Antiphospholipid Antibody Syndrome Complicated by Hemophagocytic Lymphohistiocytosis, Necrosis of the Extremities, and Mononeuropathy Multiplex

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Antiphospholipid Antibody Syndrome Complicated by
Hemophagocytic Lymphohistiocytosis, Necrosis of
the Extremities, and Mononeuropathy Multiplex

• Noboru Hagino M.D.
• Department of Allergy and Rheumatology
• University of Tokyo

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ID / CC A 55-year-old Japanese woman with
necrosis of the extremities

• ?History of Present Illness 1?
• In good health until 3 month before presentation,
  when Pt developed high fever.
• Seen by her primary care physician, and abnormal
  liver function tests (LFTs) were pointed out.
• Prescribed an antibiotic, but she developed
  seizure and altered mental status before taking
  her first dose of antibiotic.
• Admitted to another hospital.
• Laboratory data on admission showed elongation of
  prothrombin time (PT) and activated partial
  thromboplastin time (aPTT), elevation of LFTs
  ?AST 1239 IU/L, ALT 624 IU/L, T.Bil 12.3 mg/dL?

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ID / CC A 55-year-old Japanese woman with
necrosis of the extremities

• ?History of Present Illness 2?
• Tentative diagnosis of sepsis complicated by
  disseminated intravascular coagulation was made.
• Fresh frozen plasma was given repeatedly in
  addition to empirical antibiotics.
• Results of lumbar puncture and bone marrow
  aspiration was noncontributory, which yielded no
  organism from culture.
• Whole-body CT scan disclosed no space-occupying
  lesion.
• Her fever and mental status had gradually
  improved, but the necrotic lesion appeared on her
  right fingers on the 17th day of admission.

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ID / CC A 55-year-old Japanese woman with
necrosis of the extremities

• ?History of Present Illness 3?
• Fever then reappeared.
• Developed swelling and pain of lower extremities
• (rt. then lt.)
• Positivity of antinuclear antibody and anti-dsDNA
  antibody (was pointed out.
• Intravenous methylprednisolone 1,000 mg/day for 3
  days was given, followed by prednisolone 30
  mg/day.
• Transferred to the rheumatology department of
  another hospital.
• Lupus anticoagulant was positive only on one
  occation with low-titer (APTT clotting time
  method 1.32).
• Low molecular weight heparin was added, and the
  dose of prednisolone was increased to 72 mg/day.

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ID / CC A 55-year-old Japanese woman with
necrosis of the extremities

• ?History of Present Illness 4?
• Wrist drop and sensory loss of bilateral hand
  appeared on the 3rd day of transfer.
• Plasmaexchange was performed for 5 days (day
  3-7), and methylprednisolone pulse therapy was
  repeated.
• Laboratory data
• LDH 848 IU/L, soluble IL-2 receptor 11,500 U/mL,
  Ferritin 2,613 ng/mL
• Bone marrow aspiration
• Marked hemophagocytosis by the histiocytes.
• Intravenous immunoglobulin was given, which
  failed to control her fever and elevated ferritin
  level.

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ID / CC A 55-year-old Japanese woman with
necrosis of the extremities

• ?History of Present Illness 5?
• Plasmaexchange was re-introduced.
• Both cyclosporin A (200 mg/day), etoposide (150
  mg/m2/week) were started based on HLH-2004
  protocol.
• Her fever and laboratory data slowly began to
  improve.
• Transferred to our hospital for further
  evaluation and treatment.
• ?Past Medical History?
• 33yo Colorectal carcinoma w/ curative resection
• (complicated by postoperative stroke, without
  significant sequelae)
• 51yo Hyperthyroidism

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• ?Medication / Allergy?
• No medications. (-) oral contraceptive, No
  known drug allergy
• ?Social history?
• Works as an announcer, (-) smoking / EtOH
• Marietal status single, (-) illicit drug use
• ?Family history?
• Father Prostate Carcinoma, Mother
  Colorectal Carcinoma
• ?Physical Examination?
• T 36.4, BP 103/82mmHg, PR 112/min, RR 14/min,
  SpO2 99
• In no apparent distress, alert and oriented to
  time, place, and persons
• () Hoarseness
• Necrosis of right 1st-3rd fingertips and left 2nd
  fingertip
• Brachial / Radial / Femoral / Popliteal / Dorsal
  Pedal artery good palp.
• (Neuro)Cranial nerve 2-12 intact
• diminished muscle strength of wrist flexor /
  extensor, gastrocnemius, tibialis anterior, and
  extensor hallucis longus
• diminished light touch / pinprick sensation at
  all four extremities (glove and stocking pattern)
• (-) vesicorectal dysfunction
• ? Compatible with Mononeuropathy multiplex or
  Polyneuropathy

