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Administration of infliximab in Crohn’s disease does not deplete complement components C3 and C4
3326
Letters to the Editor
The pattern of expression of CD44s and CD44 isoforms suggests that CD44v6 may have an important role in macrophage differentiation and that CD44s may also have an important role in lymphocyte homing and its activation. The same pattern of expression of CD44 isoforms in granulomas of Crohn’s disease, tuberculous enteritis, and pulmonary sarcoidosis also suggest that these expressions reflect rather an immune-mediated epiphenomenon than a disease-specific mechanism. Atsushi Ikehata, M.D. Department of Gastroenterology Iwate Prefectural Central Hospital Morioka, Japan Nobukazu Tomichi, M.D. Department of Pathology Iwate Prefectural Central Hospital Morioka, Japan
REFERENCES
AJG – Vol. 95, No. 11, 2000
treatment is the prolonged duration of action, with remission lasting for about 8 wk following a single i.v. administration (2). Since recognition of membrane-bound TNF␣ is an important feature of infliximab, a hypothesis for the long duration of action is through complement-mediated lysis of immune cells, such as Th1 lymphocytes or antigen presenting cells (3). Therefore, we aimed to assess whether there is any evidence of complement consumption in Crohn’s disease patients undergoing treatment with infliximab. We prospectively assessed 10 well characterized patients with active Crohn’s disease prior to and after treatment with infliximab. There were six females and four males with a median age of 33 yr (range, 17– 41 yr). Two patients had extensive small bowel disease, four had ileocolonic, and four had colonic disease. Five had associated perianal disease. All were on prednisolone at the time of infusion except one who was unable to tolerate steroids and the indication was chronic active disease refractory to all conventional anti-inflammatory therapy. Five were on azathioprine. Infliximab was administered in a dose of 5 mg/kg over a 2-h
1. Screaton GR, Bell MV, Jackson DG, et al. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA 1992;89:12160 – 4. 2. Papadogiannakis N, Gad A, Chenard M-P, et al. Expression of CD44 variants in differential diagnosis of ulcerative colitis and Crohn’s disease. Lancet 1996;347:1413– 4. 3. Rosenberg WMC, Prince C, Kaklamanis L, et al. Increased expression of CD44v6 and CD44v3 in ulcerative colitis but not colonic Crohn’s disease. Lancet 1995;345:1205–9. 4. Hankard GF, Cezard JP, Aigrain Y, et al. CD44 variant expression in inflammatory colonic mucosa is not disease specific but associated with increase crypt cell proliferation. Histopathology 1998;32:317–21. 5. Camacho FI, Munoz C, Sanchez-Verde L, et al. CD44v6 expression in inflammatory bowel disease is associated with activity detected by endoscopy and pathological features. Histopathology 1999;35:144 –9. Reprint requests and correspondence: Atsushi Ikehata, M.D., Department of Gastroenterology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, Iwate 020-0066, Japan. Received June 13, 2000; accepted June 19, 2000.
Administration of Infliximab in Crohn’s Disease Does Not Deplete Complement Components C3 and C4 TO THE EDITOR: Infliximab (chimeric anti-TNF␣ antibody) (Remicade, Centocor) is an effective therapy for Crohn’s disease producing a striking clinical and endoscopic response in about 65% of patients. Infliximab is a mouse/human chimeric antibody and utilizes an IgG1 molecule, capable of complement activation through its Fc region (1). Activation of the classical pathway may lead to depletion of C3 and C4. A novel feature of anti-TNF␣
Figure 1. Graphical representation of the changes in complement fractions C3 (A) and C4 (B) following treatment with a single infusion of infliximab. The horizontal bars represent the median values. The changes did not reach statistical significance.
