Scandinavian Journal of Gastroenterology. 2015; Early Online, 1–9
REVIEW
5-Aminosalicylic acid, a specific drug for ulcerative colitis
Scand J Gastroenterol Downloaded from informahealthcare.com by Wayne State University on 03/24/15 For personal use only.
ØYVIND HAUSO1,2, TOM CHRISTIAN MARTINSEN1,2 & HELGE WALDUM1,2 1
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway, and 2Department of Gastroenterology and Hepatology, St. Olavs Hospital, Trondheim, Norway
Abstract Objective. The etiology of the inflammatory bowel diseases is unknown, although genetic factors play a role, and tobacco smoking has opposite effect on the two entities. Inflammation is central in the pathogenesis, and treatment is aiming to suppress it. The active part of salazopyrin, the oldest drug in use in the treatment of ulcerative colitis, is 5-aminosalicylic acid (5-ASA). In the present paper, we wanted to discuss the etiology and pathogenesis of ulcerative colitis in relation to the beneficial effects of 5-ASA and particularly whether this compound has a specific effect on ulcerative colitis. Methods/ Results. 5-ASA seems to have a selective positive effect on ulcerative colitis in inducing remission, preventing relapse and possibly reducing the risk of cancer. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA does not have any known anti-inflammatory effect on other organs or other colonic inflammatory diseases like diverticulitis. Moreover, the effect on experimental colitis in rodents is not convincing. Conclusion. 5-ASA seems to have a specific effect on the inflammation in ulcerative colitis. Research on the mechanism of its action may give information on the etiology of ulcerative colitis. 5-ASA is a first-line treatment that should be given once daily in high doses and for long term to reduce the possibility of recurrence and risk of colonic cancer. Side effects with 5-ASA are rare, and every patient with ulcerative colitis who tolerate this drug, should be treated with 5-ASA.
Key Words: 5-aminosalicylic acid, ulcerative colitis
Inflammatory bowel diseases (IBD) (ulcerative colitis and Crohn’s disease) are debilitating diseases typically affecting young people. IBD occurs not infrequently, and since we have no causal treatment that heals the diseases, the prevalence of IBD becomes relatively high. Thus, IBD becomes important not only for the affected individuals but also for the society. Salazopyrine has been in use in the treatment of ulcerative colitis for decades [1] and its active part, 5-aminosalicylic acid (5-ASA) [2] is still the cornerstone in the treatment of this disease. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA has no general anti-inflammatory effect. We therefore found it of interest to discuss 5-ASA in relation to etiology and pathogenesis of ulcerative colitis.
Etiology and pathogenesis of ulcerative colitis The etiology of most of the chronic inflammatory diseases is unknown. In many ways, it may be stated that when the etiology is known, effective treatment will soon be developed. Also for chronic IBDs, our knowledge of the etiology is lacking, although genetic factors seem to play a role based upon previous family studies and genetic studies in recent years [3–6]. Also, tobacco smoking plays a role in IBD with a protective effect on ulcerative colitis [7] and a harmful effect in Crohns disease [7]. When we do not know the etiology, there has been a tradition to ascribe psychogenic factors a role as exemplified by peptic ulcer disease which was the prototype of a psychosomatic disease
Correspondence: Øyvind Hauso, Department of Gastroenterology and Hepatology, St. Olavs Hospital HF, postbox 3250 Sluppen, N-7006 Trondheim, Norway. E-mail: [email protected]
(Received 8 December 2014; revised 2 February 2015; accepted 9 February 2015) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2015.1018937
Scand J Gastroenterol Downloaded from informahealthcare.com by Wayne State University on 03/24/15 For personal use only.
