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Evolution of the Concept of Proctosigmoiditis: Clinical Observation
Inflammatory Bowel Disease
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Evolution of the Concept of Proctosigmoiditis: Clinical Observation
Richard G. Farmer, MD, FACP*
Although ulcerative colitis has been known as a clinical and pathological entity for over a century, it has only been in the past 50 years or so that a localized distal form of the disease was recognized. Distal colitis was initially thought to be a different condition than ulcerative colitis and there was confusion in terminology used, with "hemorrhagic proctitis" probably being the most common term applied to the condition. 48 The characteristics of distal colon colitis were similar to universal ulcerative colitis, with rectal bleeding as the predominant manifestation, but the condition remained localized and the prognosis appeared to be much better than for patients with universal colitis. Although attempts were made to identify a bacterial cause for ulcerative colitis in the 1930s, these were unsuccessful, and likewise the consideration that there was a parasitic cause also proved unfounded. However, confusion as to whether or not the localized form of distal colitis represented an entity different from universal ulcerative colitis made data collection and long-term follow-up difficult, as well as assessment of therapy. In the 1950s it became apparent, particularly through the work of Truelove,49 that hydrocortisone enemas were beneficial as treatment for patients with the distal colon form of ulcerative colitis, whether proctitis (inflammation limited to the rectal mucosa) or proctosigmoiditis (inflammation involving the rectum and sigmoid colon). As steroid enemas became available they were utilized, and there were anecdotal, uncontrolled observations purporting therapeutic effectiveness of topical steroids. However, the almost complete lack of objectivity in clinical design was a significant deterrent to widespread scientific acceptance of these findings, and it was *Chairman, Division of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
Medical Clinics of North America-Vo\. 74, No. 1, January 1990
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difficult to assess therapeutic results and to predict clinical responsiveness to specific regimens. To confuse the situation further, in the 1960s it became recognized that Crohn's disease could affect the large intestine exclusively. It was further noted that Crohn's disease could also be localized to the distallarge boweP9 and/or the anorectum. 52 Crohn's disease, however, did not result in a form of proctitis similar to that observed among patients with ulcerative colitis, and the distinction from Crohn's disease and the recognition of ulcerative proctitis or proctosigmoiditis as a distinct clinical entity developed. lI . 18. 27. 45 Thus, the proctitis form of inflammatory bowel disease has remained in the ulcerative colitis category rather than being associated with Crohn's disease. Furthermore, it was extremely rare that there were any perianal manifestations and, when present, represented only minor fissures and almost never the perianal fistulae and abscesses characteristic of anorectal Crohn's disease. Nevertheless, the problem of definition of the condition as an entity remained, particularly with the difficulty of assessing the proximal limit of the inflammatory process. Since barium enema was the only mode of assessing the colon proximal to the extent visualized by the rigid sigmoidoscope, the definition of proctitis or proctosigmoiditis was therefore dependent on an abnormal sigmoidoscopic examination with a radiographically normal colon proximal to the rectosigmoid on barium enema. 11. 13. 16. 18. 19. 25, 28. 44, 45 There were repeated observations that the visualized mucosa in patients with the limited form of the inflammatory process was identical to that of mucosa in those whose disease extended throughout the entire large intestine, 13. 27. 34. 45 and likewise biopsies did not differentiate the two conditions. 10, 19, 46 Therefore, the concept that there was a distal colon form of ulcerative colitis became increasing apparent clinically, and there were attempts to follow patients for a longer period of time than simply in the observation or diagnostic phase, to determine if possible the prognosis and the degree of extent of disease that might occur during the course of the inflammatory process. 11, 14. 31, 34. 35 All of this was significantly complicated by the apparent spontaneous remissions and subsequent exacerbations that made assessments of therapeutic effectiveness, extent of disease, and prognosis difficult. In the 1960s there were attempts to define both proctitis and proctosigmoiditis, and it was thought important that these conditions be differentiated. In 1966,11 we reported our experience with ulcerative proctitis being a clearly visualized upper limit of the inflammation of the mucosa seen on rigid sigmoidoscopic examination as well as a normal barium enema. The inflammatory process was truly proctitis in these patients, with inflammation extending approximately 15 cm proximal to the dentate line, and inevitably beginning at the dentate line. The mucosa was diffusely friable with fine ulceration, and involvement was almost always uniform with little variability in one area or another and touch friability present almost throughout the inflamed mucosa. Discrete ulceration, mucosal thickening, strictures, and perianal lesions were almost always absent. Occasionally, pseudopolyps appeared, and in longstanding cases there was visual evidence of mucosal atrophy. When the rectal mucosa was biopsied
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in inflamed areas, there was diffuse inflammation with leukocyte infiltration, usually polymorphonuclear leukocytes, crypt abscesses, loss of goblet cells, and distorted architecture of the mucosa. H . 13.27.34.45.46 Biopsies sometimes revealed abnormalities in visually normal mucosa proximal to the visual line of demarcation, but the significance of these findings was somewhat controversial, particularly if one attempted to correlate the pathologic findings with prognosis. 10. 15. 19 Therefore, the visual appearance of the mucosa was most often used by clinicians for assessment of the activity of the disease and, therefore, of therapeutic responsiveness. 36 This, of course, compounded the scientific difficulty for measuring therapeutic effectiveness. In the instances in which a clear upper limit could not be visualized and the mucosa appeared inflamed (as far as one could examine with the rigid sigmoidoscope) generally between 15 and 25 cm proximal to the dentate line, the term "proctosigmoiditis" was used. The implication was that this might have a greater propensity for extension or might represent diffuse mucosal disease throughout the entire colon that could not be observed on barium enema because the changes were too subtle. 13. 14. 25. 34. 44 Despite the clinical and scientific limitations noted, there were observations that the incidence or frequency of the distal colon form of ulcerative colitis appeared to be increasing when the total number of cases of ulcerative colitis appeared to be decreasing, particularly in relation to a number of patients diagnosed with Crohn's disease. 5. 6. 33. 43 The concept that distal colon inflammation actually represented "mild" ulcerative colitis,45 and should therefore be defined on the basis of clinical severity rather than extent of disease became popular. There were several reasonably long-term follow-up studies that clearly indicated that the long-term prognosis for patients with distal colon ulcerative colitis, proctitis, or proctosigmoiditis was considerably better than for patients with total colon ulcerative colitis, and that extension of disease to involve the entire colon occurred in about 10 per cent of cases. H. 14. 18.31.34.35.40 When extension of the disease occurred, it usually did so relatively early in the course of the disease, usually about 2 years, and rarely after 5 years. 14 However, the problem of remission and exacerbation continued, and patients with ulcerative proctitis or proctosigmoiditis visited physicians relatively more often than had been anticipated, in view of the relative lack of severity of the condition. In addition, there was often much anxiety expressed by the patient because of fear of cancer or rectal bleeding. In the experience at a referral center, it was remarkable how often patients came for second opinions because of a conflict with the treating physician either on the basis of inability to control the rectal bleeding and to prevent further recurrences, and the fear of extended disease, severe disease, need for surgery (with stoma), or cancer. Our own studies during the 1960s and 1970s13. 14 emphasized the difficulty of determining exactly the distinction between proctitis and proctosigmoiditis, but did observe the extension rate of about 10 per cent, similar to observations by others,27. 34 the unpredictability of exacerbations and remissions, the difficulty in therapeutic assessment, the relative rarity of other symptoms (extra-intestinal manifestations and systemic features), and the relatively good long-term prognosis. Significantly influenced by the work of Truelove in England and by
