International Journal of Rheumatic Diseases 2014
CORRESPONDENCE
A fatal case of systemic lupus erythematosus complicated by macrophage activation syndrome, portal vein thrombosis and acute colitis Dear Editor, Systemic lupus erythematosus (SLE) may be associated with a wide variety of complications.1 Macrophage activation syndrome (MAS) is a severe, potentially lifethreatening systemic condition. It has been described in association with systemic juvenile idiopathic arthritis (sJIA), SLE and Kawasaki disease.1 The mechanism is excessive proliferation and activation of T lymphocytes and macrophages leading to secretion of toxic levels of proinflammatory cytokines.2 Diagnosis is based on the following criteria: persistent fever, splenomegaly, cytopenias involving at least two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia and hemophagocytosis in the bone marrow.3 Thrombosis in SLE is attributed to a number of thrombophilic defects, including lupus anticoagulant and anticardiolipin antibodies.4 Lupus enteritis in SLE patients is mostly caused by small vessel vasculitis of the bowel wall, although severe infectious colitis in SLE patients has also been reported.5 We describe a fatal case of SLE, complicated by MAS, portal vein thrombosis (PVT) and acute colitis. The patient was a 60-year-old white female with long-standing SLE, Sj€ ogren’s syndrome, hypertension and chronic kidney disease. She presented to our emergency department with diarrhea, nausea and vomiting. At the time of presentation, her SLE therapy was low-dose prednisone (10 mg daily) and hydroxychloroquine (200 mg daily). Abdominal computed tomography (CT) scan showed colitis involving the transverse colon/splenic flexure extending into the descending colon. She was admitted with sepsis from infectious versus ischemic colitis and was treated with intravenous fluids, hydrocortisone, vancomycin, ciprofloxacin, metronidazole and meropenem. Admission blood cultures as well as post-treatment blood cultures were negative. Colon biopsy demonstrated necrotic debris and fibrinopurulent exudate; special stains showed no fungi or cytomegalovirus (CMV). Polymerase chain reaction on
plasma for CMV DNA was also negative. No test for Epstein–Barr virus (EBV) was done. She developed altered mental status, hemodynamic instability and lactic acidosis. Continuous renal replacement therapy (CRRT) was begun. There was a concern for MAS. Her ferritin levels were significantly increased, along with positive disseminated intravascular coagulation (DIC) lab results, extremely abnormal hepatic function panel, high lactate dehydrogenase, and low red blood cell count (Table 1). Her white cell counts were high (40–50 9 103/mm3) which was attributed to sepsis, masking the expected low white cell counts in MAS. Despite therapy, she expired on hospital day 8. Autopsy confirmed acute colitis involving a 60-cm segment. Acute PVT with extensive associated hepatic necrosis was revealed and the bone marrow showed increased numbers of macrophages with hemophagocytosis consistent with MAS. The immediate cause of Table 1 Laboratory results Test Ferritin D-dimer Fibrinogen Platelet RBC WBC LDH Triglyceride INR ALT AST Albumin ALK phosphatase Bilirubin total Lactic acid
Value
Reference range
Units
1776–8944 5000–20 000 87–195 39.2–64.1 1.91–3.66 7.66–49.73 936–3416 139–161 3.15–7.8 1472–6208 1547–10 861 1.7–3.1 126–266 1.9–9.9 3.8–14.5
10–291 110–240 220–498 150–400 3.8–5.2 4–11 120–240 40–150
ng/mL ng/mL mg/dL 9 103/cmm 9 106/cmm 9 103/cmm U/L mg/dL
10–14 14–40 3.4–5.0 39–117 0.4–1.4 0.5–2.2
U/L U/L g/dL U/L mL/dL mmol/L
RBC, red blood cells; WBC, white blood cells; LDH, lactic dehydrogenase; INR, international normalization ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALK, alkaline.
