Cutaneous manifestations of gastrointestinal disorders. Part II

JOURNA.l

of the

AmeRiCaN ACaDemy OF

DerMaTOLOGY VOLUME 26

NUMBER 3

MARCH 1992

Continuing medical education Cutaneous manifestations of gastrointestinal disorders. Part II Brian Gregory, MD, FRCrC, and Vincent C. Ho, MD, FRCPC

Vancouver, British Columbia, Canada The cutaneous manifestations of inflammatory bowel disorders, vascular disorders of the gastrointestinal tract, celiac disease, and bowel-associated dermatosis-arthritis syndrome are reviewed. The significance ofthese signs, guidelines for their management, and investigations are discussed. (J AM ACAD DERMATOL 1992;26:371-83.) Many gastrointestinal tract (GIT) disorders have cutaneous manifestations that may be the presenting feature. Dermatologists should be familiar with these signs and symptoms, their medical significance, and the appropriate investigations and management of both the cutaneous and extracutaneous manifestations. In part I ofthis article ( 1992;26: 15366) we discussed the GIT polyposis syndromes and GIT malignancies. In part II, the cutaneous manifestations of bowel disorders, vascular disorders of the GIT, celiac disease and bowel-associated dermatosis-arthritis syndrome are reviewed. CUTANEOUS MANIFESTATIONS OF INFLAMMATORY BOWEL DISORDERS

Ulcerative colitis and Crohn's disease These two disorders share several cutaneous manifestations and therefore are considered in the same section. Differences between the two are delineated. Ulcerative colitis and Crohn's disease are the two major forms of inflammatory bowel disease (IBD).

\tI

TheCME articles are made possible through an educational grant from the Dermatological Division, Ortho Pharma· \J) ceutical Corporation. From the Division of Dermatology, University of British Columbia. Reprint requests: Vincent C. Ho, MD, 855 West 10th Ave" Vancouver, B.C., Canada V5Z 117.

ORTHO

16/2/32407

Ulcerative colitis is a chronic, recurrent, inflammatory and ulcerative disease of the colon that manifests most frequently as bloody diarrhea. Colonic involvement begins distally in the rectum and is continuous without any intervening normal mucosa; inflammation is confined to the mucosa without penetration to deeper layers. Ulcerative colitis usually begins in young adulthood but may start at any age. Its incidence is five cases per 100,000 POp~ ulation. 1 Disease activity is intermittent in approximately two thirds of patients and continuous in one third. In approximately 5% of the patients the disease has a rapid and fulminant course. 2 Serious complications include toxic megacolon, perforation, and a greater than tenfold increase in risk of colonic carcinoma over that of the general population. 2 Crohn's disease differs from ulcerative colitis in several ways: (l) any part of the GIT from the mouth to the anus may be affected; (2) the disease is often discontinuous, with normal "skip areas" separating areas of severely diseased gut; (3) the inflammation extends throughout all the layers of the GIT wall and may involve the mesentery and regional lymph nodes; (4) the rectum is often spared although anal and perianal lesions are present in most patients; and (5) histology reveals granulomatous inflammation that does not occur in ulcerative colitis. 3 Crohn's disease may begin at any age but most often the onset is between 15 and 40 years of age.

371

372 Gregory and Ho Table I. Cutaneous manifestations of inflammatory bowel diseases Specific lesions Fissures and fistulas (more common in CD than DC) Oral CD (specific for CD) Metastatic CD (specific for CD) Reactive lesions Erythema nodosum (more common in DC than CD) Pyoderma gangrenosum (more common in DC than CD) Aphthous ulcers (more common in DC than CD) Vesiculopustular eruption (described only in DC) Pyoderma vegetans (described only in DC) Necrotizing vasculitis (more common in DC than CD) Cutaneous polyarteritis nodosa (described only in CD) Miscellaneous associations Epidermolysis bullosa acquisita Clubbing Vitiligo Psoriasis Secondary amyloidosis Bowel-associated dermatosis-arthritis syndrome Cutaneous manifestations secondary to disease complications Secondary to malabsorption-acrodermatitis entero pathica (zinc), scurvy (vitamin C), purpura (vitamin C and K), pellagra (niacin), stomatitis-glossitis-.:.-angular cheilitis (vitamin B), nonspecific eczema and dry skin (? essential fattyacids), abnormal hair and nails (protein) Cutaneous manifestations secondary to treatment Drug eruption Peristomal dermatitis CD, Crohn's disease; UC, ulcerative colitis.

