Lupus Challenging Cases

Richard Furie, MD

Professor of Medicine

Hofstra North Shore LIJ School of Medicine

Albert Einstein College of Medicine

Chief, Division of Rheumatology and Allergy-Clinical Immunology

North Shore-Long Island Jewish Health System

Lake Success, NY

CASE 1

Case: 58 y/o female

– 30 year history of SLE, which was quiet on no

medicines until 2009

– Onset of AHA controlled with mycophenolate

and rituximab

– During initial visit in 2009:

• Beta-2 glycoprotein I IgG Ab: >150 (<15)

• Anticardiolipin IgG Ab: 120 (<15)

– No history of miscarriage or thrombosis

CASE 1

Would you advise therapy for thrombosis prevention?

If so, which medicine?

1. ASA

2. Clopidogrel

3. Warfarin

4. Prednisone

5. Direct thrombin inhibitor

CASE 1

Case continued

– Placed on ASA 81 mg per day in 2009

– Stroke Oct 2010

– Treated with heparin and then warfarin

Predictors of Thrombotic Risk?

• Titer of aPL Ab

• Isotype of aPL Ab

– IgG > IgA > IgM

• Degree of PTT elevation

• Other factors

– Nephrosis

– Smoking

– BCP

Predictors of Thrombotic Risk

• Triple positivity (LAC, β2GPI Ab, aCL Ab)

– 104 asymptomatic patients

– Mean F/U: 4.5 years

• 25 first thrombotic events

– 5.3%/y vs. 1.4% in single positivity patients

– 37% cumulative incidence over 10 y

Pengo et al. Blood 2011

Predictors of Thrombotic Risk

• Additional risk factors:

– Male gender

– Venous thrombosis risk factors

• Thrombosis rates on:

– ASA: 7/37 (not protective)

– Hydroxychloroquine: 2/18: 11%

Pengo et al. Blood 2011

Preventing the First Clot

• Risk of thrombosis < 4% per year

• Confounded by other factors

• APLASA (Erkan 2007): ASA 81 mg vs placebo

– N=98; f/u 2.3 years

– ASA (3 events); placebo (0)

– ASA did not protect against thrombosis

• ?? ASA for primary prevention ??

Preventing the Second Clot

• Retrospective Studies

– Warfarin better than ASA

– Warfarin HD better than LD

• Prospective Studies

– Warfarin Mod Intensity = High Intensity

Targeting a specific INR is

easier said than done

Khamashta M et al. N Engl J Med 1995;332:993-997

Comparison of Antithrombotic Treatments Used

Crowther M et al. N Engl J Med 2003;349:1133-1138

Outcomes and Duration of Follow-up in the High-Intensity and Moderate-Intensity Warfarin Groups

6

CASE 2

Medical History

A 24 year old female with recently diagnosed steroid-

responsive thrombocytopenia was referred for evaluation

of possible SLE. She had no other inflammatory

manifestations. During the interview, she had

spontaneous flailing movements of the right wrist as well

as choreic movements of the fingers of the right hand.

CASE 2 Physical Exam

BP: 110/70 P: 70

HEENT normal

Chest normal

Cardiac normal

Abdomen normal

Skin livedo reticularis

Joints normal

Neurologic flailing movements of the right wrist;

choreic movements of the right fingers;

occasional contractions of the right side

of her face

CASE 2

CASE 2

All of the following tests would be appropriate to

order except:

1. Antiphospholipid antibodies

2. Lupus serologies

3. ASO titer

4. Cerebral angiogram

5. PET scan

CASE 2

Laboratory Results

WBC normal

Hb normal

Plt 125,000

ANA 1/160 (speckled)

DNA absent (as was Sm, RNP, SSA, SSB)

PTT 39 seconds (<35 seconds)

LAC positive (by dRVVT and PNP)

RPR positive

ACL GPL: 51 MPL: <5 APL: <5

ASO normal

Brain MRI normal

EEG normal

CASE 2 PET Scan

CASE 2

Course The patient was diagnosed with PAPS and referred to the Center

for Movement Disorders at NSUH. A diagnosis of right hemichorea

was made, and the patient underwent PET. This study demonstrated

contralateral striatal 18F-fluorodeoxyglucose hypermetabolism.