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Brown and Turnbull at the Cleveland Clinic, we embarked on therapeutic trials in the mid-1960s using hydrocortisone enemas consisting of 100 mg of hydrocortisone in a vehicle of60 ml. l2 Brown and Turnbull had previously worked together since the late 1940s, and Turnbull had pioneered the Brooke ileostomy in the United States in the 1950s. Together, they observed a large number of patients and had extensive personal experience dealing with patients with inflammatory bowel disease. Since many of these patients were referred, there were more complicated or unusual cases and those seemingly refractory to therapy. Brown and Turnbull used a large number of therapeutic measures including sulfasalazine enemas, methylprednisolone enemas, neomycin-hydrocortisone suppositories, and systemic steroids including both oral prednisone and adrenocorticotropic hormone (ACTH)releasing factor. In the early 1960s, in refractory cases of inflammatory bowel disease, they utilized nitrogen mustard, which was a forerunner to modern day immunosuppressive therapy. In attempting to evaluate the therapeutic effectiveness of hydrocortisone enemas for patients with distal colon ulcerative colitis, the problems mentioned were assessed and a prospective clinical trial was established that evolved into the use of hydrocortisone enemas once daily on a nightly basis for a 3-week period, with a "rest" period of 1 week and another 3week course of treatment if necessary. 12 Studies were done to assess adrenal suppression and/or responsiveness, and clinical observations were made as to therapeutic effectiveness based on: (1) decrease in the amount of rectal bleeding observed by the patient, and (2) visual improvement in the rectal mucosa as seen by sigmoidoscopy, with decrease in the degree of friability, its extent, and lessening of fine mucosal ulceration. Systemic steroid measurements were obtained, which indicated that approximately one third of the steroid enema was absorbed but that adrenal responsiveness remained intact in the majority of cases and that there was no therapeutic risk to the use of the hydrocortisone enemas. Improvement in symptoms and resolution of the abnormalities of the rectum mucosa occurred so that the effect topically appeared to be confirmed. Nevertheless, it was extremely difficult to assess all factors scientifically and objectively. This problem plagued not only our studies but those of others, 34 and is undoubtedly one of the major reasons why, despite the relative frequency of the condition, there has been a relative dearth of scientific and clinical publications studying specific therapeutic responsiveness to topical steroids until recently. 50 In our follow-up study 10 years ago,14 we found once again that the prognosis for 90 per cent of patients was good despite a high rate of recurrence, but that the 10 per cent who extended did so in a clinically aggressive manner and frequently required operation because of severity of inflammation; when extension occurred, it usually did so within 2 years after original diagnosis. Prior to the development of colonoscopy as a diagnostic tool, the rapid extension of inflammation was often thought to have represented subtle mucosal changes throughout the entire large intestine which were undetectable by barium enema. We performed a study of 100 consecutive patients 15 observed in the late 1970s who were thought to have distal colon ulcerative colitis. We found that about 40 per cent had changes proximal
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to the area in which the inflammation had been thought to be confined. However, in most cases, the inflammation did not extend proximal to the splenic flexure and therefore represented what has subsequently been referred to as "left-sided" colitis. 22 Assessment of the clinical course of these patients indicated that there was not much variance from those with distal colon ulcerative colitis and the course was significantly milder than that of patients with total colon colitis. Attempts have been made to correlate the appearances and other measures of disease activity by means of endoscopy and colonscopy.36, 37 Therefore, in the past decade, there has emerged a clinical concept of a tripartite form of idiopathic colonic inflammation, usually referred to as ulcerative colitis. Patients who have ulcerative proctitis and proctosigmoiditis can usually be differentiated fairly readily, both clinically and endoscopically, from those patients who have ulcerative pancolitis. There is a group "in between" that is now referred to as "leftsided colitis" in which the inflammatory changes extend approximately to the level of the splenic flexure. Both clinically and prognostically, these patients appear to lie between the severity of patients with pancolitis and the relatively benign clinical course of those with proctitis or proctosigmoiditis. 37 There has been a significant change in the clinical pattern of patients with ulcerative colitis in the past 20 to 30 years, with a substantial increase in the number of cases of distal colon disease (and therefore a milder clinical course) and a relative decrease in the number of cases of ulcerative pancolitis with its relatively more severe clinical course. In a recent epidemiologic study by Shivananda et al 43 in the Netherlands, 42 per cent of patients were found to have the distal colon form of the disease and only 11 per cent had pan colitis at the time of diagnosis. As an additional clinical observation, in the 1950s or 1960s at a referral center, one would find four to six times the number of cases of ulcerative colitis hospitalized versus patients with Crohn's disease (then usually called regional enteritis). Exactly the opposite occurred in the 1980s with the vast majority of patients hospitalized because of complications of their inflammatory bowel disease being those with Crohn's disease, A factor of considerable significance in the long-term prognosis for patients with ulcerative colitis is the potential for cancer. The ability to perform sequential mucosal biopsies and the recognition that dysplasia may be precancerous has considerably altered the prognostic evaluation of such patients in recent years. The relative frequency of cancer in ulcerative colitis as well as dysplasia have both correlated with the anatomic distribution of disease. 22, 30 In the experience at the Cleveland Clinic,30 fewer than 10 per cent of patients with ulcerative colitis have been found to have dysplasia on surveillance colonoscopy, and the vast majority of those with dysplasia are patients with ulcerative pancolitis. In our experience, the development of cancer of the large intestine among patients with ulcerative colitis is greatest among patients with pancolitis, and is Significantly higher than the general population. For patients who develop cancer in conjunction with ulcerative pancolitis, the mean duration in the Cleveland Clinic experience from onset of colitis to diagnosis of cancer is 18 years. For patients with left-sided colitis, the incidence of dysplasia is much less, the
