Crohns Disease and Ulcerative Colitis

Maria T. Abreu and Junsuke Maki

Department of Medicine, Division of Gastroenterology, Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, New York, U.S.A.

■ Introduction 298

■ Definition 298

■ Epidemiology 298

■ Pathogenesis 298

■ Clinical Manifestations 299

■ Treatment 304

■ Complications 304

■ References 305

INTRODUCTION

Crohn's disease (CD) and ulcerative colitis, collectively part of the inflammatory bowel diseases (IBD), are both diseases of the gastrointestinal tract that arise in genetically susceptible individuals. Both CD and ulcerative colitis, though clinically different entities, are thought to be part of a spectrum of diseases where environmental and immunologic factors determine the extent and severity of clinical manifestations.

DEFINITION

These disorders are characterized by a loss of controlled mucosal immune responses, leading to acute and chronic inflammation within the gut. Ulcerative colitis is restricted to the mucosa of the colon and a colectomy is curative. CD can manifest in any portion of the intestinal tract but predominantly affects the distal ileum and colon.

EPIDEMIOLOGY

The incidence and prevalence of both CD and ulcerative colitis depend significantly on geographic locations and ethnic background. The countries of North America and northern Europe, which include most of the industrialized nations, encompass the highest rates of disease activity. In North America, the incidence of CD and ulcerative colitis ranges from 3.1 to 14.6 and 2.2 to 14.3 cases per 100,000 person-years, respectively. The prevalence rates range from 26 to 199 cases for CD and 37 to 246 cases for ulcerative colitis per 100,000 persons (1). Comparatively, South America, Asia, and Africa represent regions of low incidence and prevalence of IBD, although there seems to be an increasing incidence in these areas, as well. Within these geographic variations, there are also ethnic and racial differences in the incidence of IBD. CD and ulcerative colitis are estimated to be four to eight and two to four times higher in Jewish populations, respectively (2). Even within the Jewish population, IBD is seen more frequently in Americans and Europeans of Ashkenazi descent, compared with those of Sephardic and Oriental Jews of Asian or African origin. In the United States, the African American population has remained significantly lower in overall incidence and prevalence compared with Caucasians, but the differences seem to be diminishing.

Studies indicate that over the past few decades, the incidence of ulcerative colitis and CD has stabilized in areas of high incidence but continues to rise in other geographic locations (1). It is hard to say if these overall increases are true increases in incidence related to changes in environmental factors, or whether there is increased reporting and better diagnostic techniques used for diagnosis.

The age of onset for both CD and ulcerative colitis ranges from 15 to 40 years. Some studies further suggest a bimodal age distribution with a lesser peak between the ages of 55 and 65 years (3). The etiology of the second peak remains to be elucidated. Some data also indicate a higher incidence of ulcerative colitis among men and a higher incidence of CD among women. It is unclear whether environmental factors play a role in the differences found between the two genders.

PATHOGENESIS

A family history of IBD increases the risk of developing CD or ulcerative colitis. Roughly, 15% of IBD patients have had at least one first-degree relative affected by IBD (4). It is now believed that IBD is a heterogeneous disease involving genetic, immunologic, and environmental factors. Research models have suggested an inappropriate immunologic response at the mucosal level against normally symbiotic gut bacterial flora. CARD15, a gene found on the IBD1 loci on chromosome 16, was the first gene to be associated with CD. It is a cytosolic protein expressed in monocytes that functions as a receptor for intracellular liposaccharides and is an activator of nuclear factor kappaB. In approximately 15% of Crohn's patients, there is a mutation of CARD15, resulting in an aberrantly functioning protein that may lead to chronic gut inflammation. Since only a small portion of the Crohn's population has this defective gene mutation, it is assumed that several other mechanisms are involved in the activation of the mucosal immune response.

CLINICAL MANIFESTATIONS

Extraintestinal manifestations associated with IBD may occur months to years before the onset of intestinal disease. Approximately 25% to 33% of patients with IBD are reported to have some type of extraintestinal manifestation (5). In most cases, however, these manifestations are found concurrently with or after the diagnosis of disease. Although CD and ulcerative colitis are found under the heading of IBD, the associations of extraintestinal manifestations are not equally distributed between the two diseases. The majority of these manifestations are associated with CD, but there are certain disorders that affect both diseases equally.