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?Laboratory data 1?(on transfer day1)
CRP 1.02 mg/dL IgG 1006 mg/dL IgA
238 mg/dL IgM 26 mg/dL C3 145 mg/dL C4
45 mg/dL CH50 87.0 IU/mL IC(C1q) Negative RF
Negative Antinuc.Ab 40(Homo.) ds-DNA 48.0
IU/mL SS-A/SS-B Negative MPOPR3-ANCA
Negative Cryoglobulin Negative
?Chemistry? TP 5.9 g/dL Alb 3.4 g/dL T.Bil 1.2 mg/
dL ALP 396 IU/L AST 16 IU/L ALT 20
IU/L LDH 183 IU/L CK 3 IU/L Na 131 mEq/L K 5.2
mEq/L Cl 98 mEq/L BUN 20.9 mg/dL Cre
0.49 mg/dL
?CBC? WBC 1,400/µL Neu 88.0 Eos 0.0 Lym
6.0 RBC 212104/µL Hb 6.9 g/dL Ht
20.1 Plt 15.8104/µL
?Coagulation? PT 11.1 sec PT-INR
1.05 APTT 23.1 sec Fib 310
mg/dL D-dimer 10.3µg/dL
ESR 49 mm/hr
?Urinalysis? Within Normal Limits
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?Laboratory data 2?
Soluble IL-2R (sCD25R) 1188 U/L Ferritin
2109 ng/mL Haptoglobin 16
mg/dL Direct Cooms test Positive Anti-Ribosoma
l P Ab Negative
ADAMTS13 activity 15 (Ref. 70-120) ADAMTS13
inhibitor Negative Anti-Cardiolipin
antiboty IgG Negative IgA Weakly
Positive IgM Negative Phosphatidylserine-depe
ndent antiprothrombin antibody Negative
EBV-DNA PCR Negative ParvovirusB19
IgM Negative ParvovirusB19 PCR Negative CMV
IgM Negative
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• ?Pathology Skin?
• ()thrombosis in the small vessels (less than 150
  micrometer in diameter) at subcutaneous tissue.
• Mild infiltration of inflammatory cells into the
  vessel walls.
• ?Pathology Bone Marrow Biopsy?
• ()infiltration of the histiocytes, with engulfed
  RBCs.
• No signs of malignancy.

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Pathology Bone marrow
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• ?Clinical course in our hospital?
• Prednisolone and Cyclosporin A were continued.
• 3 courses of Etoposide were added, then
  discontinued.
• Limb necrosis didnt need amputation.
• Patient is now doing well with 20 mg/day of
  Prednisolone and 200 mg/day of Cyclosporin A and
  followed up as an outpatient.

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?Problem List?
1 Limb Necrosis 2 (Possible) Mononeuropathy
Multiplex 3 Hemophagocytic Lymphohistiocytosis (
Biopsy-proven Hemophagocytosis with fever,
increased ferritin and soluble IL-2R level) 4
Altered Mental Status (?Plasmapheresis
responsive) 5 Laboratory Data Abnormality 5-1
Positive Lupus Anticoagulant (only in one
measurement) 5-2 Weakly positive IgA
Anti-Cardiolipin Antibody 5-3 Decreased
activity of ADAMTS-13 5-4 Weakly positive
ds-DNA (ANA 40) 5-5 Positive Coombs test
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Question 1 Is this the manifestation of CAPS,
TTP, or both?

• Decreased ADAMTS-13 activity
• Positive Coombs test
• Weakly positive IgA Anti-Cardiolipin antibody
• (Only once not on two or more occasions)
• Preliminary criteria for classification of CAPS
• ? Not fulfilled
• Microangiopathic APS
• Thrombotic microangiopathy and demonstrable
  antiphospholipid antibodies

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Question 2 What is the cause of HLH?

• Autoimmune-associated Hemophagocytic syndrome
  (AAHS)
• Positive ANA, ds-DNA, ()cytopenia
• No other clinical signs and symptoms of SLE
• Lymphoma-associated Hemophagocytic syndrome
  (LAHS)
• Pathology of bone marrow and skin were negative
  for infiltration of lymphoma
• ?Asian-variant intravascular lymphoma
• Virus-associated Hemophagocytic syndrome (VAHS)
• No signs of EBV, CMV, Parvo B19 infection
• CAPS itself can cause systemic inflammatory
  response
• ? Might have been the cause of macrophage-activati
  on in this case.

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Question 3 Is there any similar report?

• Lazurova I, Macejova Z et al.
• Severe limb necrosis primary thrombotic
  microangiopathy or seronegative catastrophic
  antiphospholipid syndrome? A diagnostic dilemma
• Clin Rheumatol 2007 Jan (Online publication)
• Amoura Z, Costedoat-Chalumeau N et al.
• Thrombotic thrombocytopenic purpula with severe
  ADAMTS-13 deficiency in two patients with primary
  antiphospholipid syndrome
• Arthritis Rheumatism 2004 Oct 50(10) 3260-4

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• Assumed Pathogenesis of Various Symptoms
• in This Case

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Discussion