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incidence of cancer is less, and the duration from the onset of colitis to the diagnosis of cancer is a mean of 22 years. There has not been an increased incidence of either dysplasia or cancer for patients with proctitis or proctosigmoiditis over the general population, in our experience. 30 In our recent study of proctosigmoiditis in children,29 we observed that the prognosis was not as favorable as for patients who are adults at the time of onset of the proctitis or proctosigmoiditis. Approximately one third of the patients with childhood onset appear to have a much more chronic course, frequent exacerbations, and extension of disease. Gryboski 23 has also made a similar observation, but it is difficult to determine whether age alone is a factor in the clinical significance of the inflammation. However, as a clinical ohservation, proctitis or proctosigmoidits in children and young adults appears to be more clinically significant than in older patients. Conversely, patients over the age of 40 often have a fairly benign course when affiicted with proctitis or proctosigmoiditis,8, 53 and there has been no evidence that ischemic colitis was present even in very old patients with proctitis or proctosigmoiditis. Furthermore, it has been observed that patients with distal colon colitis are often older than the typical young adult group of patients with ulcerative pancolitis, and the prognosis often relates to other clinical problems experienced by the patient rather than the colitis itself. 8, 53 Although rare, distal ulcerative colitis may occasionally result in toxic megacolon,24 and operation may be necessary.14 In addition, even without extension of disease, distal colon ulcerative colitis may be severe enough to warrant removal of the distal colon only, although that circumstance is likewise rare. 32 There have recently been attempts to use physiologic techniques to study patients with ulcerative proctitis in order to determine prognostic factors. Transit time in the large bowel has been utilized by Black and coworkers 4 who found a delay in the transit time of patients with active disease from 50 hours in controls to over 70 hours in those with active disease, and over 80 hours for those with inactive proctitis. However, physiologic measurements to assess prognosis have yet to be established. An interesting recent observation was that of a condition referred to as "lymphoid follicular proctitis. "17 This was observed in a group of patients with clinical features suggestive of inflammatory bowel disease confined to the rectum whose rectal biopsies showed lymphoid follicular hyperplasia. About half of the patients appeared to be quite similar clinically to distal colon ulcerative colitis, but the others did not. This observation raises yet another intriguing bit of evidence concerning the nature of inflammation in the distal colon and its relative specificity. There has been a considerable renaissance in interest in recent years relating to infectious causes of colitis, often with clinical and endoscopic characteristics similar to those found in ulcerative proctitis or proctosigmoiditis. In the mid-1970s and subsequently, there were dramatic changes in the understanding of certain infectious diarrheas-including traveler's diarrhea, antibiotic-associated diarrhea, and Campylobacter colitis. This interest has been greatly intensified because of the gastrointestinal manifestations of patients with the acquired immunodeficiency syndrome (AIDS),
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although the clinical appearance of the rectal or colonic mucosa in patients with AIDS more closely resembles Crohn's disease than it does ulcerative colitis and the severity of the illness with its attendant systemic features is much greater than that usually seen in patients with ulcerative proctitis or proctosigmoiditis. However, there has been a remarkable increase in the recognition of types of distal colon inflammation found in homosexual males, with or without AIDS. Most of these clinical conditions have been a form of acute proctitis frequently with significant rectal pain as well as small volume stools, diarrhea, and tenesmus. Andrews et aP studied 50 male patients with proctitis and compared the findings with a similar number of male homosexuals attending a clinic at the same hospital. For patients with proctitis who were homosexual, there was typically a short history of bowel symptoms, minor sigmoidoscopic and histologic changes, and positive serological markers of sexually transmitted infection. They found three patients with inflammatory bowel disease who were homosexual, and cultures were positive for cryptosporidium and cytomegalovirus. These authors concluded that patients with inflammatory bowel disease who are homosexual may have a coexisting form of sexually transmitted proctitis as well as a flare of the colitis. In another study of 388 homosexual or bisexual patients,26 assessment of the "gay bowel syndrome" was performed. There were 68 patients with proctitis and Campylobacter species was the most common organism found. Others included herpes simplex virus and Neisseria gonorrhoeae, Giardia lamblia, and Shigella species. There has been recognition of the spectrum of the "gay bowel syndrome" for the last several years 38 with a great variety of clinical features and organisms observed. An empirical therapeutic program for the management of acute proctitis in homosexual men has recently been advocated41 as a result of a randomized trial of 129 homosexual men who presented with acute proctitis. The empirical regimen of 4.8 million units of aqueous penicillin G procaine intramuscularly and 1.0 g of probenecid orally, followed by 100 mg of oral doxycycline twice-daily for 7 days was beneficial for the majority of cases. This response would certainly be beneficial in the clinical distinction from ulcerative proctitis or proctosigmoiditis. The sigmoidoscopic characteristics reported in sexually transmitted proctitis have not been typical for patients with ulcerative colitis and have included mucoid purulent exudate, ulcerations, erosions, and vesicles, 41 in contrast to the characteristic mucosal changes in ulcerative proctitis. Another condition sometimes confused with ulcerative proctitis is infection caused by Clostridium difficile. 20 While there typically is a history of antibiotic use within the 8 weeks prior to onset of diarrhea, this history can sometimes be confusing or nonspecific. Sigmoidoscopy may be somewhat nonspecific unless, of course, the highly characteristic pseudomembrane is visible. However, the mucosa generally does not have the visual characteristics associated with ulcerative proctitis. Although the recent interest in infectious diarrhea has been stimulated by studies in homosexual men, proctitis may occur as a result of infection with salmonella, shigella, and campylobacter organisms. Salmonellosis is generally not associated with mucosal friability and can usually be differentiated. Shigellosis may have severe mucosal friability, and there also may
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be a severe systemic reaction associated with the bacterial infection. However, it has been Campylobacter colitis that has been most frequently confused with ulcerative colitis in the recent past and it is certainly necessary to exclude Campylobacter colitis by means of stool culture in a patient with a new onset of suspected proctitis or proctosigmoiditis. One of the important clinical differential features favoring ulcerative colitis is the persistence of the inflammation, the relative resistance to antibiotic therapy, and the tendency for exacerbations as well as having negative stool cultures. It has been increasingly recognized that radiation proctitis may closely mimic the clinical and endoscopic features of ulcerative proctitis. An additional characteristic is frequent therapeutic refractoriness creating a significant clinical problem. A recent study2 of 1418 patients treated with radiation for carcinoma of the uterus found 4.3 per cent (61 patients) to have developed significant radiation induced complications of the intestine, of which 93 per cent involved the rectum. About one third of the cases of proctitis resolved within 2 years of onset but surgery was necessary for 39 per cent of patients, often a difficult clinical decision in a patient with a history of or evidence for carcinoma. Another studyl utilized laser therapy for patients with severe radiation injury resulting in proctosigmoiditis. It has also been known for some time that proctitis can occur following diversion of the fecal stream, as with colostomy.21 However, both radiation proctitis and diversion colitis can generally be distinguished from ulcerative colitis or proctitis on clinical and endoscopic grounds. Previously, there had been a substantial increase in scientific activity relating to the treatment of ulcerative proctitis, particularly in the use of topical agents. In 1980, Ruddell and colleagues 42 reported on a comparative study of hydrocortisone enemas and rectal hydrocortisone foam with relatively positive findings for each type of agent. A recent study compared beclomethasone dipropionate and prednisolone 21-phosphate enemas 50 that showed a more favorable response with the latter but less adrenal suppression with the former. Because of concern over both therapeutic efficacy and adrenal suppression with topical steroids, as well as development of 5-amjnosalicyclic acid topical preparations, recent interest has focused on the study of these agents, with the pioneering work of Campierj1 indicating clinical efficacy and spurring other clinical trials. Sutherland et al,47 in a multicenter clinical trial, assessed 5-aminosalicyclic acid enemas in the treatment of distal colon ulcerative colitis and used a 4-g dosage for ulcerative colitis involving up to 50 cm of distal colon in 153 patients (76 received active medication and 77 received a placebo). After 6 weeks of therapy, 63 per cent receiving the 5-aminosalicyclic acid were improved in comparison with only 29 per cent of those patients on placebo. A disease activity index based on patients' symptoms and sigmoidoscopic appearance was used to assess efficacy. 36 Rapid onset of efficacy was shown by significant reduction in rectal bleeding within 3 days of beginning treatment. A Danish study9 compared topical 5-aminosalicyclic acid versus prednisolone in ulcerative proctosigmoiditis with a randomized double-blind multicenter trial of 1000 mg of 5-aminosalicyclic acid compared with 25 mg of prednisolone, both administered rectally. There were 123 patients in the
