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pANCA and Classification Resistance in Ulcerative Colitis
Editorial pANCA and Classification Resistance in Ulcerative Colitis In comparison with the rheumatic diseases, classification of the inflammatory bowel diseases (ulcerative colitis and Crohn's disease) has been hampered by the absence of subclinical or serologic markers. The recognition of rheumatoid factor and specific antinuclear antigens led to the ability of rheumatologists to separate overlapping clinical syndromes into more predictable disease patterns with therapeutic and prognostic implications. To date, ulcerative colitis and Crohn's disease remain the classic inflammatory bowel diseases with similar epidemiologic patterns and overlapping clinicopathologic features. Nonetheless, clinicians are beginning to recognize a wider spectrum of colitides (such as microscopic colitis and collagenous colitis) and heterogeneity within the clinical spectra of ulcerative colitis and Crohn's disease based on the location (mucosal extent), pattern of inflammation (fibrostenotic or penetrating Crohn's disease), systemic complications, and response to various therapeutic regimens.P Approximately 20% of patients with idiopathic, chronic "colitis" have indeterminate features between ulcerative colitis and Crohn's disease. Thus far, the only recognized epidemiologic distinctions between ulcerative colitis and Crohn's disease are the familial (and twin) concordance of disease patterns and the opposite effects of cigarette smoking, which protects against ulcerative colitis and is detrimental to the development and prognosis in Crohn's disease. Potential Marker.-The recent identification of a novel, perinuclear pattern of antineutrophil cytoplasmic antibodies (pANCA) associated with ulcerative colitis promised a potential new marker for disease classification and possible prognosis. The original reports by Targan and collaborators (including Mayo investigators) suggested that pANCA might provide a sensitive and specific test to diagnose ulcerative colitis.' distinguish ulcerative colitis from Crohn's disease and other colitides," and provide a prognostic feature pertaining to the risk of pouchitis after colectomy and ileoanal anastomoses.' Therapeutic Responsiveness.-The article by Sandborn and colleagues in this issue of the Mayo Clinic Proceedings (pages 431 to 436) attempts to use pANCA for further subclassification of ulcerative colitis into prognostic categories pertaining to potential response to treatment. Prior series Address reprint requests to Dr. S. B. Hanauer, Section of Gastroenterology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 4076, Chicago, IL 60637. Mayo Clin Proc 1996; 71:517-518
have already suggested that the presence ofpANCA does not correlate with disease activity or even curative colectomy" and that pANCA might precede the clinical disease or identify susceptible family members." Sandborn and associates attempt to correlate disease responsiveness, or lack thereof, to the pANCA status. In two small and differently recruited groups of patients with left-sided ulcerative colitis (41 "treatment-resistant" patients enrolled in trials of novel therapies in comparison with 13 "treatment-responsive" patients from the community and routine practice), they have demonstrated a difference in the proportion of pANCA-positive versus pANCA-negative patients. In the group of 41 treatment-resistant patients, 90% were pANCA positive versus 62% in the group of treatment-responsive patients. These proportions are compared with the background prevalence of pANCA positivity between 45 and 86% in patients with ulcerative colitis in series from around the world. Thus far, studies have failed to demonstrate a difference in pANCA positivity correlating with the mucosal extent of ulcerative colitis; therefore, whether these proportions extrapolate to patients with more extensive colitis or even within the confines of left-sided colitis (that is, proctitis, proctosigmoiditis, or disease distal to the splenic flexure) is unknown. Indeed, many clinicians find that patients with distal ulcerative colitis or ulcerative proctitis are, in general, more difficult to treat (that is, are treatment resistant) than are patients with proximal involvement. 