Department of Pathobiology, University of Connecticut, 61 North Eagleville Road, Unit 3089, Storrs, CT 06269-3089, USA
Academic Editor: Tony C. K. Tham
Special Issue: New and Old Therapeutic Options for Crohn’s Disease
Received: April 05, 2019 | Accepted: September 26, 2019 | Published: September 30, 2019
OBM Hepatology and Gastroenterology 2019, Volume 3, Issue 3, doi:10.21926/obm.hg.1903036
Recommended citation: Van Kruiningen H. Missing the Target to Treat in Crohn’s Disease. OBM Hepatology and Gastroenterology 2019;3(3):7; doi:10.21926/obm.hg.1903036.
© 2019 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
It is fashionable these days to read of treatment toward endoscopic remission or deep remission in Crohn’s disease (CD) and more recently transmural remission  the latter addressing the thickening of the bowel wall as shown by CT. More recently, target to treat is in vogue  and the suggestion that pharmaceuticals might address the fibrosis of CD . Current television ads speak of “treatment of the symptoms of Crohn’s disease”.
It’s troubling to read or hear of such treatment options, when, after all, each misses the real target, the obstructed intestinal lymphatic vasculature [5,6,7,8,9,10,11]. It’s not a cytokine cascade nor an imbalance of microbiome nor dysregulated immune responses that causes Crohn’s disease. There is, and always has been, lymphatic obstruction – just as sure as there’s a thrombus in myocardial infarction, ischemic stroke or peripheral arterial disease (PAD). It would be ludicrous to treat cardiac fibrosis or the skin and fascial damage of PAD with the intent of resolving a cytokine cascade of some sort. It would be ludicrous to treat cerebral artery or carotid thrombosis as though we had to interrupt or enhance some cytokine irregularity and suppress some immune cells. Yet, that’s what’s done in modern gastroenterology to attempt to resolve Crohn’s disease.  We change the immune regulation, and perhaps we give the patient antibiotics or biologics to change the cellular and biochemical traffic. None resolves the irreversibly damaged lymphatic vasculature of Crohn’s disease .
The histopathology of resection specimens demonstrates the damaged vessels in the submucosa, muscularis, and serosa, sometimes also in the mucosa.  In the latter ascertaining the presence or absence of granulomas detracts from what’s really going on beneath. [10,11] Treatment of the surface is of little more than cosmetic value. Textbook descriptions of Crohn’s disease make no mention of lymphatic disease. Is that because the lymphedema is regarded as secondary and resolvable? It is not; the lymphatic damage is the cause of Crohn’s disease. [9,11] Obstructed lymphatics and lymphedema do not occur in other forms of colitis, where they might be expected to occur if they were only secondary to surface damage. The lymphatic damage is not a consequence of surface penetration; it represents primary elephantiasis  – something the early pathologists described (when the lesions were unchanged by steroids, antibiotics or immunosuppressants) [5,6]. Why is there reluctance to accept what great teams of pathologists have described and illustrated?
The pattern of Crohn’s disease is overwhelmingly vascular. If only we had a means to demonstrate the intestinal lymphatic vasculature with contrast media like we do the mesenteric arteries! Unfortunately we don’t have that. Pietro Tonelli recognized the vascular distribution; he, being a surgeon, made us aware of the difference in Crohn’s disease of the jejunum vs that of the ileocolic region, a difference dictated by the mesenteric vascular rete of the respective parts. His illustration, reproduced here  (Figure 1) should appear in every description of Crohn’s disease, along with the words lymphatic obstruction, lymphedema  and, most importantly, elephantiasis .
In the last 10 to 12 years D2-40 immunolabeling of lymphatic endothelium and anti-CD68 labeling of the granulomas make the obstructions clear, at every level, submucosa, muscularis, and serosa [10,11]. Here we present a montage of obstructed lymphatics, the obstructed intestinal lymphatic vasculature of Crohn’s disease (Figure 2).
