Sle and Apls

8/21/2019 Sle and Apls

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Systemic Lupus

Erythematosus SLE

and APLS


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Case Study

22 year old college student

New onset of red cheeks, hives in the

sun, fatigue, Raynauds, weight loss,hair loss and stiff hands in the morning

Her cousin has JRA


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What is the most likely

diagnosis?


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Lupus

Represent a range of diseaseprocesses characterized by the

development of autoantibodies withassociated manifestations and organdamage

Some forms limited to skin , or occurafter exposure to a drug


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SLE

Systemic lupus erythematosus:

Prototypical form of lupus

Multiorgan autoimmune disease that oftenpresents insidiously with significantheterogeneity of expression in individuals

Severity from mild to life threatening

depending on the affected organ Medications used for treatment increase

morbidity - organ damage


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Chronic Cutaneous Lupus

(CCL) Limited to the skin

No systemic manifestations

Includes:

Discoid lupus

Subacute cutaneous lupus erythematosus

Lupus paniculitis

Only 5% of CCL develop SLE


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Drug induced Lupus (DILE)

Triggered by certain medications

Resolution after DC of the drug

Anti-Histone ab test positive

Absence of anti-DsDNA


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Drug-induced lupus: definite

drug associations Hydralazine

Procainamide

Minocycline

Chlorpromazine

Isoniazid

Penicillamine Methyldopa

Interferon-alpha


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Drug-induced lupus: possible

drug associations Anticonvulsants Diltiazen

Quinidine Hydrazine

Propylthiouracil Interferon gamma

Sulfonamides TNF inhibitors

Lithium

Beta-blockers

Nitrofurantoin Sulfasalazine


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SLE

More common in Female than male

Female : Male ratio 9:1

Incidence of SLE in US is :

Women 9.4 per 100,000

Men 1.54 per 100,000 More common in African-American and

Hispanic population


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SLE

Disease onset more common in the 20s,

and 30s

May occur at any age Symptoms/disease activity waxes and

wanes

Flares sometimes evident by clinicalsymptoms, other times only by laboratory

results changes


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SLE

Pathogenesis :

Exact cause is unk.

Genetic factors -10% of SLE patientshave a family member with lupus

Environmental factors - UV light (most

important) Possible Also infections, smoking, and

toxin exposure


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SLE

Autoantibodies bind to proteins and

tissues

Deposition of immune - complexesleads to an inflammatory cascade

With activation of complement system

And production of inflammatory

cytokines


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SLE Clinical Presentation

Most commonly affected organ

systems:

Musculoskeletal

Dermatological

Renal

Hematological

Any organ can be affected


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Musculoskeletal lupus

Isolated arthralgias ( more often stiffness

rather than pain) Synovitis.arthritis similar to RA

Morning stiffness

Gel phenomenon after immobility Small joints of the hands( MTPs,PIPs)

Wrists


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Knees are less affected

Jaccouds arthropathy:

Progressive ulnar deviation

Swan-necking deformaties

Reversible or correctible

Typically non erosive bony changes


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Jaccouds Arthropathy


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SLE Dermatological

Several skin manifestations

Malar RashButterfly Rash

Erythematous

Photosensitive

Flat or raised - maculopapular

On the cheeks and Bridge of the nose

Spares naso-labial folds


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Malar RashButterfly Rash


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Systemic lupus erythematosus:

bullous lesions, palate


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SLE Dermatological

Maculopapular rash also common on:

V-area of the neck, and extremities

Areas associated to sun exposure

Biopsy of the skindemonstrate

immunoglobulin and complement

deposition at the dermal-epidermaljunction: lupus band sign


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SLE Dermatological-neck rash


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SLE Dermatological Discoid lupus(chronic cutaneous)

Involve deeper Dermis, raised patches,

keratotic scaling, follicular plugging

May lead to permanent loss of hair follicle

Disfiguring hyper- or hypopigmented scars

may occur after resolution

Typically on face ( inside ears, above eyebrows, upper palate )

