SLE Update 2014Donald Thomas, MD, FACP, FACR

Arthritis and Pain Associates of PG CountyAssistant Professor of Medicine

Uniformed Services University of the Health Sciences, Bethesda

SLE Update:What we will cover

- New “classification criteria” for systemic lupus- ANA up dates- “No evidence of lupus” workup- Plaquenil in all SLE patients- Prevent lupus triggers - AAO Anti-malarial guidelines

- Required tests + proper dosing

- “New” vaccine recommendations- IM steroids treatment for SLE (FLOAT trial)

SLICC- Systemic Lupus International Collaborating Clinics

- Formed in 1991 to develop lupus damage index for research

- 1998 expanded its work:- Establish cohort of newly diagnosed patients- Collect blood samples for future evaluation- Evaluate accelerated atherosclerosis- Evaluate neuropsychiatric disorders in lupus- Study cancer in lupus

American College of Rheumatology (ACR) Classification Criteria for SLE

1982- 4 out of 14 criteria = SLE- Classification criteria = for research purposes only

- Not recommended for diagnostic purposes

- 2004 SLICC embarked upon revision

SLICC: classification criteria improvements

- Missing in 1982 criteria- Low complements- Antiphospholipid antibodies

- 1982 weighted towards cutaneous dz (4 of 14 criteria)- Excluded biopsy proven lupus nephritis as sole

manifestation- Neuro lupus only included psychosis and seizures

- ACR lists 18 potential neurologic disorders in neuropsychiatric lupus

- Could only use one type of low blood count- LE cell prep no longer used

SLICC: classification criteria improvements

- Diagnosed SLE patients vs those meeting classification

- Many patients with early SLE don’t meet criteria- By the time they do they are:

- Older- Had established disease longer- More end-organ damage

- Confirmed by Alarcón, et al, 2013- SLICC criteria allowed earlier diagnosis of SLE

SLICC: SLE classification criteria- SLE occurs if

- Biopsy proven lupus nephritis + ANA or dsDNA

- OR- 4 out of 17 criteria- At least 1 from “Clinical Criteria” and from

“Immunologic Criteria”

SLICC SLE classification criteriaClinical Criteria (11)

- Renal (*** expanded definition) - Alopecia, nonscarring ***- Serositis (*** expanded definition) - Hemolytic anemia ***

- Oral and nasal ulcers- Neurologic (*** expanded definition)

- Synovitis (*** expanded definition) - Chronic cutaneous lupus (*** expanded definition) - Acute cutaneous lupus (*** expanded definition)- Leucopenia/lymphopenia ***- Platelets, low ***

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SLE Clinical Criteria:Renal

- Random urine protein/creatinine ratio ≥ 0.500- 25 hour urine protein ≥500 mg protein/24 hours- Red blood cell casts on urine microscopy

SLE Clinical Criteria:Alopecia, nonscarring

- Diffuse thinning- Hair fragility, broken hair- “Lupus hair”- Rule out alopecia areata, drugs, iron deficiency,

androgenic alopecia- Grows back

CellCept

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SLE Clinical Criteria:Serositis

- Pleuritis- “Typical pleurisy” > 1 day- Pleural effusions- Pleural rub

- Pericarditis- “Typical pericardial pain” > 1 day (worse with lying,

better sitting forward)- Pericardial effusion- Pericardial rub- + ECG

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SLE Clinical Criteria:Neuropsychiatric

- Seizures- Psychosis- Mononeuritis multiplex

- in absence of a 1° vasculitis- Myelitis- Peripheral or Cranial neuropathy

- R/o diabetes, infection (Lyme), 1° vasculitis- Acute confusional state

- R/o toxic, metabolic, uremia, infection, drugs

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SLE Clinical Criteria:Synovitis

- ≥ 2 joints- Swelling or effusion OR- Tender joints + AM stiffness ≥ 30 minutes

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SLE Clinical Criteria:Chronic cutaneous lupus