AJG – November, 2000
infusion. This was the first infusion in all patients. Complement fractions C3 and C4 were assayed in serum just prior to and 4 h following the infusions. Complement was assayed in serum by laser nephalometry. The median plasma concentration of C3 prior to infusion was 1.45 g/L (0.85–2.06 g/L). This compared to a median value of 1.36 g/l (0.82–1.95 g/L) after infusion, p ⫽ ns. Similarly the median plasma C4 prior to the infusion was 0.29 g/L (0.1– 0.46 g/L) and post infusion was 0.27 g/L (0.1– 0.52 g/L), p ⫽ ns (Fig. 1). Plasma C3 concentration decreased after infliximab infusion in seven patients and the decrease ranged from 0.26 g/L to 0.03 g/L. However, the plasma C3 concentration increased after infusion in three patients ranging from 0.26 g/L to 0.01 g/L. The serum C4 concentration decreased after infliximab infusion in five patients, ranging from 0.01 g/L to 0.04 g/L and increased in three patients, ranging from 0.01 g/L to 0.06 g/L. It was unchanged in two patients. Of the 10 patients, 5 responded and 5 did not. There was no correlation between complement changes and clinical response. We have seen no evidence of complement depletion following anti-TNF␣ antibody therapy for Crohn’s disease. This contradicts the hypothesis that the mode of action, in particular the prolonged action, is due to the binding of membrane-bound TNF with the resultant complement lysis of immunological cells. Other modes of action that have been hypothesized include a reduction in lymphocyte tracking to inflamed tissue through a reduction in adhesion molecules (4) and the preferential modulation of activated as opposed to naive T cells (5). Membrane-bound TNF␣ may also play a role in cell death and infliximab sharply increases the ratio of BAX to Bcl-2 to accelerate T lymphocyte apoptosis (6). Ian D. R. Arnott, M.D. Alan Shand, M.R.C.P. Subrata Ghosh, M.D. Gastrointestinal Unit University Department of Medical Sciences Western General Hospital Edinburgh, Scotland
REFERENCES 1. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety. Inflammatory Bowel Diseases 1999;5:119 –33. 2. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s disease cA2 study group. New Engl J Med 1997;337:1029 –35. 3. Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNFalpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251–9.
Letters to the Editor
3327
4. Murthy S, Cooper HS, Yoshitake H, et al. Combination therapy of pentoxifylline and TNFalpha monoclonal antibody in dextran sulphate-induced mouse colitis. Alimentary Pharmacology and Therapeutics 1999;13:251– 60. 5. Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunology 1997;159:6276 – 82. 6. Srinivas G, Kusumakumary P, Nair MK, et al. Mutant p53 protein, Bcl-2/Bax ratios and apoptosis in paediatric acute lymphoblastic leukaemia. J Cancer Research and Clinical Oncology 2000;126:62–7.
Reprint requests and correspondence: Subrata Ghosh, Gastrointestinal Laboratory, Western General Hospital, Crewe Road, Edinburgh, Scotland. Received June 15, 2000; accepted June 19, 2000.
Spontaneous Rectus Sheath Hematoma and an Anterior Pelvic Hematoma as a Complication of Anticoagulation TO THE EDITOR: The paper by Adenoigbgbe et al. (1) is of interest to both general surgeons and gastroenterologists as it highlights the importance of spontaneous rectus sheath hematoma in the differential diagnosis of patients on anticoagulant therapy who develop sudden abdominal pain or mass. In addition, appropriate radiological investigation especially computer-assisted tomography (CAT) scan is invaluable in confirming the diagnosis, thus, preventing unnecessary surgical intervention. In the last 6 months we have managed two patients who developed rectus sheath hematoma while on anticoagulants. In retrospect, both had an unnecessary laparotomy that could have been prevented if a CAT scan was done. Case 1: A 65-yr-old female was admitted with a suspected pulmonary embolism: 2-day history of pleuritic chest pain, hemoptysis, and dyspnea. Clinical examination was unremarkable apart from right basal crepitations. The chest x-ray showed slight shadowing in the left midzone, Ddimers were 500 (N ⫽ ⬍250 U), arterial blood gases showed hypoxia (PaO2 was 8.76 kPa) in room air. She was treated with 1.5 mg/kg of low molecular weight heparin (LMWH) and was commenced on coumarin. The ventilation-perfusion scan done the next day was reported as normal. Two days later, she complained of left lumbar pain, and had an episode of hematemesis. Her hemoglobin had dropped from 15 g/dl to 12 g/dl, white blood cell (WBC) was 15,000 ⫻ 109/l and the INR was 3.9. Coumarin treatment was withheld. Abdominal examination revealed tenderness, guarding, and rigidity in the left iliac fossa. Provisional diagnosis was acute diverticulitis. She was managed conservatively: nil per os, i.v. fluids, and broad-spectrum antibiotics. Emergency abdominal ultrasound (US) scan of the abdomen showed a small amount of free fluid in the left
