diagnosis and key points in the management of systemic ... · lupus: the essential clinicians...

Diagnosis and Key Points in the Management of Systemic Lupus

Erythematosus

Amish J. Dave, MD, MPH

Virginia Mason Medical Center

© 2014 Virginia Mason Medical Center

Disclosures

No faculty, provider or planning committee member in a position to influence or control the

content of this presentation has any relevant financial relationships to disclose.

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Learning Objectives

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1. Understand common manifestations of SLE and differences between

SLE, cutaneous lupus, and drug-induced lupus

2. Describe initial work-up of SLE

3. Consider initial management approaches and recent updates in

therapy

4. Learn where to find rheumatology patient and provider education

materials


Clinical Case

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26 year old woman with depression, new onset joint pain in the hands and

feet, fatigue, and hair loss. She notes fingers turning colors in the cold since

age 13

Meds: fluoxetine, oral contraceptive pill

Labs: CBC: 3.1 / 12.5 / 129

CMP notable for albumin 3.0,creatinine 0.8

AST 20, ALT 20, and AP 90

ESR: 43 CRP <3.0

TSH: 3.95

ANA: 1:160 (homogenous)


Does this woman have SLE?

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Does this woman have SLE?

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- Young woman

- Positive ANA?

- ESR elevation with normal CRP

- Hypoalbuminemia

- Leukopenia and thrombocytopenia

- Raynaud’s?


Review of Systems for SLE

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Alopecia

Oral/nasal ulcers (painless)

New headaches

Hx of migraines

Hx of uveitis/scleritis

Hx of pleuritis or pericarditis

Blood in the stool or urine

Joint pain or swelling

Morning stiffness

Fevers

Muscle pain

Focal weakness

Numbness/tingling

Rashes (malar)

Photosensitivity

Dry eyes/mouth

Hx of miscarriages

Hx of blood clots

Hx of seizures

Hx of Raynaud’s


Further history provided…

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• Fatigue despite adequate sleep.

• Pain and swelling of the wrists, knees, ankles (worse in mornings and

improved with NSAIDs)

• Patchy hair loss without scarring, fingers have white/blue/red color changes


Raynaud’s phenomenon

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Images courtesy of

Google Images

What Is Systemic Lupus Erythematosus?

• Systemic lupus erythematosus (SLE) is a progressive chronic autoimmune disease that results in inflammation and tissue damage

• Characterized by flares, spontaneous remission, and relapses

• SLE can affect any part of the body but often results in damage to the skin, joints, heart, kidneys, lungs, and nervous system

Wallace DJ. Lupus: The Essential Clinicians Guide. New York, NY: Oxford University Press; 2009.

Slide courtesy of Dr.

Daniel J. Wallace, MD

(UCLA): Disorders

that overlap with

scleroderma

Who Gets SLE?

• 85% of SLE patients are women (ratio peaks in middle age)

• SLE affects

– 1 in 250 African American women

– 1 in 1000 white women

– 1 in 10,000 white men

– Highest prevalence of SLE occurs in African Americans, Hispanics, Asians, and Native Americans

– 50% with SLE develop organ-threatening involvement

Petri M. Best Pract Res Clin Rheumatol. 2002;16:847-858.Petri M. Systemic Lupus Erythematosus. In: Imboden JB, Hellmann DB, and Stone JH, eds.Current Rheumatology Diagnosis and Treatment. USA: McGraw Hill; 2007.Uramoto KM, et al. Arthritis Rheum. 1999;42(1):46-50.

Types of Lupus Erythematosus

• Cutaneous (discoid) lupus erythematosus (40%)

• Systemic lupus erythematosus (50%)

– Nonorgan-threatening disease (25%)

– Organ-threatening disease (25%)

• Drug-induced lupus erythematosus (<1%)

• Crossover or overlap syndrome and/or mixed connective tissue disease (MCTD) (10%)

• Neonatal lupus (<1%)

Wallace DJ. The Lupus Book. New York, NY: Oxford University Press; 2013.

Epidemiology of Lupus Erythematosus (LE) (cont)

• Only 1 in 3 diagnosed with lupus fulfills ACR criteria,1 suggesting prevalence in US between 500,000 and 1,000,000; many have undifferentiated connective tissue disease (UCTD)

• UCTD: presence of autoantibodies with either evidence for inflammatory arthritis or Raynaud’s that does not fulfill criteria for systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or scleroderma

• Highest prevalence of SLE in US is among African-American women in San Francisco (1/250); lowest is among white men (1/5000)

1. Hochberg MC. Lupus. 1996.


Diagnostic versus Classification Criteria

Diagnostic criteria

Diagnosis may be defined as the determination of the cause or nature of an illness by evaluation of the signs, symptoms and supportive tests in an individual patient.

Diagnostic criteria are a set of signs, symptoms, and tests for use in routine clinical care to guide the care of individual patients.

