bs_bs_banner
THOUGHTS AND PROGRESS
Dose-Intensified Granulocyte-Monocyte Apheresis in Therapy Refractory Ulcerative Colitis *Caroline Schultheiß, *René Weischenberg, *Andrea Herrmann, †Bernhard Haller, *Roland M. Schmid, *Wolfgang Reindl, and *Wolfgang Huber *II. Medizinische Klinik und Poliklinik; and †Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany Abstract: Granulocyte-monocyte apheresis (GMA) is an emerging therapeutic option in active course of ulcerative colitis (UC). Appropriate GMA dose, including total number, frequency, and duration of the individual GMA session, is a matter of debate. It was the aim of the present study to evaluate the efficacy of a dose-intensified GMA regimen in patients with moderately to severely active UC. A prospective open-label, single-center study was performed in 10 patients with active UC (Rachmilewitz Clinical Activity Index [CAI] ≥ 8 points; Rachmilewitz Endoscopic Index ≥ 7 points). Patients had failed to improve after treatment with steroids and/or immunomodulators. GMA was performed twice weekly for 2 h to a maximum of 10 sessions. In each GMA session, the adsorber was changed after 1 h of treatment time. Four patients achieved remission with a CAI ≤ 4 points. Three patients had a response with an improvement of CAI of ≥3 points. Three patients showed no benefit from GMA. The quality of life score determined by the inflammatory bowel disease questionnaire-Deutschland increased by 26 points in median. First and second filters had similar efficiency in granulocyte and monocyte adsorption. No major adverse effects were observed. Dose-intensified GMA as reported in this study provided an encouraging short-term response rate of 70% in patients with moderately to severely active UC not responding to standard steroid or immunomodulator therapy. Although all patients relapsed not later than 16 weeks, GMA might be useful to reduce steroid and immunomodulator usage, or to delay surgery in this patient group. Key Words: Granulocyte—monocyte apheresis—Ulcerative colitis—Dose intensification— Double filters—Rachmilewitz index—Platelet count.
The pathogenesis of ulcerative colitis (UC) is characterized by a disturbed interaction between the mucosal immune system and the intestinal microbiota leading to active mucosal inflammation with infiltration of the colonic mucosa by granulodoi:10.1111/aor.12329 Received August 2013; revised March 2014. Address correspondence and reprint requests to Mrs. Caroline Schultheiß, II. Medizinische Klinik, ward 2/11, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany. E-mail: [email protected]
187
cytes and macrophages (1). Despite a number of potent drugs being available for UC therapy, about 7–22% of patients suffer from chronically active or steroid-dependent disease (2,3). In these patients, nonsurgical options are scarce. Granulocytemonocyte apheresis (GMA) might be a therapeutic option to delay or even prevent colectomy in these patients. Several pilot studies on GMA showed promising results, with response rates of up to 75% without major side effects (4–7). GMA was especially effective in steroid-naive patients with mild UC activity (Rachmilewitz Clinical Activity Index (CAI) 4–8 points) (8,9), first UC episode, and short disease duration (10). Furthermore, in steroid-dependent patients, GMA has been reported to be superior compared with a further increase of the steroid dose (7), whereas highly active UC has been reported to be refractory to GMA (11,12). However, dosing of GMA is still a matter of debate. GMA has been applied with considerable variations in frequency and duration. GMA frequency differs between 5 (13,14) and 10 or more consecutive GMA treatments once weekly. Most of the GMA sessions lasted for 1 h (15,16). Evidence on effective duration, frequency, and total number of treatment sessions is scarce (17). It was the aim of the present study to investigate a dose-intensified GMA regimen in patients with moderate to severe UC not responding to standard therapy with steroids or immunomodulators. The dose intensification was achieved by performing GMA twice weekly using a set of two GMA filters during each treatment session. The primary study endpoint was the improvement of the CAI and the Rachmilewitz Endoscopic Index (REI) (18). Secondary study endpoints were differences in the quality of life, markers of inflammation, and the analysis of filter efficiency and safety. PATIENTS AND METHODS Inclusion and exclusion criteria Patients with moderate to severe UC affecting at least the rectosigmoid despite treatment with steroids and/or immunomodulators were eligible for this study. A moderate course of UC was defined as a CAI ≥ 8–10 points and a REI ≥ 7 points; a severe course was defined as a CAI ≥ 11 points and a REI ≥ 7 points. The CAI includes the clinical criteria blood in stool, number of stools per week, investigator’s global assessment of symptomatic state, abdominal pain, body temperature, extraintestinal manifestations, and laboratory findings. For REI Artif Organs, Vol. 39, No. 2, 2015