2
O. Hauso et al.
before Helicobacter pylori (Hp) was recognized to be the cause [8]. In the recent decade, there has been a focus on the gut microbiota and its relationship to IBD [9,10]. Quantitative and necessarily qualitative changes in gut microbiota have been ascribed to play a role in the etiology of IBD. The role of Clostridium difficile in etiology of pseudomembranous colitis is perhaps the best example of how quantitative changes may cause colitis [11]. Qualitative changes may of course be at least of equal importance. It is to be stressed that we have only limited knowledge of the gut microbiome. The identification of Hp as the cause of gastritis and peptic ulcer disease [12] showed us that even in the stomach, an organ where only few types of microbes can live, an important pathogen may be overlooked for decades. In the gut with an enormous magnitude and diversity of microbes, detection of a pathogenic microbe may be much more difficult. Dysbiosis has been focused on particularly in Crohn’s disease [13], but the changes have to be assessed by caution because stenosis and motor disturbances may be expected to change the microbiome. Thus, differences from normal may be secondary and not primary phenomenons. In the upper gastrointestinal tract, there were discussions whether gastric and duodenal peptic ulcers represented one or two different diseases. We now know that they both are caused by the same agent, Hp, and that localization of the peptic ulcer depends on the localization of the infection. Even more challenging is the fact that for duodenal ulcer, the Hp infection is in the antral mucosa and not the duodenal mucosa [14]. Parallel to gastric and duodenal peptic ulcer diseases, there are similarities and differences between ulcerative colitis and Crohn’s disease, which raise the question whether IBD is one or two diseases or even represents a large group of diseases [15]. In chronic inflammatory disease without a known cause autoimmunity is often used to explain the inflammation which is the case in IBD, but also in diseases like rheumatoid arthritis and ankylosing spondylitis. From an evolutionary point of view, it seems highly unlikely that disturbance of our immune system, which is there to defend ourselves against diseases, should be such an important cause of disease. Moreover, it is hard to accept that for instance a disease like Crohn’s disease showing segmental affection can be explained by a general abnormality in the immune system. As we see it, only nerves show a segmental distribution, and we have previously suggested that Crohn’s disease was caused by viral ganglionic infection [16]. Ulcerative colitis generally always affects the rectal mucosa and shows a continuous distribution sometimes only affecting the rectum, sometimes the recto-sigmoid colon or all
the way to the splenic flexure (left-sided colitis). When the affection goes beyond the splenic flexure, we talk about total colitis, although the colitis not necessarily involves the ascending part of colon. There is a good correlation between the severity of the clinical condition and the distribution of the colitis with troublesome symptoms like bloody diarrhea, but good general health when only the rectum is affected, whereas total colitis may be a life-threatening condition. The often localized anal start and further progressive oral spread of colonic inflammation in ulcerative colitis show that there must be subtle differences in the mucosa of the rectum/colon making it more or less susceptible to ulcerative colitis. Interestingly, the border between the hind and mid gut is rather close to the splenic flexure, which is the border between left-sided and total colitis. Treatment of ulcerative colitis Although the etiology of IBD is unknown, it is agreed that inflammation plays the central role in the pathogenesis. It is therefore peculiar that non-steroid anti-inflammatory drugs (NSAIDs) by themselves may induce colitis [17] and aggravate ulcerative colitis [18]. This apparent discrepancy may perhaps be explained by prostaglandins having a special protective effect on the gastrointestinal mucosa, which exceeds the general anti-inflammatory effects of these drugs? Acetyl salicylic acid (ASA) is also an antiinflammatory drug, but it is more uncertain whether this compound is incriminated in the worsening of ulcerative colitis [19]. Glucocorticosteroids in sufficient doses can in most cases of IBD remove the inflammation and improve the condition. In ulcerative colitis, corticosteroids have been used in the acute situation for more than 50 years [20–22]. Many patients go into remission by such treatment [21], but unfortunately, the doses required to maintain remission are so high that long-term side effects preclude prolonged treatment. Cytotoxic drugs, and among them particularly azathioprine, also aiming to suppress the immune apparatus, have been used in the treatment of ulcerative colitis, but with limited effect [23–25]. During the last decades, antibodies directed against tumor necrosis factor-a (TNF-a) have been used in the treatment [26–33]. TNF-a represents a central mediator in the inflammation cascade and its neutralization by antibodies has been used with variable success in most of the chronic inflammatory diseases of unknown etiology including IBD. Among IBDs, such treatment has shown better results for Crohn’s disease to sustain a long-term remission compared with ulcerative colitis [29,31]. For both IBDs, approximately two thirds of the
5-ASA in ulcerative colitis
3
Table I. Oral 5-aminosalicylate formulations. Generic name
Proprietary name
Formulation
Sites of delivery
Mesalazine Mesalazine Mesalazine Mesalazine Olsalazine Sulfasalazine
Mezavant Asacol Salofalk Pentasa Dipentum Salazopyrin
Multi-matrix system (MMX) (release at pH ‡7.0) Eudragit-S-coated tablets (release at pH ‡7.0) Eudragit-L-coated tablets (release at pH ‡6.0) Ethylcellulose-coated microgranules (time-dependent release) 5-ASA dimer linked by azo-bond 5-ASA linked to sulfapyridine by azo-bond
Colon Terminal ileum, colon Distal ileum, colon Duodenum, jejunum, ileum, colon Colon Colon
Scand J Gastroenterol Downloaded from informahealthcare.com by Wayne State University on 03/24/15 For personal use only.
