Staci Smith DO Nephrology Grandview Hospital Lupus neprhitis Staci Smith DO Nephrology Grandview Hospital

Today’s objectives Overview of Lupus Common manifestations Types of lupus History Common manifestations SLE Nephritis WHO classification Biopsy Indications Biopsy Findings Treatment

Differential Diagnosis hematuria proteinuria glomerulonephritis red blood cell casts

DDx : Glomerulonephritic Dz SLE Minimal Change Dz Membranous GN FSGS MPGN RPGN Ig A Nephropathy Anti GBM Dz Goodpasture’s Wegener’s Hepatitis B, C AIDS Amyloidosis HSP Cryoglobulinemia Vasculitides Poststrept/ Poststaph GN                                                         

Red Blood Cell Casts red cell casts virtually diagnostic of glomerulonephritis or vasculitis only one needed absence does not exclude diagnosis

Types Of Lupus Systemic Lupus: most common and affects major organs Discoid Lupus: affects only the skin not fatal, but can cause severe scarring Drug-induced Lupus: is systemic Lupus caused by medications when the medicine is stopped, the disease goes away

What is Systemic Lupus Erythematous? autoimmune disorder multisystem microvascular inflammation defined by clinical picture and generation of autoantibodies mostly against double stranded DNA

Pathogenesis of SLE autoantibodies mostly against double stranded DNA and the Smith antigen Ab to Smith (Sm) antigen is very specific for SLE 25% of patients

History of SLE not known when Lupus first appeared Hippocrates noted similar diseases in Ancient Greece facial rash that resembles the markings of a wolf 1851 French-man named Pierre Cazenave first clinical records more than 1.4 million Americans are affected by SLE

SLE Manifestations

SLE Dermopathy

Serological Tests to Aid Diagnosis of SLE % positive in SLE ANA 95% Anti-nDNA 60% Anti-nRNP 80% Anti-Sm 20% Anti-Ro 30% Anti-La 10%

ANA Antibodies Rim Diffuse Speckled Nucleolar

Lupus Criteria American College of Rheumatology presence of 4 of 11 criteria can establish SLE Dx 96% sensitive and specific updated 1995

American College of Rheumatology Criteria for Diagnosis of SLE Serositis –pleuritis, pericarditis Oral ulcers - painless Arthritis – 2 or more peripheral joints Photosensitivity Blood Abnormalities – thrombocytopenia, lymphopenia, lymphopenia (x2),hemolytic anemia Renal – casts, proteinuria, hematuria ANA positive Immune Abnormalities – ANA, Anti DS DNA, Smith Ag, false (+) syphilis Neurologic - seizures, psychosis Malar Rash- spares nasolabial folds Discoid Rash – scaling,scaring SOAP BRAIN MD

Lupus and the Kidney Lupus nephritis one of the most serious manifestations of SLE typically arises within 5 years of diagnosis commonly within the first 6 to 36 months Renal failure rarely occurs before American College of Rheumatology classification criteria are met.

Lupus and the Kidney total incidence of renal involvement among patients with SLE exceeds 90 % abnormal urinalysis with or without an elevated Cr in approximately 50% at diagnosis time proteinuria present in 80% 40% have hematuria and/or pyuria

Lupus and the Kidney ‘Silent’ lupus nephritis normal urinalysis no proteinuria normal serum creatinine levels However, renal biopsy reveals pathological changes

Lupus Nephritis Six types of renal involvement with SLE Why do renal biopsy? to determine stage of disease histological evidence is present in most SLE pts even if they do not have clinical manifestations of renal disease Pattern of glomerular injury related to the site of formation of the immune deposits is primarily due to anti DS DNA

Indications for Renal Biopsy with SLE Patients Proteinuria of >1g/day conventionally 1-2g/day Less proteinuria does not preclude biopsy if major serologic abnormalities, especially hypocomplementemia At the other extreme, the presence of full-blown nephrotic and nephritic syndromes Progressive azotemia Decreasing renal function in assocation with active urinary sediment Ambiguity or inconsistency of data Lupus nephritis of indeterminate duration, severity and potential responsiveness Overlapping clinical features Situations where clinical and laboratory data are compatible with different classes of lupus nephritis, for which different approaches to management are warranted Redirection of therapy Partially treated or incompletely responsive lupus nephritis

(modified WHO Classification) Morphological Classification of Lupus Nephritis (modified WHO Classification) Class Biopsy finding I Normal glomerulus II Pure mesangial alteration III Focal proliferative glomerulonephritis IV Diffuse proliferative glomerulonephritis V Membranous glomerulopathy VI Advanced glomerulosclerosis

Normal Glomerulus light micrograph capillary lumens open glomerular capillary wall thickness similar to that of the tubular basement membranes mesangial cells and matrix are located in the central or stalk regions of the tuft

Mesangial Proliferative Lupus Nephritis: Class II segmental areas of increased mesangial matrix and cellularity light micrograph Can also be seen in Ig A nephropathy

Focal Proliferative Nephritis (Class III) Subsets Divided by active and/or chronic lesions: Class III (A): active lesions Class III (A/C): active and chronic pathology Class III (C): chronic inactive lesions with scarring a.k.a. focal sclerosing lupus nephritis