Pathophysiology of Extraintestinal Manifestations

The etiology of extraintestinal manifestations is a topic that is still not well understood; however, there is data supporting the concept of a dysregulation of mucosal defenses in the intestinal tract of IBD, leading to a systemic inflammatory response in extraintestinal sites. There is also evidence suggesting that an important initiating factor in the pathogenesis of IBD resides in intestinal bacterial products and foreign proteins interacting with local mucosal defenses. Interestingly, animal studies in HLA B-27 transgenic mice grown in germ-free environments do not exhibit either intestinal or extraintestinal pathology (6). There are also genetic considerations that go hand in hand with these immunologic factors. Connections between certain major histocompatibility complexes (MHC) and IBD have been well known, but studies also indicate that certain extraintestinal manifestations are also associated with specific MHC loci. HLA-A2, HLA-DR1, and HLA-DQw5 are all associated with extraintestinal manifestations related to CD, and HLA-DR103 has been associated with patients with ulcerative colitis (7).

Ocular Manifestations

Although ocular manifestations in IBD are found in less than 10% of patients with CD and ulcerative colitis (8), they are often overlooked or mistaken for other ocular disorders and can cause significant morbidity in patients who do not receive proper therapy. Many of the ocular complaints are nonspecific and may include tearing, burning, pruritis, ocular pain, photophobia, blurry vision, and blindness. Ocular pathology associated with IBD has also been linked to other extraintestinal manifestations, especially those involving joints.

Conjunctivitis is a common cause of red eyes in the general population, and it may share many of the symptoms of IBD-related ocular disease; however, conjunctivitis is never acutely painful. Although conjunctivitis is common in IBD populations, there is no known correlation between conjunctivitis and IBD. Since eye pathology in IBD can mimic benign eye conditions, physicians must take extra care in making correct diagnoses.

Episcleritis. Inflammation of the episclera is the most common ocular manifestation of IBD and is found in roughly 2% to 5% of IBD patients (9). It is more commonly seen in patients with CD, especially when the colon is involved. Episcleritis is usually seen during flares of systemic IBD and generally subsides with resolution of intestinal symptoms. Episcleritis should be suspected in patients with complaints of eye irritation, burning, or redness in one or both eyes during an IBD flare. The eye examination may reveal areas of focal or diffuse redness interspersed with patches of white sclera between the dilated episcleral vessels. Treatment is dependent on the severity of eye disease and its associated intestinal disease activity. Cold compresses and topical steroids in conjunction with appropriate intestinal treatment are usually sufficient and resolve the problem rapidly. There have been recent case reports in patients with active CD and refractory episcleritis, who have responded to infliximab (Fig. 1) (11).

Uveitis. Uveitis is not seen as commonly as episcleritis, only occurring in 0.5% to 3% of the IBD population; however, the morbidity associated with uveitis is far greater than that of episcleritis. It is associated with arthralgias and skin manifestations; therefore, in any patient presenting with ocular findings along with skin or joint symptoms, uveitis must be considered. Unlike episcleritis, uveitis can occur during periods of gastrointestinal flares or quiescence and may sometimes even precede the initial IBD symptoms. It is therefore vital to elicit any type of eye symptom when evaluating a patient with IBD. Affected individuals complain of eye pain, blurry vision, photophobia, and headaches caused by an inflammatory reaction of the vascular coat of the eye. In anterior uveitis, the iris and ciliary body are affected. These patients often exhibit painful eyes with photophobia and blurry vision. In a seriously affected eye, there may be an abnormal pupillary light reflex due to a fixed miotic eye. Although less common than anterior uveitis, posterior segment uveitis does occur. Posterior uveitis includes areas affected from the vitreous to the retina; therefore, these patients present differently from those patients affected with anterior uveitis (8). The patient with posterior uveitis presents with acute changes in visual acuity and should be evaluated with a slit lamp for a definitive diagnosis. Untreated long-term complications of uveitis include glaucoma and cataracts secondary to intraocular adhesions, macular dysfunction, and papillary abnormalities. Treatment of uveitis includes topical steroids and cycloplegics, but systemic corticosteroids and other immunosuppressants are often

required. Recent case reports have shown the success of infliximab for the treatment of acute uveitis (Fig. 2) (12). Chapter 6 contains a detailed discussion of uveitis.