Letters to the Editor
The pattern of expression of CD44s and CD44 isoforms suggests that CD44v6 may have an important role in macrophage differentiation and that CD44s may also have an important role in lymphocyte homing and its activation. The same pattern of expression of CD44 isoforms in granulomas of Crohn’s disease, tuberculous enteritis, and pulmonary sarcoidosis also suggest that these expressions reflect rather an immune-mediated epiphenomenon than a disease-specific mechanism. Atsushi Ikehata, M.D. Department of Gastroenterology Iwate Prefectural Central Hospital Morioka, Japan Nobukazu Tomichi, M.D. Department of Pathology Iwate Prefectural Central Hospital Morioka, Japan
REFERENCES
AJG – Vol. 95, No. 11, 2000
treatment is the prolonged duration of action, with remission lasting for about 8 wk following a single i.v. administration (2). Since recognition of membrane-bound TNF␣ is an important feature of infliximab, a hypothesis for the long duration of action is through complement-mediated lysis of immune cells, such as Th1 lymphocytes or antigen presenting cells (3). Therefore, we aimed to assess whether there is any evidence of complement consumption in Crohn’s disease patients undergoing treatment with infliximab. We prospectively assessed 10 well characterized patients with active Crohn’s disease prior to and after treatment with infliximab. There were six females and four males with a median age of 33 yr (range, 17– 41 yr). Two patients had extensive small bowel disease, four had ileocolonic, and four had colonic disease. Five had associated perianal disease. All were on prednisolone at the time of infusion except one who was unable to tolerate steroids and the indication was chronic active disease refractory to all conventional anti-inflammatory therapy. Five were on azathioprine. Infliximab was administered in a dose of 5 mg/kg over a 2-h
1. Screaton GR, Bell MV, Jackson DG, et al. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA 1992;89:12160 – 4. 2. Papadogiannakis N, Gad A, Chenard M-P, et al. Expression of CD44 variants in differential diagnosis of ulcerative colitis and Crohn’s disease. Lancet 1996;347:1413– 4. 3. Rosenberg WMC, Prince C, Kaklamanis L, et al. Increased expression of CD44v6 and CD44v3 in ulcerative colitis but not colonic Crohn’s disease. Lancet 1995;345:1205–9. 4. Hankard GF, Cezard JP, Aigrain Y, et al. CD44 variant expression in inflammatory colonic mucosa is not disease specific but associated with increase crypt cell proliferation. Histopathology 1998;32:317–21. 5. Camacho FI, Munoz C, Sanchez-Verde L, et al. CD44v6 expression in inflammatory bowel disease is associated with activity detected by endoscopy and pathological features. Histopathology 1999;35:144 –9. Reprint requests and correspondence: Atsushi Ikehata, M.D., Department of Gastroenterology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, Iwate 020-0066, Japan. Received June 13, 2000; accepted June 19, 2000.
Administration of Infliximab in Crohn’s Disease Does Not Deplete Complement Components C3 and C4 TO THE EDITOR: Infliximab (chimeric anti-TNF␣ antibody) (Remicade, Centocor) is an effective therapy for Crohn’s disease producing a striking clinical and endoscopic response in about 65% of patients. Infliximab is a mouse/human chimeric antibody and utilizes an IgG1 molecule, capable of complement activation through its Fc region (1). Activation of the classical pathway may lead to depletion of C3 and C4. A novel feature of anti-TNF␣
Figure 1. Graphical representation of the changes in complement fractions C3 (A) and C4 (B) following treatment with a single infusion of infliximab. The horizontal bars represent the median values. The changes did not reach statistical significance.