Diagnostic criteria are generally broad and must reflect the different features of a disease (heterogeneity), with a view to accurately identify as many people with

the condition as possible. Given this complexity, the development and validation of diagnostic criteria can be quite challenging. The Diagnostic and Statistical Manual of

Mental Disorders (DSM) is likely the best-known example of diagnostic criteria. Its initial development was prompted by the observation of extremely poor agreement among

providers regarding patients’ psychiatric diagnoses. There are only a few validated diagnostic criteria in rheumatology, and clinicians commonly establish a diagnosis

based on subjective combination of clinical signs/symptoms, available clinical tests, and knowledge about the epidemiology of their geographical area.

Classification criteria

Classification criteria are standardized definitions that are primarily intended to create well-defined, relatively homogenous cohorts for clinical research; they are

not intended to capture the entire universe of possible patients, but rather to capture the majority of patients with key shared features of the condition. Hence the

goal of classification differs from the intent of diagnostic criteria. Validated classification criteria are considered critical to the interpretation of study findings and comparisons of

results between studies. Despite facilitating the comparison of study results, classification criteria have the potential to restrict the external validity of studies, as interventions

may perform differently in the study participants who fulfill classification criteria for a disease than in the broader group of persons having been diagnosed with the same

disease, i.e., those that share only some but not other disease manifestations considered in classification criteria.

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Aggarwal R, et al. Arthritis Care Res

(Hoboken). 2015 Jul; 67(7): 891–897.

https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=25776731

2019 ACR/EULAR Classification criteria

for systemic lupus erythematosus

Martin Aringer et al. Ann Rheum Dis 2019;78:1151-1159

©2019 by BMJ Publishing Group Ltd and European League Against Rheumatism

SLICC CRITERIA FOR SLE: 2012

• CLINICAL– SKIN

• Acute cutaneous LE

• Chronic cutaneous LE

– ORAL ULCERS

– ALOPECIA

– SYNOVITIS

– SEROSITIS

– RENAL• Prot/Cr ≥0.5

• RBC casts

• BIOPSY*******

– NEUROLOGIC• Sz, psychosis, mononeuritis,

myelitis, p or c neuropathy, acute confusional state

– HEMOLYTIC ANEMIA

– LEUKOPENIA (<4000) or LYMPHOPENIA (<1000)

– THROMBOCYTOPENIA(100k)

• IMMUNOLOGIC

– ANA > normal value

– ANTI-dsDNA

– ANTI-Sm

– ANTI-PHOSPHOLIPID

– LOW COMPLEMENT

– DIRECT COOMB’S POS

93% specificity; 92% sensitivity

Petri M et al for SLICC, Arthritis Rheum 2012

≥4 out of 17 criteria (≥1 clinical and ≥ 1 immunologic) = classify as SLE

© 2014 Virginia Mason Medical Center 17

Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64:2677.


SLICC Clinical Criteria


SLICC Clinical Criteria

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SLICC Immunologic criteria

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ANA: >1:160

The majority of individuals with ANA detected at

a dilution of 1:40 (approx. 30% of normal

population) have a false positive result

Ds-DNA- specific for SLE (by ELISA ~70%)

- fluctuate with SLE disease activity

- association w/ active glomerulonephritis

Anti-Smith (Sm)- presents in10 to 50% SLE patients

- specificity: 55 to 100 percent

- does not mirror disease activity

Antiphospholipid antibodies- lupus anticoagulant

*screening tests: dilute Russell viper

venom time (dRVVT) and activated partial

thromboplastin time (aPTT)

* can’t check on anti-coagulation

- anticardiolipin antibody

>40 GPL or MPL, or > the 99th %ile

Venereal Disease Research

Laboratory (VDRL) and rapid plasma

reagin (RPR) tests contains cardiolipin

- anti-beta-2 glycoprotein-I antibody

in titer >the 99th percentile

* association of the IgA isotypes with clinical

thrombosis remains controversial


Further work-up

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CBC (with differential), CMP

ANA (with titer) including ds-DNA (quantitated), Smith, RNP, SSA/SSB

Anti-TPO, thyroglobulin

ESR, CRP

C3/C4 levels

UA (urine protein and creatinine)

APS (anti-cardiolipin, B2-glycoprotein, lupus anticoagulant), Coombs

HIV, Quantiferon, hepatitis B and C serologies, RPR


Clinical Case

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26 yo F with hx of hypothyroidism presents with joint pain, fatigue, and hair loss. Meds: fluoxetine, OCP

Exam: swelling of wrist and ankle joints, non-scarring alopecia, ulceration on oral palate

Labs: CBC: 3.1 / 12.5 / 129

CMP notable for albumin 3.0

ESR: 43 CRP: <3

TSH: 3.95

ANA: 1:160 (homogenous), ds-DNA: 300, + SSA

APS negative, Coombs negative

UA wnl, low C3 with normal C4 level

2019 ACR/EULAR Classification criteria

for systemic lupus erythematosus

Martin Aringer et al. Ann Rheum Dis 2019;78:1151-1159

©2019 by BMJ Publishing Group Ltd and European League Against Rheumatism


Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64:2677.


