Digestion / 9 : 197 201 (1979)
Plasmapheresis in C rohn’s Disease G.E. Holdstock, J.A. Fisher, T.J. Hamblin and C. Loehry Royal Victoria Hospital, Bournemouth
Key Words. Crohn’s disease • Immune complexes • Plasmapheresis
Introduction
Crohn’s disease is associated with a relatively high morbidity but low mortality rate. At present, steroid therapy is the mainstay of treatment and most cases require only small amounts. It has been suggested that steroid therapy may account for some of the increased mortality (8), and hence much interest has been shown in possible steroid-sparing agents (1, 11). Unfortunately, the benefit gained from the drugs currently available seems to be limited. The pathogenesis of Crohn’s disease is un known, although many favour a transmissible agent. Immune complexes have been demon strated in patients with Crohn’s disease (2, 3, 5, 6) and, while these may be a secondary phe nomenon, they may play a role in the patho
genesis of the intestinal or extra-intestinal mani festations of the disease (10). In Crohn’s disease, circulating immune com plexes are found in higher titre during relapse (3, 5) and they are the most likely explanation for the extra-gastrointestinal ‘serum sickness’ or ‘vasculitic’ complications occasionally seen during the course of the disease. In other conditions in which similar vasculitic phe nomena occur, for example systemic lupus erythematosus, circulating immune complexes are also well documented. In these patients, plasmapheresis has been shown both to remove these complexes and to result in some symp tomatic improvement (12). In this paper we report on the preliminary results of a trial of plasmapheresis in patients with Crohn’s disease.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
Abstract. 6 patients with Crohn’s disease for 1—14 years have been treated with plasmapheresis for periods of up to 6 months. The symptoms of the one newly diagnosed patient were controlled by plasmapheresis alone, and 5 steroid-dependent patients were able to reduce their steroid requirements. During the study period, 13 clinical relapses were managed without increasing steroid dosage. There was evidence of circulating soluble immune complexes in all the patients and these levels were lowered by plasmapheresis. A possible role of plasmapheresis in the management of Crohn’s disease is discussed.
198
Holdstock/Fisher/Hamblin/Loehry
Table I. Summary of effect of plasmapheresis on the 6 patients Patient No.
1 2 3 4 5 6
age
56 25 24 34 28 27
Duration sex
F F F F F M
3 months 6 years 4 years 12 years 2 years 7 years
Average prednisolone dosage, mg
ESR mm/h
at entry to trial
at end of trial
0 15 20 12.5 10 10
0 2.5 2.5 2.5 2.5 5.0
at entry to trial
at end of trial
20 46 70 18 42 20
8 40 75 10 19 8
Number Duration of plasma trial phereses months
5 8 8 8 5 6
3 5 5 6' 5‘ 6‘
1 Still ongoing in study.
Initially 5 patients with long-standing disease were studied, chosen because of their unacceptably high corticosteroid requirements. Later, 1 newly diagnosed patient was also studied. All patients gave informed written consent. Plasmapheresis was performed, using the Haemonctics model 30 blood cell separator. It was performed twice in the 1st week and once in the 2nd week after entry into the trial. Plasmapheresis was then repeated if there was a clinical relapse, and again performed twice in 1 week. For the purpose of this study, a clinical relapse was taken as being any prolonged deterioration in the patient’s general condition, i.e. a situation under which patients would normally have increased their steroid dosage. Approximately 2 litres of patient plasma were exchanged for plasma protein fraction at each session, which took between 60 and 90 min. Soluble circulating immune complexes were tested by anticomplementary activity (9). platelet aggrega tion (7) and by binding to Clq-coated' plastic tubes 1 Complement is formed of nine protein components (Cl-9) of which Cl consists of three major subfrac tions Clq, Clr, Cls.
(4). Patients were assessed clinically, and serial re cordings of haemoglobin, ESR and albumin levels were taken.
