INFLAMMATORY BOWEL DISEASE - PART 8 pot

256 Keith and Sitrin Chapter 13 / Manifestations of IBD 257 257 From: Clinical Gastroenterology: Inflammatory Bowel Disease: Diagnosis and Therapeutics Edited by: R. D. Cohen © Humana Press Inc., Totowa, NJ 13 Extraintestinal Manifestations of Inflamamtory Bowel Disease Elena Ricart, MD and William J. Sandborn, MD CONTENTS INTRODUCTION PATHOGENESIS MUSCULOSKELETAL MANIFESTATIONS DERMATOLOGIC MANIFESTATIONS HEPATOBILIARY MANIFESTATIONS OCULAR MANIFESTATIONS RENAL/UROLOGIC MANIFESTATIONS PANCREATIC MANIFESTATIONS PULMONARY MANIFESTATIONS CARDIAC MANIFESTATIONS NEUROLOGIC MANIFESTATIONS HEMATOLOGIC MANIFESTATIONS METABOLIC AND ENDOCRINE MANIFESTATIONS SUMMARY REFERENCES INTRODUCTION Ulcerative colitis (UC) and Crohn’s disease (CD) are associated with a wide variety of extraintestinal manifestations (EIM) that often make their management difficult and are significant causes of morbidity and mortality (Fig. 1). An EIM can occur before, concomitant with, or after 258 Ricart and Sandborn the diagnosis of the specific type of inflammatory bowel disease (IBD), and in some cases may even follow surgical removal of the diseased bowel. Large case studies have demonstrated that between 25% and 35% of patients with either type of IBD will have at least one EIM (1,2). Multiple EIMs may occur in the same patient with the triad of joint-eye- skin involvement being the most common. There have been several attempts to classify the EIMs of IBD (Table 1). Greenstein classified them into three groups according to the location of intestinal inflammation: colon related (joint, eye, skin, and oral mani- festations); small bowel related (malabsorption, nephrolithiasis, cholelithiasis); and nonspecific manifestations (osteoporosis, liver dis- ease, amyloidosis) (1). An alternative classification based on the Fig. 1. Extraintestinal Manifestations of Inflammatory Bowel Disease Chapter 13 / Manifestations of IBD 259 inflammatory bowel activity divided EIMs into three categories: those related to the intestinal disease activity that usually respond to treat- ment of the underlying bowel disease (colitic arthritis, episcleritis, erythema nodosum); those whose course appears to be independent of the underlying bowel disease activity (ankylosing spondylitis, pyoderma gangrenosum, primary sclerosing cholangitis); and those that are a direct result of the presence of diseased bowel (fistulas, ureteral obstruction, nutritional deficiencies) (3). This chapter provides an overview of the clinical aspects of the more common extraintestinal manifestations associated with UC and CD. PATHOGENESIS Little is known about the basis for the different organ distribution and the characteristic combinations of EIMs in IBD patients. While some extracolonic manifestations have clear etiologic factors (e.g., cholelithi- asis, fistulous communications, or side effects of drugs used to treat IBD), the pathophysiology of the main groups of EIM is not clearly understood, and both autoimmunity and genetic susceptibility seem to play an important role. Several observations support the importance of autoimmunity in the pathogenesis of the EIM in IBD: relationship between EIM and the extent of colonic involvement, association of IBD with a number of autoimmune diseases (e.g., psoriasis, rheumatoid arthri- tis, thyroid diseases), increased incidence of autoimmune disorders in Table 1 Classification of EIM of IBD 1. According to the location of intestinal inflammation a a. Colon-related manifestations: joint, eye, skin, and oral manifestations b. Small bowel related manifestations: malabsorption, cholelithiasis, genitourinary manifestations c. Nonspecific manifestations: osteoporosis, liver disease, amyloidosis 2. According to the inflammatory bowel activity b a. Bowel disease activity related: colitic arthritis, episcleritis, erythema nodosum b. Bowel disease activity unrelated: ankylosing spondylitis, pyoderma gangrenosum, primary sclerosing cholangitis c. Direct result of diseased bowel: fistulas, ureteral obstruction, nutritional deficiencies a Greenstein AJ, Janowitz HD, Sachar DB. The extraintestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients. Medicine 1976;55:401–411. b Monsen U, Sorstad J, Hellers G, Johansson C. Extracolonic diagnosis in ulcerative colitis: an epidemiological study. Am J Gastroenterol 1990;85:711–716. 