Abbreviation: 5-ASA = 5-Aminosalicylic acid.
patients respond, and there is a reduced effect with time [27,34]. As could be expected from TNF-a’s central position in the immune response, side effects and even serious side effects occur, most often related to infections [35–37]. 5-Aminosalicylic acid 5-ASA has been used in the treatment of ulcerative colitis for 70 years [1]. The discovery of 5-ASA as an effective drug in this disease is a fascinating story. In the 1930s, the first antibacterial agents, the sulfonamids, were recognized and taken into clinical use [38]. This was a breakthrough in modern medicine, and suddenly, the doctors had efficient drugs to treat common infections. With the hope that chronic inflammatory diseases like rheumatoid arthritis also could have bacterial etiology, it was started a study in Sweden with long-term treatment with sulfonamids of patients with arthritis. A sulfonamide covalently bound to ASA was constructed with the hope to combine the symptomatic effect of ASA on arthritis with a possible curative role of the sulfonamide. In order to achieve a binding site on ASA, this molecule was amidated and thus 5-ASA was created. This molecule was subsequently covalently bound to a sulfonamide leading to salazopyrine, the first drug having an effect on ulcerative colitis. Salazopyrine had no effect on rheumatoid arthritis, but among the patients studied some had arthritis secondary to ulcerative colitis, and these patients experienced improvement of their colonic symptoms. From that time, salazopyrine was recognized as an effective drug in ulcerative colitis, although the mechanism of its action was not known. With the discovery of the profound antiinflammatory effect of glucocorticosteroids, the tradition of using these agents to induce remission and then start with salazopyrine to maintain remission was established [39]. However, salazopyrine has side effects which can be severe [40,41]. With time, it was recognized that most of the side effects were related to the sulfa component. Moreover, it was established that
the therapeutic effect of salazopyrine was caused by the 5-ASA part of the molecule and that the sulfa part only prevented absorption of 5-ASA in the small intestine. 5-ASA is released from salazopyrine in the large intestine where the covalent binding is broken by enzymes from colonic bacteria [42,43]. In other words, 5-ASA has its effect on the colonic mucosa from the luminal side; it is a locally effective drug. Other ways than covalent binding to a sulfonamide for bringing 5-ASA to the colonic lumen were subsequently developed (Table I) like coating capsules with a substance resistant towards fluids with a pH below 7.0, but destructed at alkaline pH as is found in the colonic lumen [44]. A further step in that direction was achieved when a matrix of small granules with active drugs were covered with such a coat to ascertain release of active drug in the left part of colon which are most often affected, the so-called MMX technology [45]. Another, and an elegant, approach was to bind two 5-ASA molecules covalently to each other [46]. With colitis only affecting the rectum, hemorrhagic proctitis, anal application of 5-ASA is the best option [47,48]. Even when the colitis is affecting a larger part of the colon/rectum, local treatment can be valuable to reduce symptoms like bleeding and diarrhea. From a theoretical point of view, it may be feared that only local application will not protect against the natural course of the disease and the potential spread in oral direction of the inflammation 5-ASA has also been used in Crohn’s disease, but its effect in this condition is much more disputed [49–51] which is to be expected, taking into consideration that in Crohn’s disease the inflammation is not confined to the mucosa as seen in ulcerative colitis, but affects the whole thickness of the gut wall. A drug acting locally from the luminal side would not be expected to penetrate into the deeper layers of the gut wall. 5-ASA efficacy 5-ASA has effect in >70% of patients and induces remission
REVIEW
5-Aminosalicylic acid, a specific drug for ulcerative colitis
Scand J Gastroenterol Downloaded from informahealthcare.com by Wayne State University on 03/24/15 For personal use only.