Results
Clinical details are summarised in table I. In a total of 30 patient-months, there were 13 clinical relapses. All these were treated successfully by repeated plasmapheresis and in no case was it necessary to increase steroid dosage. On global assessment, no patient felt any the worse for the reduced corticosteroid dosage. There was no significant change in the levels of haemoglobin or albumin during the study periods. The course of the newly diagnosed patient is shown in figure 1. The results of the immune-complex studies in all the patients on entry into the trial are shown in table II. Sequential Clq-binding levels and their relation to repeated plasmapheresis in 2 patients are shown in figure 2. These are representative of all 6 patients.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
Methods
Plasmapheresis in Crohn’s Disease
199
Table II. Initial results for immune complexes Patient No.
Clq binding, ng/ml Anticomplcmentary activity Platelet aggregation
Normal
1
2
3
4
5
6
76.5 0 1/2
54.4 0 0
54.1 1/128 1/16
64.2 0 0
59.2 0 0
51.7 0 1/2
up to 25 0 0
Prednisolone
Fig. 1. Clinical course of patient 1 newly diag nosed as Crohn’s disease. I indicates timing of plas mapheresis.
♦
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
♦ ♦ f t
Holdstock/Fisher/Hamblin/Loehry
200
Discussion
The course of Crohn’s disease fluctuates to such an extent that it is difficult to assess new forms of treatment, particularly with plasma pheresis, as the psychological effect of per forming the rather complex-looking procedure can be expected to have a considerable placebo effect. Assessment is further complicated as we feel that plasmapheresis can only be justifiably used in severe cases of Crohn’s disease, making it difficult to study large groups or to have an adequate control group. In this preliminary study, plasmapheresis appears to be of some benefit to patients with severe Crohn’s disease in as much as their corticosteroid requirements are reduced. In 2 of
our patients, Cushingoid features present at the beginning of the study period were noted to regress. There is no evidence that the actual disease process has been altered, as in 2 patients who underwent repeat barium enema examina tion similar changes were found to those do cumented in a prior examination. Those pa tients who later stopped plasmapheresis again required larger doses of corticosteroids to con trol their symptoms. All our 6 patients had high levels of Clq binding and this probably mirrors the severity of their disease. Some disparity between the three methods of measuring immune complexes is to be expected, as results depend on a number of factors, including the size of the complex.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
Fig. 2. Effect of plasmapheresis on Clq levels in patients 2 and 4. l indicates timing of plasmapheresis.
Plasmapheresis in Crohn’s Disease
It is tempting to attribute the beneficial effect of plasmapheresis to the removal of the immune complexes, particularly as we have shown that these levels are temporarily lowered by plasmapheresis. It may be that other factors, such as altered macrophage function, are in volved. Only 1 of our patients suffered from extra-gastrointestinal manifestation. Patient 2 suffered from a non-specific arthralgia in her shoulders and knees, which dramatically re sponded to each plasmapheresis but recurred after approximately 2 weeks. While it is unlikely that plasmapheresis will ever become the first line of treatment in the management of Crohn’s disease, and despite the uncontrolled nature of our trial, we feel that our results are of interest for two reasons. Firstly, plasmapheresis may have a steroid sparing effect and this may have therapeutic implications, and secondly, further studies in volving plasmapheresis may help to elucidate the role of immune complexes in the patho genesis of the disease.