Scleritis. Scleritis is an uncommon but severe ocular finding in IBD and may cause deterioration of vision. The diagnosis may precede or occur after onset of intestinal symptoms. These patients often complain of severe eye pain that is tender to palpation. Unlike conjunctivitis or episcleritis, the deeper vascular beds are affected in scleritis, causing dilated vessels set on a pink sclera. This condition, if left untreated, can cause retinal detachment and optic nerve edema, and therefore requires prompt evaluation by an ophthalmologist. Treatment includes aggressive therapy with systemic corticosteroids, immunosuppressants, and Non-Steroidal Anti-Inflammatory Drug to deter loss of vision.

Other Ocular Conditions. Although rare, there are other ocular pathologies associated with IBD. Some of these include par planitis, keratitis, retinitis, central and retinal artery occlusions, central retinal vein occlusions, optic neuritis, and retinal vasculitis (13). Side effects from IBD treatment, especially systemic corticosteroids, also cause ocular pathology. Chronic use of steroids can cause cataracts, increased intraocular pressure, and open-angle glaucoma (this is more often caused by topical steroids) (14). It is important that patients on chronic steroid usage be evaluated regularly by an ophthalmologist.

Oral Manifestations

Oral lesions are common in both CD and ulcerative colitis. Intraoral pathology is seen in roughly 9% of patients diagnosed with CD (15). Aphthous ulcers and angular stomatitis are findings frequently seen in IBD patients. Aphthous ulcerations in CD tend to be widespread and severe, and they may present prior to intestinal disease activity or result as a consequence of intestinal pathology. It should be noted, however, that these conditions are also found commonly in the general population and therefore are nonspecific for IBD. Pyostomatitis vegetans, a pustular lesion with cobblestoning appearance, mucosal tags, mucogingivitis, and persistent rubbery lip swelling are some of the specific findings associated with CD. In a retrospective study done in children with CD, inspection of the oral cavity by a dentist yielded an increased number of oral CD, suggesting an underestimated percentage of patients with extraintestinal (oral) CD (16). In addition, a recent study involving 49 children with CD found roughly 40% of patients with oral disease specific to CD when evaluated by a pediatric dental surgeon. Of the 30 patients with oral CD, only nine patients (45%) were identified to have oral CD by gastroenterologists. Interestingly, patients with oral CD were more likely to have perianal disease compared to those with nonoral CD (50% vs. 17%, p = 0.023) (Fig. 3) (18).

Orofacial granulomatosis is a syndrome comprised of a spectrum of conditions with possibly numerous etiologies that all contain noncaseating granulomas in the oral cavity

FIGURE 2 Acute anterior uveitis. Source: From Ref. 10.

FIGURE 2 Acute anterior uveitis. Source: From Ref. 10.

FIGURE 3 Mucogingivitis in relation to the maxillary permanent incisors. Source: From Ref. 17.

and face similar or identical to lesions found in CD. It is a clinical finding that includes cheilitis granulomatosis, Melkersson-Rosenthal syndrome, and sarcoidosis (19). Cheilitis granulomatosa is an idiopathic inflammatory disorder and is considered a variant of Melkersson-Rosenthal syndrome. It is associated with swelling of one or both lips, angular cheilitis, and noncaseating granulomatous lesions on histology. A rare extraintestinal manifestation, the diagnosis of cheilitis granulomatosa often precedes the diagnosis of Crohn's by several years. Treatment of cheilitis granulomatosa consists of local intralesional injections of triamcinolone or systemic corticosteroids (20).

In ulcerative colitis, oral manifestations, including ulcers similar to pyoderma gangrenosum and other hemorrhagic lesions, may be present. In over 50% of oral ulcers found in IBD, topical steroids have proven successful. With refractory oral lesions, systemic corticosteroids, azathioprine, and methotrexate have been used with good results (21).

Aural Manifestations

Sensorineural hearing loss (SNHL) has been reported in both CD and ulcerative colitis. Although there is no clear-cut association between IBD and SNHL, there have been numerous case reports in other types of autoimmune diseases such as rheumatoid arthritis (Chapter 1), systemic lupus erythematosus (Chapter 1), Wegener's granulomatosis (Chapter 8), and primary Sjögren's disease (Chapter 2). In 1979, McCabe reported 18 patients with progressive bilateral hearing loss, which he coined autoimmune SNHL (22). Since then, there have been a few case reports of SNHL with IBD, and growing evidence reveals a higher incidence found in ulcerative colitis than in CD. Notably, however, a study in 1982 found a higher incidence of SNHL in patients with Crohn's colitis (11/20) than in those with CD of the small bowel (0/5) (23).