188
THOUGHTS AND PROGRESS
assessment, rectoscopy was performed within 2 weeks before the first and after the last GMA session. The REI is composed of the subitems granulations, vascular pattern, vulnerability of mucosa, and mucosal damage. Concomitant immunomodulator dosage was kept stable during the study period. Prednisolone was allowed to be tapered in 5-mg steps per week in case of a response to GMA. Clostridium difficile toxin had to be negative in stool before study entry. Exclusion criteria were pregnancy, breastfeeding, patients with known allergy to heparin, acute intestinal bleeding affecting hemoglobin levels, and patients with isolated right-sided colitis. Study setting and design This is a prospective, noncontrolled, open-label, single-center study performed from January 2011 to April 2012 in a German university hospital. At least five GMAs were performed at twice-weekly intervals. Patients with a rapid response were allowed to discontinue GMA after the 5th session. GMA treatment GMA was performed using the CF 200 hemoperfusion machine equipped with the disposable Immuloc-adsorber and extracorporal system (all components produced by Infomed, Geneva, Switzerland). The Immuloc-adsorber is CE certified and based on cellulose filaments. Activated granulocytes and monocytes bind to the hydroxyl groups of the cellulose filaments and are removed from the blood circulation by adsorption to the filaments. Set-up and priming of the extracorporeal devices were performed according to the manufacturer’s instructions. Blood access of the patient to the extracorporeal circuit was performed by two indwelling venous needles. Heparin was given at a dose of 50–100 IU per kg body weight to achieve an activated clotting time (ACT) of 200 s determined by ACTester (Quest Medical, Inc., Allen, TX, USA). Blood flow rate was held constant at 30 mL/min. The two GMA adsorbers were connected in the extracorporal circuit via two Y-pieces (Aquaspike by Haemotronic S.p.A., Mirandola, Italy) equipped with clamps. At the beginning of the session, the first adsorber was perfused while the blood lines of the other were locked with clamps. After 1 h, the blood flow was diverted to the second filter by opening its clamps at the Y-connector and closing the clamps to the first adsorber. The adsorber efficiency was evaluated by determining the granulocyte and monocyte cell counts pre- and postfilter after 20 and 60 min use of each filter. To adjust for interindividual variation Artif Organs, Vol. 39, No. 2, 2015
of the cell counts, the prefilter values were set to be 100% for each cell row and at every time point (20, 60, 80, 120 min). Inflammatory parameters, platelets and quality of life At baseline and at the end of each session, the blood count, C-reactive protein (CRP), and the erythrocyte sedimentation rate (ESR) were measured. At 20, 40, 60, and 120 min, postfilter platelets were compared to prefilter values. To adjust for interindividual variations of the cell counts, the prefilter values were set to be 100%. Before the first and after the final GMA treatment, a stool sample was investigated for calprotectin levels. The inflammatory bowel disease questionnaire-Deutschland (IBDQ-D) was filled out weekly to evaluate the patients’ health-related quality of life. The IBDQ-D consists of 32 items in four domains: bowel symptoms, systemic symptoms, emotional function, and social function. Each item is rated on a seven-point scale (7 = no problem, 1 = very severe problem); so the total score ranges from 32 to 224 points. A higher score indicates a better quality of life. A change in the score of 16–30 points reports a significant clinical change. In the healthy population, the average score was 213 points compared with 175 points in UC patients (19–21). Statistics Quantitative data are described by median and range, presented as minimum–maximum, or interquartile range (IQR), presented as 1st quartile– 3rd quartile, respectively. For qualitative data, absolute