The incidence is 10 to 20 cases per 100,000 population and has been increasing in recent decades. Manifestations include chronic diarrhea, pain, fever, weight loss, and the development of abscesses, fistulae, strictures, and bowel obstruction. Extraintestina1 manifestations of arthritis, episcleritis, and uveitis are common. The disease is characterized by a chronic course punctuated by exacerbations and remissions. Serious complications such as perforation, sepsis, inanition, or carcinoma are rare. 3 Cutaneous manifestations are common in IBD. In an early study, the incidence was reported to be as high as 34%.4 However, this study included urticaria, maculopapular eruptions, pigmentary abnormalities, and palmar erythema, which may not be closely related to the bowel disorder. Recent studies provide a more reasonable estimate of cutaneous involvement in patients with ulcerative colitis

Journal of the American Academy of Dermatology

(9% to 19%) and Crohn's disease (9% to 23%).5-7 Greenstein et al.,? in a study of 498 patients with Crohn's disease, noted that cutaneous manifestations are more common when the large intestine is involved. Mucocutaneous manifestations of IBD may be classified as specific lesions, reactive lesions, and miscellaneous associations (Table I). For completeness, cutaneous manifestations secondary to malabsorption8 or treatment should also be included. Specific lesions refer to those lesions that are due to direct involvement of the skin by the same disease process that affects the GIT. This includes fissures, fistulas, and metastatic Crohn's disease. In contrast, reactive lesions do not show the same pathologic features as are found in the GIT but represent a reaction to the underlying IBD. The pathogenesis of reactive lesions remains speculative; some may be immunologically mediated because of cross-antigenicity between the skin and the gut. 5 In this article, only the more common and important specific and reactive cutaneous manifestations of IBD will be discussed. The reader is referred to other recent reviews for discussion of the cutaneous signs caused by malabsorptive states or treatment complications of IBD.8-13 Specific cutaneous lesions of ulcerative colitis and Crohn's disease Fissures and fistulas. Fissures and fistulas are probably the most common cutaneous manifestations and may be the presenting complaint in Crohn's disease. In contrast, they occur infrequently in ulcerative colitis. The most commonly affected site is the perineum, especially the perianal region, although peristomal skin and the abdominal wall may also be affected. In a study of 569 patients with Crohn's disease, perianal fissures and fistulas were found in 36% of patients. 14 Only 25% of those patients with small bowel disease alone had perianal involvement, whereas more than 40% of patients with colonic involvement demonstrated such findings. 14 The perianal fissures and fistulas of IBD are typically multiple and involve the anus circumferentially. They are usually associated with marked edema and chronic inflammation. Abscesses, undermined ulcers, and skin tags or pseudoskin tags formed by edematous skin are often present on the perineum. Histologic examination of the perianal inflammatory lesions shows transmural inflammation with lymphoid aggregates and frequently multiple granulomas characteristic of Crohn's disease.

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373

Fig. 1. Oral Crohn's disease. Patient with Crohn's disease has deep ulcer on side of the tongue. Histologically, this lesion is identical to bowel lesions of Crohn's disease. Fig. 2. Pyoderma gangrenosum in patient with ulcerative colitis. Small vesiculopustules (top) rapidly enlarge to form ulcers with violaceous border (bottom).

Oral Crohn's disease. Uncommonly, Crohn's disease may affect the oral mucosa, which shows edema, a cobblestone appearance, ulcerations, and tiny nodules identical in appearance to the bowe1lesions when viewed endoscopically (Fig. I). The ulcers are often tiny, occasionally linear, and may resemble aphthous ulcers. Nodules are most commonly found on the gingival and alveolar mucosa. IS A biopsy specimen of these oral mucosal lesions reveals granulomas and inflammatory changes characteristic of Crohn's disease. 15 Metastatic Crohn's disease. Metastatic Crohn's disease refers to nodules, plaques, or ulcerated lesions that demonstrate a granulomatous histology identical to that of the bowel disease and that are located in the skin and subcutaneous tissue at sites distant from GIT lesions of Crohn's disease. Metastatic cutaneous Crohn's disease is rare. The usual location is on extremities or in intertriginous areas, although any area may be involved. On the legs these lesions may mimic erythema nodosum.1 6 Reactive cutaneous lesions of mD Erythema nodosum. Erythema nodosum typically presents as tender red nodules on the anterior aspect of the lower legs that gradually resolve in several weeks. Erythema nodosum has been reported in 1% to 10% of patients with ulcerative coli-