In ulcerative colitis, there seem to be two types of hearing loss: a mild subclinical type and a severe type that leads to deafness. The pathogenesis of SNHL in both ulcerative colitis and CD is still unknown, but is postulated that a T lymphocyte mediated response, an immune complex deposition, or a vasculitis affecting the inner ear is responsible. SNHL at this point is a clinical diagnosis, because there is very little laboratory data to confirm the diagnosis; however, recent studies have reported certain antibodies that link SNHL with IBD. In one case report, antibodies directed against collagen type II, located in the inner ear, were found in a patient with CD (24). There is also growing evidence for an anti-68 kDa antibody found in patients with rapidly progressive SNHL in ulcerative colitis. Recent studies have focused on the utility of bovine heat shock protein (bHSP) 70 in treatment of corticosteroid-responsive SNHL. A bHSP assay study found that sera taken from patients with suspected autoimmune inner ear disease was low in sensitivity (42%) but highly specific (92%) with a positive predictive value of 91% (25). These findings suggest a possible immune-mediated response with SNHL, especially with ulcerative colitis. Most of these patients respond well to systemic corticosteroids, with or without the addition of immunosuppressants, as long as therapy is initiated rapidly. Given the treatable nature of SNHL, along with the complications associated with use of corticosteroids and immunosuppressants, it is important to find a useful diagnostic tool for this condition. SNHL is discussed in detail in Chapter 28.

Nasal Manifestations

There has been limited information regarding the connection between IBD and sinonasal disease. Case reports have described patients with parasinusitis with polypoidal changes, bilateral nasal congestion without ulceration or polyposis, nasal stenosis, and chronic nasal congestion with crusting, all of which resolved with oral corticosteroid treatment. A cross-sectional study in IBD patients at a tertiary care outpatient clinic explored the possible relationship between IBD and chronic sinonasal disease. The study concluded there was an elevated prevalence of sinonasal disease in IBD, especially in those patients with CD, who had experienced obstructive bowel complications (26). Although the increased prevalence of sinonasal disease in IBD could be an extraintestinal manifestation of IBD, there is little data at this time to suggest a relationship between the two.

Laryngeal Manifestations

Although rare extraintestinal manifestations of IBD, upper airway disease has been described in association with IBD. In most cases of laryngeal pathology, the disease is found after gastrointestinal diagnosis, but there have been some cases where it has preceded the development of IBD. Subglottic stenosis has been associated with other granulomatous diseases such as sarcoidosis and tuberculosis, but there have been case reports linking it to IBD (27). Cough and voice hoarseness are some of the symptoms associated with subglottic stenosis. Nonspecific edema with ulcerations of the larynx has also been found in patients with CD and ulcerative colitis (28). Treatment includes intravenous steroids for patients with airway compromise from subglottic stenosis and oral corticosteroids for most other forms of laryngeal pathology. For refractory cases of laryngeal disease, infliximab has been used with good results (29).

Dermatologic Manifestations

Erythema Nodosum and Pyoderma Gangrenosum. Skin disorders associated with IBD occur in roughly 15% of the population (30). The two most common skin manifestations associated with IBD are erythema nodosum and pyoderma gangrenosum. The former parallels intestinal disease activity and treatment is usually directed at controlling bowel symptoms. Erythema nodosum is usually located on the extensor surfaces of the extremities, especially the anterior tibial surface. Pyoderma gangrenosum parallels IBD activity in 50% of cases and typically is seen in the lower extremities but can develop anywhere on the body.

Metastatic Crohn's Disease. Metastatic Crohn's disease (MCD) is a rare condition that involves cutaneous noncaseating granulomatous lesions distant from the affected intestinal tract. It is considered a primary inflammatory process seen outside of the gut. The lesions are typically dermal inflammatory reactions with multinucleated giant cells, histiocytes, and epithelioid cells. These lesions usually present in patients with established disease. MCD is often observed in patients in their forties or older with colonic and rectal involvement where granulomatous lesions are seen most commonly in the anterior abdominal wall. There have, however, been some case reports involving the malar area, retroauricular folds, and forehead (31,32). MCD responds well to mesalmine and oral corticosteroids, and some case reports show good response with infliximab (33).