Her symptoms remitted spontaneously. A follow-up PET was normal.

Nearly one year later, the patient developed chorea on the opposite

side of the body. PET once again demonstrated contralateral striatal 18F-fluorodeoxyglucose hypermetabolism. The patient was treated

with haloperidol 4 mg/d with improvement over the ensuing 4 weeks.

CASE 2

Chorea

• Associated with SLE and with PAPS

• Striatal hypermetabolism

• Pathogenesis unknown

• microvascular occlusion

• aPL binding to striatal tissue

CASE 3

Medical History A 27 year old female with a 5 year history of SLE received 60 mg/d of

prednisone for lupus nephritis. Three weeks after the dosage

increase, she heard a “pop” while stepping on a bus. The leg gave

out, and a few seconds later, she heard a second “pop.” Both legs

gave out, and she was not able to stand. She otherwise felt fine.

Physical Exam Joints: mild Jaccoud’s arthropathy

high-riding patellae bilaterally; no knee effusions

CASE 3

What is the most likely diagnosis?

1. Torn menisci

2. Ruptured ACLs

3. Tibial plateau fractures from osteonecrosis

4. Ruptured quadriceps tendons

5. Ruptured patellar tendons

CASE 3

CASE 3

Tendon Rupture

• Acute in onset

• May be bilateral

• Knee (patellar tendon), Achilles’ tendon

• Steroids, trauma as risk factors

• Mild inflammation

• Repair approached surgically or medically

CASE 4

Medical History A 44 year old female with a 9 year history of SLE was

hospitalized in septic shock complicated by DIC and

oliguric renal failure. Prior manifestations of lupus

included arthritis and nephritis. However, she never had

required steroids or other immunosuppressive therapies.

Physical Exam BP: 100/60 P: 100 T: 39

Skin scattered raised violaceous papules with necrotic

centers; ischemic toes

CASE 4

CASE 4

What is the most likely diagnosis?

1. Vasculitis from active SLE

2. Libman-Sacks with peripheral embolization

3. Infection with Neisseria meningitidis

4. Cholesterol embolization syndrome

5. Infection with Streptococcus pneumoniae

CASE 4

Laboratory Results WBC 58,000 (91% PMN, 6 Bands K/uL)

Hb 12.8 g/dL

Plt 127 K/uL

Blood cultures Streptococcus pneumoniae

Smear Howell-Jolly Bodies

CASE 4

Why?

• Pneumococcal sepsis

• No immunospressive therapy

• Howell-Jolly bodies

without splenectomy

CASE 4

CASE 4

Functional Asplenia

• Anatomic presence but functional absence of spleen

• Seen in SLE, celiac sprue

• Infections with Salmonella or Pneumococcus

• 3% of SLE patients observed to have H-J bodies

• Pathogenesis unknown

• Pneumococcal vaccination recommended

CASE 5 Medical History

A 52 year old female with a history of stroke (maintained

on warfarin) was hospitalized for evaluation of 2 months of

fever, diarrhea, and weight loss.

Physical Exam was unremarkable except for T= 39.3 and

mild synovitis of the PIP joints.

Laboratory:

WBC: 1.2 (50% PMN’s; 50% L) AST: 173

Hb: 7.6 ALT: 104

Plt: 66,000 Ferritin: 2597

LDH: 728

Haptoglobin: 49 (normal) Creat: 0.8

Coombs (direct): negative No schistocytes

ANA: 1/320

CASE 5

Hospital Course Extensive evaluation included imaging studies and serologies.

Body CT: normal

CT brain: old left cerebellar infarct

ANA: 1:320 (H)

DNA: 562

APL Ab: neg

CASE 5

Impression: Systemic Lupus complicated by fever, arthritis and

pancytopenia

CASE 5

What are possible causes of the pancytopenia?

1. Lymphoma

2. Autoimmune hemolytic anemia and thrombocytopenia

3. Macrophage activation syndrome with

hemophagocytosis

4. Aplastic anemia

5. Thrombotic microangiopathy

CASE 5

Impression: Systemic Lupus complicated by pancytopenia

Pancytopenia: ? peripheral destruction vs. central failure

• Central failure

• Aplastic (hypoplastic) anemia (rare in SLE)

• Peripheral destruction

• Autoimmune: (haptoglobin normal; Coombs neg)

• TMA (WBC low; no schistocytes)

• Something else?