Neck, scalp and forearms


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Discoid Lupus


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Discoid Lupus


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SLE Dermatological

Subacute Cutaneous Lupus

Erythematosus (SCLE)

Photosensitive lesions

Nonscaring rash

Psoriaform form

Annularpolycyclic form

of patients with SCLE have SLE


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SCLE- Annular rash


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SLE Renal Involvement Proteinuria alone

Proteinuria and Hematuria

Cellular casts in urine : RBCs

Glomerular involvement

Elevated serum creatinine level

Possible Renal Failure May result in Nephrotic Syndrome:

Low serum albumin, and elevated cholesterol


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Renal Involvement International society of Nephrology

Classification for lupus nephritis

I minimal mesangial

II Mesangial proliferative III focal proliferative

IV dif fu se pro l i ferat ive

V membranous

VI irreversible renal sclerosis

Done by Kidney Biopsy

Class IV most dangerouscan rapidly progress to

Renal Failure


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Renal Involvement Membranous nephritis (V) manifested by

Nephrotic Syndrome


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SLE Serositis Pleurisy

Occurs most commonly as pleurisy:

Pain on deep inspiration

Sometimes associated with pleural effusion

Listen for inspiratory / expiratory rub

Exudative effusion if tapped

Differentiate from pulmonary emboli and

infection pleuritic chest pain


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Serositis Pericarditis:

Positional pain

Worse with recumbency

Better leaning forward

Ascites:

Possible due to serositis

r/o infarcted bowel, infection, or Budd-Chiarisyndrome (oclussion hepatic or IVC)


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Hematological abnormalities

Most common

Leukopenia and Lymphopenia

Medication induced cytopenias

Corticosteroids associated lymphopenia

Thrombocytopenia

Antiphospholipid antibodies

Immunosupressive drugs

Heparin administration


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Hematological abnormalities

Hemolytic anemia

Coombs positive

Elevated reticulocyte count

Decreased haptoglobin

Anemia of chronic disease

(inflammation)

Anemia from chronic renal disease

Iron deficiency anemia


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Neurologic manifestations

Most likely as a result of immunecomplexdeposition in small blood vessels

Rarely attributable to vasculitis

Most common neurologic complaint in SLE: Cognitive impairment80%of SLE patients by 10

years after Dx.

Represents accumulated damage and not ongoingCNS SLE

Formal cognitive function testing to establishbaseline


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Mild to severe

Seizures: also from thrombosis,uremia,toxic

Psychosis: think about steroids psychosis

Encephalopathy

Coma


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Meningitis

Stroke: vasculitis or APhospholipids Abs

thrombosis, HTN, atherosclerosis Mononeuritis multiplex

Transverse myelitis

Peripheral neuropathy Cranial neuropathy


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Organ Damage In >50% of SLE patients over time

Significant % from corticosteroids therapy

Obesity/ Diabetes

HTN/ Hyperlipedimia

Cataracs/Glaucoma

Osteoporosis/Osteonecrosis

Infections

Depression/Psychosis


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Organ Damage

Accelerated Atherosclerosisthe major

cause of death in SLE

Risk of MIincreased 50 fold

Counsel about modifiable

cardiovascular risks


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Organ Damage

Renal damage occurs in at least 25% of

patients with lupus nephritis in spite of

maximal therapy Recommendation for renal biopsy:

In patients with 500mg/day proteinuria

Active urinary sediment Rising serum creatinine


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Malignancy risk

Lymphoma and Solid tumors risk is

increased independent to therapy

Patients with secondary Sjogrenssyndrome may have special risk of non-

Hodgkins Lymphoma


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Diagnosis Often difficultmultiple manifestations

which evolve over time / more in the early

stage

Clinical diagnosis supported by Hx,Physical Exam and Laboratory tests

Make take months to years for the typical

picture to unfold ACR classification criteria for SLE is

helpful but not needed for Dx

Cli i l M if i f SLE


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Clinical Manifestations of SLE


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Laboratory tests/Ab testing for

SLE Tests for diagnosis

Tests for prognosis

Tests to determine appropriate

treatment (What organ involvement is

occurring?)


