitors, antifungal agents, TNF-alpha inhibitors improvement in the clinical manifestations of SCLE within eight weeks of drug withdrawal and a decrease in anti-Ro/SSA antibodies within eight months following drug withdrawal ●Localized DLE – 5 to 10 [10] ●Generalized DLE – 15 to 28 [10] SCLE annular rash, +Ro/La, photosensitive, non-scarring, associated with med use

Forms of Lupus Systemic lupus erythematosus (SLE) Cutaneous Lupus Discoid lupus Subacute cutaneous lupus Drug-induced lupus Neonatal lupus

Question 3 Your 73-year-old male patient is undergoing evaluation because of low-grade fever, fatigue, anorexia, weight loss, and arthralgia. Labs showed positive anti-histone antibody, among others.

Isoniazid Hydrochlorothiazide Metformin Tamoxifen Question 3 Which of these medications is most likely responsible for these symptoms? Isoniazid Hydrochlorothiazide  Metformin Tamoxifen

Drug-induced Lupus Procainamide Hydralazine Diltiazem Penicillamine Isoniazid Interferon alpha Methyldopa Chlorpromazine Sulfasalazine Minocycline Etanercept Infliximab

Drug-induced Lupus Constitutional symptoms- fever, arthritis, rash, serositis Positive ANA, anti-histone antibodies C3 and C4 usually normal Anti-ds DNA usually negative (exception TNF inhibitors) Kidney and CNS involvement not common Improvement 4-8 weeks, antibody persistence

Forms of Lupus Systemic lupus erythematosus (SLE) Cutaneous Lupus Discoid lupus Subacute cutaneous lupus Drug-induced lupus Neonatal lupus

Question 4 Which of the following statements about neonatal lupus is true? Majority of infants have persistent anti-SSA/Ro Ab persistent in blood at 9 months Highest incidence of hematological and liver tests alterations are when the infant is 9 months old Highest incidence of hematological and liver tests alterations are when the infant is 12 months old Hydroxychloroquine use is associated with decrease risk for congenital heart block

Neonatal Lupus Rash Hemolytic Anemia Thrombocytopenia Leukopenia Hepatitis Cardiac Involvement Neonatal lupus is caused by maternally transferred autoantibodies from the mother to the baby. Most mothers of of NLE babies have not been diagnosed with SLE. They are however anti-Ro and sometimes also anti-La antibody positive. Other manifestations of NLE include autoimmune cytopenias, hepatitis, rash and myositis. Typically the rash is not present at birth, but developes during the first days to months of life. The rash heals without scarring over the next 1 to 2 years of life.The babies are not at an increased risk to develop SLE themselves

Cardiac involvement Congenital Heart Block Myocarditis, Pericarditis Hydrops Fetalis Risk 1-2%, 15% in subsequent pregnancies Fetal echo at 16-18 weeks Hydroxychloroquine decreases risk (6-10 wks) Fluorinated glucocorticoids Pericardial effusion () discordant artial and ventricular rhythm CCHB is the most seroius manifestation of NLE. Neonatal lupus the most common cause of congenital heartblock. The anti-Ro antibody recognized the cardiac conduction system of the fetus and can leads to fibrosis of the conduction pathways. It typically persents between the 16-22 week of gestation and results in fetal bradycardia. It can also lead percarditis and myocardiditis to hydrops

Neonatal Lupus Only 10% of infants have anti-SSA/Ro Ab persistent in blood at 9 months. The highest incidence of hematological features and liver tests alterations are observed when the infant is 3 months old.

Undifferentiated Connective tissue disease (UCTD)

UCTD - Definition Symptoms, physical findings, or positive serology consistent with a connective tissue disease Do not fulfill the established classification criteria for a specific disease 20-25% of patients with rheumatic diseases and systemic symptoms cannot be definitively diagnosed Patients have clinical features that can be seen in RA, Sjogren’s, SLE, SSc, PM

Epidemiology Female predominance similar to RA and SLE Age: Onset similar to most CTD, peaking in the middle age; has been described in children

Most Common Symptoms Fever, fatigue, weight loss Raynaud’s Undifferentiated polyarthritis Mucocutaneous manifestations Sicca symptoms

Morbidity and Mortality Most patients with UCTD diagnosed after 12 months of the onset of symptoms remain undifferentiated after 10 years of disease Survival better than in RA and SLE Mortality and morbidity related to extent of organ involvement (ILD, PH, Vascular) Progression to RA or SLE 10-20%

Management Prolonged follow up Treat the predominant feature: Arthritis Rash Raynaud’s Lung disease

Thanks! Questions? minara@ucmail.uc.edu