KEEP CALM AND PLEX ON? N OV EM BER 3 , 2 0 1 7 DR. M I CH ELA - PowerPoint PPT Presentation

KEEP CALM AND… PLEX ON? N OV EM BER 3 , 2 0 1 7 DR. M I CH ELA FEBBRARO, PGY 3 I N T ERN AL M EDI CI N E, N OSM DR. SI RAJ M I T H OOWAN I , PGY 5 H EM AT OLOGY, M CM AST ER DR. K I M LEGAU LT, DI V I SI ON OF RH EU M AT OLOGY, M CM AST ER DR. ALI I QBAL, DI V I SI ON OF N EPH ROLOGY, M CM AST ER DR. AZ I M GAN GJ I , DI V I SI ON OF N EPH ROLOGY, M CM AST ER DR. DEBORAH SI EGAL, DI V I SI ON OF H EM AT OLOGY, M CM AST ER 1

CASE An 18 year old Hispanic male with a history of Raynaud’s phenomenon was admitted with: • Acute left leg deep vein thrombosis • Hypertension • Acute kidney injury • Creatinine: 127 micromol/L (normal: 61 – 97 micromol/L) • Urinalysis demonstrating 2+ blood and 3+ protein. One week earlier, he was admitted for splenic laceration and left-sided pleural effusion attributed to recreational trauma. 2

CASE Auto-immune work up: • Positive ANA: titre > 1:640, speckled pattern Positive anti-dsDNA : 8 IU/mL (negative ≤ 4 IU/mL) • • Positive anti-Smith antibody: > 8 AI (normal < 1 AI) • Positive anti-RNP antibody: > 8 AI (normal < 1 AI) • Low C3: 0.48 g/L (normal: 0.79 - 1.52 g/L) • Low C4: 0.12 g/L (normal: 0.16 – 0.38 g/L) • Negative anti-cardiolipin antibody • Negative non-specific inhibitor 3

CASE A renal biopsy demonstrated class IV lupus nephritis. Immunosuppression for SLE was initiated with: Mycophenolate mofetil 750mg QID • • Hydroxychloroquine 200mg daily • Prednisone 70 mg daily (dosed at 1 mg/kg) DVT was managed: Initially with Apixaban • • Switched to Warfarin given kidney function Hypertension was managed with: • Ramipril Furosemide • 4

CASE – ONE MONTH LATER Patient was transferred to our tertiary care hospital following 5 days in a regional hospital with: Worsening kidney function: • • Creatinine: 384 micromol/L (normal: 61 – 97 micromol/L) • Anemia • Hemoglobin: 88 g/L (normal: 130 – 180 g/L) • Thrombocytopenia • Platelets: 42 x 10^9/L (normal: 150 – 400 x 10^9/L) • Evidence of hemolysis • Reticulocytes: 217 x 10^9/L (normal: 10 – 86 x 10^9/L) • LDH: 591 U/L (normal: 130 – 250 U/L) • Low Haptoglobin • Moderate schistocytes on blood film The patient was diagnosed with thrombotic thrombocytopenic purpura and daily plasma exchange (PLEX) was initiated. 5

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) • Initially described as a pentad of clinical features: • Microangiopathic hemolytic anemia (MAHA) • Thrombocytopenia • Neurologic abnormalities • Renal abnormalities • Fever • Fatal in 90% of patients prior to the availability of effective treatment George JN. NEJM 2006. 354(18): 1927 6 Vesely SK, et al. Blood 2003; 102(1): 60

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) • Initially described as a pentad of clinical features: • Microangiopathic hemolytic anemia (MAHA) • Thrombocytopenia • Neurologic abnormalities • Renal abnormalities • Fever • Fatal in 90% of patients prior to the availability of effective treatment Early initiation of treatment has brought the mortality rate to < 20% George JN. NEJM 2006. 354(18): 1927 7 Vesely SK, et al. Blood 2003; 102(1): 60