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study; after 14 days, patients in total remission discontinued treatment while the others were treated for another 2-week period. Improvement or remission was seen in 77 per cent of the 5-aminosalicyclic acid-treated patients and in 72 per cent of the prednisolone-treated patients. These authors concluded that 5-aminosalicyclic acid is at least as efficient as prednisolone for topical treatment of patients with moderately active proctosigmoiditis. 9 Williams and colleagues51 treated proctitis with 5-aminosalicyclic acid suppositories (500 mg three times daily) or placebo for 6 weeks. They assessed activity using a disease activity index derived from four categories: (1) number of bowel movements per day; (2) bloody diarrhea; (3) sigmoidoscopic appearance; and (4) overall assessment. For patients treated with the active medication, there was a 78 per cent remission rate at 6 weeks and no significant change in the placebo group. It is interesting that six of their patients and six controls were given 99mTc-Iabeled 5-aminosalicyclic acid suppositories that showed that the extent of topical spread from the suppository was limited to the rectum and the suppositories were retained for 3 hours with no absorbed radioactivity. Thus, these authors concluded that 5-aminosalicyclic acid suppositories are therapeutically beneficial for patients with proctitis. Although all of these recent studies are short-term, they follow the pattern established in the past in studying the effects of steroid enemas or suppositories, and appear to be of potentially significant benefit for patients with distal colon ulcerative colitis. There have been many observations to indicate that the number of patients with proctitis, proctosigmoiditis, or distal colon colitis has steadily increased, while the number of patients with ulcerative pancolitis has decreased: thus, the latter, more severe form of the disease currently occurs in fewer than 50 per cent of cases overall. 5, 6, 43 This has created the "impression" that ulcerative colitis has become "milder," and may perhaps lead to less surveillance than is indicated in view of the potential for cancer developing in patients with pancolitis. For patients with proctitis, the primary clinical problem is recurrence and the difficulty to predict or prevent recurrences by either clinical assessment or therapeutic manipulation. The use of topical steroids, sulfasalazine and related agents, and other forms of therapy does not seem to alter the "natural history" of proctitis, although it is a common clinical observation that after a period of approximately 10 to 15 years the inflammation appears to "burn out," making therapeutic assessment in the long term even more difficult. There are many reasons why the study of patients with distal colon ulcerative colitis is worthwhile and clinical observations are of value. The relative frequency of the condition, its unpredictable nature, the unpleasant symptoms for the patient, the difficulty of therapeutic responsiveness, and the overriding fear of worsening of the condition or progression to cancer all make the condition of distal colon ulcerative colitis, whether proctitis or proctosigmoiditis, a relatively frequent and relatively "severe" form of a relatively "benign" disease. However, it is only by careful clinical observation, compilation of data over a long period of time, and meticulous follow-up of such patients and their clinical, endoscopic, and therapeutic
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characteristics that further understanding of this enigmatic condition will occur.
REFERENCES 1. Alexander TJ, Dwyer RM: Endoscopic Nd:YAG laser treatment of severe radiation injury of the lower gastrointestinal tract: Long-term follow-up. Gastrointest Endosc 34:407, 1988 2. Allen-Mersh TG, Wilson EJ, Hope-Stone HF, et al: The management of late radiationinduced rectal injury after treatment of carcinoma of the uterus. Surg Gynecol Obstet 164:521, 1987 3. Andrews H, Wike J, Lane M, et al: Prevalence of sexually transmitted disease among male patients presenting with proctitis. Gut 29:332, 1988 4. Black DA, Ainley CC, Senapapapi A: Transit time in ulcerative proctitis. Scand J Gastroenterol 22:872, 1987 5. Both H, Torp-Pederson K, Kreiner S, et al: Clinical appearance at diagnosis of ulcerative colitis and Crohn's disease in a regional patient group. Scand J Gastroenterol 18:987, 1983 6. Calkins BM, Lilienfeld AM, Garland CF, et al: Trends in incidence rates of ulcerative colitis and Crohn's disease. Dig Dis Sci 29:913, 1984 7. Campieri M, Lanfranchi GA, Boschi S, et al: Topical administration of 5-aminosalicyclic acid enemas in patients with ulcerative colitis. Studies on rectal absorption and excretion. Gut 26:400, 1985 8. Carr N, Schofield PF: Inflammatory bowel disease in the older patient. Br J Surg 69:223, 1982 9. Danish 5-ASA Group: Topical 5-aminosalicyclic acid versus prednisolone in ulcerative proctosigmoiditis. A randomized, double-blind multicenter trial. Dig Dis Sci 32:598, 1987 10. Das KM, Morecki R, Nair P, et al: Idiopathic proctitis: The morphology of proximal colonic mucosa and its clinical significance. Am J Dig Dis 22:524, 1977 11. Farmer RG, Brown CH: Ulcerative proctitis: course and prognosis. Gastroenterology 51:219, 1966 12. Farmer RG, Schumacher OP: Treatment of ulcerative colitis with hydrocortisone enemas: Relationship of hydrocortisone absorption, adrenal suppression, and clinical response. Dis Colon Rectum 13:355, 1970 13. Farmer RG, Brown CH: Emerging concepts of proctosigmoiditis. Dis Colon Rectum 15:142, 1972 14. Michener WM, Farmer RG, Mortimer EA: Long-term prognosis of ulcerative colitis with onset in childhood or adolescence. J Clin Gastroenterol 1:301, 1979 15. Farmer RG, Whelan G, Sivak MV Jr: Colonscopy in distal colon ulcerative colitis. Clin Gastroenterol 9:297, 1980 16. Farmer RG: Nonspecific ulcerative proctitis. Gastroenterol Clin North Am 16:157, 1987 17. Flejou JF, Potet F, Bogomoletz WV, et al: Lymphoid follicular proctitis. A condition different from ulcerative proctitis? Dig Dis Sci 33:314, 1988 18. Folley JH: Ulcerative proctitis. N Engl J Med 282:1362, 1970 19. Gabrielsson N, Granqvist S, Sundelin P, et al: Extent of inflammatory lesions in ulcerative colitis assessed by radiology, colonoscopy and endoscopic biopsies. Gastrointest Radiol 4:395, 1979 20. Gerding DN: Disease associated with Clostridium difficile infection. Ann Intern Med 110:255, 1989 21. Glotzer DJ, Glick ME, Goldman H: Proctitis and colitis following diversion of the fecal stream. Gastroenterology 80:438, 1981 22. Greenstein AJ, Sachar DB, Smith H, et al: Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 77:290, 1979 23. Gryboski JD: Extension of proctosigmoiditis in children. J Pediatr Gastroenterol Nutr 5:842, 1986 24. Kisloff B, Adkins JC: Toxic megacolon developing in a patient with longstanding distal ulcerative colitis. Am J Gastroenterol 75:451, 1981