201
4 Hay, F.C.; Nineham, L.J., and Roitt, I.M.: Routine assay for the detection of immune complexes of known immunoglobulin class using solid phase Clq. Clin. exp. Immunol. 24: 396-400 (1976). 5 Hodgeson, H.J.; Porter, B.J., and Jewell, D.P.: Immune complexes in ulcerative colitis and Crohn’s disease. Clin. exp. Immunol. 29: 187-196 (1977). 6 Jewell, D.P. and MacLennan, I.C.M.: Circulating immune complexes in inflammatory bowel disease. Clin. expl. Immunol. 14: 219-226 (1973). 7 Penttinen, K. and Myllyla, G.: Interaction in hu man blood platelets, viruses and antibodies. I. Platelet aggregation test with microequipment. Lancet/: 1135-1137 (1970). 8 Prior, P.; Fielding, J.F.; Waterhouse, J.A., and Cooke, W.T.: Mortality in Crohn’s disease. Lancet i: 1135-1137 (1970). 9 Roitt, I.M. and Doniach, D.: in Manual on autoim mune serology, p. 13 (WHO, Geneva 1966). 10 Thayer, W.R.: Are the inflammatory bowel dis eases immune complex diseases? Gastoenterology 70: 136-137 (1976). 11 Ursing, B. and Kamme, C.: Metronidazole for Crohn’s disease. Lancet i: 775-777 (1975). 12 Verrier Jones, J.; Cumming, R.H.; Bucknall, R.C.; Asplin, C.M.; Fraser, I.D.; Bothomley, J.; Davis, P., and Hamblin, T.J.: Plasmapheresis in the manage ment of acute systemic lupus erythematosus. Lancet/: 709-711 (1976).
References
Received: November 1, 1978 Received in revised form: December 18, 1978 G.E. Holdstock, Professorial Medical Unit, Level F, Centre Block, Southampton General Hospital, Southampton, S09 4XY (England)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
1 Brooke, B.N.; Cave, D.R., and King, D.W.: Place of azothiaprin in Crohn’s disease. Lancet /: 1041-1042 (1976). 2 Doe, W.F.; Booth, C.C., and Brown, D.L.: Evi dence for complement-binding immune complexes in adult coeliac disease, Crohn’s disease and ulcer ative colitis. Lancet /: 402-403 (1973). 3 Fiasse, R.; Lurhuma, A.Z.; Cambiaso, C.L.; Mas son, P.L., and Dive, C.: Circulating immune com plexes and disease activity in Crohn’s disease. Gut 19: 611 617 (1978).
Plasmapheresis in C rohn’s Disease G.E. Holdstock, J.A. Fisher, T.J. Hamblin and C. Loehry Royal Victoria Hospital, Bournemouth
Key Words. Crohn’s disease • Immune complexes • Plasmapheresis
Introduction
Crohn’s disease is associated with a relatively high morbidity but low mortality rate. At present, steroid therapy is the mainstay of treatment and most cases require only small amounts. It has been suggested that steroid therapy may account for some of the increased mortality (8), and hence much interest has been shown in possible steroid-sparing agents (1, 11). Unfortunately, the benefit gained from the drugs currently available seems to be limited. The pathogenesis of Crohn’s disease is un known, although many favour a transmissible agent. Immune complexes have been demon strated in patients with Crohn’s disease (2, 3, 5, 6) and, while these may be a secondary phe nomenon, they may play a role in the patho
genesis of the intestinal or extra-intestinal mani festations of the disease (10). In Crohn’s disease, circulating immune com plexes are found in higher titre during relapse (3, 5) and they are the most likely explanation for the extra-gastrointestinal ‘serum sickness’ or ‘vasculitic’ complications occasionally seen during the course of the disease. In other conditions in which similar vasculitic phe nomena occur, for example systemic lupus erythematosus, circulating immune complexes are also well documented. In these patients, plasmapheresis has been shown both to remove these complexes and to result in some symp tomatic improvement (12). In this paper we report on the preliminary results of a trial of plasmapheresis in patients with Crohn’s disease.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
Abstract. 6 patients with Crohn’s disease for 1—14 years have been treated with plasmapheresis for periods of up to 6 months. The symptoms of the one newly diagnosed patient were controlled by plasmapheresis alone, and 5 steroid-dependent patients were able to reduce their steroid requirements. During the study period, 13 clinical relapses were managed without increasing steroid dosage. There was evidence of circulating soluble immune complexes in all the patients and these levels were lowered by plasmapheresis. A possible role of plasmapheresis in the management of Crohn’s disease is discussed.