- Discoid lupus- Hypertrophic (verrucous) lupus- Lupus panniculitis (profundus)- Discoid lupus/lichen planus overlap- Lupus erythematosus tumidus- Chilblains lupus- Mucosal lupus

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SLE Clinical Criteria:Acute cutaneous lupus ORSubacute cutaneous lupus

- Malar rash (don’t count discoid)- Toxic necrolysis variant of SLE- Maculopapular lupus rash- Photosensitive lupus rash- Bullous lupus- SCLE:

- Non-indurated psoriasiform- Annular polycyclic

SLE Immunologic Criteria (6)- ANA- Anti-ds DNA- Anti-Smith- Antiphospholipid antibodies

- Lupus anticoagulant- False positive RPR- Anticardiolipin antibody- Beta-2 glycoprotein antibody

- Low complements (C3, C4, CH50)- Direct Coombs’ test (in absence of hemolytic anemia)

Labs to add during your SLE workup:- If positive ANA by IFA

- CH50 complements- Direct Coombs’ test- Antiphospholipid antibodies

- RPR with reflex FTA- Anticardiolipin antibodies (IgM, IgG, IgA)- Lupus anticoagulant- Beta-2 glycoprotein I antibodies (IgM, IgG, IgA)

2012 criteria vs 1982criteria- Out of 702 patient scenarios……….- Misclassified patients: 7% vs 10%- Sensitivity: 94% vs 86%- Specificity: 92% vs 93% (not statistically different)

“… if you use the classification

criteria to diagnose SLE... I promise not

to tell anyone.”

Michelle Petri, MD: Medical Director Lupus Clinic Johns Hopkins

Order ANA by IIFA- Order ANA by IIFA

- Indirect Immunofluorescent Assay- Detects up to 150 autoantigens- Results = titer with pattern (eg 1:160 speckled)- Formal recommendation of the ACR- Recent international group = same recommendation

- Cheaper solid phase assays- Only detect 6-8 autoantigens- Higher number of false negatives- Value results given as a # units or as “neg” or “pos”

What to do with a negative ANA solid phase?

- Order ANA by IIFA- Can’t rule out a false negative in the workup of SLE

Antibodies occur before SLE dx- 115 out of 130 SLE patients

- Up to 9.4 years before diagnosis- Many times + earliest available samples- Most likely occur significantly earlier

- Average of 3.3 years- ANA (78%)- dsDNA (55%)- SSA (47%); SSB (34%)- Smith (32%); RNP (26%)- APLAs (18%)

What to do with that ANA consult- If nonspecific symptoms or fibromyalgia… check

autoantibodies. Don’t assume fibromyalgia- If specific autoantibodies are all negative:

- “You do not have any evidence for lupus or a systemic autoimmune disease at this time” … “this does not mean that you may not develop one in the future”

- If any clinical problems (low WBC, Raynaud’s, CTS)… follow the patient

- If + RNP, SSA, SSB, antiphospholipid antibody- Follow the patient clinically- RNP is very rare in the normal population- SSA/SSB are seen in “normal” population

- Doesn’t account for under diagnosis of Sjögren's syndrome

- +Smith or +dsDNA- Most likely will develop a systemic autoimmune disease- Follow closely

All SLE patients should be on Hydroxchloroquine (HCQ)

- Even if also on a strong immunosuppressant- HCQ more than doubles response to CellCept

- 2006: Johns Hopkins Lupus Cohort- WHO V lupus nephritis- Those on HCQ: 64% in remission after 12 months- Those not on HCQ: 22% in remission

Prevent triggers of lupus- Low vitamin D levels- UV light- Smoking- Sulfa antibiotics

Low vitamin D and SLE- WBC cellular membranes have Vit D receptors- Higher prevalence of low Vit D in SLE patients- More severe SLE at presentation associated with lower

Vit D- Lower Vit D levels occur during SLE flares- Low vitamin D correlated with flares (like dsDNA and

low complements)

Correcting low vitamin D as tx- Petri M et al, Vitamin D and SLE, Arthr &

Rheum;65(7):1865-71- 1006 patients, 128 weeks- 25[OH]D < 40 ng/mL- TX = 50,000 IU ergocalciferol (vit D2) + daily calcium with