a reasonable figure is probably 4%.1 The incidence is about 1% to 2% in patients with CD. I , 18, 19 It appears to occur more often in female patients. It may appear before the diagnosis of IBD or in conjunction with a flare-up ofthe IBD and may occur in atypical locations and in chronic forms. I, 5 In children it may be the most common extracolonic manifestation of the disease. 18 IBD-associated erythema nodosum is usually responsive to bed rest, systemic or intralesional corticosteroids, nonsteroidal antiinflammatory agents, potassium iodide, colchicine, and/or dapsone. I Pyoderma gangrenosum. Pyoderma gangrenosum usually begins with small papules, pustules, or hemorrhagic blisters that rapidly enlarge and ulcerate with dusky undermined edges (Fig. 2). These may occur anywhere on the skin but most frequently are located on the lower extremities. Patients may give a history of preceding minor trauma to the area. Lesions are sterile and contain a dense dermal infiltrate of neutrophils. Pyoderma gangrenosum has been noted in approximately 5% of patients with ulcerative colitis and is roughly three times more common with ulcerative colitis than with Crohn's disease. I, 20 However, one series found a higher incidence of pyoderma gangrenosum in Crohn's disease; it occurred in 8% of these patients. I ApproxitiS4-7 , 17;

374 Gregory and Ho mately 50% of patients with pyoderma gangrenosum have underlying ulcerative colitis. I, 18 This makes ulcerative colitis by far the most common identifiable underlying cause. The course of IBOassociated PG tends to parallel that of the underlying GIT disorder,5, 6 but some authors have emphasized that sometimes the course of pyoderma gangrenosum may be independent of the bowel disease I and may even begin years before the onset of bowel symptoms. 21 Oral aphthous ulcers. The association of aphthae with IBD is well known. The incidence has been estimated at 8% and 6% in patients with ulcerative colitis and Crohn's disease, respectively. The cause of these aphthae is probably multifactorial; in some patients, they may result from deficiencies of iron, folic acid, andjorvitamin B l2 . Aphthous ulcers associated with IBD cannot be differentiated from common aphthous ulcers clinically or histologically. Vesiculopustular eruption. A vesiculopustular eruption that can be localized or generalized has been described in some patients with ulcerative colitis. 22 The lesions consist of grouped erythematous vesiculopustules (3 to 5 mm) that sequentially crust and heal with postinflammatory hyperpigmentation. Some authors consider this to be an abortive form of pyoderma gangrenosum5, 18; cases have been reported in which most lesions of a vesiculopustular eruption have evolved while a few lesions developed into typical pyoderma gangrenosum.23,.24 Histologic examination reveals intraepidermal neutrophilic abscesses with mixed inflammatory dermal inilltrates. 22 Pyoderma vegetans. Pyoderma vegetans has been described in several patients with ulcerative colitis. 22, 25, 26 It initially appears mainly in intertriginous areas with vegetating plaques and vesiculopustules that resolve with postinflammatory hyperpigmentation; mucosal involvement may also occur (pyostomatitis vegetans). Histologically, the main features are pseudoepitheliomatous hyperplasia and intraepidermal abscesses that contain neutrophils and eosinophils. Pyoderma vegetans may also represent an incomplete form of pyoderma gangrenosum. 5,27 Cutaneous vasculitis and polyarteritis nodosa. Cutaneous vasculitis is a rare cutaneous manifestation of IBD.28 Both necrotizing (leukocytoc1astic) vasculitis and benign cutaneous polyarteritis nodosa have been reported; the former is more commonly