8 The authors appropriately describe many of the potential pitfalls of their "pilot" study: the retrospective assignment of patients into arbitrarily defined resistant versus responsive groups, the diversity of therapeutic regimens, selection biases in the comparison groups, small sample sizes (only 13 treatment-responsive patients), and the possibility of a type II statistical error. Future trials should, as the authors suggest, randomly enroll patients who are prospectively assigned on the basis of objective variables into larger subgroups with clear definitions of disease extent, severity, and intestinal and extraintestinal patterns (for example, recognizing that complications such as primary sclerosing cholangitis already are known to have a strong pANCA association). Clinical Significance ofpANCA.-Thus far, the clinical relevance of pANCA positivity remains confusing. In potential surgical candidates with indeterminate colitis, positive pANCA findings have good and bad implications. At colectomy, the findings are more likely to be categorized as ulcerative colitis than Crohn's disease (implying curability), but the patient is at higher risk of developing refractory pouchitis.' Clarification and development of more clinical pathophysiologic and, eventually, genetic associations are needed to determine whether pANCA will be a clinically 517
© 1996 Mayo Foundation/or Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
518
EDITORIAL
Mayo Clio Proc, May 1996, Vol 71
useful marker in inflammatory bowel disease. Already, develop a future nosology of inflammatory bowel disease to some preliminary findings ascribe unique attributes of pa- define the subclasses of what will be recognized as the tients with pANCA-positive Crohn's disease with features "ulcerative colitides" and "Crohu's diseases." similar to distal ulcerative colitis (Targan SR. Personal Stephen B. Hanauer, M.D. communication). Furthermore, the authors' contention that Section of Gastroenterology pANCA production is a "primary event rather than a secondUniversity of Chicago Medical Center ary response to antigen stimulation" remains to be conChicago, Illinois firmed and seems in doubt, now that patients followed longitudinally have been found to have fluctuating pANCA REFERENCES positivity.' Meanwhile, the current proportions still do not allow a 1. Sachar DB, Andrews HA, Farmer RG, Pallone F, Pena AS, Prantera C, et al. Proposed classification of patient subgroups predictable distinction between potential treatment response in Crohn's disease. GastroenterolInt 1992; 5:141-154 (to conventional therapies) and treatment resistance. Even if 2. Pefia AS, Meuwissen SGM. Evidence for clinical subgroups in the authors' proportions are confirmed, 45 to 86% of the inflammatory bowel disease. In: Targan SR, Shanahan F, editors. Inflammatory Bowel Disease: From Bench to Bedbackground population of patients with ulcerative colitis will side. Baltimore: Williams & Wilkins, 1994: 272-278 have pANCA positivity. The authors contend that 80% of 3. Shanahan F. Neutrophil autoantibodies in inflammatory bowel patients with left-sided ulcerative colitis will respond to disease: are they important? [editorial]. Gastroenterology "standard" medical therapy. This percentage, however, is 1994; 107:586-589 not reflected in their actual samples, in which only 8 of 45 4. Duerr RH, Targan SR, Landers CJ, Sutherland LR, Shanahan F. Anti-neutrophil cytoplasmic antibodies in ulcerative colitis: (18%) of their combined groups of pANCA-positive patients comparison with other colitides/diarrheal illnesses. Gastroen(from Table 3) were treatment responsive. Again.prospecterology 1991; 100:1590-1596 tive, larger series will need to be studied to confirm the 5. Sandborn WJ, Landers CJ, Tremaine WJ, Targan SR. potential utility of pANCA as a prognostic marker in ulcerAntineutrophil cytoplasmic antibody correlates with chronic pouchitis after ileal pouch-anal anastomosis. Am J ative colitis. Gastroenterol 1995; 90:740-747 Current and Future Investigations.