SLE Management

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Initial Management:

• Rheumatology referral!

• Start hydroxychloroquine

Up to 6.5 mg/kg* if tolerating

Baseline eye exam

Caution if G6PD deficient

• NSAIDs if no renal involvement

• +/- low dose prednisone (10-15 mg) for arthritis


DMARD Use in SLE

• Hydroxychloroquine (Plaquenil)

• Azathioprine (Imuran)

• Belimumab (Benlysta)

• Mycophenolate (CellCept)

• Cyclophosphomide (Cytoxan)

• Rituximab (Rituxan)*

• Avoid Sulfa Medications (especially

Bactrim!!!)

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Mechanisms of Benefit of

Hydroxychloroquine• Reduce cytokine secretion: IFNalpha, IL1, IL6, TNFa

• Inhibit lysosomal activity by altering acidic state : reduction

of Ag processing/presentation by DC and M/M

• Inhibit autophagy

• Inhibit signaling through TLR7 and TLR9

• Reduce phospholipase A2 activation

• Reduce synthesis of cholesterol

• Reduce platelet adhesiveness

• Clinical Effects in SLE: Reduce disease flares (?), reduce

damage, reduce thrombosis, reduce cholesterol levels, reduce

HgA1c levels

Fessler BJ et al 2005; Costedoat-Chalumeau N et al

2013: PubMed Search Oct 2015

Slide courtesy of Dr.

Bevra Hahn, MD

(UCLA): SLE 2015 –

Arthritis and Joint

Pain

Fessler BJ et al, Arthritis & Rheum, 2005

PREVENTION OF RETINAL DAMAGE: HYDROXYCHLOROQUINE

Hydroxychloroquine and Retinal Toxicity

• Am Association Ophthalmology recommends

– Do not exceed 6.5 mg/kg/day dose.

– Eye exams every 5 years for low risk patients.

– Eye exams every 6-12 months for high risk or retinal

findings.

• High Risk: >8 yrs of Rx, age >60, obesity, renal dz, hepatic dz,

cumulative dose >1000 g

• Expect in Ophth exam: one test of visual field (subjective) and

at least one objective test: spectral domain optical coherence

tomography(OCT), ERG, autofluorescence.

Browning D 2013; Dubois book 2013: Marmor et al 2011

Ophthalmologists Tools for Antimalarial Toxicity

Visual field

Optical Coherence

Tomography

AutofluorescenceERG

Marmor et al 2011

Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid

arthritis and systemic lupus erythematosus

Arthritis Care & Research Wolfe F et al 2010

Volume 62, Issue 6, pages 775-784, 12 FEB 2010 DOI: 10.1002/acr.20133

http://onlinelibrary.wiley.com/doi/10.1002/acr.20133/full#fig2

Toxicity increases at 8 yrs.

Increase is 5-fold.

Cumulative dose is 1000 g

http://onlinelibrary.wiley.com/doi/10.1002/acr.v62:6/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/acr.20133/full#fig2

MP/DC

HLA

TCR

Inosinic acidInosinic acid purines

IMPDH

purines

IMPDH

CD28 B7 B CellT Cell

CD20

CD22

BCMA

TACI

BAFF-R

Y

DNA-

binding

BCR

By BH Hahn

Targeted Therapies in SLE

IMPDH= inosine monophosphate dehydrogenase

CD40L CD 40

Anti-CD40L

LJP394

Treg

Edratide, Lupuzor

BLyS

aBLySTACI Ig

MP/DC

CTLA4 Ig

ICOS B7RP1

Hydroxychloroquine (Laquinimod, OGN for TLR, anti-IFNa)

Cyclophosphamide

Azathioprine

FcγR

Syki

Mycophenolate Mycophenolate

IL6R

Anti-IL6

Rituximab

Ocrelizumab

Epratuzumab

IC C’

Anti-C5a

Syk

CaMK4

NFAT

mTOR

Inhibitors

Tacrolimus

Rapamycin

GLUCOCORTICOIDS

Anti-TWEAK

Proteosome inh

Annual Costs of SLE-related Medications (2015)

• HCQ $ 1,080

• Prednisone $ 156

• Methotrexate $ 408

• Azathioprine $ 1,560

• Mycophenolate $ 5,668

• Belimumab $41,760 (w/o infusion costs)

Hahn BH, data from Epocrates Oct 2015, based on www.goodrx.com

Neuropsychiatric SLE

• SLICC Criteria

– Seizures

– Psychosis

– Mononeuritis

– Myelitis

– Peripheral neuropathy

– Cranial neuropathy

– Acute Confusional State

– ?Depression?Petri et al, Arthritis Rheum 2012

Key Questions in Neuro Lupus

• Is the problem due to lupus or something else (e.g.

infection, meds, atherosclerosis)

– 50/50

• If lupus, is it vascular or non-vascular?