Sweet's Syndrome. Sweet's syndrome, or acute febrile neutrophilic dermatosis, is a rare condition associated with both CD and ulcerative colitis, although it is seen with certain types of cancer, as well. It is classically characterized by fever, tender red plaques, leukocytosis, and neutrophilic infiltrate with leukocytoclasis on histology. The tender plaques usually involve all extremities and the face, including ocular symptoms such as conjunctivitis and iridocyclitis. Women are commonly more affected than men, and symptoms usually coincide with intestinal disease activity (34). Most patients respond to systemic corticosteroids. There has been one case report of a patient who developed Sweet's syndrome after use of azathioprine in Crohn's colitis (35).

TREATMENT

Treatment of each manifestation in this chapter is discussed in the individual section for that manifestation.

COMPLICATIONS

Several different types of medications are used to treat a range of disease pathology in both CD and ulcerative colitis. The common complications resulting from medical therapy are listed in Table 1. The most frequent head and neck side effects are caused by steroid therapy. Patients who use steroids for ocular pathology are at risk for increased intraocular pressure. Although the exact mechanism is unknown, it is believed there is activation of steroid receptors in the trabecular meshwork, resulting in increased deposition of extracellular material (36,37). One study has reported that a six-week course of potent topical steroid therapy increased intraocular

TABLE 1 Head and Neck Complications Associated with Medical Therapeutics in

Inflammatory Bowel Diseases

TABLE 1 Head and Neck Complications Associated with Medical Therapeutics in

Inflammatory Bowel Diseases

Medications

Complications

Frequency

Mesalamine

Rhinitis

5%

Tinnitus

<1%

Conjunctivitis

<2%

Eye pain and blurry vision

<1%

Alopecia

<1%

Corticosteroids

Cataracts

2.5-60%

Increased intraocular pressure (topical)

20%

Methotrexate

Alopecia

3-10%

Photosensitivity

3-10%

Stomatitis

3-10%

Cyclosporine

Hirsutism

0-2%

Gingival hyperplasia

4-6%

Source: Data extracted from various sources including Micromedex and Moseby's Drug Consult 2005.

Source: Data extracted from various sources including Micromedex and Moseby's Drug Consult 2005.

pressure by >5 mmHg in roughly 20% of the study population (17). In most cases, discontinuation of steroid therapy decreases intraocular pressure to normal levels.

REFERENCES

1. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004; 126(6):1504-1517.

2. Gilat T, Grossman A, Fireman Z, et al. Inflammatory bowel disease in Jews. In: McConnell R, Rosen P, Langman M, et al., eds. The Genetics and Epidemiology of Inflammatory Bowel Disease. Basel, Switzerland and New York, NY: Karger, 1986:135-140.

3. Ekbom A, Helmick C, Zack M, et al. The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden. Gastroenterology 1991; 100(2):350-358.

4. Weterman IT, Pena AS. Familial incidence of Crohn's disease in The Netherlands and a review of the literature. Gastroenterology 1984; 86(3):449-452.

5. Lichtenstein DR, Park PD, Lichtenstein GR. Extraintestinal manifestations of inflammatory bowel disease. Probl Gen Surg 1999; 16(2):23-39.

6. Rath HC, Herfarth HH, Ikeda JS, et al. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human ß2 microglobulin transgenic rats. J Clin Invest 1996; 98(4):945-953.

7. Roussomoustakaki M, Satsangi J, Welsh K, et al. Genetic markers may predict disease behavior in patients with ulcerative colitis. Gastroenterology 1997; 112(6):1845-1853.

8. Mintz R, Feller ER, Bahr RL, et al. Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2004; 10(2):135-139.

9. Petrelli EA, McKinley M, Troncale FJ. Ocular manifestations of inflammatory bowel disease. Ann Ophthalmol 1982; 14(4):356-360.

10. Leibowitz H. Primary care: the red eye. NEJM 2000; 343:345 © 2000 Massachusetts Medical Society.

11. Finkelstein W. Treatment of acute episcleritis associated with Crohn's disease with Infliximab. Am J Gastroenterol 2002; 97:S152.

12. Fries W, Giofre MR, Catanoso M, et al. Treatment of acute uveitis associated with Crohn's disease and sacroileitis with infliximab. Am J Gastroenterol 2002; 97(2):499-500.

13. Matsuo T, Yamaoka A. Retinal vasculitis revealed by fluorescein angiography in patients with inflammatory bowel disease. Jpn J Ophthalmol 1998; 42(5):398-400.

14. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin 1992; 10(3):505-512.