Journal of the American Academy of Dermatology

associated with ulcerative colitis whereas polyarteritis nodosa has been documented only in association with Crohn's disease. Necrotizing vasculitis presents as palpable purpura, ulcerations, and even gangrene. I The usual sites of involvement are the legs and acral areas. Mixed cryoglobulinemia may sometimes be demonstrated in these patients. Histologic examination shows typicalleukocytoc1astic vasculitis with leukocytoclasia, hemorrhage, and vessel wall damage. Cutaneous polyarteritis nodosa is characterized by tender or painful erythematous nodules, which often ulcerate. They are typically located on the legs but may affect other areas of the body. The lesions can be clinically mistaken for erythema nodosum, metastatic Crohn's disease, or pyoderma gangrenosum. 29 The biopsy specimen reveals a necrotizingleukocytoclasticpanarteritis that may show granulomatous features when associated with Crohn's disease. 28-34 Associated features of cutaneous polyarteritis nodosa include starburst livedo reticularis, peripheral neuropathy, arthralgias, and myalgias; severe systemic involvement does not occur. Cutaneous polyarteritis nodosa runs a benign but recurreht and chronic course that is usually unrelated to the activity of the bowel disease I , 28, 29; it usually presents after the diagnosis of Crohn's disease has been established I but may occur before the diagnosis of IBO.32 Circulating immune complexes have been demonstrated and may contribute to the pathogenesis. 29,33

Miscellaneous associations Epidermolysis hullosa acquisita. There appears to be a greater than chance association between this disorder and IBO, especially Crohn's disease. Epidermolysis bullosa acquisita is an acquired chronic blistering disorder that occurs mainly on the knees, elbows, hands, and feet. It is mediated by antibody deposition and immune activation at the dermoepidermal junction (Fig. 3). There are several case reports that demonstrate a link between epidermolysis bullosa acquisita and Crohn's disease. 35 -38 When it occurs in relation to Crohn's disease, it usually begins many years after the onset of the bowel disease; it may be best considered a long-term complication of Crohn's disease. 32 Other associations. Reactive eruptions such as erythema multiforme and urticaria may occur in patients with IBO.I, 18 These may be due in part to a response to the disease or its treatment. An increased incidence ofthromboembolic events, clubbing, psoriasis, and vitiligo has also been noted in

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Skin manifestations of gastrointestinal disorders. II. 375

patients with IBD.1, 18,39-43 The association of psoriasis and vitiligo with IBD may be related to HLA linkage rather than a true cause-and-effect relation. 18 Secondary amyloidosis may rarely develop in the setting of chronic inflammatory disorders. Bowel-associated dermatosis-arthritis syndrome are discussed later in this article. Management of cutaneous lesions of ulcerative colitis and Crohn's disease In general, therapy should be directed at the underlying IBD. This may include sulfasalazine, antibiotics, parenteral hyperalimentation, corticosteroids, and immunosuppressants such as azathioprine, cyclophosphamide, and cyclosporine. 44-47 Bowelsurgery may be necessary. Management ofthe cutaneous lesions of IBD such as erythema nodosum and pyoderma gangrenosum is otherwise the same as for their non-IBD-associated counterparts. Recently, cyclosporine has been found to be highly efficacious in the treatment of IBD-associated as well as non-IBD-associated pyoderma gangrenosum. 48 Metastatic cutaneous CD may respond to intralesional corticosteroids.1 8 Diverticulitis Diverticulitis is an inflammatory disease of the colon caused by inflammation of one or more diverticula that presents with abdominal tenderness and pain, fever, leukocytosis, and occasionally rectal bleeding. The disorder may be acute, recurrent, or chronic and may be complicated by fistulas, obstruction, perforation, and peritonitis. In 1988, Klein et a1. 47 documented three patients with diverticulitis in whom the disorder was accompanied by pyoderma gangrenosum and arthritis. Medical treatment, including intralesional and systemic corticosteroids, hyperbaric oxygen, and immunosuppressive agents, was ineffective whereas surgical resection of the bowel involved with diverticulitis resulted in prompt and complete resolution. 49 It has been suggested that the cutaneous manifestations of diverticulitis, ulcerative colitis, and Crohn's disease may have a common pathogenetic mechanism that is still unknown. Hermansky-Pudlak syndrome Hermansky-Pudlak syndrome is a rare autosomal recessive disorder most prevalent in Puerto Rico and in the southern Netherlands. It consists of the triad of tyrosinase-positive albinism, a bleeding diathesis resulting from a platelet storage pool defect, and ac-