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SLE CBC,diff, ESR, CRP

Creatinine, urinalysis

Chemistry Panel

ANA, anti DsDNA, anti-SM, anti-RNP

anti-SSA /SSB, RF, C3,C4,total

complement


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Ab testing for SLE

ANA(anti-nuclear antibodies)

Positive in 95-99% of SLE

Occurs in 20% of healthy people,

elderly, with drugs, thyroid disease,

RA,SS, pulmonary fibrosis.

If positive + clinical symptoms continueworkup


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What is ANA?

Antinuclear antibody is an autoantibody

against part of the cell nucleus

It is a screening test for SLE: so ifnegative, it makes SLE highly unlikely


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Frequent ANA patterns

Speckled

Homogeneous / Diffuse

Nucleolar

Rim / Peripheral

Centromere


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Positive test

Titers: stronger positive, the dilution is

larger (higher denominator)

Ex. 1/1280 is a strong positive

Pattern can change depending on the

dilution

Ex. 1/80 speckled and homogenous and1/640 homogenous


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Is there utility in following the

titer? No

In general repeating the test is a waste

of money A positive test in past or at any time can

count in the diagnostic criteria for SLE


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When do I order anti DNA?

It is an auto-antibody directed against

the DNA in the cells nuclei

Only order anti DNA in the presence ofa positive ANA, when you are clinically

suspecting SLE

It is very specific for SLE, but veryinsensitive


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What does anti DNA correlate

with? It is highly specific for SLE

It correlates with renal SLE (but not

100%) Thus, it can be a bad prognosticator

and it is part of the diagnostic criteria


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What is an ENA

ENA is extractable nuclear antigens

The lab will do a screen to see if it is

positive or negative If positive, more assays are done to

determine which antibody is positive


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ENA examples

Anti Ro, (anti SSA)

Anti La, (anti SSB)

Anti Sm (Smithfairly sensitive for SLE)

Anti RNP (goes with MCTD and SLE) Anti Scl 70 (Topoisomerase 1)goes with

diffuse scleroderma esp with interstitial lungdisease

Other: anti Jo1(myositis)


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Anti-Ro(anti-SSA) and

La(anti-SSB) + Anti Ro:

is associated with cutaneous SLE features

including rash and photosensitivity is often + in ANA negative SLE

can go with anti La in Sjogrens S.

can increase the risk of congenital heartblock in babies whose moms are +


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The results of the college

student WBC 2.8, Hbg 11.1, Plt 43

Creatinine 1.0, urine neg for protein and

blood ANA 1/320 speckled

ENA: + for anti Smith (Sm)

antiDNA negative


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Does she have SLE?

+ ANA

Low WBC and plt

+ anti Sm

Malar rash

Photosensitivity

Possible inflammatory arthritis

She has at least 5 criteria



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SLE


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Antiphospholipid antibody

syndrome (APS) Half are associated with SLE

Occurs in 10-20% of SLE patients

Syndrome of arterial and or venousclotting (CVA, DVT, PE), recurrent

abortions and often livedo reticularis,

low platelets


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Antiphospholipid antibody

syndrome (APS) Positive tests may include

Lupus anticoagulant (false prolongation of PTT)

Anticardiolipin antibody (aCL) or other

antiphospholipid antibodies

False positive VDRL

Abnormal RVV time (Russel venon viper time)


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APS

Treatment varies on symptoms and

signs

ASA or LMW heparin in pregnancy Warfarin if DVT

ASA and possibly warfarin if CVA

(Cerebro-vascular-accident)


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SLE Management - treatment No curechronic condition

TTo aimed at:

Reducing inflammation

Suppressing immune system

Closely monitoring patients to ID and to treat

disease features as early as possible

Minimize therapy adverse effects


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Management - treatment Patient Education and prophylactic measures

to avoid flares :

Sunscreens SPF >30 and protective clothing

Photosensitivity, Raynauds Phen.