frequencies are shown. Significances are determined by the Mann–Whitney rank sum test. Ethics This prospective observational study was approved by the institutional review board of our hospital (Ethikkommission der Fakultät für Medizin der Technischen Universität München) and performed adhering to the Declaration of Helsinki. According to the German medicinal devices act, the study was registered and approved by the higher federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM, register number 00118598). Prior to any study-related procedure, written informed consent was obtained from each patient. RESULTS Patients’ characteristics The median age of the 10 study patients was 54.5 years; four patients suffered from pancolitis, six
THOUGHTS AND PROGRESS patients from left-sided colitis; median duration of ongoing activity of UC was 2.25 years. Six patients had a moderately active (CAI 8–10 points) and four patients had a severely active UC course (CAI ≥ 11 points). Eight of the 10 patients received 10 GMA treatments. One patient dropped out after the 4th GMA because of worsening of UC symptoms under GMA; one patient stopped GMA after the 8th session after having achieved remission. CAI and REI Remission was defined as a CAI and/or an REI ≤ 4 points. Response was defined as improvement of the CAI of ≥3 points and/or the decrease of the sum of CAI + REI of ≥3 points. Using these criteria, four patients achieved remission, three patients showed response to GMA, and three patients did not improve. Median CAI at study start was 9 points (minimum 8, maximum 17 points). It was lowest after the 8th GMA, with a median of 4 points (IQR 3.0–8.5 points, P = 0.017) and increased slightly until the 10th GMA to a median of 6 points (IQR 4–7 points). REI remained unchanged throughout the study duration with a median of 10 points before the first and after the last GMA session. Quality of life and inflammatory parameters Quality of life pictured by the IBDQ-D increased continuously from a median score of 124 points (IQR 105–138 points) at study start to a median score of 150 points (IQR 138–187 points, P = 0.034) after the 10th GMA. The median CRP level of 0.9 mg/dL (IQR 0.4–2.2 mg/dL) before GMA start decreased to its minimum of 0.3 mg/dL (IQR 0.2–0.8 mg/dL) after the 5th GMA session. The median ESR was lowest at the 8th GMA, with 30 mm in the 1st and 63 mm in the 2nd hour (30/63 mm; reference value
THOUGHTS AND PROGRESS
Dose-Intensified Granulocyte-Monocyte Apheresis in Therapy Refractory Ulcerative Colitis *Caroline Schultheiß, *René Weischenberg, *Andrea Herrmann, †Bernhard Haller, *Roland M. Schmid, *Wolfgang Reindl, and *Wolfgang Huber *II. Medizinische Klinik und Poliklinik; and †Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany Abstract: Granulocyte-monocyte apheresis (GMA) is an emerging therapeutic option in active course of ulcerative colitis (UC). Appropriate GMA dose, including total number, frequency, and duration of the individual GMA session, is a matter of debate. It was the aim of the present study to evaluate the efficacy of a dose-intensified GMA regimen in patients with moderately to severely active UC. A prospective open-label, single-center study was performed in 10 patients with active UC (Rachmilewitz Clinical Activity Index [CAI] ≥ 8 points; Rachmilewitz Endoscopic Index ≥ 7 points). Patients had failed to improve after treatment with steroids and/or immunomodulators. GMA was performed twice weekly for 2 h to a maximum of 10 sessions. In each GMA session, the adsorber was changed after 1 h of treatment time. Four patients achieved remission with a CAI ≤ 4 points. Three patients had a response with an improvement of CAI of ≥3 points. Three patients showed no benefit from GMA. The quality of life score determined by the inflammatory bowel disease questionnaire-Deutschland increased by 26 points in median. First and second filters had similar efficiency in granulocyte and monocyte adsorption. No major adverse effects were observed. Dose-intensified GMA as reported in this study provided an encouraging short-term response rate of 70% in patients with moderately to severely active UC not responding to standard steroid or immunomodulator therapy. Although all patients relapsed not later than 16 weeks, GMA might be useful to reduce steroid and immunomodulator usage, or to delay surgery in this patient group. Key Words: Granulocyte—monocyte apheresis—Ulcerative colitis—Dose intensification— Double filters—Rachmilewitz index—Platelet count.