Fig. 3. Bullae and milia in patient with epidermolysis bullosa acquisita and Crohn's disease.

cumulation of ceroidlike material in the mononuclear phagocytic system. An inflammatory colitis has been documented in up to one third of patients with this disorder. 50 Although this syndrome has been described variously as ulcerative colitis5o or Crohn's disease I , a recent case report and analysis of the literature by Sherman et al. 51 concluded that this is a unique form of IBD.51 Clinically, patients had signs, symptoms, and endoscopic findings consistent with ulcerative colitis.52 However, the pathologic features resembled Crohn's disease with transmural noncaseating granulomatous inflammation; nevertheless, the characteristic involvement of terminal ileum was not present.51,52 That this may be a unique inflammatory bowel disorder is further corroborated by the fact that the typical cutaneous manifestations of ulcerative colitis and Crohn's disease have not yet been documented in patients with this form of colitis. l , 50, 51 The cutaneous features of HermanskyPudlak syndrome include hypopigmentation of the skin, hair, and irides; increased numbers of pigmented nevi and freckles; other evidence of actinic damage, including premalignant and malignant cutaneous neoplasms; nystagmus and photophobia; and history and signs of easy bruising and bleeding.so Present management is preventive and symptomatic.

376 Gregory and Ho CUTANEOUS MANIFESTATIONS OF VASCULAR DISORDERS OF THE GIT Hereditary hemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia, or OslerWeber-Rendu disease, is a systemic fibrovascular dysplasia in which telangiectases, arteriovenous malformations, and aneurysms may develop. 53 Manifestations of hereditary hemorrhagic telangiectasia include recurrent epistaxis and GIT bleeding as well as problems secondary to pulmonary, central nervous system, and hepatic arteriovenous malformations. Although this is known to be an autosomal dominant-inherited disorder, between 18% and 46% of cases occur without a known family history. 54 Its prevalence is 1 to 2 per 100,000 population. 53 Epistaxis is the most common manifestation of hereditary hemorrhagic telangiectasia and occurs in 80% of cases.53, 54 It starts early in childhood and is often the presenting sign. 54 GIT bleeding, which occurs in 13% to 40% of cases, is the second most common sign of hereditary hemorrhagic telangiectasia and usually begins after 50 years of age. Bleeding arises from nodular angiomas similar in form and size to those found on the skin; these are predominantly located in the stomach and duode~ num. 54, 55 A characteristic anemic halo may surround lesions viewed endoscopically.54 Severe hemorrhagic anemia and even death may occur as a result of OIT bleeding. 53 , 56 The most distinctive cutaneous feature is the numerous sharplydermarcated macular telangiectases, 1 to 3 rom in diameter, located on the face, lips, tongue, palate, nares, ears, hands, chest, and feet. The lesions are usually macular but may also be papular.56 Telangiectasia usually begins in the third decade of life but rarely may be extensive in early childhood.53, 56 Histologic examination demonstrates irregularly dilated capillaries in the papillary dermis, along with degenerative changes in the perivascular supporting tissue. 56 The main clinical differential diagnosis for the dermatologist is the CREST variant ofsc1eroderma, which may demonstrate similar cutaneous findings years before the onset of any systemic features 57 and which may also be accompanied by bleeding from gastrointestinal telangiectases.58 Differential features include (1) a positive family history of HHT; (2) a history of recurrent epistaxis, which is not a feature of CREST syndrome55 ; and (3) negative se-

Journal of the American Academy of Dermatology

rology for antinuclear and anticentromere antibodies, which are regularly present in CREST syndrome but not in hereditary hemorrhagic telangiectasia. 52 Treatment of the cutaneous lesions may be indicated for cosmetic reasons and generally consists of destructive modalities such as electrosurgery or laser therapy. The nasal lesions that cause epistaxis have been successfully treated with topical estrogen to induce squamous metaplasia ofthe septum as well as by laser therapy and by skin grafting (septal dermoplasty).55, 58 Gastrointestinal lesions can be treated endoscopically with electrosurgery and laser therapy; other possible approaches include inhibition of fibrinolysis with E-aminocaproic acid and surgical resection of severely affected GIT segments. 53, 55, 58 Anemia may be treated with iron supplements and transfusions as required. The longterm prognosis is generally good; less than 10% of patients die of complications related to hereditary hemorrhagic telangiectasia. 53 Genetic counseling is important because 50% of the offspring of an affected person may inherit the disorder. The rare homozygous form is usually associated with severe bleeding and early mortality. 59