Avoid estrogen containing oral contraceptives

Lupus flares, hyperthrombotic states

Avoid medications such as:

Sulfonamides, Echinacea, and Melatonin

Management treatment


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Managementtreatment

Low dose ASAfor patients with

+Antiphospholipid Abs Potentially avoid thrombosis

Psychological support

Depression and anxiety Routine immunizations

Influenza (yearly) and pneumococcus vaccine

(every 5-10 years)- Live virus vaccines not recommended


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Managementtreatment

Enforce regularly scheduled:

Colonoscopy

Pap smears Mammograms

Increased risk of cancer


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Managementtreatment

Baseline and periodic bonedensitometry

Biphosphonatesnot given to patientswith renal insufficiency or potential tohave pregnancies

Osteopenic patients: Biphosphonates,

CaCO3 and Vit D

Management of HTN and Lipid levels


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Managementtreatment

Pregnancy

High risk

90 % successful Flares can occur

High disease activity with increasedDsDNA level and decreased complement

levels Increased pre-eclampsia, preterm births,

and fewer live births


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Managementtreatment Risk of Neonatal Lupus in + Ro(anti SSA) AB

Cross placenta

2-5 % risk of congenital heart block in the

baby, hemolytic anemia, and rashes

Women with medium to high titer

anticardiolipin /anti-B2 glycoprotein, hx of

pregnancy loss or severe preeclampsiaASA and Heparin during pregnancy and 6

months after.


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Managementtreatment

Cutaneous Lupus:

Hydroxychloroquine (Plaquenil)

200 mg PO BID

Risk for retinopathy (


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Managementtreatment Musculoskeletal symptoms

NSAIDSmild arthralgias

COX 2 inhibitors

Do not use for long periods of time Proton pump inhibitors- PRN

Hydroxychloroquine200mg PO BID

LowDose Prednisone


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Managementtreatment

Persistent Synovitis

Methotrexate

LeflunomideAbatacet

Rituximab


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Managementtreatment

Serositis

Mild serositis: may respond to NSAIDS

Moderate S: Triamcinolone 100mg IMx1 Severe : Methylprednisolone IV pulse

(1000mg over 90minutes x 3days ) followed

by oral Prednisone tapering dose

Maintenance immunosupressive regimen if

persistent / recurrent serositis


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Managementtreatment

Lupus Nephritis

Mycophenolate Mofetil (Cellcept)

induction and maintenance therapy Recent studies show potential

superiority of Cellcept as induction and

safety profile when compared toCytoxan


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Neprhitis (cont)

Cyclophosphamide (Cytoxan)induction therapy- IV pulse

Induction IV 500-750 mg/m2 bodysurface, monthly, for 6 months

Maintenance IV quaterly for 2 years

Hemorrhagic Cystitis

Long term risk for Urinary Bladdermalignancy


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Managementtreatment

CNS Lupus

IV Methylprednisolone pulse

IV monthly Cyclophosphamide

Additional antiepileptic medication in the

case of seizures/ Neuro-consult

Psychosis-antipsychotic drugs andmood stabilizers


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Managementtreatment

Hematological Lupus

Plt count < 30,000 bleeding may occur

Severe hemolytic anemia /thrombocytopenia

High dose steroids, if no improvement

intravenous immunoglobulin Rituximab


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Case study

Patient Name: Melisa T.

Age: 19

Sex: Female

Description: Melisa, a young Latina student, is taking

mycophenolate mofetil (MMF) for lupus nephritis

(LN) has come in for a routine follow-up visit. How

would you monitor progress, and, based on the labresults, are there any changes you would make to

her regimen?