200 IU vit D3

- Results:- - ≥ 20 ng/mL increase 25[OH]D associated with:

- .22 decrease in SELENA/SLEDAI (P = .032)- 21% decrease in having a SELENA/SLEDAI ≥ 5- Random urine/protein decreased by 2% (P = .0001)- 15% decrease in odds of having urine/prot > .5

Vit D as treatment for SLE- Treat patients with 25[OH]D < 40 ng/mL- Aim for a level of around 40 ng/mL or higher

Ultraviolet light

Ultraviolet light

Skin

cellNUCLEUS

Ultraviolet light

Skin

cellNUCLEUS cell

NUCLEUS

damage

Ultraviolet light

Skin

cellNUCLEUS

Antinuclear antibodiesCause increased lupus activity

Dose of UV light = Strength X Time

X 15 minutes

Dose of UV light = Strength X Time

X 15 minutes

X all day long

UV protection = SLE treatment- Wear sunscreen daily even if don’t go outside- Reapply if go outside- Use sunscreen vs UVA and UVB + waterproof + high

SPF- Wide brimmed hat- UV protectant clothes- Add Rit Sunguard to wash- Avoid outside 10 AM – 3 PM

Stop smoking if have lupus- Tobacco contains hydrazine

- Hydrazine known to increase lupus activity

- Smoking decreases effectiveness of Plaquenil- Smoking is associated with increased lupus prevalence- Smoking associated with more severe lupus

Avoid sulfa antibiotics in SLE- Increased risk for lupus flares- Ask patients to include Bactrim and Septra in

allergies

2011 Revised recommendations for HCQ: American Academy of Ophthalmology

- Base HCQ dosing on ideal body weight (<6.5 mg/kg)- Most SLE patients are overweight or obese- HCQ doesn’t distribute in fat- Table included in handout

- Women 5’1/2” – 5’6.5”= 300 mg a day

- Baseline eye exams within year 1; Yearly at year 5- Earlier or more often in elderly, DM, renal/hepatic

insufficiency- Eye tests of choice:

- VF 10-2 every time +- Either:

- SD-OCT (spectral domain optical coherence tomography)- FAF (fundus autofluorescence)- mfERG (multifocal electroretinogram)

Infection = #2 cause of death in SLE- Make sure all patients get yearly flu shot- Pneumovax if immunosuppressed or ≥ 65 yo

- Repeat after 5 years

- Prevnar PCV-13 pneumococcal vaccine- Immunosuppressed patients per CDC 2013- 8 weeks prior to getting Pneumovax OR- Must wait at least 1 year after Pneumovax

HPV-associated cancers = high in SLE- Dreyer L et al, High Incidence of Potentially Virus-

Induced Malignancies in SLE, Arth & Rheum, 2011;63(10):3032-37

- Increased HPV-associated cancers - Anal cancer- Vulvovaginal- Cervical- Non-melanoma skin cancer

- Nath R et al, High risk of Human Papillomavirus Type-16 infections and of development of squamous intraepithelial lesions in systemic lupus erythematosus patients, A&R, 2007;57(4):619-25

- High levels of HPV-16 infection and abnormal colposcopy in newly diagnosed SLE women

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All patients ≤ 26 yo should receive Gardasil series

IM steroids for mild – moderate flare- FLOAT (Flares in Lupus: Outcomes Assessment

Trial)- Johns Hopkins Lupus Cohort: 2006- 50 patients randomized, mild – moderate flare- Medrol dose pak vs 100 mg triamcinolone IM (2.5cc

Kenalog-40)- 4% of IM steroids flare resolved day 1- No patients on Medrol Dose Pak responded the first few days- Week 1 = similar improvements- Week 4:

- Medrol Dose Pak = ¼ complete response, 67% at least partial response

- IM steroid = 1/3 complete response, 74% at least partial response

- IM steroids work faster and may last longer

Summary- SLICC new SLE classification criteria

- 4 out of 17: at least 1 from “clinical” and 1 from “immunologic”- Initial workup: Include ANA IIF, direct Coombs, CH50,