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
death was attributed to MAS, PVT and acute colitis. The underlying cause of death was SLE. The incidence of MAS is unknown as there is a wide spectrum of clinical manifestations, and episodes may remain unrecognized. A recent article suggested that secondary MAS is more common than previously recognized and may be associated with virtually any rheumatic disease.6 The association of MAS and sJIA has been well-established with an incidence between 7% and 13%.3 In contrast, the incidence of MAS in SLE is about 0.9–4.6%, although it has been increasingly reported, especially in association with juvenile SLE.1,7 A few reports also describe MAS associated with Sj€ ogren’s syndrome.1,6 The major hematological manifestations of SLE are anemia, leukopenia, thrombocytopenia and antiphospholipid syndrome. Thrombosis is attributed to a number of thrombophilic defects, including lupus anticoagulant and anticardiolipin antibodies. PVT in SLE patients after abdominal surgery has been reported4; however, no statistical data is found in nonsurgery-related SLE cases. In our case, there was no evidence of lupus anticoagulant (LA) by two screening tests (partial thromboplastin time-LA and diluted Russell viper venom test) performed 12 weeks before the patient died. Tests for antibodies against beta-2-glycoprotein I and cardiolipin were also done at the same time and were negative. However, since these antibodies wax and wane,8 we were unable to completely rule out the contribution of antiphospholipid syndrome to her PVT. Gastrointestinal manifestations are common in SLE patients and any area of the gastrointestinal tract may be involved. Most cases of lupus enteritis are caused by small vessel vasculitis of the bowel wall, although severe infectious colitis in SLE patients has been seen.9 In this case, acute colitis was confirmed at autopsy but no vasculitis was observed, but this may reflect response to treatment. This case had three distinct pathologic processes documented at autopsy: MAS, PVT and acute colitis, any of which could be fatal. While MAS, PVT and colitis have each been reported in association with SLE, a review of the literature did not identify any other relationship among these complications. Infection-associated hemophagocytic syndrome (HPS) and MAS have similar clinical features. Infectious agents associated with HPS include bacteria, fungi, parasites and viruses; among virus-associated infections, EBV is the most commonly reported trigger agent.10 In our case, tests for EBV were not performed, but CMV infection was excluded; all cultures were negative and
2
no infectious agents were identified in tissue samples. Given these findings, we are of the opinion that MAS, PVT and acute colitis all contributed to her immediate cause of death, and that SLE was the underlying cause of death. To our knowledge, this is the first reported case of MAS, PVT and acute colitis in a SLE patient. It highlights the importance of considering rare but potentially fatal complications and the need for early recognition and timely therapeutic intervention.
CONFLICT OF INTEREST The authors have declared no conflicts of interest. Yihong MA, Vishnu REDDY and Stephanie REILLY
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA Correspondence: Dr Yihong Ma, emails: [email protected], [email protected]
REFERENCES 1 Li X, Qu B, Nie Y, Zhu G, Li W, Mu F (2014) Clinical features of macrophage activation syndrome in the adult northern Chinese population. Lupus 23, 785–92. 2 Maruyama J, Inokuma S (2010) Cytokine profiles of macrophage activation syndrome associated with rheumatic diseases. J Rheumatol 37 (5), 967–73. 3 Davi S, Consolaro A, Guseinova D et al. (2011) An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 38 (4), 764–8. 4 Cavallasca JA, Musuruana JL, Granero G (2011) Portal vein thrombosis in systemic lupus erythematosus associated with anticardiolipin antibodies. Int J Rheum Dis 14 (1), e5–7. 5 Hallegua DS, Wallace DJ (2000) Gastrointestinal manifestations of systemic lupus erythematosus. Curr Opin Rheumatol 12 (5), 379–85. 6 Atteritano M, David A, Bagnato G et al. (2012) Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci 16 (10), 1414–24. 7 Vilaiyuk S, Sirachainan N, Wanitkun S, Pirojsakul K, Vaewpanich J (2013) Recurrent macrophage activation syndrome as the primary manifestation in systemic lupus erythematosus and the benefit of serial ferritin measurements: a case-based review. Clin Rheumatol 32 (6), 899–904. 8 Pengo V, Tripodi A, Reber G et al. (2009) Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody
International Journal of Rheumatic Diseases 2014
Correspondence
of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 7 (10), 1737–40. 9 Lee J, Jung HS, Nam HC et al. (2012) Fulminant amoebic colitis mimicking intestinal vasculitis in a patient
International Journal of Rheumatic Diseases 2014
with systemic lupus erythematosus. Lupus 21 (12), 1351–5. 10 Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C (2007) Infections associated with haemophagocytic syndrome. Lancet Infect Dis 7 (12), 814–22.