15. Asquith P, Thompson RA, Cooke WT. Oral manifestations of Crohn's disease. Gut 1975; 16(4): 1249-1254.

16. Pittock S, Drumm B, Fleming P, et al. The oral cavity in Crohn's disease. J Pediatr 2001; 138 (5):767-771.

17. Wordinger RJ, Clark AF. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retin Eye Res 1991; 18(5):629-667.

18. Harty S, Fleming P, Rowland M, et al. A prospective study of the oral manifestations of Crohn's disease. Clin Gastroenterol Hepatol 2005; 3(9):886-891.

19. van de Scheur MR, van der Waal RI, Volker-Dieben HJ, et al. Orofacial granulomatosis in a patient with Crohn's disease. J Am Acad Dermatol 2003; 49(5):952-954.

20. van de Scheur MR, van der Waal RI, Bodegraven AA, et al. Cheilitis granulomatosa and optic neuropathy as rare extraintestinal manifestations of Crohn's disease. J Clin Gastroenterol 2002; 34 (5):557-559.

21. Bradley PJ, Ferlito A, Devaney KO, et al. Crohn's disease manifesting in the head and neck. Acta Otolaryngol 2004; 124(3):237-241.

22. McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1979; 88(5 Pt 1):585-589.

23. Loft DE, Dowd AB, Khan MZH, et al. Auditory dysfunction in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1989; 1:129-132.

24. Bachmeyer C, Leclerc-Landgraf N, Laurette F, et al. Acute autoimmune sensorineural hearing loss associated with Crohn's disease. Am J Gastroenterol 1998; 93(12):2565-2567.

25. Bloch DB, Gutierrez JA, Guerriero V Jr, et al. Recognition of a dominant epitope in bovine heat-shock protein 70 in inner ear disease. Laryngoscope 1999; 109(4):621-625.

26. Book DT, Smith TL, McNamar JP, et al. Chronic sinonasal disease in patients with inflammatory bowel disease. Am J Rhinol 2003; 17(2):87-90.

27. Camus P, Piard F, Ashcroft T, et al. The lung in inflammatory bowel disease. Medicine (Baltimore) 1993; 72(3):151-183.

28. Yang J, Maronian N, Reyes V, et al. Laryngeal and other otolaryngologic manifestations of Crohn's disease. J Voice 2002; 16(2):278-282.

29. Ottaviani F, Schindler A, Capaccio P, et al. New therapy for orolaryngeal manifestations of Crohn's disease. Ann Otol Rhinol Laryngol 2003; 112(1):37-39.

30. Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore) 1976; 55(5):401-412.

31. Gilson MR, Elston LC, Pruitt CA. Metastatic Crohn's disease: remission induced by mesalamine and prednisone. J Am Acad Dermatol 1999; 41(3 Pt 1):476-479.

32. Biancone L, Geboes K, Spagnoli LG, et al. Metastatic Crohn's disease of the forehead. Inflamm Bowel Dis 2002; 8(2):101-105.

33. Van Dullemen HM, de Jong E, Slors F, et al. Treatment of therapy-resistant perineal metastatic Crohn's disease after proctectomy using anti-tumor necrosis factor chimeric monoclonal antibody, cA2: report of two cases. Dis Colon Rectum 1998; 41(1):98-102.

34. Kemmet D, Hunter JA. Sweet's syndrome: a clinicopathologic review of twenty-nine cases. J Am Acad Dermatol 1990; 23(3 Pt 1):503-507.

35. Padda S, Ramirez F, Berggreen PJ. Sweet's syndrome associated with the use of azathioprine in a patient with Crohn's colitis. Am J Gastroenterol 1998; 93:A1735.

36. Weinreb RN, Bloom E, Baxter JD, et al. Detection of glucocorticoid receptors in cultured human trabecular cells. Invest Ophthalmol Vis Sci 1981; 21(3):403-407.

37. Wordinger RJ, Clark AF. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retin Eye Res 1991; 18(5):629-667.

Hair Loss Prevention

Hair Loss Prevention

The best start to preventing hair loss is understanding the basics of hair what it is, how it grows, what system malfunctions can cause it to stop growing. And this ebook will cover the bases for you. Note that the contents here are not presented from a medical practitioner, and that any and all dietary and medical planning should be made under the guidance of your own medical and health practitioners. This content only presents overviews of hair loss prevention research for educational purposes and does not replace medical advice from a professional physician.

Get My Free Ebook


Post a comment