-Efforts are under way to classify ulcerative colitis and Crohn's disease on 6. Oudkerk Pool M, Ellerbroek PM, Ridwan BU, Goldschmeding R, von Blomberg BM, Pena AS, et al. Serum antineutrophil clinical, pathophysiologic, molecular, and genetic bases. To cytoplasmic autoantibodies in inflammatory bowel disease are do so will require the recognition of different clinical patmainly associated with ulcerative colitis: a correlation study terns of mucosal disease and systemic or extraintestinal corbetween perinuclear antineutrophil cytoplasmic autoantibodies and clinical parameters, medical, and surgical treatment. Gut relates. Individual markers such as pANCA, 45-kd proteins, 1993; 34:46-50 IL-lra production, human leukocyte antigen (HLA) link7. Shanahan F, Duerr RH, Rotter Jl, Yang H, Sutherland LR, ages, and specific genotypes must be applied and compared McElree C, et al. Neutrophil autoantibodies in ulcerative in patients or familial clusters with homogeneous patterns of colitis: familial aggregation and genetic heterogeneity. Gasdisease rather than loosely assembled or arbitrarily ascribed troenterology 1992; 103:456-461 populations. Eventually, the inflammatory bowel disease 8. Griffin MG, Miner PB. Review article: refractory distal colitis-explanations and options. Aliment Pharmacol Ther community will "catch up" to rheumatologists, who can now 1996; 10:39-48 predict the course and therapeutic requisites of rheumatoid 9. Weyand CM, Hicok KC, Conn DL, Goronzy n. The influence arthritis on the basis of HLA subtype at the "hypervariable of HLA-DRB 1 genes on disease severity in rheumatoid arthriregion."? From this point forward, the goal should be to tis. Ann Intern Med 1992; 117:801-806
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
have already suggested that the presence ofpANCA does not correlate with disease activity or even curative colectomy" and that pANCA might precede the clinical disease or identify susceptible family members." Sandborn and associates attempt to correlate disease responsiveness, or lack thereof, to the pANCA status. In two small and differently recruited groups of patients with left-sided ulcerative colitis (41 "treatment-resistant" patients enrolled in trials of novel therapies in comparison with 13 "treatment-responsive" patients from the community and routine practice), they have demonstrated a difference in the proportion of pANCA-positive versus pANCA-negative patients. In the group of 41 treatment-resistant patients, 90% were pANCA positive versus 62% in the group of treatment-responsive patients. These proportions are compared with the background prevalence of pANCA positivity between 45 and 86% in patients with ulcerative colitis in series from around the world. Thus far, studies have failed to demonstrate a difference in pANCA positivity correlating with the mucosal extent of ulcerative colitis; therefore, whether these proportions extrapolate to patients with more extensive colitis or even within the confines of left-sided colitis (that is, proctitis, proctosigmoiditis, or disease distal to the splenic flexure) is unknown. Indeed, many clinicians find that patients with distal ulcerative colitis or ulcerative proctitis are, in general, more difficult to treat (that is, are treatment resistant) than are patients with proximal involvement. 8 The authors appropriately describe many of the potential pitfalls of their "pilot" study: the retrospective assignment of patients into arbitrarily defined resistant versus responsive groups, the diversity of therapeutic regimens, selection biases in the comparison groups, small sample sizes (only 13 treatment-responsive patients), and the possibility of a type II statistical error. Future trials should, as the authors suggest, randomly enroll patients who are prospectively assigned on the basis of objective variables into larger subgroups with clear definitions of disease extent, severity, and intestinal and extraintestinal patterns (for example, recognizing that complications such as primary sclerosing cholangitis already are known to have a strong pANCA association). Clinical Significance ofpANCA.-Thus far, the clinical relevance of pANCA positivity remains confusing. In potential surgical candidates with indeterminate colitis, positive pANCA findings have good and bad implications. At colectomy, the findings are more likely to be categorized as ulcerative colitis than Crohn's disease (implying curability), but the patient is at higher risk of developing refractory pouchitis.' Clarification and development of more clinical pathophysiologic and, eventually, genetic associations are needed to determine whether pANCA will be a clinically 517
© 1996 Mayo Foundation/or Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