260 Ricart and Sandborn patients with UC compared to the general population, clinical response of EIM to immunosuppressive therapy, and humoral and cellular abnor- malities in patients with IBD (activation of complement, presence of antineutrophilic cytoplasmic antibodies (ANCAs) in patients with UC and primary sclerosing cholangitis, and autoantibodies against pancreas, skin, and intestinal extracts) (4–7). The importance of genetic suscep- tibility is supported by the observation that the incidence of EIM is higher in familial IBD (8). Whatever genetic or environmental factors initiate IBD, the presence of altered mucosal permeability, reduced oral tolerance, cytokine imbalances, and influx of protein sequences allow constant stimulation of an abnormally regulated inflammatory reaction. Increased permeability of endothelial cells allows the combination of bacteria, their antigens and metabolic products, proinflammatory cytokines, and activated lymphocytes and neutrophils to get into the gen- eral circulation. Distant organs, such as the eyes or the peripheral joints, lose their normal immunologic tolerance and develop an inflammatory response that corresponds to an extraintestinal manifestation (9). MUSCULOSKELETAL MANIFESTATIONS Peripheral arthritis, axial arthropathy, and ankylosing spondylitis are the three more important patterns of musculoskeletal manifestations in patients with IBD. Peripheral colitic arthritis is the most common EIM in IBD and occurs in about 20% of patients. A recent clinical classification describes two types of peripheral arthropathy that are immunogenetically distinct entities: type 1 (pauciarticular) is related to HLA-B27 and is an acute, self-limiting arthropathy lasting a median of 5 wk, affects less than five joints, correlates with relapses of IBD, and is strongly associated with both erythema nodosum and uveitis; type 2 (polyarticular) is a sym- metrical seronegative polyarthropathy not associated with HLA-B27, that runs a course independent of IBD, affects more than five joints, tends to cause persistent symptoms with a median duration of 3 yr, and is associated with uveitis but not with other extraintestinal manifesta- tions (10,11) (Table 2). Both forms are migratory, and nondeforming arthritis that mostly affect the large joints of the lower extremities. The knees are most commonly affected followed by the hips, ankles, wrists, and elbows, and less often the hands and shoulders. The involved joints are swollen, erythematous, warm, and painful. The risk for peripheral arthri- tis increases with the amount of involved colon, although episodes of acute arthritis have been reported in patients with disease limited to the rectum, or after a colectomy with ileoanal anastomosis (12). Treat- Chapter 13 / Manifestations of IBD 261 ment of peripheral arthropathy associated with IBD should be directed toward decreasing gut inflammation; and total proctocolectomy usually resolves it. If joint symptoms persist, additional therapies may include nonsteroidal antiinflammatory agents (NSAIDs), intraarticular corti- costeroid injections, and physical therapy. NSAIDs should be used with caution because exacerbation of IBD with NSAID has been reported (13). Axial arthropathy occurs in 3–5% of IBD patients. It frequently pre- sents before identification of IBD and does not parallel bowel disease activity. It involves sacroiliac joints (more frequently), spine, hips, and shoulders. Asymptomatic sacroiliitis is a common radiographic finding, but this entity may also be a cause of low back pain. Most of the patients with sacroiliitis are HLA-B27 negative and do not progress to ankylosing spondylitis (14). Ankylosing spondylitis (AS) affects 3–6% of patients with IBD, whereas 2%–18% of patients with AS have associated IBD (15). It is related to HLA-B27 in 50–80% of patients compared to over 90% of those with non-IBD associated AS (16). Typical symptoms of AS include insidious onset of back pain and morning stiffness. The pain typically exacerbates with rest and relieves with exercise. Progression of the disease is variable and does not run parallel to the severity of bowel symptoms. In early cases, radiographs may be normal or show only minimal sclerosis, whereas in advanced cases there are squaring of vertebral bodies, and marginal syndesmophytes leading to bony prolif- eration and ankylosis called “bamboo spine” (Figs. 2A,B). Treatment for AS with IBD is the same as for idiopathic AS, and includes NSAIDs and physiotherapy, with some reported benefits with other agents includ- Table 2 Classification of Peripheral Arthropathy in Inflammatory Bowel Disease Type 1 (pauciarticular) - Less than five joints - Acute, self-limiting attacks (<10 wk) - Associated with relapses of IBD - Strongly associated with extraintestinal manifestations of IBD Type 2 (polyarticular) - Five or more joints - Symptoms usually persist for months to years - Runs a course independent of IBD - Associated with uveitis, but not with other extraintestinal manifestations Adapted from Orchard TR, Wordsworth BP, Jewell DP. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998;42:387–39. 