3
CORRESPONDENCE
A fatal case of systemic lupus erythematosus complicated by macrophage activation syndrome, portal vein thrombosis and acute colitis Dear Editor, Systemic lupus erythematosus (SLE) may be associated with a wide variety of complications.1 Macrophage activation syndrome (MAS) is a severe, potentially lifethreatening systemic condition. It has been described in association with systemic juvenile idiopathic arthritis (sJIA), SLE and Kawasaki disease.1 The mechanism is excessive proliferation and activation of T lymphocytes and macrophages leading to secretion of toxic levels of proinflammatory cytokines.2 Diagnosis is based on the following criteria: persistent fever, splenomegaly, cytopenias involving at least two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia and hemophagocytosis in the bone marrow.3 Thrombosis in SLE is attributed to a number of thrombophilic defects, including lupus anticoagulant and anticardiolipin antibodies.4 Lupus enteritis in SLE patients is mostly caused by small vessel vasculitis of the bowel wall, although severe infectious colitis in SLE patients has also been reported.5 We describe a fatal case of SLE, complicated by MAS, portal vein thrombosis (PVT) and acute colitis. The patient was a 60-year-old white female with long-standing SLE, Sj€ ogren’s syndrome, hypertension and chronic kidney disease. She presented to our emergency department with diarrhea, nausea and vomiting. At the time of presentation, her SLE therapy was low-dose prednisone (10 mg daily) and hydroxychloroquine (200 mg daily). Abdominal computed tomography (CT) scan showed colitis involving the transverse colon/splenic flexure extending into the descending colon. She was admitted with sepsis from infectious versus ischemic colitis and was treated with intravenous fluids, hydrocortisone, vancomycin, ciprofloxacin, metronidazole and meropenem. Admission blood cultures as well as post-treatment blood cultures were negative. Colon biopsy demonstrated necrotic debris and fibrinopurulent exudate; special stains showed no fungi or cytomegalovirus (CMV). Polymerase chain reaction on
plasma for CMV DNA was also negative. No test for Epstein–Barr virus (EBV) was done. She developed altered mental status, hemodynamic instability and lactic acidosis. Continuous renal replacement therapy (CRRT) was begun. There was a concern for MAS. Her ferritin levels were significantly increased, along with positive disseminated intravascular coagulation (DIC) lab results, extremely abnormal hepatic function panel, high lactate dehydrogenase, and low red blood cell count (Table 1). Her white cell counts were high (40–50 9 103/mm3) which was attributed to sepsis, masking the expected low white cell counts in MAS. Despite therapy, she expired on hospital day 8. Autopsy confirmed acute colitis involving a 60-cm segment. Acute PVT with extensive associated hepatic necrosis was revealed and the bone marrow showed increased numbers of macrophages with hemophagocytosis consistent with MAS. The immediate cause of Table 1 Laboratory results Test Ferritin D-dimer Fibrinogen Platelet RBC WBC LDH Triglyceride INR ALT AST Albumin ALK phosphatase Bilirubin total Lactic acid
Value
Reference range
Units
1776–8944 5000–20 000 87–195 39.2–64.1 1.91–3.66 7.66–49.73 936–3416 139–161 3.15–7.8 1472–6208 1547–10 861 1.7–3.1 126–266 1.9–9.9 3.8–14.5
10–291 110–240 220–498 150–400 3.8–5.2 4–11 120–240 40–150
ng/mL ng/mL mg/dL 9 103/cmm 9 106/cmm 9 103/cmm U/L mg/dL
10–14 14–40 3.4–5.0 39–117 0.4–1.4 0.5–2.2
U/L U/L g/dL U/L mL/dL mmol/L
RBC, red blood cells; WBC, white blood cells; LDH, lactic dehydrogenase; INR, international normalization ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALK, alkaline.