Figure 1 Diagramatic illustration of long segment ileocecal and short segment jejunal Crohn's disease (left) along with representation of the shorter vasa recta of the jejunum and the longer lymphatic collecting ducts of the ileum (right). Short and long segment lymphatics influence the spatial pattern of inflammatory lesions. Reproduced with permission from P. Tonelli .
Obstructed lymphatic vasculature also occurs in metastatic Crohn’s disease. [13,14,15,16,17] There is elephantiasis of the part or parts, be they male genitalia, vulva, lips or oral cavity. The obstructed lymphatics shown by Alexakis et al and those before him are identical to those of intestinal Crohn’s disease. [14,15,18] Metastatic CD sometimes precedes, sometimes follows, the intestinal disease. That CD occurs in these locations, where there is no abscessation, fistulas, or microbiome attests to the vascular basis of disease. For these reasons, metastatic Crohn’s disease may be a better place to define etiopathogenesis.
Del Gaudio recognized the lymphatic defect and attempted to bring new lymphatics to anastomotic sites by wrapping them with omentum.  While an admirable idea, expecting that lymphatics would grow from omentum into subserosa, muscularis, and submucosa was perhaps unreasonable, and not very successful.
Perhaps a cutout of our montage should be mounted in the offices of gastroenterologists, similar to the photos of macular degeneration that adorn every ophthalmologist’s exam room. How many obstructed lymphatics will resolve? Will biologics resolve the issue? If surgery is done, will unseen foci of lymphangitis and lymphedema occur in parts left intact, above or below the site of anastomosis? Can we expect that lymphatics will anastomose with one another when the edges of a resection are pulled together? If biologics or immune suppressants kill a few granuloma cells in an obstructed vessel will that have any value?
Figure 2 A montage of obstructed lymphatics, from resection specimens of patients with Crohn’s disease. Some stained with haematoxylin and eosin, others immunolabeled with D2-40 antibody to demonstrate lymphatic endothelium. Original magnifications 200 or 400X.
BigPharma might be called upon to create animal models of obstructed lymphatic vasculature, similar to the pig model described recently.  Current mouse models do not reproduce the primary lesion of Crohn’s disease; they merely create cell and cytokine inflammatory reaction. [21,22] Endothelial cells can be grown in cell culture and perhaps even grown in tubules. But then, in search of a model system, one would need to induce granulomas within those tubules; not any easy task, but closer to a real model of Crohn’s disease. And, not a model created with beads or caustic chemical agents, as in the past. It must be added that an in vitro model would not address contractility as in vivo systems would, nor the return of function or lack of it after experimental obstruction and lysis of same.
What are we to do? Presently, we can’t demonstrate obstructed lymphatic vasculature with contrast agents, MRI, US or standard or cross-sectional CT. And, if we could demonstrate them, how would modern medicine (or surgery) respond? Endoscopists might benefit from sitting with pathologists and seeing the D2-40 labeled lymphatics in resection specimens for themselves; they won’t see them in endoscopic biopsies because biopsies are too superficial. Perhaps Pietro Tonelli can be recognized for having shown us the vascular basis of Crohn’s disease. Descriptions and lectures might acknowledge that “Crohn’s disease is a segmental elephantiasis of the intestine, and sometimes other body parts”.
The author thanks Dr. Antonio Garmendia for manuscript review and Jeremy Doucette for help with the montage.
HJ Van Kruiningen has been supported by the Broad Medical Research Foundation.
The author declares no financial conflict.
- Serban ED. Treat-to-target in Crohn's disease: Will transmural healing become a therapeutic endpoint? World J Clin Cases. 2018; 6: 501-513. [CrossRef]
- Bouguen G, Levesque BG, Feagan BG, Kavanaugh A, Peyrin-Biroulet L, Colombel JF, et al. Treat to target: a proposed new paradigm for the management of Crohn's disease. Clin Gastroenterol Hepatol. 2015; 13: 1042-1050. e1042. [CrossRef]
- Danese S, Bonovas S, Lopez A, Fiorino G, Sandborn WJ, Rubin DT, et al. Identification of endpoints for development of antifibrosis drugs for treatment of Crohn's disease. Gastroenterology. 2018; 155: 76-87. [CrossRef]
- Van Kruiningen HJ. Missing the target to treat in Crohn's disease. Clin Gastroenterol Hepatol. 2015; 13: 2381-2382. [CrossRef]
- Warren S, Sommers SC. Cicatrizing enteritis (regional ileitis) as a pathologic entity: Analysis of one hundred and twenty cases. Am J Pathol. 1948; 24: 475-501.