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25. Laufer I, Mullens JE, Hamilton J: Correlation of endoscopy and double-contrast radiography in the early stages of ulcerative and granulomatous colitis. Radiology ll8:1, 1976 26. Laughon BE, Druckman DA, Vernon A, et al: Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterology 94:984, 1988 27. Lennard-Jones JE, Cooper GW, Newell AC, et al: Observations on idiopathic proctitis. Gut 3:201, 1962 28. Marshall JB, Butt JH: Proctitis: approach to diagnosis, causes and treatment. J Clin Gastroenterol 4:431, 1982 29. Mir-Madjlessi SH, Michener WM, Farmer RG: Course and prognosis of idiopathic ulcerative protosigmoiditis in young patients. J Pediatr Gastroenterol Nutr 5:570, 1986 30. Mir-Madjlessi SH, Farmer RG, Easley KA, et al: Cancer in ulcerative colitis. Cancer 58:1569-1574, 1986 31. Myers A, Humphreys DM, Cox EV: A 1O-year follow-up of haemorrhagic proctitis. Postgrad Med J 52:224, 1976 32. Nakano G, Ritchie JK, Thomson JPS: Ulcerative colitis treated by excision of the distal large bowel along. Postgrad Med J 60:278, 1984 33. Nordenvall B, Brostrom 0, Berglund M, et al: Incidence of ulcerative colitis in Stockholm County. Scand J Gastroenterol 7:783, 1985 34. Nugent FW, Veidenheimer MC, Zuberi S, et al: Clinical course of ulcerative proctosigmoiditis. Am J Dig Dis 15:321, 1970 35. Powell-Tuck J, Ritchie JK, Lennard-Jones JE: Prognosis of idiopathic proctitis. Scand J Gastroenterol 12:727, 1977 36. Powell-Tuck J, Day DW, Buckell NA, et al: Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis. Dig Dis Sci 27:533, 1982 37. Prantera C, Davoli M, Lorenzetti R, et al: Clinical and laboratory indicators of extent of ulcerative colitis. Serum C-reactive protein helps the most. J Clin Gastroenterol1O:41, 1988 38. Quinn TC: Gay bowel syndrome. The broadened spectrum of nongenital infection. Postgrad Med 76:197, 1984 39. Ritchie JK, Lennard-Jones JE: Crohn's disease of the distal large bowel. Scand J Gastroenterol II :433, 1976 40. Ritchie JK, PoweIl-Tuck J, Lennard-Jones JE: Clinical outcome of the first ten years of ulcerative colitis and proctitis. Lancet 1:1140, 1978 41. Rompalo AM, Roberts P, Johnson K, et al: Empirical therapy for the management of acute proctitis in homosexual men. JAMA 260:348, 1988 42. Ruddell WS, Dickinson RJ, Dixon MF, et al: Treatment of distal ulcerative colitis (proctosigmoiditis) in relapse: Comparison of hydrocortisone enemas and rectal hydrocortisone foam. Gut 21:885, 1980 43. Shivananda S, Pena AS, Mayberry JF, et al: Epidemiology of proctocolitis in the region of Leiden, The Netherlands. A population study from 1979 to 1983. Scand J Gastroenterol 22:993, 1987 44. Simpkins KC, Steven GW: The modified Malmo double-contrast barium encma in colitis: an assessment of its accuracy in reflecting sigmoidoscopic findings. Br J Radiol 45:486, 1972 45. Sparberg M, Fennessy J, Kirsner JB: Ulcerative proctitis and mild ulcerative colitis: A study of 220 patients. Medicine 45:391, 1966 46. Surawicz CM, Belic L: Rectal biopsy helps to distinguish acute self~limited colitis from idiopathic inflammatory bowel disease. Gastroenterology 86: 104, 1984 47. Sutherland LR, Martin F, Greer S, et al: 5-Aminosalicyclic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology 92:1894, 1987 48. Thaysen TEH: Simple hemorrhagic proctitis and proctosigmoiditis. Acta Med Scand 84:1, 1934 49. Truelove SC: Treatment of ulcerative colitis with local hydrocortisone. Br Med J 2:1267, 1956 50. van-der-Heide H, van-den-Brandt-Gradel V, Tytgat GN, et al: Comparison of beclomethasone dipropionate and prednisolone 21-phosphate enemas in the treatment of ulcerative proctitis. J Clin Gastroenterol 10: 169, 1988
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51. Williams CN, Haber G, Aquino JA: Double-blind, placebo-controlled evaluation of 5ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories. Dig Dis Sci 32:71S, 1987 52. Wolf BC, Culp CE, Beart RW Jr, et al: Anorectal Crohn's disease. A long-term perspective. Dis Colon Rectum 28:709, 1985 53. Zimmerman J, Cavish 0, Rachmilewitz 0: Early and late onset ulcerative colitis: Distinct clinical features. J Clin Castroenterol 7:492, 1985
Address reprint requests to Richard C. Farmer, MD Division of Medicine Cleveland Clinic Foundation One Clinic Center 9500 Euclid Avenue Cleveland, OH 44195-5123
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Evolution of the Concept of Proctosigmoiditis: Clinical Observation
Richard G. Farmer, MD, FACP*
Although ulcerative colitis has been known as a clinical and pathological entity for over a century, it has only been in the past 50 years or so that a localized distal form of the disease was recognized. Distal colitis was initially thought to be a different condition than ulcerative colitis and there was confusion in terminology used, with "hemorrhagic proctitis" probably being the most common term applied to the condition. 48 The characteristics of distal colon colitis were similar to universal ulcerative colitis, with rectal bleeding as the predominant manifestation, but the condition remained localized and the prognosis appeared to be much better than for patients with universal colitis. Although attempts were made to identify a bacterial cause for ulcerative colitis in the 1930s, these were unsuccessful, and likewise the consideration that there was a parasitic cause also proved unfounded. However, confusion as to whether or not the localized form of distal colitis represented an entity different from universal ulcerative colitis made data collection and long-term follow-up difficult, as well as assessment of therapy. In the 1950s it became apparent, particularly through the work of Truelove,49 that hydrocortisone enemas were beneficial as treatment for patients with the distal colon form of ulcerative colitis, whether proctitis (inflammation limited to the rectal mucosa) or proctosigmoiditis (inflammation involving the rectum and sigmoid colon). As steroid enemas became available they were utilized, and there were anecdotal, uncontrolled observations purporting therapeutic effectiveness of topical steroids. However, the almost complete lack of objectivity in clinical design was a significant deterrent to widespread scientific acceptance of these findings, and it was *Chairman, Division of Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
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difficult to assess therapeutic results and to predict clinical responsiveness to specific regimens. To confuse the situation further, in the 1960s it became recognized that Crohn's disease could affect the large intestine exclusively. It was further noted that Crohn's disease could also be localized to the distallarge boweP9 and/or the anorectum. 52 Crohn's disease, however, did not result in a form of proctitis similar to that observed among patients with ulcerative colitis, and the distinction from Crohn's disease and the recognition of ulcerative proctitis or proctosigmoiditis as a distinct clinical entity developed. lI . 18. 27. 45 Thus, the proctitis form of inflammatory bowel disease has remained in the ulcerative colitis category rather than being associated with Crohn's disease. Furthermore, it was extremely rare that there were any perianal manifestations and, when present, represented only minor fissures and almost never the perianal fistulae and abscesses characteristic of anorectal Crohn's disease. Nevertheless, the problem of definition of the condition as an entity remained, particularly with the difficulty of assessing the proximal limit of the inflammatory process. Since barium enema was the only mode of assessing the colon proximal to the extent visualized by the rigid sigmoidoscope, the definition of proctitis or proctosigmoiditis was therefore dependent on an abnormal sigmoidoscopic examination with a radiographically normal colon proximal to the rectosigmoid on barium enema. 11. 13. 16. 18. 19. 25, 28. 44, 45 There were repeated observations that the visualized mucosa in patients with the limited form of the inflammatory process was identical to that of mucosa in those whose disease extended throughout the entire large intestine, 13. 27. 34. 45 and likewise biopsies did not differentiate the two conditions. 10, 19, 46 Therefore, the concept that there was a distal colon form of ulcerative colitis became increasing apparent clinically, and there were attempts to follow patients for a longer period of time than simply in the observation or diagnostic phase, to determine if possible the prognosis and the degree of extent of disease that might occur during the course of the inflammatory process. 11, 14. 31, 34. 35 All of this was significantly complicated by the apparent spontaneous remissions and subsequent exacerbations that made assessments of therapeutic effectiveness, extent of disease, and prognosis difficult. In the 1960s there were attempts to define both proctitis and proctosigmoiditis, and it was thought important that these conditions be differentiated. In 1966,11 we reported our experience with ulcerative proctitis being a clearly visualized upper limit of the inflammation of the mucosa seen on rigid sigmoidoscopic examination as well as a normal barium enema. The inflammatory process was truly proctitis in these patients, with inflammation extending approximately 15 cm proximal to the dentate line, and inevitably beginning at the dentate line. The mucosa was diffusely friable with fine ulceration, and involvement was almost always uniform with little variability in one area or another and touch friability present almost throughout the inflamed mucosa. Discrete ulceration, mucosal thickening, strictures, and perianal lesions were almost always absent. Occasionally, pseudopolyps appeared, and in longstanding cases there was visual evidence of mucosal atrophy. When the rectal mucosa was biopsied