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
death was attributed to MAS, PVT and acute colitis. The underlying cause of death was SLE. The incidence of MAS is unknown as there is a wide spectrum of clinical manifestations, and episodes may remain unrecognized. A recent article suggested that secondary MAS is more common than previously recognized and may be associated with virtually any rheumatic disease.6 The association of MAS and sJIA has been well-established with an incidence between 7% and 13%.3 In contrast, the incidence of MAS in SLE is about 0.9–4.6%, although it has been increasingly reported, especially in association with juvenile SLE.1,7 A few reports also describe MAS associated with Sj€ ogren’s syndrome.1,6 The major hematological manifestations of SLE are anemia, leukopenia, thrombocytopenia and antiphospholipid syndrome. Thrombosis is attributed to a number of thrombophilic defects, including lupus anticoagulant and anticardiolipin antibodies. PVT in SLE patients after abdominal surgery has been reported4; however, no statistical data is found in nonsurgery-related SLE cases. In our case, there was no evidence of lupus anticoagulant (LA) by two screening tests (partial thromboplastin time-LA and diluted Russell viper venom test) performed 12 weeks before the patient died. Tests for antibodies against beta-2-glycoprotein I and cardiolipin were also done at the same time and were negative. However, since these antibodies wax and wane,8 we were unable to completely rule out the contribution of antiphospholipid syndrome to her PVT. Gastrointestinal manifestations are common in SLE patients and any area of the gastrointestinal tract may be involved. Most cases of lupus enteritis are caused by small vessel vasculitis of the bowel wall, although severe infectious colitis in SLE patients has been seen.9 In this case, acute colitis was confirmed at autopsy but no vasculitis was observed, but this may reflect response to treatment. This case had three distinct pathologic processes documented at autopsy: MAS, PVT and acute colitis, any of which could be fatal. While MAS, PVT and colitis have each been reported in association with SLE, a review of the literature did not identify any other relationship among these complications. Infection-associated hemophagocytic syndrome (HPS) and MAS have similar clinical features. Infectious agents associated with HPS include bacteria, fungi, parasites and viruses; among virus-associated infections, EBV is the most commonly reported trigger agent.10 In our case, tests for EBV were not performed, but CMV infection was excluded; all cultures were negative and
2
no infectious agents were identified in tissue samples. Given these findings, we are of the opinion that MAS, PVT and acute colitis all contributed to her immediate cause of death, and that SLE was the underlying cause of death. To our knowledge, this is the first reported case of MAS, PVT and acute colitis in a SLE patient. It highlights the importance of considering rare but potentially fatal complications and the need for early recognition and timely therapeutic intervention.
CONFLICT OF INTEREST The authors have declared no conflicts of interest. Yihong MA, Vishnu REDDY and Stephanie REILLY
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA Correspondence: Dr Yihong Ma, emails: [email protected], [email protected]
REFERENCES 1 Li X, Qu B, Nie Y, Zhu G, Li W, Mu F (2014) Clinical features of macrophage activation syndrome in the adult northern Chinese population. Lupus 23, 785–92. 2 Maruyama J, Inokuma S (2010) Cytokine profiles of macrophage activation syndrome associated with rheumatic diseases. J Rheumatol 37 (5), 967–73. 3 Davi S, Consolaro A, Guseinova D et al. (2011) An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol 38 (4), 764–8. 4 Cavallasca JA, Musuruana JL, Granero G (2011) Portal vein thrombosis in systemic lupus erythematosus associated with anticardiolipin antibodies. Int J Rheum Dis 14 (1), e5–7. 5 Hallegua DS, Wallace DJ (2000) Gastrointestinal manifestations of systemic lupus erythematosus. Curr Opin Rheumatol 12 (5), 379–85. 6 Atteritano M, David A, Bagnato G et al. (2012) Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci 16 (10), 1414–24. 7 Vilaiyuk S, Sirachainan N, Wanitkun S, Pirojsakul K, Vaewpanich J (2013) Recurrent macrophage activation syndrome as the primary manifestation in systemic lupus erythematosus and the benefit of serial ferritin measurements: a case-based review. Clin Rheumatol 32 (6), 899–904. 8 Pengo V, Tripodi A, Reber G et al. (2009) Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody
International Journal of Rheumatic Diseases 2014
Correspondence
of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 7 (10), 1737–40. 9 Lee J, Jung HS, Nam HC et al. (2012) Fulminant amoebic colitis mimicking intestinal vasculitis in a patient
International Journal of Rheumatic Diseases 2014
with systemic lupus erythematosus. Lupus 21 (12), 1351–5. 10 Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C (2007) Infections associated with haemophagocytic syndrome. Lancet Infect Dis 7 (12), 814–22.
3