198
Holdstock/Fisher/Hamblin/Loehry
Table I. Summary of effect of plasmapheresis on the 6 patients Patient No.
1 2 3 4 5 6
age
56 25 24 34 28 27
Duration sex
F F F F F M
3 months 6 years 4 years 12 years 2 years 7 years
Average prednisolone dosage, mg
ESR mm/h
at entry to trial
at end of trial
0 15 20 12.5 10 10
0 2.5 2.5 2.5 2.5 5.0
at entry to trial
at end of trial
20 46 70 18 42 20
8 40 75 10 19 8
Number Duration of plasma trial phereses months
5 8 8 8 5 6
3 5 5 6' 5‘ 6‘
1 Still ongoing in study.
Initially 5 patients with long-standing disease were studied, chosen because of their unacceptably high corticosteroid requirements. Later, 1 newly diagnosed patient was also studied. All patients gave informed written consent. Plasmapheresis was performed, using the Haemonctics model 30 blood cell separator. It was performed twice in the 1st week and once in the 2nd week after entry into the trial. Plasmapheresis was then repeated if there was a clinical relapse, and again performed twice in 1 week. For the purpose of this study, a clinical relapse was taken as being any prolonged deterioration in the patient’s general condition, i.e. a situation under which patients would normally have increased their steroid dosage. Approximately 2 litres of patient plasma were exchanged for plasma protein fraction at each session, which took between 60 and 90 min. Soluble circulating immune complexes were tested by anticomplementary activity (9). platelet aggrega tion (7) and by binding to Clq-coated' plastic tubes 1 Complement is formed of nine protein components (Cl-9) of which Cl consists of three major subfrac tions Clq, Clr, Cls.
(4). Patients were assessed clinically, and serial re cordings of haemoglobin, ESR and albumin levels were taken.
Results
Clinical details are summarised in table I. In a total of 30 patient-months, there were 13 clinical relapses. All these were treated successfully by repeated plasmapheresis and in no case was it necessary to increase steroid dosage. On global assessment, no patient felt any the worse for the reduced corticosteroid dosage. There was no significant change in the levels of haemoglobin or albumin during the study periods. The course of the newly diagnosed patient is shown in figure 1. The results of the immune-complex studies in all the patients on entry into the trial are shown in table II. Sequential Clq-binding levels and their relation to repeated plasmapheresis in 2 patients are shown in figure 2. These are representative of all 6 patients.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
Methods
Plasmapheresis in Crohn’s Disease
199
Table II. Initial results for immune complexes Patient No.
Clq binding, ng/ml Anticomplcmentary activity Platelet aggregation
Normal
1
2
3
4
5
6
76.5 0 1/2
54.4 0 0
54.1 1/128 1/16
64.2 0 0
59.2 0 0
51.7 0 1/2
up to 25 0 0
Prednisolone
Fig. 1. Clinical course of patient 1 newly diag nosed as Crohn’s disease. I indicates timing of plas mapheresis.
♦
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
♦ ♦ f t
Holdstock/Fisher/Hamblin/Loehry
200
Discussion
The course of Crohn’s disease fluctuates to such an extent that it is difficult to assess new forms of treatment, particularly with plasma pheresis, as the psychological effect of per forming the rather complex-looking procedure can be expected to have a considerable placebo effect. Assessment is further complicated as we feel that plasmapheresis can only be justifiably used in severe cases of Crohn’s disease, making it difficult to study large groups or to have an adequate control group. In this preliminary study, plasmapheresis appears to be of some benefit to patients with severe Crohn’s disease in as much as their corticosteroid requirements are reduced. In 2 of
our patients, Cushingoid features present at the beginning of the study period were noted to regress. There is no evidence that the actual disease process has been altered, as in 2 patients who underwent repeat barium enema examina tion similar changes were found to those do cumented in a prior examination. Those pa tients who later stopped plasmapheresis again required larger doses of corticosteroids to con trol their symptoms. All our 6 patients had high levels of Clq binding and this probably mirrors the severity of their disease. Some disparity between the three methods of measuring immune complexes is to be expected, as results depend on a number of factors, including the size of the complex.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
Fig. 2. Effect of plasmapheresis on Clq levels in patients 2 and 4. l indicates timing of plasmapheresis.