ØYVIND HAUSO1,2, TOM CHRISTIAN MARTINSEN1,2 & HELGE WALDUM1,2 1
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway, and 2Department of Gastroenterology and Hepatology, St. Olavs Hospital, Trondheim, Norway
Abstract Objective. The etiology of the inflammatory bowel diseases is unknown, although genetic factors play a role, and tobacco smoking has opposite effect on the two entities. Inflammation is central in the pathogenesis, and treatment is aiming to suppress it. The active part of salazopyrin, the oldest drug in use in the treatment of ulcerative colitis, is 5-aminosalicylic acid (5-ASA). In the present paper, we wanted to discuss the etiology and pathogenesis of ulcerative colitis in relation to the beneficial effects of 5-ASA and particularly whether this compound has a specific effect on ulcerative colitis. Methods/ Results. 5-ASA seems to have a selective positive effect on ulcerative colitis in inducing remission, preventing relapse and possibly reducing the risk of cancer. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA does not have any known anti-inflammatory effect on other organs or other colonic inflammatory diseases like diverticulitis. Moreover, the effect on experimental colitis in rodents is not convincing. Conclusion. 5-ASA seems to have a specific effect on the inflammation in ulcerative colitis. Research on the mechanism of its action may give information on the etiology of ulcerative colitis. 5-ASA is a first-line treatment that should be given once daily in high doses and for long term to reduce the possibility of recurrence and risk of colonic cancer. Side effects with 5-ASA are rare, and every patient with ulcerative colitis who tolerate this drug, should be treated with 5-ASA.
Key Words: 5-aminosalicylic acid, ulcerative colitis
Inflammatory bowel diseases (IBD) (ulcerative colitis and Crohn’s disease) are debilitating diseases typically affecting young people. IBD occurs not infrequently, and since we have no causal treatment that heals the diseases, the prevalence of IBD becomes relatively high. Thus, IBD becomes important not only for the affected individuals but also for the society. Salazopyrine has been in use in the treatment of ulcerative colitis for decades [1] and its active part, 5-aminosalicylic acid (5-ASA) [2] is still the cornerstone in the treatment of this disease. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA has no general anti-inflammatory effect. We therefore found it of interest to discuss 5-ASA in relation to etiology and pathogenesis of ulcerative colitis.
Etiology and pathogenesis of ulcerative colitis The etiology of most of the chronic inflammatory diseases is unknown. In many ways, it may be stated that when the etiology is known, effective treatment will soon be developed. Also for chronic IBDs, our knowledge of the etiology is lacking, although genetic factors seem to play a role based upon previous family studies and genetic studies in recent years [3–6]. Also, tobacco smoking plays a role in IBD with a protective effect on ulcerative colitis [7] and a harmful effect in Crohns disease [7]. When we do not know the etiology, there has been a tradition to ascribe psychogenic factors a role as exemplified by peptic ulcer disease which was the prototype of a psychosomatic disease
Correspondence: Øyvind Hauso, Department of Gastroenterology and Hepatology, St. Olavs Hospital HF, postbox 3250 Sluppen, N-7006 Trondheim, Norway. E-mail: [email protected]
(Received 8 December 2014; revised 2 February 2015; accepted 9 February 2015) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2015.1018937
Scand J Gastroenterol Downloaded from informahealthcare.com by Wayne State University on 03/24/15 For personal use only.