AJG – November, 2000
infusion. This was the first infusion in all patients. Complement fractions C3 and C4 were assayed in serum just prior to and 4 h following the infusions. Complement was assayed in serum by laser nephalometry. The median plasma concentration of C3 prior to infusion was 1.45 g/L (0.85–2.06 g/L). This compared to a median value of 1.36 g/l (0.82–1.95 g/L) after infusion, p ⫽ ns. Similarly the median plasma C4 prior to the infusion was 0.29 g/L (0.1– 0.46 g/L) and post infusion was 0.27 g/L (0.1– 0.52 g/L), p ⫽ ns (Fig. 1). Plasma C3 concentration decreased after infliximab infusion in seven patients and the decrease ranged from 0.26 g/L to 0.03 g/L. However, the plasma C3 concentration increased after infusion in three patients ranging from 0.26 g/L to 0.01 g/L. The serum C4 concentration decreased after infliximab infusion in five patients, ranging from 0.01 g/L to 0.04 g/L and increased in three patients, ranging from 0.01 g/L to 0.06 g/L. It was unchanged in two patients. Of the 10 patients, 5 responded and 5 did not. There was no correlation between complement changes and clinical response. We have seen no evidence of complement depletion following anti-TNF␣ antibody therapy for Crohn’s disease. This contradicts the hypothesis that the mode of action, in particular the prolonged action, is due to the binding of membrane-bound TNF with the resultant complement lysis of immunological cells. Other modes of action that have been hypothesized include a reduction in lymphocyte tracking to inflamed tissue through a reduction in adhesion molecules (4) and the preferential modulation of activated as opposed to naive T cells (5). Membrane-bound TNF␣ may also play a role in cell death and infliximab sharply increases the ratio of BAX to Bcl-2 to accelerate T lymphocyte apoptosis (6). Ian D. R. Arnott, M.D. Alan Shand, M.R.C.P. Subrata Ghosh, M.D. Gastrointestinal Unit University Department of Medical Sciences Western General Hospital Edinburgh, Scotland
REFERENCES 1. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety. Inflammatory Bowel Diseases 1999;5:119 –33. 2. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s disease cA2 study group. New Engl J Med 1997;337:1029 –35. 3. Scallon BJ, Moore MA, Trinh H, et al. Chimeric anti-TNFalpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251–9.
Letters to the Editor
3327
4. Murthy S, Cooper HS, Yoshitake H, et al. Combination therapy of pentoxifylline and TNFalpha monoclonal antibody in dextran sulphate-induced mouse colitis. Alimentary Pharmacology and Therapeutics 1999;13:251– 60. 5. Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunology 1997;159:6276 – 82. 6. Srinivas G, Kusumakumary P, Nair MK, et al. Mutant p53 protein, Bcl-2/Bax ratios and apoptosis in paediatric acute lymphoblastic leukaemia. J Cancer Research and Clinical Oncology 2000;126:62–7.
Reprint requests and correspondence: Subrata Ghosh, Gastrointestinal Laboratory, Western General Hospital, Crewe Road, Edinburgh, Scotland. Received June 15, 2000; accepted June 19, 2000.
Spontaneous Rectus Sheath Hematoma and an Anterior Pelvic Hematoma as a Complication of Anticoagulation TO THE EDITOR: The paper by Adenoigbgbe et al. (1) is of interest to both general surgeons and gastroenterologists as it highlights the importance of spontaneous rectus sheath hematoma in the differential diagnosis of patients on anticoagulant therapy who develop sudden abdominal pain or mass. In addition, appropriate radiological investigation especially computer-assisted tomography (CAT) scan is invaluable in confirming the diagnosis, thus, preventing unnecessary surgical intervention. In the last 6 months we have managed two patients who developed rectus sheath hematoma while on anticoagulants. In retrospect, both had an unnecessary laparotomy that could have been prevented if a CAT scan was done. Case 1: A 65-yr-old female was admitted with a suspected pulmonary embolism: 2-day history of pleuritic chest pain, hemoptysis, and dyspnea. Clinical examination was unremarkable apart from right basal crepitations. The chest x-ray showed slight shadowing in the left midzone, Ddimers were 500 (N ⫽ ⬍250 U), arterial blood gases showed hypoxia (PaO2 was 8.76 kPa) in room air. She was treated with 1.5 mg/kg of low molecular weight heparin (LMWH) and was commenced on coumarin. The ventilation-perfusion scan done the next day was reported as normal. Two days later, she complained of left lumbar pain, and had an episode of hematemesis. Her hemoglobin had dropped from 15 g/dl to 12 g/dl, white blood cell (WBC) was 15,000 ⫻ 109/l and the INR was 3.9. Coumarin treatment was withheld. Abdominal examination revealed tenderness, guarding, and rigidity in the left iliac fossa. Provisional diagnosis was acute diverticulitis. She was managed conservatively: nil per os, i.v. fluids, and broad-spectrum antibiotics. Emergency abdominal ultrasound (US) scan of the abdomen showed a small amount of free fluid in the left