Plasmapheresis in Crohn’s Disease
It is tempting to attribute the beneficial effect of plasmapheresis to the removal of the immune complexes, particularly as we have shown that these levels are temporarily lowered by plasmapheresis. It may be that other factors, such as altered macrophage function, are in volved. Only 1 of our patients suffered from extra-gastrointestinal manifestation. Patient 2 suffered from a non-specific arthralgia in her shoulders and knees, which dramatically re sponded to each plasmapheresis but recurred after approximately 2 weeks. While it is unlikely that plasmapheresis will ever become the first line of treatment in the management of Crohn’s disease, and despite the uncontrolled nature of our trial, we feel that our results are of interest for two reasons. Firstly, plasmapheresis may have a steroid sparing effect and this may have therapeutic implications, and secondly, further studies in volving plasmapheresis may help to elucidate the role of immune complexes in the patho genesis of the disease.
201
4 Hay, F.C.; Nineham, L.J., and Roitt, I.M.: Routine assay for the detection of immune complexes of known immunoglobulin class using solid phase Clq. Clin. exp. Immunol. 24: 396-400 (1976). 5 Hodgeson, H.J.; Porter, B.J., and Jewell, D.P.: Immune complexes in ulcerative colitis and Crohn’s disease. Clin. exp. Immunol. 29: 187-196 (1977). 6 Jewell, D.P. and MacLennan, I.C.M.: Circulating immune complexes in inflammatory bowel disease. Clin. expl. Immunol. 14: 219-226 (1973). 7 Penttinen, K. and Myllyla, G.: Interaction in hu man blood platelets, viruses and antibodies. I. Platelet aggregation test with microequipment. Lancet/: 1135-1137 (1970). 8 Prior, P.; Fielding, J.F.; Waterhouse, J.A., and Cooke, W.T.: Mortality in Crohn’s disease. Lancet i: 1135-1137 (1970). 9 Roitt, I.M. and Doniach, D.: in Manual on autoim mune serology, p. 13 (WHO, Geneva 1966). 10 Thayer, W.R.: Are the inflammatory bowel dis eases immune complex diseases? Gastoenterology 70: 136-137 (1976). 11 Ursing, B. and Kamme, C.: Metronidazole for Crohn’s disease. Lancet i: 775-777 (1975). 12 Verrier Jones, J.; Cumming, R.H.; Bucknall, R.C.; Asplin, C.M.; Fraser, I.D.; Bothomley, J.; Davis, P., and Hamblin, T.J.: Plasmapheresis in the manage ment of acute systemic lupus erythematosus. Lancet/: 709-711 (1976).
References
Received: November 1, 1978 Received in revised form: December 18, 1978 G.E. Holdstock, Professorial Medical Unit, Level F, Centre Block, Southampton General Hospital, Southampton, S09 4XY (England)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 11:49:54 PM
1 Brooke, B.N.; Cave, D.R., and King, D.W.: Place of azothiaprin in Crohn’s disease. Lancet /: 1041-1042 (1976). 2 Doe, W.F.; Booth, C.C., and Brown, D.L.: Evi dence for complement-binding immune complexes in adult coeliac disease, Crohn’s disease and ulcer ative colitis. Lancet /: 402-403 (1973). 3 Fiasse, R.; Lurhuma, A.Z.; Cambiaso, C.L.; Mas son, P.L., and Dive, C.: Circulating immune com plexes and disease activity in Crohn’s disease. Gut 19: 611 617 (1978).