CASE 5

Hospital Course Methylprednisolone 60 mg daily resulted in resolution of

fever, although each attempt to taper was unsuccessful as

the fever returned.

Despite eventual improvement in fever and constitutional

symptoms, pancytopenia persisted. A bone marrow

aspirate and biopsy was performed.

CASE 5

Hospital Course Bone marrow aspirate and biopsy demonstrated

hemophagocytosis, increased histiocytes and macrophages;

increased iron stores.

Cyclosporin 300 mg per day was added with improvement

in panyctopenia.

Outpatient Course

Arthritis, fever, pancytopenia all disappeared. Steroids

and CsA were tapered and eventually discontinued.

David Fisman, MD

Erythrocyte Phagocytosis Neutrophil Phagocytosis

CASE 5

Thrombotic Microangiopathy

LDH

Haptoglobin

Reticulocyte count

Direct Coombs test

Blood smear

1200

not detectable

15.5 %

negative

CASE 5 Hemophagocytic Syndrome

• Seen in JIA (triggered by viral infections)

• = Macrophage Activation Syndrome

• Manifestations ─ Pancytopenia

─ Fever

─ Liver, spleen, and lymph node enlargement

─ DIC (predicts a poor prognosis)

─ Abnormal LFT’s, increased ferritin

• T cells, macrophages (TNF, IL-6, IL-1)

• Rx: high dose steroids, CsA, pheresis, IVIG

CASE 5 Key Teaching Points

• Cytopenias (other than anemia of chronic disease)

typically result from peripheral destruction

− Antibody-mediated

− ADCC >> CDC

− Hypercellular marrow

• Marrow hypoplasia/aplasia is rare

• Consider central problem especially when:

− Pancytopenia exists

− Initial steroid therapy is unsuccessful

CASE 6 Medical History A 22 year old female with a 3 year history of SLE underwent a kidney

biopsy for worsening proteinuria (13 grams/24 hours). She had a

creatinine of 0.5, very elevated anti-DNA antibodies, and

hypocomplementemia. The histology was consistent with WHO class

IV; little chronicity was present. She received pulse steroids but

refused cyclophosphamide. However, she agreed to mycophenolate

mofetil 2000 mg/day and enalapril. Seven months later she had 4

grams/24 hour of proteinuria, creatinine 0.8, hypocomplementemia,

and anti-DNA antibodies. A repeat biopsy once again showed a WHO

class IV lesion and surprisingly little in the way of chronicity. She

agreed to parenteral cyclophosphamide for 6 months and was

maintained on mycophenolate and cyclosporin.

A subsequent major relapse treated with rituximab resulted in

miraculous results with normalization of proteinuria, DNA Ab, and C’.

CASE 6

Comment: • Is mycophenolate mofetil equal in efficacy

to cyclophosphamide?

• Is mycophenolate mofetil safer than

cyclophosphamide?

• Is rituximab the answer when all else fails?

• Where have we been and where are we

going in drug development in SLE?

CASE 7

Medical History A 47 year old female with a 5 year history of severe discoid

lupus had unsuccessfully tried numerous topical steroids,

azathioprine, methotrexate, hydroxychloroquine, and

systemic steroids. She was given 100 mg/d of thalidomide

with an amazing response. Active skin lesions regressed,

and hair began to grow on her scalp.

CASE 7

Discoid Lupus

CASE 7

Biologic Properties of Thalidomide

1. Inhibition of angiogenesis

2. Inhibition of TNF, IL8

3. Inhibition of COX-2

4. Down regulation of IL6

5. Increased IL10 production

CASE 7

Side Effects of Thalidomide

1. Somnolence

2. Rash

3. Leukopenia

4. Orthostatic hypotension

5. Peripheral neuropathy (primarily sensory)

6. Constipation

7. BIRTH DEFECTS

CASE 1

Medical History

A 27 year old female with a 5 year history of SLE was

admitted to the hospital because of confusion and fever.