2
O. Hauso et al.
before Helicobacter pylori (Hp) was recognized to be the cause [8]. In the recent decade, there has been a focus on the gut microbiota and its relationship to IBD [9,10]. Quantitative and necessarily qualitative changes in gut microbiota have been ascribed to play a role in the etiology of IBD. The role of Clostridium difficile in etiology of pseudomembranous colitis is perhaps the best example of how quantitative changes may cause colitis [11]. Qualitative changes may of course be at least of equal importance. It is to be stressed that we have only limited knowledge of the gut microbiome. The identification of Hp as the cause of gastritis and peptic ulcer disease [12] showed us that even in the stomach, an organ where only few types of microbes can live, an important pathogen may be overlooked for decades. In the gut with an enormous magnitude and diversity of microbes, detection of a pathogenic microbe may be much more difficult. Dysbiosis has been focused on particularly in Crohn’s disease [13], but the changes have to be assessed by caution because stenosis and motor disturbances may be expected to change the microbiome. Thus, differences from normal may be secondary and not primary phenomenons. In the upper gastrointestinal tract, there were discussions whether gastric and duodenal peptic ulcers represented one or two different diseases. We now know that they both are caused by the same agent, Hp, and that localization of the peptic ulcer depends on the localization of the infection. Even more challenging is the fact that for duodenal ulcer, the Hp infection is in the antral mucosa and not the duodenal mucosa [14]. Parallel to gastric and duodenal peptic ulcer diseases, there are similarities and differences between ulcerative colitis and Crohn’s disease, which raise the question whether IBD is one or two diseases or even represents a large group of diseases [15]. In chronic inflammatory disease without a known cause autoimmunity is often used to explain the inflammation which is the case in IBD, but also in diseases like rheumatoid arthritis and ankylosing spondylitis. From an evolutionary point of view, it seems highly unlikely that disturbance of our immune system, which is there to defend ourselves against diseases, should be such an important cause of disease. Moreover, it is hard to accept that for instance a disease like Crohn’s disease showing segmental affection can be explained by a general abnormality in the immune system. As we see it, only nerves show a segmental distribution, and we have previously suggested that Crohn’s disease was caused by viral ganglionic infection [16]. Ulcerative colitis generally always affects the rectal mucosa and shows a continuous distribution sometimes only affecting the rectum, sometimes the recto-sigmoid colon or all
the way to the splenic flexure (left-sided colitis). When the affection goes beyond the splenic flexure, we talk about total colitis, although the colitis not necessarily involves the ascending part of colon. There is a good correlation between the severity of the clinical condition and the distribution of the colitis with troublesome symptoms like bloody diarrhea, but good general health when only the rectum is affected, whereas total colitis may be a life-threatening condition. The often localized anal start and further progressive oral spread of colonic inflammation in ulcerative colitis show that there must be subtle differences in the mucosa of the rectum/colon making it more or less susceptible to ulcerative colitis. Interestingly, the border between the hind and mid gut is rather close to the splenic flexure, which is the border between left-sided and total colitis. Treatment of ulcerative colitis Although the etiology of IBD is unknown, it is agreed that inflammation plays the central role in the pathogenesis. It is therefore peculiar that non-steroid anti-inflammatory drugs (NSAIDs) by themselves may induce colitis [17] and aggravate ulcerative colitis [18]. This apparent discrepancy may perhaps be explained by prostaglandins having a special protective effect on the gastrointestinal mucosa, which exceeds the general anti-inflammatory effects of these drugs? Acetyl salicylic acid (ASA) is also an antiinflammatory drug, but it is more uncertain whether this compound is incriminated in the worsening of ulcerative colitis [19]. Glucocorticosteroids in sufficient doses can in most cases of IBD remove the inflammation and improve the condition. In ulcerative colitis, corticosteroids have been used in the acute situation for more than 50 years [20–22]. Many patients go into remission by such treatment [21], but unfortunately, the doses required to maintain remission are so high that long-term side effects preclude prolonged treatment. Cytotoxic drugs, and among them particularly azathioprine, also aiming to suppress the immune apparatus, have been used in the treatment of ulcerative colitis, but with limited effect [23–25]. During the last decades, antibodies directed against tumor necrosis factor-a (TNF-a) have been used in the treatment [26–33]. TNF-a represents a central mediator in the inflammation cascade and its neutralization by antibodies has been used with variable success in most of the chronic inflammatory diseases of unknown etiology including IBD. Among IBDs, such treatment has shown better results for Crohn’s disease to sustain a long-term remission compared with ulcerative colitis [29,31]. For both IBDs, approximately two thirds of the
5-ASA in ulcerative colitis
3
Table I. Oral 5-aminosalicylate formulations. Generic name
Proprietary name
Formulation
Sites of delivery
Mesalazine Mesalazine Mesalazine Mesalazine Olsalazine Sulfasalazine
Mezavant Asacol Salofalk Pentasa Dipentum Salazopyrin
Multi-matrix system (MMX) (release at pH ‡7.0) Eudragit-S-coated tablets (release at pH ‡7.0) Eudragit-L-coated tablets (release at pH ‡6.0) Ethylcellulose-coated microgranules (time-dependent release) 5-ASA dimer linked by azo-bond 5-ASA linked to sulfapyridine by azo-bond
Colon Terminal ileum, colon Distal ileum, colon Duodenum, jejunum, ileum, colon Colon Colon
Scand J Gastroenterol Downloaded from informahealthcare.com by Wayne State University on 03/24/15 For personal use only.
