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Outline

• Epidemiology/Natural History Systemic Erythematosus • Diagnosis: ACR Criteria (SLE) • Clinical Manifestations • Laboratory Manifestations Scott Vogelgesang, MD Division of Immunology/Rheumatology • Therapy University of Iowa • Summary

Epidemiology Natural History

• Women: Men 5-10:1 • Varies according to which organ systems • Peak incidence ages 15-40 are affected and how severely. • 1:2000 • In 1950’s: 50% 5 year survival • Genetics • Now (under optimal conditions) 90% – Identical twin concordance 25-50% survival at 10 years – Non-identical twin concordance 4% – Sister/Mother with SLE • Premature atherosclerosis (early MI) is • 4% chance of developing SLE now a concern • 30% chance of positive ANA

Pathophysiology

• Genetics – HLA-DR, DQ, DP associated with SLE susceptibility • – defective clearing of apoptotic cells • Innate activation Diagnosis –TLRs –IFN-1 • Adaptive Immune System Clinical – T cells (TH1, TH17?) – B cells – Autoantibodies – Immune complexes

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SLE Criteria (ACR) (Slicc - 2012) Mnemonic: SOAP BRAIN MD SLE Criteria

S erositis Classify a patient as having SLE if The patient satisfies four of the criteria listed below, including at least one clinical criterion and one immunologic criterion … or - •Blood The patient has biopsy-proven nephritis compatible with SLE and ANA or anti-dsDNA . O ral ulcers .WBC < 4.0K .Hemolytic Anemia • Clinical • Immunologic A rthritis Utility: give an .Plts < 100,000 – Acute cutaneous lupus P hotosensitvity organized way of –ANA .Lymphs < 1500 – Chronic cutaneous lupus thinking about a – DsDNA •Renal – Oral ulcers disease with –Sm B lood .Proteinuria – Nonscarring alopecia . > 500 mg/24h many –APLs R enal – Synovitis . > 3+ dip – Low complement manifestations – Serositis A NA .RBC casts – Renal – Direct Coombs I mmunologic testing •Immunologic – Neurologic N europsychiatric .DsDNA .Sm – Hemolytic Anemia .Antiphospholipid Aby – Leukopenia M alar rash •Neuropsychiatric – Thrombocytopenia D iscoid rash .Seizure .Psychosis

Arthritis Rheum. 2012 August ; 64(8): 2677–2686. doi:10.1002/art.34473.

SLE Criteria (Slicc - 2012)

Classify a patient as having SLE if The patient satisfies four of the criteria listed below, including at least one clinical criterion and one immunologic criterion … or - The patient has biopsy-proven nephritis compatible with SLE and ANA or anti-dsDNA antibodies.

• Designed by clinical researchers to include patients with renal disease that most Clinical Manifestations rheumatologists would agree is SLE (they can be included in clinical studies)

• Not (yet) widely adopted

Arthritis Rheum. 2012 August ; 64(8): 2677–2686. doi:10.1002/art.34473.

Oral/Nasal Ulcers Cutaneous • Acute (photosensitive)

• Soft palate, buccal A. Malar rash: spares mucosa most the nasolabial fold common B. Diffuse • Classically painless erythema

C. Interarticular • Difficult to distinguish from common aphthous ulcers

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Cutaneous (continued) Cutaneous (continued) • Subacute: SCLE (subacute cutaneous )

• Chronic – Discoid – Papulosquamous – Annular – Annular • Erythema and scale – Erythematous • Central clearing • No scarring/no atrophy – Central Clearing – Scarring/Atrophy – Associated with SSA and SSB antibodies

Photosensitivity Serositis

• Pleurisy •Not photophobia – Chest pain that worsens with breathing – May (not) be associated with pleural effusion • Development of a rash from sunlight • Pericarditis exposure – Chest pain worsens with leaning forward – May (not) be associated with pericardial effusion • Immunologic reaction that may cause other manifestations (i.e. arthritis, serositis)

Pulmonary Cardiac

• Pleurisy • Pericarditis • Pneumonitis •Myocarditis • Pulmonary Hemorrhage • Endocarditis • Pulmonary Embolism •CAD • Pulmonary Hypertension • “Shrinking Lung Syndrome”

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Musculoskeletal Neuropsychiatric

• Arthralgias/myalgias common • Seizures • Distinguish Arthritis from Arthralgia • Psychosis • Organic Brain Syndrome – most common • Arthritis • Depression – Polyarticular – Inflammatory •Stroke – Non erosive (non-destructive) • Peripheral neuropathies – Reducible deformities