518
EDITORIAL
Mayo Clio Proc, May 1996, Vol 71
useful marker in inflammatory bowel disease. Already, develop a future nosology of inflammatory bowel disease to some preliminary findings ascribe unique attributes of pa- define the subclasses of what will be recognized as the tients with pANCA-positive Crohn's disease with features "ulcerative colitides" and "Crohu's diseases." similar to distal ulcerative colitis (Targan SR. Personal Stephen B. Hanauer, M.D. communication). Furthermore, the authors' contention that Section of Gastroenterology pANCA production is a "primary event rather than a secondUniversity of Chicago Medical Center ary response to antigen stimulation" remains to be conChicago, Illinois firmed and seems in doubt, now that patients followed longitudinally have been found to have fluctuating pANCA REFERENCES positivity.' Meanwhile, the current proportions still do not allow a 1. Sachar DB, Andrews HA, Farmer RG, Pallone F, Pena AS, Prantera C, et al. Proposed classification of patient subgroups predictable distinction between potential treatment response in Crohn's disease. GastroenterolInt 1992; 5:141-154 (to conventional therapies) and treatment resistance. Even if 2. Pefia AS, Meuwissen SGM. Evidence for clinical subgroups in the authors' proportions are confirmed, 45 to 86% of the inflammatory bowel disease. In: Targan SR, Shanahan F, editors. Inflammatory Bowel Disease: From Bench to Bedbackground population of patients with ulcerative colitis will side. Baltimore: Williams & Wilkins, 1994: 272-278 have pANCA positivity. The authors contend that 80% of 3. Shanahan F. Neutrophil autoantibodies in inflammatory bowel patients with left-sided ulcerative colitis will respond to disease: are they important? [editorial]. Gastroenterology "standard" medical therapy. This percentage, however, is 1994; 107:586-589 not reflected in their actual samples, in which only 8 of 45 4. Duerr RH, Targan SR, Landers CJ, Sutherland LR, Shanahan F. Anti-neutrophil cytoplasmic antibodies in ulcerative colitis: (18%) of their combined groups of pANCA-positive patients comparison with other colitides/diarrheal illnesses. Gastroen(from Table 3) were treatment responsive. Again.prospecterology 1991; 100:1590-1596 tive, larger series will need to be studied to confirm the 5. Sandborn WJ, Landers CJ, Tremaine WJ, Targan SR. potential utility of pANCA as a prognostic marker in ulcerAntineutrophil cytoplasmic antibody correlates with chronic pouchitis after ileal pouch-anal anastomosis. Am J ative colitis. Gastroenterol 1995; 90:740-747 Current and Future Investigations.-Efforts are under way to classify ulcerative colitis and Crohn's disease on 6. Oudkerk Pool M, Ellerbroek PM, Ridwan BU, Goldschmeding R, von Blomberg BM, Pena AS, et al. Serum antineutrophil clinical, pathophysiologic, molecular, and genetic bases. To cytoplasmic autoantibodies in inflammatory bowel disease are do so will require the recognition of different clinical patmainly associated with ulcerative colitis: a correlation study terns of mucosal disease and systemic or extraintestinal corbetween perinuclear antineutrophil cytoplasmic autoantibodies and clinical parameters, medical, and surgical treatment. Gut relates. Individual markers such as pANCA, 45-kd proteins, 1993; 34:46-50 IL-lra production, human leukocyte antigen (HLA) link7. Shanahan F, Duerr RH, Rotter Jl, Yang H, Sutherland LR, ages, and specific genotypes must be applied and compared McElree C, et al. Neutrophil autoantibodies in ulcerative in patients or familial clusters with homogeneous patterns of colitis: familial aggregation and genetic heterogeneity. Gasdisease rather than loosely assembled or arbitrarily ascribed troenterology 1992; 103:456-461 populations. Eventually, the inflammatory bowel disease 8. Griffin MG, Miner PB. Review article: refractory distal colitis-explanations and options. Aliment Pharmacol Ther community will "catch up" to rheumatologists, who can now 1996; 10:39-48 predict the course and therapeutic requisites of rheumatoid 9. Weyand CM, Hicok KC, Conn DL, Goronzy n. The influence arthritis on the basis of HLA subtype at the "hypervariable of HLA-DRB 1 genes on disease severity in rheumatoid arthriregion."? From this point forward, the goal should be to tis. Ann Intern Med 1992; 117:801-806
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.