The pathogenesis of ulcerative colitis (UC) is characterized by a disturbed interaction between the mucosal immune system and the intestinal microbiota leading to active mucosal inflammation with infiltration of the colonic mucosa by granulodoi:10.1111/aor.12329 Received August 2013; revised March 2014. Address correspondence and reprint requests to Mrs. Caroline Schultheiß, II. Medizinische Klinik, ward 2/11, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, Munich 81675, Germany. E-mail: [email protected]
187
cytes and macrophages (1). Despite a number of potent drugs being available for UC therapy, about 7–22% of patients suffer from chronically active or steroid-dependent disease (2,3). In these patients, nonsurgical options are scarce. Granulocytemonocyte apheresis (GMA) might be a therapeutic option to delay or even prevent colectomy in these patients. Several pilot studies on GMA showed promising results, with response rates of up to 75% without major side effects (4–7). GMA was especially effective in steroid-naive patients with mild UC activity (Rachmilewitz Clinical Activity Index (CAI) 4–8 points) (8,9), first UC episode, and short disease duration (10). Furthermore, in steroid-dependent patients, GMA has been reported to be superior compared with a further increase of the steroid dose (7), whereas highly active UC has been reported to be refractory to GMA (11,12). However, dosing of GMA is still a matter of debate. GMA has been applied with considerable variations in frequency and duration. GMA frequency differs between 5 (13,14) and 10 or more consecutive GMA treatments once weekly. Most of the GMA sessions lasted for 1 h (15,16). Evidence on effective duration, frequency, and total number of treatment sessions is scarce (17). It was the aim of the present study to investigate a dose-intensified GMA regimen in patients with moderate to severe UC not responding to standard therapy with steroids or immunomodulators. The dose intensification was achieved by performing GMA twice weekly using a set of two GMA filters during each treatment session. The primary study endpoint was the improvement of the CAI and the Rachmilewitz Endoscopic Index (REI) (18). Secondary study endpoints were differences in the quality of life, markers of inflammation, and the analysis of filter efficiency and safety. PATIENTS AND METHODS Inclusion and exclusion criteria Patients with moderate to severe UC affecting at least the rectosigmoid despite treatment with steroids and/or immunomodulators were eligible for this study. A moderate course of UC was defined as a CAI ≥ 8–10 points and a REI ≥ 7 points; a severe course was defined as a CAI ≥ 11 points and a REI ≥ 7 points. The CAI includes the clinical criteria blood in stool, number of stools per week, investigator’s global assessment of symptomatic state, abdominal pain, body temperature, extraintestinal manifestations, and laboratory findings. For REI Artif Organs, Vol. 39, No. 2, 2015
188
THOUGHTS AND PROGRESS
assessment, rectoscopy was performed within 2 weeks before the first and after the last GMA session. The REI is composed of the subitems granulations, vascular pattern, vulnerability of mucosa, and mucosal damage. Concomitant immunomodulator dosage was kept stable during the study period. Prednisolone was allowed to be tapered in 5-mg steps per week in case of a response to GMA. Clostridium difficile toxin had to be negative in stool before study entry. Exclusion criteria were pregnancy, breastfeeding, patients with known allergy to heparin, acute intestinal bleeding affecting hemoglobin levels, and patients with isolated right-sided colitis. Study setting and design This is a prospective, noncontrolled, open-label, single-center study performed from January 2011 to April 2012 in a German university hospital. At least five GMAs were performed at twice-weekly intervals. Patients with a rapid response were allowed to discontinue GMA after the 5th session. GMA treatment GMA was performed using the CF 200 hemoperfusion machine equipped with the disposable Immuloc-adsorber and extracorporal system (all components produced by Infomed, Geneva, Switzerland). The Immuloc-adsorber is CE certified and based on cellulose filaments. Activated granulocytes and monocytes bind to the hydroxyl groups of the cellulose filaments and are removed from the blood circulation by adsorption to the filaments. Set-up and priming of the extracorporeal devices were performed according to the manufacturer’s instructions. Blood access of the patient to the extracorporeal circuit was performed by two indwelling venous needles. Heparin was given at a dose of 50–100 IU per kg body weight to achieve an