19-year-old Latina patient with systemic


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lupus erythematosus (SLE) is seen todayfor a routine follow-up visit. She was

referred 1 year ago with polyarthritis,thought by her primary care provider tobe due to rheumatoid arthritis (RA). Afterconfirmation of SLE, she was found to

have 3+ proteinuria, 10 RBCs/HPF, andclass IV diffuse proliferative nephritisseen on renal biopsy. Treatment withhigh-dose prednisoneplus

mycophenolate mofetil(MMF; first 2g/day, then 3 g/day) stabilized her lupusnephritis (LN): urine protein decreased to0.3 g/day and revealed no RBCs.

Eventually, prednisone was tapered down to10 T d h d i i ifi t j i t i
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10 mg.Today she deniessignificant joint painor swelling, rashes, chest pains, skin ormucous membrane abnormalities, orneurological symptoms. Past history andfamily history are unremarkable. She hasnever been pregnant, but is determined tohave children with her fiance in the future. At

present she uses barrier methods (estimated90% of the time). She is willing to use otherforms of contraception for a period of time,but despite her present monogamy she

rejects use of an IUD due to prior pelvicinflammatory disease. Review of systems isotherwise normal. Physical exam revealsobesity without evidence of malar or other

rash.


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Current Conditions

Lupus nephritis

Obesity

Systemic lupus erythematosus

Current Medications

10 mg prednisone daily

1500 mg mycophenolate mofetil bid

600 mg-200 units calcium-vitamin D bid

Daily multivitamin


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Original Lab results

Anticardiolipin antibodies: mediumpositive titer

Lupus Anticoagulant: not detected Beta2 Glycoprotein I: negative

Urine hCG Negative

Urine protein/creatinine ratio =0.3, which correlates with 300 mgproteinuria/day.


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Renal Biopsy 24 Apr 07 - Renal biopsy from 13 months ago was consistent with lupus nephritis

Class IV (no crescents noted).

QuickTime an d a

decompressorare needed to see this picture.


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anti-CCP 2 IU/mL

Note:

0-19 (negative)

20-39 (weak positive)

40-59 (moderate positive)

>60 (strong positive)


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AB testing

Anti-Sm (Smith): Positive

ANA positive at 320 in a homogeneouspattern

DsDNA Positive at 1:80

C3 Complement 61 mg/dL

82 - 235

C4 Complement 44 mg/dL 16 - 70

Glucose (FPG) 92 mg/dL

70 110


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70 - 110

Creatinine 0.8 mg/dL

0.6 - 1.3 Albumin 3.7 g/dL

3.4 - 5.0

Bilirubin, Total 0.7 mg/dL

0.0 - 1.0 Alkaline Phosphatase 121 IU/L

50 - 136

AST (SGOT) 23 IU/L

15 - 37 ALT (SGPT) 18 IU/L

15 - 37


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Current lab tests

A CBC should be ordered severaltimes a year in patients with SLE

(every 3 months if taking MMF) toscreen for leukopenia,thrombocytopenia, and/or anemia.

Hb (Hemoglobin) 9.8 g/dL


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( g ) g

9.6 - 18.0

HCT (Hematocrit) 29 % 37 - 47

Platelet Count 214 1000/mm3

50 - 350

WBC (White Blood Cell Count) 3.2

1000/mm3

4.0 - 10.8

A chemistry panel that checks


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fasting glucose, creatinine, lipids,and hepatic enzymes should be

ordered several times a year(every 3 months if taking MMF) inpatients with SLE.