262 Ricart and Sandborn Fig. 2. (A) and (B) Ankylosing Spondylitis. Spine radiographs of a patient with long-standing ankylosing spondylitis showing squaring of vertebral bodies, marginal and symmetric syndesmophytes, and bilateral sacroiliitis. ing sulfasalazine, methotrexate, and azathioprine. Proctocolectomy does not affect AS (14). Recent reports suggest marked improvement with the anti-tumor necrosis factor agents etanercept and infliximab. Chapter 13 / Manifestations of IBD 263 Numerous other rheumatic conditions have been reported in patients with IBD (15): osteomalacia and osteoporosis (secondary to vitamin D and calcium deficiency from impaired dietary intake, malabsorption, or corticosteroid use), hypertrophic osteoarthropathy, polymyositis, iso- lated atlantoaxial subluxation, and avascular necrosis of the hip second- ary to corticosteroids use. Fig. 2. Continued 264 Ricart and Sandborn DERMATOLOGIC MANIFESTATIONS More than 40 different dermatologic manifestations have been des- cribed in IBD (17). The incidence of dermatologic manifestations varies from 9% to 19%, with a higher incidence when the large intestine is involved (1,18). Conversely, an increased risk of pouchitis after total colectomy with ileal pouch anal anastomosis has been reported in patients with extraintestinal manifestations, particularly on the skin and the eyes (19). Erythema nodosum (EN) and pyoderma gangrenosum (PG) are the most common dermatologic conditions observed. EN appears in up to 9% of patients with UC and 15% of patients with CD (17). It usually reflects increasing bowel activity, but not severity or extent of the bowel disease. EN presents as one or several hot, red, tender, and symmetri- cally distributed subcutaneous nodules, generally on the extensor sur- faces of the lower legs but occurring also on the ankles, calves, thighs, and arms (Fig. 3). Approximately 75% of patients developing EN also present with peripheral arthritis. Most lesions usually respond to medi- cal or surgical treatment of the bowel disease; however, recurrences are common and may be seen after colectomy (20). PG has been associated classically with UC with a reported incidence of 5% of patients with UC, although it can also occur in CD, particularly in Crohn’s colitis. PG develops commonly during earlier stages of IBD, but does not show any relation to the clinical activity of the bowel disease. PG begins as pustules or fluctuant nodules that increase rapidly involving adjacent areas of healthy skin. Lesions then ulcerate showing violaceous edges delimited by a margin of erythema (Fig. 4). Lesions can be single or multiple and vary in size and location, although they occur more frequently on extensor surfaces of the lower limbs or other sites susceptible to trauma (surgical scars, and skin adjacent to ileo- stomy can often be the site for PG). Up to 50% of patients with PG have associated manifestations involving joints and/or eyes. Total colectomy, dapsone, cyclosporine A, and more recently thalidomide and infliximab have been found to be effective for the treatment of PG (20–22). Aphthous stomatitis appears in 20% of CD patients and in 5% of UC patients. Oral lesions occur spontaneously, with or without rela- tion to the bowel disease activity and, in general, cause minimal dis- comfort, although some patients may complain of debilitating pain. Treatment regimens have included systemic or topical steroids, immunosuppressives, clofazimine, dapsone, and cyanoacrylate adhe- sive. Thalidomide, chloroquine, and infliximab can be tried for patients with refractory lesions (22). Chapter 13 / Manifestations of IBD 265 Metastatic Crohn’s disease (MCD) is a rare cutaneous manifestation defined as the presence of granulomatous dermatitis occurring distant from, or non-contiguous with, the bowel lesions in CD. Clinical presen- tation may be diverse and includes genitalia ulcerations, papules and nodules of trunk and extremities, ulcerating and nonulcerating plaques, and hidradenitis or erysipelas-like facial eruption (23) (Figs. 5A,B). Therapy for MCD includes corticosteroids, dapsone, sulfasalazine, aza- thioprine, 6-mercaptopurine, metronidazole, and in resistant cases, hyperbaric oxygen (17). Most recently, the chimeric monoclonal anti- body anti-TNF α, infliximab, showed efficacy in two cases of therapy- resistant perineal MCD (24). Other skin manifestations include vesiculopustular eruption and pyoderma vegetans that occur mainly in UC; aphthous ulcers, necrotiz- ing vesiculitis, and cutaneous polyarteritis nodosa which are more com- mon in CD; and other autoimmune diseases such as psoriasis, vitiligo, and epidermolysis bullosa acquisita. Other cutaneous changes are caused by nutritional deficiencies. Acrodermatitis enteropathica, as a Fig. 3. Erythema Nodosum. The lesions of erythema nodosum are character- ized as raised, red, tender subcutaneous nodules characteristically located on the anterior tibial surfaces of the lower extremities. (Adapted with permission from: Callen, Greer, Hood, Paller, Swinyier. Color Atlas of Dermatology. W.B. Saunders, Philadelphia, PA, 1993.) 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