Focal Proliferative Nephritis (Class III) usually associated with subendothelial deposits areas of cellular proliferation thickening of glomerular capillary “wire loop” Long arrow= cellular proliferation….short arrows are wire loops

Diffuse Proliferative Nephritis Class IV subendothelial deposits deposition of immunoglobulins and complement results in thickening of the glomerular capillary wall subsets segmental = < 50% of glomeruli diffuse = >50% of glomeruli

Diffuse Proliferative Nephritis: Class IV subendothelial deposits thickening of glomerular capillary wall

Membranous Nephritis Class five the one form of lupus nephritis that may present with no other clinical or serologic manifestations of SLE typically presents with signs of nephrotic syndrome microscopic hematuria and hypertension also may be seen Cr concentration is usually normal or only slightly elevated

Sclerosing Nephritis :Class VI sclerosis of more than 90% of glomeruli represents healing of previous inflammatory injury as well as the advanced stage of chronic class III, IV, or V lupus nephritis immunosuppressive therapy is NOT likely to be beneficial

severe or progressive membranous lupus (class V) diffuse (class IV) or severe focal (class III) proliferative glomerulonephritis, severe or progressive membranous lupus (class V) marked nephrotic syndrome rising serum creatinine membranous in association with class III or class IV disease mixed disease

Therapy for lupus patients with arthritis No internal organ involvement First line: NSAID’s Cyclooxygenase-2 specific inhibitor may induce thrombotic risk in patients with antiphospholipid antibodies Low dose hydroxychloroquine 200mg twice a day

Manifestations not often responsive to glucocorticoids Thrombosis—includes strokes Glomerulonephritis Resistant thrombocytopenia or hemolytic anemia

Therapy for patients with lupus nephritis Previously untreated patients Active lupus nephritis or severe manifestations decreased renal function and /or high-grade proteinuria First line: high doses of corticosteroids about 1mg/kg/day Cytotoxic drugs or other immunosuppressive drugs

The indications of cytotoxic drugs use in the treatment of lupus nephritis Active and severe GN depsit high dose steroids Responded to corticosteroids but require an unacceptably high dose to maintain a response. Side effects from corticosteroids Chronic damage on a renal biopsy

Use of Cytotoxic Drugs in SLE : Azathioprine requires 6–12 months to work well 1–3 mg/kg/day(initial dose) 1–2 mg/kg/day(maintenance dose) Advantage:probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement Side effects: Bone marrow suppression, leukopenia, infection(herpes zoster), infertility, malignancy, early menopause, hepatic damage, nausea zathioprine; requires 6–12 months to work well 1–3 mg/kg/day 1–2 mg/kg/day Probably reduces flares, reduces renal scarring, reduces glucocorticoid dose requirement Bone marrow suppression <5 Leukopenia 15 Infections (herpes zoster) 10 Malignancies Infertility Early menopause Hepatic damage

Advantage Side effects reduces flares, reduces renal scarring, reduces glucocorticoid doses Side effects bone marrow suppression, leukopenia, infection, malignancy, nausea,etc

Use of Cytotoxic Drugs in SLE: Cyclophosphamide requires 2–16 weeks to work well Initial dose:1-3 mg/kg/day orally or 8–20 mg/kg intravenously once a month plus mesna Maintenance dose:0.5–2 mg/kg/day orally or 8– 20mg/kg intravenously every 4–12 wks Mesna

mycophenoalte mofetil may be an alternative to cyclophosphamide as initial therapy particularly among patients who refuse or cannot tolerate cyclophosphamide Biggest side effect is diarrhea, also myelosuppression fewer side effects than cyclophosphamide

Rituximab interferes with the activation and differentiation of B cells lysis mediated by: Complement Fc receptor-bearing cytotoxic cell Inducing apoptosis selective transient depletion of the CD20+ B- cell subpopulation

Other management principles in the treatment of lupus patients Avoid possible disease triggers-sulfa antibiotics, sun, high estrogen-containing birth control pills,alfalfa sprouts Prevent atherosclerosis Prevent osteoporosis Prevent infection Prevent progression of renal disease Prevent clots in patients with antiphospholipid antibodies

Differential Diagnosis hematuria proteinuria glomerulonephritis red blood cell casts

What is Systemic Lupus Erythematous? autoimmune disorder multisystem microvascular inflammation defined by clinical picture and generation of autoantibodies mostly against double stranded DNA

American College of Rheumatology Criteria for Diagnosis of SLE Serositis –pleuritis, pericarditis Oral ulcers - painless Arthritis – 2 or more peripheral joints Photosensitivity Blood Abnormalities – thrombocytopenia, lymphopenia, lymphopenia (x2),hemolytic anemia Renal – casts, proteinuria, hematuria ANA positive Immune Abnormalities – ANA, Anti DS DNA, Smith Ag, false (+) syphilis Neurologic - seizures, psychosis Malar Rash- spares nasolabial folds Discoid Rash – scaling,scaring SOAP BRAIN MD

(modified WHO Classification) Morphological Classification of Lupus Nephritis (modified WHO Classification) Class Biopsy finding I Normal glomerulus II Pure mesangial alteration III Focal proliferative glomerulonephritis IV Diffuse proliferative glomerulonephritis V Membranous glomerulopathy VI Advanced glomerulosclerosis

Happy Thanksgiving !