Glucose (FPG) 82 mg/dL

70 110


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70 - 110

Creatinine 1.2 mg/dL

0.6 - 1.3 Albumin 3.6 g/dL

3.4 - 5.0

Bilirubin, Total 0.6 mg/dL

0.0 - 1.0 Alkaline Phosphatase 113 IU/L

50 - 136

AST (SGOT) 28 IU/L

15 - 37 ALT (SGPT) 18 IU/L

15 - 37

In anticipation of obtaining a renal


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In anticipation of obtaining a renalbiopsy, coagulation studies are

indicated. Prothrombin Time 12 seconds

11 - 15

Partial Thromboplastin Time 29 seconds

25 - 40

International Normalized Ratio 1.0

0.8 - 1.2

Dyslipidemia is a potential consequence of


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y p p qproteinuria; LDL-C levels should be checked

regularly. Abnormal lipid levels deserve vigorous

treatment. Triglycerides 173 mg/dL

0 - 150

Total Cholesterol 225 mg/dL

0 - 200

LDL Cholesterol 110 mg/dL

62 - 130

HDL Cholesterol 79 mg/dL 50 - 60

Renal biopsy:

Class IV lupus nephritis with a high level of activity


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Class IV lupus nephritis with a high level of activity

(crescents)

QuickTime and a

decompressorare needed to see this picture.

Color yellow

Turbidity cloudy


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Turbidity cloudy

Specific Gravity 1.013 1.006 - 1.030

Urine Glucose negative

Ketones negative

Blood negative

Protein 2+

Bilirubin negative Urobilinogen negative

Nitrites negative

Leukocyte Esterase negative

Casts negative RBCs negative

Crystals negative

WBCs negative

A urine protein/creatinine ratio is an efficientand reasonably accurate method to quantitate


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and reasonably accurate method to quantitateproteinuria. Values > 0.5 (correlating to > 0.5g (500 mg)/24 h) suggest the need for a renalbiopsy to stage possible lupus nephritis(3659).

Urine protein/creatinine ratio = 2.0

Antiphospholipid Antibodies: With her

t dl iti ti di li i


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.repeatedly positive anticardiolipin

antibody determinations and intrinsic

high risk for thrombotic complications,continued monitoring is prudent.

Anticardiolipin antibodies: 80 GPL U/mL

(high positive)

Lupus anticoagulant: not present

Beta2 Glycoprotein I: negative


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Possible options

Due to the failure of MMF for decreasing

proteinuria to below 500-1,000 mg/day in this

patient, discontinuation of its use and

substitution of rituximab, or the combinationof cyclophosphamide with leuprolide

premedication, or perhaps azathioprine is a

reasonable next step.

Patients with lupus nephritis and this degreef i th l i ti it i f


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of ongoing pathologic activity require use ofan immunosuppressive agent, such as

cyclophosphamide lyophilized, azathioprine,tacrolimus, or an experimental therapy suchas rituximab

Although cyclophosphamide remains the

standard for use in rapidly-progressivecrescentic lupus nephritis, its use is highlyassociated with infertility noted in about 50%of patients using this drug. The incidence of

infertility can be decreased to approximately15%, however, with leuprolide injections 2weeks prior to the monthly cyclophosphamide

Some success has been reported inl b l i i it i b hi h


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open-label series using rituximab ,whichperipherally depletes B-lymphocytes

and is approved for use in rheumatoidarthritis.

While not FDA-approved for use inlupus nephritis, the anti-rejection agenttacrolimus has been associated withsome degree of success in a small

number of patients


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Azathioprine has been shown to have

equivalent efficacy to MMF in

maintenance trials, but patients areunlikely to have a better response to

azathioprine than they had to MMF.

Standard Dosing Ranges


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1,000-1,500 mg of mycophenolate mofetil500 mg oral tablet BID maximum, 2,000-

3,000 mg daily maximum 1-80 mg of predniSONE 10 mg oral tablet

QID maximum, 1-80 mg daily maximum

1-4 ea of calcium-vitamin D 600 mg-200 unitsoral tablet QID maximum, 1-4 ea dailymaximum

1 ea of Multiple Vitamins oral capsule once aday maximum

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Sle and Apls

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