CNS Lupus Renal

•Stroke • Multiple etiologies • Immune Complex Deposition on glomerular •Coma – Vasculopathy basement membrane • DsDNA and complement likely pathogenic • Cranial neuropathy – Anti-neuronal antibodies •WHO • others – Vasculitis I Normal Glomeruli II Mesangial (Proliferative) – Anti-phospholipid III Focal Proliferative antibodies IV Diffuse Proliferative V Membranous – Others VI Advanced Sclerosing

Renal Others

• To biopsy or not to biopsy… • Lymphadenopathy • Splenomegaly – Pt w obvious SLE: Urine with , red cell casts, ↑ creatinine •GI and ↑ BP: Probably Not – Mesenteric vasculitis – Exclude ATN, AIN, Drug effects: Probably Yes – Protein-losing enteropathy – Hepatomegaly – ?pancreatitis • Therapy: later… • Vasculitis • Ophthalmologic

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Hematologic

• Leukopenia: WBC < 4.0 x 103 • Lymphopenia: Lymphs < 1500 Laboratory • Thrombocytopenia: Platelets < 100,000 • Hemolytic Anemia • Anemia chronic disease - most common

Immunologic Immunologic (continued)

• Sm antibodies • Antiphospholipid • Complement – (Smith not Smooth Muscle) antibodies – Consumed in immune – High specificity for SLE (>90%) –ACLA complex disease • DsDNA – Elevated PTT (doesn’t correct with plasma) – Reflects disease – (native or double-stranded) antibodies activity – High specificity for SLE (> 90%) – False positive VDRL (RPR) – DRVVT (dilute Russell –C3 • SSA (Ro) Antibodies Viper venom time) –C4 – ß-2 glycoprotein-1 – CH50 • SSB (La) Antibodies antibodies – SLE, SCLE, Neonatal Lupus & 2° Sjogren’s

ANA (AntiNuclear Antibodies) New!

• Found in 93% of patients with SLE (up to 30% general population) • “ANA” is now outdated and even confusing • Antibodies against cellular entities: • Indirect Immunofluorescence – Nucleus – Most common method – Cytoplasm –Titers (< 1:80, … 1:640, > 1:640) – Cell Membrane – Titers do not change with disease activity • “…one may suggest changing… to… anti- – Patterns (homogeneous, speckled, centromere, nucleolar) cellular antibodies” (ACA rather than ANA?) • Elisa – No titers or patterns – Results in Elisa units – Lower sensitivity (higher false negatives)

Ann Rheum Disease 2014;73:17-23

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NSAIDS

• Useful: arthralgias/myalgias & mild arthritis

Therapy • May be treatment of choice for serositis • Use with caution • No therapeutic difference in agents Therapeutic decisions guided by clinical manifestations.

Hydroxychloroquine

• Useful in rash, arthritis, fatigue, serositis • Work quickly • Prevents flares • Can be life/organ saving therapy

• 300-400 mg/day (keep dose < 6.5 mg/kg lean body weight – adjust by height) • Many side effects

• Retinal toxicity (rare at doses < 6.5 mg/kg)…still recommend annual ophthalmologic examinations • Limit dose and length of therapy • Nausea, most common side effect • Arthritis: 5-15 mg • Rare cytopenias • Major Organ Involvement: –1 mg/kg – 1000 mg IV pulses

Cyclophosphamide Mycophenolate

• Indicated in proliferative (sometimes used for • Indicated in proliferative nephritis other manifestations) • Better outcome than alone or • Non-inferior to • 2000-3000 mg daily •Toxic • Side effects – Cytopenias – Cytopenias – Bladder – Ovary/Sperm – Gastrointestinal • 0.5 -1 g/m2 IV monthly for 6 months

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Belimumab

• Newest • Inhibits B cells • Inhibits B cells – against CD20 – BAFF/BLYS • Clinical trials failed to show benefit (???) • Not tested for those with renal disease • “Recue medication” in recalcitrant SLE • Adverse Effects • Adverse Effects – Infusion reactions – Infusion reaction – Depression – Hypogammaglobulinema – Infections – Infections

Others Avoid

• Colchicine – useful in serositis • Azathioprine – used as steroid-sparing agent – Sulfa – Estrogen (replacement doses) • – Tetracyclines – used as steroid-sparing agent – Useful in inflammatory arthritis – Associated with flares of SLE

Summary

• Remember SOAP BRAIN MD • References – Petri M, et al. Arthritis Rheum. 2012 August ; 64(8): 2677–2686. • ANA found in 93% of patients with SLE doi:10.1002/art.34473 – Ann Rheum Disease 2014;73:17-23 • Therapy guided by clinical manifestations – Squatrito D, et al. Autoimmun Highlights 2014; 5:33-45. – Hahn BH, et al. Arthritis Care & Res 2012; 64(6): 797-808. • Sm and DsDNA are very specific for SLE (in the right clinical setting) • SLE can vary from a life-threatening illness to very mild disease that hardly affects lifestyle

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