- Van Patter WN. Pathology and pathogenesis of regional enteritis. Minneapolis: PhD Dissertation, University of Minnesota; 1952.
- Warren S, Sommers SC. Pathology of regional ileitis and ulcerative colitis. JAMA. 1954; 154: 189-193. [CrossRef]
- Mooney EE, Walker J, Hourihane DO. Relation of granulomas to lymphatic vessels in Crohn's disease. J Clin Pathol. 1995; 48: 335-338. [CrossRef]
- Tonelli P. Il Linfedema dell'Intestino (malattia di crohn). Nicola Gd, editor. Napoli: Global Press S.R.L.; 2001. 407 p.
- Sura R, Colombel JF, Van Kruiningen HJ. Lymphatics, tertiary lymphoid organs and the granulomas of Crohn's disease: an immunohistochemical study. Aliment Pharmacol Ther. 2011; 33: 930-939. [CrossRef]
- Van Kruiningen HJ, Hayes AW, Colombel JF. Granulomas obstruct lymphatics in all layers of the intestine in Crohn's disease. APMIS. 2014; 122: 1125-1129. [CrossRef]
- Colombel JF, Narula N, Peyrin-Biroulet L. Management Strategies to improve outcomes of patients with Inflammatory Bowel Diseases. Gastroenterology. 2017; 152: 351-361. e355. [CrossRef]
- Murphy MJ, Kogan B, Carlson JA. Granulomatous lymphangitis of the scrotum and penis. Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation. J Cutan Pathol. 2001; 28: 419-424. [CrossRef]
- Saracino A, Gordon K, Ffolkes L, Mortimer PS. Intralymphatic granulomas in lymphoedema secondary to anogenital granulomatosis. Australasian J Dermatol. 2013; 54: 59-61. [CrossRef]
- Alexakis C, Gordon K, Mellor R, Chong H, Mortimer P, Pollok R. Ano-genital granulomatosis and Crohn's disease: A case series of males presenting with genital lymphoedema. J Crohn's Colitis. 2017; 2017: 454-459. [CrossRef]
- Laftah Z, Bailey C, Zaheri S, Setterfield J, Fuller LC, Lewis F. Vulval Crohn's disease: A clinical study of 22 patients. J Crohns Colitis. 2015; 9: 318-325. [CrossRef]
- Sanderson J, Nunes C, Escudier M, Barnard K, Shirlaw P, Odell E, et al. Oro-facial granulomatosis: Crohn's disease or a new inflammatory bowel disease? Inflamm Bowel Dis. 2005; 11: 840-846. [CrossRef]
- Murphy M, Kogan B, Carlson J. Granulomatous lymphangitis of the scrotum and penis. J Cutan Pathol. 2001; 28: 419-424. [CrossRef]
- Del Gaudio A, Bragaglia R, Boschi L, Del Gaudio G, Accorsi D. A new approach in the management of Crohn's disease: Observations in 20 consecutive cases. Hepatogastroenterolgy. 1997; 44: 1095-1103.
- Van Kruiningen HJ. An infectious pig model of Crohn's disease. Inflamm Bowel Dis. 2016; 22: 2106-2111. [CrossRef]
- Pizarro TT, Arseneau KO, Bamias G, Cominelli F. Mouse models for the study of Crohn's disease. Trends Mol Med. 2003; 9: 218-222. [CrossRef]
- Cominelli F, Arseneau KO, Rodriguez-Palacios A, Pizarro TT. Uncovering pathogenic mechanisms of Inflammatory Bowel Disease using mouse models of Crohn's disease-like ileitis: What is the right model? Cell Mol Gastroenterol Hepatol. 2017; 4: 19-32. [CrossRef]