Past manifestations of SLE have included polyarthritis,

rash, recurrent episodes of pericarditis, and anemia. A

flare 2 months prior to admission, consisting of

pericarditis, fever, hypocomplementemia, and a 2-fold

rise in anti-DNA antibodies, was successfully treated with

prednisone 40 mg/day; prednisone was subsequently

tapered. At the time of admission, medicines included

hydroxychloroquine 400 mg/day, prednisone 15 mg/day,

calcium, and a vitamin.

CASE 1

Physical Exam

BP: 120/70 P: 90 T: 104

HEENT normal; neck supple

Chest normal

Cardiac normal

Abdomen normal

Skin lower extremity petecchiae

Joints mild Jaccoud’s arthropathy

Neurologic delirious, disoriented

symmetric motor and sensory findings

diffuse hyperreflexia

Babinski signs present bilaterally

CASE 1 Laboratory Results WBC 15.7 K/uL

(87% PMN, 4 Bands, 5 Lymph, 4 Mono)

Hb 6.8 g/dL

Plt 12 K/uL

PT/PTT 12/26 seconds

DIC screen normal

Creatinine 1.9 mg/dL

Hepatic function normal

Urinalysis 5 WBC; 20 RBC; trace proteinuria

CSF 1 WBC; 10 RBC; protein 45; glucose 76

Brain MRI normal

ANA 1/160 (homogeneous)

DNA low positive

C3/C4 normal / normal

CASE 1

1. Sepsis

2. Bacterial meningitis

3. Fungal meningitis

4. Viral encephalitis

5. Vasculitis

6. Central Nervous System Lupus

7. Intracranial Hemorrhage

8. Drug intoxication

What is the Differential Diagnosis?

CASE 1

Hospital Course The patient was given broad spectrum antibiotics for the treatment

of sepsis and/or bacterial meningitis. Methylprednisolone 60 mg/day

was also administered. However, the patient’s mental status

worsened, and she became comatose. All cultures were sterile.

The impression was that of a flare of SLE complicated by

autoimmune thrombocytopenia and CNS disease. “Pulse” steroids

were administered for 3 days without subsequent improvement.

Intravenous gamma-globulin (IVIG) failed to improve the

thrombocytopenia, and cyclophosphamide was being considered.

What should be done next? Rheumatology to the rescue!

CASE 1

The Rheumatologist’s View

A consulting rheumatologist asked the following:

1. If this is a lupus flare, why…

a. no hypocomplementemia?

b. only a modest elevation of anti-DNA antibodies?

c. no response to high doses of steroids?

d. no response to IVIG?

2. What is the origin of the anemia and thrombocytopenia?

3. What is the pathogenesis of the cerebral dysfunction?

CASE 1

The Rheumatologist’s View

1. Is this “difficult to treat SLE”?

a. Vasculitis

b. Vasculopathy

2. Is the anemia autoimmune, microangiopathic, or from

marrow failure?

3. Is the thrombocytopenia autoimmune,

microangiopathic, or marrow failure?

4. What is the pathogenesis of the cerebral dysfunction?

CASE 1

Needed Lab Tests

LDH

Haptoglobin

Reticulocyte count

Direct Coombs test

Blood smear

1200

not detectable

15.5 %

negative

CASE 1

Diagnosis

Thrombotic Microangiopathy

1. thrombocytopenia

2. microangiopathic hemolytic

anemia (schistocytes)

3. organ dysfunction (kidney; brain)

Treatment

Plasmapheresis with complete response

within one week

CASE 1

Thrombotic Microangiopathy

• Hemolytic-uremic syndrome

• TTP

• Familial TTP

• SLE

• aPL

• Drug-induced (mitomycin, cyclosporine)

• Pregnancy/post-partum

• Scleroderma renal crisis

CASE 1

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CASE 1 Summary

1. Manifestations of TM can mimic more typical

“inflammatory” complications of SLE.

2. In the presence of thrombocytopenia and anemia,

think of TM to explain new neurologic and/or

renal disease.

3. Look for schistocytes!!; determine haptoglobin, LDH,

reticulocyte count, and direct Coomb’s.

4. Although patients are typically treated with high dose

steroids before the diagnosis is recognized, consider

initiating plasmapheresis.

5. Affected organs include brain, kidney, and heart.

6. TM can occur in PAPS.