APLAs, random urine protein/creatinine- Don’t dismiss patient with + autoantibodies- TX: HCQ, Vitamin D, sunscreen, no cigarettes- VF 10-2 + either FAF, SD-OCT, or mfERG yearly after 5 years- <400 mg HCQ in most (300 mg/d if female < 5’7” tall)- Vaccines:

- Diligent with flu shots and Pneumovax- Gardasil series if ≤ 26yo- Prevnar-13 if on immunosuppressants

- IM steroids work faster for flares + safe

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The Walk to End Lupus: April 19, Pennsylvania AveLupus Foundation of America DC/MD/VA

DCLupusWalk.org

Nick CannonGrand Marshall

References 1:Agmon-Levin N et al. International recommendations for the

assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis. 2014;73:17-23

Amital H et al. Serum concentration of 25-OH vitamin D in patients with SLE are inversely related to disease activity. Ann Rheum Dis.2010,69:1155-57.

Arbuckle MR et al. Development of Autoantibodies before the clinical onset of systemic lupus erythematosus. NEJM. 2003;349(16):1526+

Birmingham DJ et al. Evidence that abnormally large seasonal declines in vitamin D status may trigger SLE flare in non-African Americans. Lupus. 2012;21(8):855-64

Bonakdar ZS et al. Vitamin D deficiency and its association with disease activity in new cases of systemic lupus erythematosus. Lupus.2011;20:1155-60

References 2:Boeckler P et al. Association of cigarette smoking but not

alcohol consumption with cutaneous lupus erythematosus. Arch of Derm. 2009;145(9):1012-16

Cooper G et al. Occupational and environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents. Rheum (Oxford). 2010;49(11):2172-80

Danowski A et al. Flares in lupus: Outcomes assessment trial (FLOAT), a comparison between oral methylprednisolone and intramuscular triamcinolone. J of Rheum. 2006;33(1):57-60.

Dreyer L et al. High incidence of potentially virus-induced malignancies in systemic lupus erythematosus. Arth & Rheum. 2011;63(10):3032-37

References 3:Ghaussy NO et al. Cigarette smoking and disease activity in

systemic lupus erythematosus. J of Rheum. 2003;30:1215-21Kasitanon N et al. Hydroxychloroquine use predicts complete

renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus. 2006;15(6):366-70

Isenberg DA et al. The Systemic Lupus International Collaborating Clinics (SLICC) group – It was 20 years ago today. Lupus. 2011;20:1426-32

Marmor MF et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):415-22

Merrill JT. Reply to The rarity of antinuclear antibody negativity in systemic lupus erythematosus: comment on the article by Merrill et al. Arthr & Rheum. 2011;63(4):1157-58

References 4:Mok CC et al. Vitamin D deficiency as marker for

disease activity and damage in systemic lupus erythematosus. Lupus. 2012;21:36-42

Nath Ret al. High risk of human papilloma virus type 16 infections and of development of cervical squamous intraepithelial lesions in systemic lupus erythematosus patients. Arth & Rheum. 2007;57(4):619-25

Petri M et al. Vitamin D in SLE. Arth & Rheum. 2013;65(7):1865-71

Petri M et al. Derivation and validation of the systemic Lupus International Collaborating Clinics classification criteria for SLE. Arthr & Rheum. 2012:2677-86

References 5:Petri M & Magder L. Classification criteria

for SLE. Lupus. 2004;13:829-37Pons-Estel GJ et al. The ACR and the SLICC

criteria for SLE in two multiethnic cohorts. Lupus. 2014;23:3-9

Rahman P et al. Smoking interferes with efficacy of antimalarial therapy in cutaneous lupus. J of Rheum. 1998;25:1716-19

Ruiz-Irastorza G et al. Changes in vitamin D levels in patients with SLE. Arthr Care & Research. 2010;62(8):1160-65