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in inflamed areas, there was diffuse inflammation with leukocyte infiltration, usually polymorphonuclear leukocytes, crypt abscesses, loss of goblet cells, and distorted architecture of the mucosa. H . 13.27.34.45.46 Biopsies sometimes revealed abnormalities in visually normal mucosa proximal to the visual line of demarcation, but the significance of these findings was somewhat controversial, particularly if one attempted to correlate the pathologic findings with prognosis. 10. 15. 19 Therefore, the visual appearance of the mucosa was most often used by clinicians for assessment of the activity of the disease and, therefore, of therapeutic responsiveness. 36 This, of course, compounded the scientific difficulty for measuring therapeutic effectiveness. In the instances in which a clear upper limit could not be visualized and the mucosa appeared inflamed (as far as one could examine with the rigid sigmoidoscope) generally between 15 and 25 cm proximal to the dentate line, the term "proctosigmoiditis" was used. The implication was that this might have a greater propensity for extension or might represent diffuse mucosal disease throughout the entire colon that could not be observed on barium enema because the changes were too subtle. 13. 14. 25. 34. 44 Despite the clinical and scientific limitations noted, there were observations that the incidence or frequency of the distal colon form of ulcerative colitis appeared to be increasing when the total number of cases of ulcerative colitis appeared to be decreasing, particularly in relation to a number of patients diagnosed with Crohn's disease. 5. 6. 33. 43 The concept that distal colon inflammation actually represented "mild" ulcerative colitis,45 and should therefore be defined on the basis of clinical severity rather than extent of disease became popular. There were several reasonably long-term follow-up studies that clearly indicated that the long-term prognosis for patients with distal colon ulcerative colitis, proctitis, or proctosigmoiditis was considerably better than for patients with total colon ulcerative colitis, and that extension of disease to involve the entire colon occurred in about 10 per cent of cases. H. 14. 18.31.34.35.40 When extension of the disease occurred, it usually did so relatively early in the course of the disease, usually about 2 years, and rarely after 5 years. 14 However, the problem of remission and exacerbation continued, and patients with ulcerative proctitis or proctosigmoiditis visited physicians relatively more often than had been anticipated, in view of the relative lack of severity of the condition. In addition, there was often much anxiety expressed by the patient because of fear of cancer or rectal bleeding. In the experience at a referral center, it was remarkable how often patients came for second opinions because of a conflict with the treating physician either on the basis of inability to control the rectal bleeding and to prevent further recurrences, and the fear of extended disease, severe disease, need for surgery (with stoma), or cancer. Our own studies during the 1960s and 1970s13. 14 emphasized the difficulty of determining exactly the distinction between proctitis and proctosigmoiditis, but did observe the extension rate of about 10 per cent, similar to observations by others,27. 34 the unpredictability of exacerbations and remissions, the difficulty in therapeutic assessment, the relative rarity of other symptoms (extra-intestinal manifestations and systemic features), and the relatively good long-term prognosis. Significantly influenced by the work of Truelove in England and by
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Brown and Turnbull at the Cleveland Clinic, we embarked on therapeutic trials in the mid-1960s using hydrocortisone enemas consisting of 100 mg of hydrocortisone in a vehicle of60 ml. l2 Brown and Turnbull had previously worked together since the late 1940s, and Turnbull had pioneered the Brooke ileostomy in the United States in the 1950s. Together, they observed a large number of patients and had extensive personal experience dealing with patients with inflammatory bowel disease. Since many of these patients were referred, there were more complicated or unusual cases and those seemingly refractory to therapy. Brown and Turnbull used a large number of therapeutic measures including sulfasalazine enemas, methylprednisolone enemas, neomycin-hydrocortisone suppositories, and systemic steroids including both oral prednisone and adrenocorticotropic hormone (ACTH)releasing factor. In the early 1960s, in refractory cases of inflammatory bowel disease, they utilized nitrogen mustard, which was a forerunner to modern day immunosuppressive therapy. In attempting to evaluate the therapeutic effectiveness of hydrocortisone enemas for patients with distal colon ulcerative colitis, the problems mentioned were assessed and a prospective clinical trial was established that evolved into the use of hydrocortisone enemas once daily on a nightly basis for a 3-week period, with a "rest" period of 1 week and another 3week course of treatment if necessary. 12 Studies were done to assess adrenal suppression and/or responsiveness, and clinical observations were made as to therapeutic effectiveness based on: (1) decrease in the amount of rectal bleeding observed by the patient, and (2) visual improvement in the rectal mucosa as seen by sigmoidoscopy, with decrease in the degree of friability, its extent, and lessening of fine mucosal ulceration. Systemic steroid measurements were obtained, which indicated that approximately one third of the steroid enema was absorbed but that adrenal responsiveness remained intact in the majority of cases and that there was no therapeutic risk to the use of the hydrocortisone enemas. Improvement in symptoms and resolution of the abnormalities of the rectum mucosa occurred so that the effect topically appeared to be confirmed. Nevertheless, it was extremely difficult to assess all factors scientifically and objectively. This problem plagued not only our studies but those of others, 34 and is undoubtedly one of the major reasons why, despite the relative frequency of the condition, there has been a relative dearth of scientific and clinical publications studying specific therapeutic responsiveness to topical steroids until recently. 50 In our follow-up study 10 years ago,14 we found once again that the prognosis for 90 per cent of patients was good despite a high rate of recurrence, but that the 10 per cent who extended did so in a clinically aggressive manner and frequently required operation because of severity of inflammation; when extension occurred, it usually did so within 2 years after original diagnosis. Prior to the development of colonoscopy as a diagnostic tool, the rapid extension of inflammation was often thought to have represented subtle mucosal changes throughout the entire large intestine which were undetectable by barium enema. We performed a study of 100 consecutive patients 15 observed in the late 1970s who were thought to have distal colon ulcerative colitis. We found that about 40 per cent had changes proximal