Abbreviation: 5-ASA = 5-Aminosalicylic acid.
patients respond, and there is a reduced effect with time [27,34]. As could be expected from TNF-a’s central position in the immune response, side effects and even serious side effects occur, most often related to infections [35–37]. 5-Aminosalicylic acid 5-ASA has been used in the treatment of ulcerative colitis for 70 years [1]. The discovery of 5-ASA as an effective drug in this disease is a fascinating story. In the 1930s, the first antibacterial agents, the sulfonamids, were recognized and taken into clinical use [38]. This was a breakthrough in modern medicine, and suddenly, the doctors had efficient drugs to treat common infections. With the hope that chronic inflammatory diseases like rheumatoid arthritis also could have bacterial etiology, it was started a study in Sweden with long-term treatment with sulfonamids of patients with arthritis. A sulfonamide covalently bound to ASA was constructed with the hope to combine the symptomatic effect of ASA on arthritis with a possible curative role of the sulfonamide. In order to achieve a binding site on ASA, this molecule was amidated and thus 5-ASA was created. This molecule was subsequently covalently bound to a sulfonamide leading to salazopyrine, the first drug having an effect on ulcerative colitis. Salazopyrine had no effect on rheumatoid arthritis, but among the patients studied some had arthritis secondary to ulcerative colitis, and these patients experienced improvement of their colonic symptoms. From that time, salazopyrine was recognized as an effective drug in ulcerative colitis, although the mechanism of its action was not known. With the discovery of the profound antiinflammatory effect of glucocorticosteroids, the tradition of using these agents to induce remission and then start with salazopyrine to maintain remission was established [39]. However, salazopyrine has side effects which can be severe [40,41]. With time, it was recognized that most of the side effects were related to the sulfa component. Moreover, it was established that
the therapeutic effect of salazopyrine was caused by the 5-ASA part of the molecule and that the sulfa part only prevented absorption of 5-ASA in the small intestine. 5-ASA is released from salazopyrine in the large intestine where the covalent binding is broken by enzymes from colonic bacteria [42,43]. In other words, 5-ASA has its effect on the colonic mucosa from the luminal side; it is a locally effective drug. Other ways than covalent binding to a sulfonamide for bringing 5-ASA to the colonic lumen were subsequently developed (Table I) like coating capsules with a substance resistant towards fluids with a pH below 7.0, but destructed at alkaline pH as is found in the colonic lumen [44]. A further step in that direction was achieved when a matrix of small granules with active drugs were covered with such a coat to ascertain release of active drug in the left part of colon which are most often affected, the so-called MMX technology [45]. Another, and an elegant, approach was to bind two 5-ASA molecules covalently to each other [46]. With colitis only affecting the rectum, hemorrhagic proctitis, anal application of 5-ASA is the best option [47,48]. Even when the colitis is affecting a larger part of the colon/rectum, local treatment can be valuable to reduce symptoms like bleeding and diarrhea. From a theoretical point of view, it may be feared that only local application will not protect against the natural course of the disease and the potential spread in oral direction of the inflammation 5-ASA has also been used in Crohn’s disease, but its effect in this condition is much more disputed [49–51] which is to be expected, taking into consideration that in Crohn’s disease the inflammation is not confined to the mucosa as seen in ulcerative colitis, but affects the whole thickness of the gut wall. A drug acting locally from the luminal side would not be expected to penetrate into the deeper layers of the gut wall. 5-ASA efficacy 5-ASA has effect in >70% of patients and induces remission