• If lupus, is it inflammatory or non-inflammatory?

CNS SLE

• Evidence that it is INFLAMMATORY

– SLE is active in other systems

– CSF contains elevated protein, cells,

oligoclonal bands, high Ig synthesis (anti-

neuronal, anti-ribosomal P Abs)

– MRI shows enhancing lesions

– Labs show evidence of inflammation; CRP,

ESR, hypocomplementemia, anemia

West, Sterling, in Dubois’ LE 2013

Sibbitt WL Jr, et al, Semin A&R, 2010

VASCULOPATHIC CNS SLE: AUTOPSY OF 14/22 PTS DIED

WITH ACTIVE CNS/SLE OUT OF 200 FOLLOWED 10y w MRI

Trevisani VFM et al, Cochrane

Review, 2009, based on Barileo –

Fabrica et al 2005

Cyclophosphamide in CNS Lupus: ? Better than Steroids

All induced with steroid pulse and maintained on 1 mg/kg/d: Cy = 750 mg/m2 quarterly

For 2 yrs, vs IV steroids monthly, then q 2 mos, then q6 mos. F/u 2 yrs. N = 32 total

3 deaths in Cy; 1 in steroids.

EULAR Guidelines

• 1A Recommendation:

– MRI analysis should include T1 T2-weighted, contrast, DWI

– GLUCOCORTICOID and IMMUNOSUPPRESSIVE THERAPY are indicated for NP manifestations reflecting an immune/inflammatory process with other causes excluded

• Acute confusional state

• Aseptic meningitis

• Myelitis

• Cranial or peripheral neuropathy

• Psychosis

• Optic neuritis (may consider steroids alone)

Bertsias et al ARD 2010


Non-pharmacologic management

• Sun protection

- Exposure to ultraviolet (UV) light may flare SLE

- Sunscreens that block both UV-A and UV-B, SPF ≥55

- Avoid medications that can cause photosensitivity

• Vitamin D (goal 30-60)*

• Herbal remedies are of unproven benefit and may cause harm

?Avoid garlic, melatonin, echinacea, alfalfa sprouts

• Immunizations

Influenza and pneumococcal vaccines are safe

Resultant antibody titers are somewhat less in patients with SLE than in controls Quadrivalent human papilloma virus (HPV) vaccine

No live vaccines:

Glucocorticoids ≥20 mg/day (for more than two weeks)

Azathioprine ≥ 3 mg/kg per day

Belimumab

• Treating comorbid conditions

Accelerated atherosclerosis

Pulmonary hypertension

Antiphospholipid syndrome

Osteopenia or osteoporosis

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Neonatal lupus

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Prior to Rheumatology Referral

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Labs:

Recent CBC/CMP

ANA (with IFA)

TSH, TPO-ab, thyroglobulin

UA with urine Protein/Cr if indicated

ESR/CRP

PT/PTT

Hepatitis panel, HIV/Quant gold

XRs hands/feet if joint pain

Dermatology evaluation if concerning rash

Differential Diagnosis of SLE• Autoimmune (RA, scleroderma, myositis, vasculitis, spondyloarthropathies,

inflammatory bowed disorders, Behcet’s, sarcoidosis, Sjogren’s syndrome, thyroiditis, polymyalgia rheumatica, undifferentiated connective tissue disease)

• Infections (TB, HIV, Lyme, CMV, bacterial endocarditis, EBV)

• Fibromyalgia

• Allergies

• Neurologic disorders (esp. myasthenia gravis, MS)

• Malignancy (esp. lymphoproliferative disorders)

• Drug-induced lupus (chlorpromazine, methyldopa, hydralazine,

procainamide, isoniazid, quinidine)

• Psychiatric disorders (eg, bipolar illness, malnutrition, substance abuse)

Wallace DJ. The Lupus Book. New York, NY: Oxford University Press; 2012.Manson JJ, et al. Orphanet Journal of Rare Diseases.2006, 1:6http://bestpractice.bmj.com/best-practice/monograph/103/diagnosis/differential.html. http://emedicine.medscape.com/article/332244-differential. Both accessed July 2013.


Drug induced SLE

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Patient Education

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American College of Rheumatology:

http://www.rheumatology.org/I-Am-A/Patient-Caregiver

Lupus Foundation: http://www.lupus.org/

http://www.rheumatology.org/I-Am-A/Patient-Caregiver


Questions?

[email protected]

Phone: (206) 223-6824

Fax: (206) 625-7288

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