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to the area in which the inflammation had been thought to be confined. However, in most cases, the inflammation did not extend proximal to the splenic flexure and therefore represented what has subsequently been referred to as "left-sided" colitis. 22 Assessment of the clinical course of these patients indicated that there was not much variance from those with distal colon ulcerative colitis and the course was significantly milder than that of patients with total colon colitis. Attempts have been made to correlate the appearances and other measures of disease activity by means of endoscopy and colonscopy.36, 37 Therefore, in the past decade, there has emerged a clinical concept of a tripartite form of idiopathic colonic inflammation, usually referred to as ulcerative colitis. Patients who have ulcerative proctitis and proctosigmoiditis can usually be differentiated fairly readily, both clinically and endoscopically, from those patients who have ulcerative pancolitis. There is a group "in between" that is now referred to as "leftsided colitis" in which the inflammatory changes extend approximately to the level of the splenic flexure. Both clinically and prognostically, these patients appear to lie between the severity of patients with pancolitis and the relatively benign clinical course of those with proctitis or proctosigmoiditis. 37 There has been a significant change in the clinical pattern of patients with ulcerative colitis in the past 20 to 30 years, with a substantial increase in the number of cases of distal colon disease (and therefore a milder clinical course) and a relative decrease in the number of cases of ulcerative pancolitis with its relatively more severe clinical course. In a recent epidemiologic study by Shivananda et al 43 in the Netherlands, 42 per cent of patients were found to have the distal colon form of the disease and only 11 per cent had pan colitis at the time of diagnosis. As an additional clinical observation, in the 1950s or 1960s at a referral center, one would find four to six times the number of cases of ulcerative colitis hospitalized versus patients with Crohn's disease (then usually called regional enteritis). Exactly the opposite occurred in the 1980s with the vast majority of patients hospitalized because of complications of their inflammatory bowel disease being those with Crohn's disease, A factor of considerable significance in the long-term prognosis for patients with ulcerative colitis is the potential for cancer. The ability to perform sequential mucosal biopsies and the recognition that dysplasia may be precancerous has considerably altered the prognostic evaluation of such patients in recent years. The relative frequency of cancer in ulcerative colitis as well as dysplasia have both correlated with the anatomic distribution of disease. 22, 30 In the experience at the Cleveland Clinic,30 fewer than 10 per cent of patients with ulcerative colitis have been found to have dysplasia on surveillance colonoscopy, and the vast majority of those with dysplasia are patients with ulcerative pancolitis. In our experience, the development of cancer of the large intestine among patients with ulcerative colitis is greatest among patients with pancolitis, and is Significantly higher than the general population. For patients who develop cancer in conjunction with ulcerative pancolitis, the mean duration in the Cleveland Clinic experience from onset of colitis to diagnosis of cancer is 18 years. For patients with left-sided colitis, the incidence of dysplasia is much less, the
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incidence of cancer is less, and the duration from the onset of colitis to the diagnosis of cancer is a mean of 22 years. There has not been an increased incidence of either dysplasia or cancer for patients with proctitis or proctosigmoiditis over the general population, in our experience. 30 In our recent study of proctosigmoiditis in children,29 we observed that the prognosis was not as favorable as for patients who are adults at the time of onset of the proctitis or proctosigmoiditis. Approximately one third of the patients with childhood onset appear to have a much more chronic course, frequent exacerbations, and extension of disease. Gryboski 23 has also made a similar observation, but it is difficult to determine whether age alone is a factor in the clinical significance of the inflammation. However, as a clinical ohservation, proctitis or proctosigmoidits in children and young adults appears to be more clinically significant than in older patients. Conversely, patients over the age of 40 often have a fairly benign course when affiicted with proctitis or proctosigmoiditis,8, 53 and there has been no evidence that ischemic colitis was present even in very old patients with proctitis or proctosigmoiditis. Furthermore, it has been observed that patients with distal colon colitis are often older than the typical young adult group of patients with ulcerative pancolitis, and the prognosis often relates to other clinical problems experienced by the patient rather than the colitis itself. 8, 53 Although rare, distal ulcerative colitis may occasionally result in toxic megacolon,24 and operation may be necessary.14 In addition, even without extension of disease, distal colon ulcerative colitis may be severe enough to warrant removal of the distal colon only, although that circumstance is likewise rare. 32 There have recently been attempts to use physiologic techniques to study patients with ulcerative proctitis in order to determine prognostic factors. Transit time in the large bowel has been utilized by Black and coworkers 4 who found a delay in the transit time of patients with active disease from 50 hours in controls to over 70 hours in those with active disease, and over 80 hours for those with inactive proctitis. However, physiologic measurements to assess prognosis have yet to be established. An interesting recent observation was that of a condition referred to as "lymphoid follicular proctitis. "17 This was observed in a group of patients with clinical features suggestive of inflammatory bowel disease confined to the rectum whose rectal biopsies showed lymphoid follicular hyperplasia. About half of the patients appeared to be quite similar clinically to distal colon ulcerative colitis, but the others did not. This observation raises yet another intriguing bit of evidence concerning the nature of inflammation in the distal colon and its relative specificity. There has been a considerable renaissance in interest in recent years relating to infectious causes of colitis, often with clinical and endoscopic characteristics similar to those found in ulcerative proctitis or proctosigmoiditis. In the mid-1970s and subsequently, there were dramatic changes in the understanding of certain infectious diarrheas-including traveler's diarrhea, antibiotic-associated diarrhea, and Campylobacter colitis. This interest has been greatly intensified because of the gastrointestinal manifestations of patients with the acquired immunodeficiency syndrome (AIDS),
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although the clinical appearance of the rectal or colonic mucosa in patients with AIDS more closely resembles Crohn's disease than it does ulcerative colitis and the severity of the illness with its attendant systemic features is much greater than that usually seen in patients with ulcerative proctitis or proctosigmoiditis. However, there has been a remarkable increase in the recognition of types of distal colon inflammation found in homosexual males, with or without AIDS. Most of these clinical conditions have been a form of acute proctitis frequently with significant rectal pain as well as small volume stools, diarrhea, and tenesmus. Andrews et aP studied 50 male patients with proctitis and compared the findings with a similar number of male homosexuals attending a clinic at the same hospital. For patients with proctitis who were homosexual, there was typically a short history of bowel symptoms, minor sigmoidoscopic and histologic changes, and positive serological markers of sexually transmitted infection. They found three patients with inflammatory bowel disease who were homosexual, and cultures were positive for cryptosporidium and cytomegalovirus. These authors concluded that patients with inflammatory bowel disease who are homosexual may have a coexisting form of sexually transmitted proctitis as well as a flare of the colitis. In another study of 388 homosexual or bisexual patients,26 assessment of the "gay bowel syndrome" was performed. There were 68 patients with proctitis and Campylobacter species was the most common organism found. Others included herpes simplex virus and Neisseria gonorrhoeae, Giardia lamblia, and Shigella species. There has been recognition of the spectrum of the "gay bowel syndrome" for the last several years 38 with a great variety of clinical features and organisms observed. An empirical therapeutic program for the management of acute proctitis in homosexual men has recently been advocated41 as a result of a randomized trial of 129 homosexual men who presented with acute proctitis. The empirical regimen of 4.8 million units of aqueous penicillin G procaine intramuscularly and 1.0 g of probenecid orally, followed by 100 mg of oral doxycycline twice-daily for 7 days was beneficial for the majority of cases. This response would certainly be beneficial in the clinical distinction from ulcerative proctitis or proctosigmoiditis. The sigmoidoscopic characteristics reported in sexually transmitted proctitis have not been typical for patients with ulcerative colitis and have included mucoid purulent exudate, ulcerations, erosions, and vesicles, 41 in contrast to the characteristic mucosal changes in ulcerative proctitis. Another condition sometimes confused with ulcerative proctitis is infection caused by Clostridium difficile. 20 While there typically is a history of antibiotic use within the 8 weeks prior to onset of diarrhea, this history can sometimes be confusing or nonspecific. Sigmoidoscopy may be somewhat nonspecific unless, of course, the highly characteristic pseudomembrane is visible. However, the mucosa generally does not have the visual characteristics associated with ulcerative proctitis. Although the recent interest in infectious diarrhea has been stimulated by studies in homosexual men, proctitis may occur as a result of infection with salmonella, shigella, and campylobacter organisms. Salmonellosis is generally not associated with mucosal friability and can usually be differentiated. Shigellosis may have severe mucosal friability, and there also may