activated clotting time (ACT) of 200 s determined by ACTester (Quest Medical, Inc., Allen, TX, USA). Blood flow rate was held constant at 30 mL/min. The two GMA adsorbers were connected in the extracorporal circuit via two Y-pieces (Aquaspike by Haemotronic S.p.A., Mirandola, Italy) equipped with clamps. At the beginning of the session, the first adsorber was perfused while the blood lines of the other were locked with clamps. After 1 h, the blood flow was diverted to the second filter by opening its clamps at the Y-connector and closing the clamps to the first adsorber. The adsorber efficiency was evaluated by determining the granulocyte and monocyte cell counts pre- and postfilter after 20 and 60 min use of each filter. To adjust for interindividual variation Artif Organs, Vol. 39, No. 2, 2015
of the cell counts, the prefilter values were set to be 100% for each cell row and at every time point (20, 60, 80, 120 min). Inflammatory parameters, platelets and quality of life At baseline and at the end of each session, the blood count, C-reactive protein (CRP), and the erythrocyte sedimentation rate (ESR) were measured. At 20, 40, 60, and 120 min, postfilter platelets were compared to prefilter values. To adjust for interindividual variations of the cell counts, the prefilter values were set to be 100%. Before the first and after the final GMA treatment, a stool sample was investigated for calprotectin levels. The inflammatory bowel disease questionnaire-Deutschland (IBDQ-D) was filled out weekly to evaluate the patients’ health-related quality of life. The IBDQ-D consists of 32 items in four domains: bowel symptoms, systemic symptoms, emotional function, and social function. Each item is rated on a seven-point scale (7 = no problem, 1 = very severe problem); so the total score ranges from 32 to 224 points. A higher score indicates a better quality of life. A change in the score of 16–30 points reports a significant clinical change. In the healthy population, the average score was 213 points compared with 175 points in UC patients (19–21). Statistics Quantitative data are described by median and range, presented as minimum–maximum, or interquartile range (IQR), presented as 1st quartile– 3rd quartile, respectively. For qualitative data, absolute frequencies are shown. Significances are determined by the Mann–Whitney rank sum test. Ethics This prospective observational study was approved by the institutional review board of our hospital (Ethikkommission der Fakultät für Medizin der Technischen Universität München) and performed adhering to the Declaration of Helsinki. According to the German medicinal devices act, the study was registered and approved by the higher federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM, register number 00118598). Prior to any study-related procedure, written informed consent was obtained from each patient. RESULTS Patients’ characteristics The median age of the 10 study patients was 54.5 years; four patients suffered from pancolitis, six
THOUGHTS AND PROGRESS patients from left-sided colitis; median duration of ongoing activity of UC was 2.25 years. Six patients had a moderately active (CAI 8–10 points) and four patients had a severely active UC course (CAI ≥ 11 points). Eight of the 10 patients received 10 GMA treatments. One patient dropped out after the 4th GMA because of worsening of UC symptoms under GMA; one patient stopped GMA after the 8th session after having achieved remission. CAI and REI Remission was defined as a CAI and/or an REI ≤ 4 points. Response was defined as improvement of the CAI of ≥3 points and/or the decrease of the sum of CAI + REI of ≥3 points. Using these criteria, four patients achieved remission, three patients showed response to GMA, and three patients did not improve. Median CAI at study start was 9 points (minimum 8, maximum 17 points). It was lowest after the 8th GMA, with a median of 4 points (IQR 3.0–8.5 points, P = 0.017) and increased slightly until the 10th GMA to a median of 6 points (IQR 4–7 points). REI remained unchanged throughout the study duration with a median of 10 points before the first and after the last GMA session. Quality of life and inflammatory parameters Quality of life pictured by the IBDQ-D increased continuously from a median score of 124 points (IQR 105–138 points) at study start to a median score of 150 points (IQR 138–187 points, P = 0.034) after the 10th GMA. The median CRP level of 0.9 mg/dL (IQR 0.4–2.2 mg/dL) before GMA start decreased to its minimum of 0.3 mg/dL (IQR 0.2–0.8 mg/dL) after the 5th GMA session. The median ESR was lowest at the 8th GMA, with 30 mm in the 1st and 63 mm in the 2nd hour (30/63 mm; reference value