HEMOGLOBIN AND PLATELET TREND FOLLOWING PLEX INITIATION 120 100 80 60 Hemoglobin (g/L) 40 Platelet Count (10^9/L) 20 0 1 2 2 4 5 8 Day of Admission

CASE Hematology, Nephrology and Rheumatology services concluded that the most likely diagnosis was lupus- associated thrombotic microangiopathy (TMA). 9

CASE Hematology, Nephrology and Rheumatology services concluded that the most likely diagnosis was lupus- associated thrombotic microangiopathy (TMA). Conclusion based on: • Poor response to daily PLEX after 5 days • Normal ADAMTS-13 level • Positive autoimmune workup • Negative antiphospholipid antibody testing 10

DIFFERENTIAL DIAGNOSIS OF THROMBOCYTOPENIA AND MAHA • Autoimmune hemolytic anemia/Evans syndrome • Disseminated intravascular coagulation • Pregnancy associated (eg. HELLP, eclampsia, HUS) • Drugs • Malignant hypertension • Viral Infections (eg. CMV, adenovirus, HSV) • Bacterial Infections (eg. pneumococcus, meningococcus) • Autoimmune disease (eg. lupus nephritis, scleroderma) • Vasculitis • Shiga toxin associated hemolytic uremic syndrome • Complement mediated hemolytic uremic syndrome • Malignancy • Catastrophic antiphospholipid syndrome 11 Scully M, et al. BJH 2012; 158: 323

CASE - TREATMENT The patient was treated with: • Cyclophosphamide 500mg IV q14 days • Prednisone daily • PLEX The TMA resolved and hematologic parameters gradually normalized. 12

HEMOGLOBIN AND PLATELET TREND THROUGHOUT ADMISSION 450 400 Hemoglobin (g/L) 350 Platelets (10^9/L) 300 250 200 150 100 50 0 1 5 10 15 20 25 13 Day of Admission

HEMOGLOBIN AND PLATELET TREND THROUGHOUT ADMISSION 450 400 Hemoglobin (g/L) 350 Platelets (10^9/L) 300 250 200 150 100 50 0 1 5 10 15 20 25 14 Day of Admission

LUPUS ASSOCIATED TMA • Unexplained MAHA and thrombocytopenia in a patient meeting diagnostic criteria for SLE • May also have acute renal failure, fever, and neurologic deterioration • Not associated with a severe reduction in ADAMTS13 activity • Early initiation of plasma exchange with additional therapy has the potential to be curative 15 Blum D, et al. World J Nephrol 2015; 4(5): 528

CASE - RESOLUTION In hospital complications included: • Hypertension • Seizure secondary to posterior reversible leukoencephalopathy syndrome (PRES) • Severe volume overload Three further doses of IV cyclophosphamide have been administered as an outpatient. On follow-up, the patient continues to have stable hematologic parameters with no evidence of recurrent TMA 16

TAKE HOME MESSAGES • TMA is a rare and potentially fatal manifestation of SLE • Distinguishing SLE-associated TMA from other TMAs is important in order to administer SLE-specific therapy • Unlike TTP, the role of PLEX is less clear in the treatment of SLE-associated TMA • Mortality benefit with and without PLEX has not been studied in the context of SLE-associated TMA • Treatment is primarily directed at the underlying SLE with immunomodulator agents • There may be a delay to peak response with immunomodulator agents when treating severe manifestations of SLE • Inter-specialty collaboration is important in order to diagnose and manage a rare condition 17

SPECIAL THANKS TO: Dr. Deborah Siegal, Division of Hematology, McMaster Dr. Kimberly Legault, Division of Rheumatology, McMaster Dr. Siraj Mithoowani, PGY5 Hematology, McMaster Dr. Ali Iqbal, Division of Nephrology, McMaster Dr. Azim Gangji, Division of Nephrology, McMaster 18

THANK YOU 19

LUPUS ASSOCIATED TMA 20