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
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〕
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.
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.
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.
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
〔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”
【Laboratory data 1】（on transfer day1） CRP 1.02 mg/dL
〔CBC〕 WBC 1,400/μL Neu 88.0% Eos 0.0% Lym 6.0% RBC 212×104/μL Hb 6.9 g/dL Ht 20.1 % Plt 15.8×104/μL 〔Coagulation〕 PT 11.1 sec PT-INR 1.05 APTT 23.1 sec Fib 310 mg/dL D-dimer 10.3μg/dL 〔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 20.9mg/dL Cre 0.49mg/dL ESR 49 mm/hr 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 MPO・PR3-ANCA Negative Cryoglobulin Negative
〔Urinalysis〕 Within Normal Limits
【Laboratory data 2】
ADAMTS13 activity 15% (Ref. 70-120%） ADAMTS13 inhibitor Negative
Anti-Cardiolipin antiboty IgG Negative IgA Weakly Positive IgM Negative
Soluble IL-2R (sCD25R) 1188 U/L Ferritin 2109 ng/mL Haptoglobin 16 mg/dL Direct Cooms test Positive Anti-Ribosomal P Ab Negative
Phosphatidylserine-dependent antiprothrombin antibody Negative
EBV-DNA PCR ParvovirusB19 IgM ParvovirusB19 PCR CMV IgM
Negative Negative Negative Negative
〔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.
Pathology : Bone marrow
Hemophagocytosis by histiocytes
〔Clinical course in our hospital〕 ► Prednisolone and Cyclosporin A were continued. ► 3 courses of Etoposide were added, then discontinued.
► Limb
necrosis didn’t 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.
【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
Question 1 : Is this the manifestation of CAPS, TTP, or both?
► Decreased ADAMTS-13 ► Positive Coombs’ test
activity
? Thrombotic Microangiopathy
► Weakly
positive IgA Anti-Cardiolipin antibody (Only once – not on two or more occasions) criteria for classification of CAPS → Not fulfilled “Microangiopathic APS”
Thrombotic microangiopathy and demonstrable antiphospholipid antibodies
► Preliminary
Question 2 : What is the cause of HLH?
►
Autoimmune-associated Hemophagocytic syndrome (AAHS) Lymphoma-associated Hemophagocytic syndrome (LAHS)
Positive ANA, ds-DNA, (+)cytopenia No other clinical signs and symptoms of SLE
►
►
Virus-associated Hemophagocytic syndrome (VAHS)
No signs of EBV, CMV, Parvo B19 infection
Pathology of bone marrow and skin were negative for infiltration of lymphoma ?“Asian-variant” intravascular lymphoma
►
CAPS itself can cause systemic inflammatory response
→ Might have been the cause of macrophage-activation in this case.
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 ADAMTS13 deficiency in two patients with primary antiphospholipid syndrome” Arthritis & Rheumatism 2004 Oct; 50(10): 3260-4
Assumed Pathogenesis of Various Symptoms in This Case
（?Primary） APS / CAPS
〔Lupus-like Syndrome as a background〕
Thrombotic Microangiopathy HLH Limb Necrosis Mononeuropathy Multiplex
Fever, Altered Mental Status
Discussion