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be a severe systemic reaction associated with the bacterial infection. However, it has been Campylobacter colitis that has been most frequently confused with ulcerative colitis in the recent past and it is certainly necessary to exclude Campylobacter colitis by means of stool culture in a patient with a new onset of suspected proctitis or proctosigmoiditis. One of the important clinical differential features favoring ulcerative colitis is the persistence of the inflammation, the relative resistance to antibiotic therapy, and the tendency for exacerbations as well as having negative stool cultures. It has been increasingly recognized that radiation proctitis may closely mimic the clinical and endoscopic features of ulcerative proctitis. An additional characteristic is frequent therapeutic refractoriness creating a significant clinical problem. A recent study2 of 1418 patients treated with radiation for carcinoma of the uterus found 4.3 per cent (61 patients) to have developed significant radiation induced complications of the intestine, of which 93 per cent involved the rectum. About one third of the cases of proctitis resolved within 2 years of onset but surgery was necessary for 39 per cent of patients, often a difficult clinical decision in a patient with a history of or evidence for carcinoma. Another studyl utilized laser therapy for patients with severe radiation injury resulting in proctosigmoiditis. It has also been known for some time that proctitis can occur following diversion of the fecal stream, as with colostomy.21 However, both radiation proctitis and diversion colitis can generally be distinguished from ulcerative colitis or proctitis on clinical and endoscopic grounds. Previously, there had been a substantial increase in scientific activity relating to the treatment of ulcerative proctitis, particularly in the use of topical agents. In 1980, Ruddell and colleagues 42 reported on a comparative study of hydrocortisone enemas and rectal hydrocortisone foam with relatively positive findings for each type of agent. A recent study compared beclomethasone dipropionate and prednisolone 21-phosphate enemas 50 that showed a more favorable response with the latter but less adrenal suppression with the former. Because of concern over both therapeutic efficacy and adrenal suppression with topical steroids, as well as development of 5-amjnosalicyclic acid topical preparations, recent interest has focused on the study of these agents, with the pioneering work of Campierj1 indicating clinical efficacy and spurring other clinical trials. Sutherland et al,47 in a multicenter clinical trial, assessed 5-aminosalicyclic acid enemas in the treatment of distal colon ulcerative colitis and used a 4-g dosage for ulcerative colitis involving up to 50 cm of distal colon in 153 patients (76 received active medication and 77 received a placebo). After 6 weeks of therapy, 63 per cent receiving the 5-aminosalicyclic acid were improved in comparison with only 29 per cent of those patients on placebo. A disease activity index based on patients' symptoms and sigmoidoscopic appearance was used to assess efficacy. 36 Rapid onset of efficacy was shown by significant reduction in rectal bleeding within 3 days of beginning treatment. A Danish study9 compared topical 5-aminosalicyclic acid versus prednisolone in ulcerative proctosigmoiditis with a randomized double-blind multicenter trial of 1000 mg of 5-aminosalicyclic acid compared with 25 mg of prednisolone, both administered rectally. There were 123 patients in the
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study; after 14 days, patients in total remission discontinued treatment while the others were treated for another 2-week period. Improvement or remission was seen in 77 per cent of the 5-aminosalicyclic acid-treated patients and in 72 per cent of the prednisolone-treated patients. These authors concluded that 5-aminosalicyclic acid is at least as efficient as prednisolone for topical treatment of patients with moderately active proctosigmoiditis. 9 Williams and colleagues51 treated proctitis with 5-aminosalicyclic acid suppositories (500 mg three times daily) or placebo for 6 weeks. They assessed activity using a disease activity index derived from four categories: (1) number of bowel movements per day; (2) bloody diarrhea; (3) sigmoidoscopic appearance; and (4) overall assessment. For patients treated with the active medication, there was a 78 per cent remission rate at 6 weeks and no significant change in the placebo group. It is interesting that six of their patients and six controls were given 99mTc-Iabeled 5-aminosalicyclic acid suppositories that showed that the extent of topical spread from the suppository was limited to the rectum and the suppositories were retained for 3 hours with no absorbed radioactivity. Thus, these authors concluded that 5-aminosalicyclic acid suppositories are therapeutically beneficial for patients with proctitis. Although all of these recent studies are short-term, they follow the pattern established in the past in studying the effects of steroid enemas or suppositories, and appear to be of potentially significant benefit for patients with distal colon ulcerative colitis. There have been many observations to indicate that the number of patients with proctitis, proctosigmoiditis, or distal colon colitis has steadily increased, while the number of patients with ulcerative pancolitis has decreased: thus, the latter, more severe form of the disease currently occurs in fewer than 50 per cent of cases overall. 5, 6, 43 This has created the "impression" that ulcerative colitis has become "milder," and may perhaps lead to less surveillance than is indicated in view of the potential for cancer developing in patients with pancolitis. For patients with proctitis, the primary clinical problem is recurrence and the difficulty to predict or prevent recurrences by either clinical assessment or therapeutic manipulation. The use of topical steroids, sulfasalazine and related agents, and other forms of therapy does not seem to alter the "natural history" of proctitis, although it is a common clinical observation that after a period of approximately 10 to 15 years the inflammation appears to "burn out," making therapeutic assessment in the long term even more difficult. There are many reasons why the study of patients with distal colon ulcerative colitis is worthwhile and clinical observations are of value. The relative frequency of the condition, its unpredictable nature, the unpleasant symptoms for the patient, the difficulty of therapeutic responsiveness, and the overriding fear of worsening of the condition or progression to cancer all make the condition of distal colon ulcerative colitis, whether proctitis or proctosigmoiditis, a relatively frequent and relatively "severe" form of a relatively "benign" disease. However, it is only by careful clinical observation, compilation of data over a long period of time, and meticulous follow-up of such patients and their clinical, endoscopic, and therapeutic
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characteristics that further understanding of this enigmatic condition will occur.
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51. Williams CN, Haber G, Aquino JA: Double-blind, placebo-controlled evaluation of 5ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories. Dig Dis Sci 32:71S, 1987 52. Wolf BC, Culp CE, Beart RW Jr, et al: Anorectal Crohn's disease. A long-term perspective. Dis Colon Rectum 28:709, 1985 53. Zimmerman J, Cavish 0, Rachmilewitz 0: Early and late onset ulcerative colitis: Distinct clinical features. J Clin Castroenterol 7:492, 1985
Address reprint requests to Richard C. Farmer, MD Division of Medicine Cleveland Clinic Foundation One Clinic Center 9500 Euclid Avenue Cleveland, OH 44195-5123