Blue rubber bleb nevus syndrome Blue rubber bleb nevus syndrome was first used by Bean60 in 1958 to refer to a rare syndrome consisting of cutaneous cavernous hemangiomas and OIT hemangiomas. In a review in 1961, Oranje61 found only 30 cases in the literature. It usually occurs sporadically although familial transmission consistent with autosomal dominant inheritance has been reported. The disorder presents at birth or in early childhood; adult onset has also been· documented. Gastrointestinal lesions of blue rubber bleb nevus syndrome can be located throughout the GIT, but most often are found in the large or small bowel.50 The incidence of bleeding from these hemangiomas is high and iron deficiency anemia is almost always present.55,61 Bleeding is usually microscopic but frank melena Of hematochezia may OCCUf. Intussusception has been reported as a complication of blue rubber bleb nevus syndrome. 6l Besides the GIT, hemangiomas may also be found in the mesentery, liver, lung, eye, and central nervous system, but these lesions usually do not cause significant complications. 61 Cutaneous hemangiomas of blue rubber bleb ne-

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Skin manifestatiOns of gastrointestinal disorders. II. 377

vus syndrome can present as three morphologic types. 5The "blue rubber nipple" is the most characteristic61 and consists of a soft, rubbery tumor that is readily compressed to leave an empty, wrinkled blue sac that rapidly refills with blood. The second type consists of irregular, blue-black, punctate macules on the extremities and trunk that are often tender or painful, perhaps because of smooth muscle contractile elements within the tumors. The third type is large disfiguring hemangiomas that may interfere with limb or organ function and require surgical intervention, including amputation. 61 The histologic features consistent with cavernous hemangioma, although unusual features such as thick fibrous vascular walls, endothelial proliferation, and vascular spaces that abut directly on the epidermis have occasionally been noted. 55 ,61 The lesions of blue rubber bleb nevus syndrome do not regress spontaneously. Therapy is mainly symptomatic. Iron supplementation and transfusions are given as required for anemia. Endoscopically controlled coagulation therapy or GIT surgery is reserved for severe and uncontrollable bleeding. Cutaneous hemangiomas may be treated with laser or sclerosing agents; orthopedic abnormalities may require excision including amputation.55, 61

Kaposi's sarcoma Kaposi's sarcoma is a neoplastic disorder of lymphoreticular and endothelial cell proliferation that occurs most frequently in the skin, but may occur in various organs including the GIT. The epidemic form associated with the human immunodeficiency virus is most prevalent in North America and is the most likely to have gastrointestinal manifestations. 62 Fifty percent to 80% of patients with cutaneous lesions and almost 100% of patients with oral lesions of epidemic Kaposi's sarcoma will have GIT lesions. 62-65 Any part of the GIT may be involved. Clinically and endoscopically the disease may mimic ulcerative colitis and deep biopsies are recommended for definitive diagnosis. 66 Histologic features are similar to those of the skin lesions. Cutaneous lesions of epidemic Kaposi's sarcoma often begin as pink to red-brown macules that develop a deeper color as they enlarge and become papular or nodular. They may occur in any area of the skin and often arise in a multiple fashion, suggesting a multicentric process. The overall incidence of cutaneous Kaposi's sarcoma in patients

with acquired immunodeficiency syndrome (AIDS) is approximately 30%; higher rates occur in homosexual men compared with other risk groups.67 Histologic features include spindle cells forming interlacing bundles or lining vascular slits, the presence of erythrocyte-containing slits or clefts accompanied by ectatic capillaries and lymphatic channels, and hemosiderin deposition. 67 ,68 The prognosis for patients with epidemic Kaposi's sarcoma and AIDS is poor, with a high likelihood of fatal outcome within 2 years. Treatment modalities for cutaneous disease have included local and systemic chemotherapy, radiation therapy, cryotherapy, and interferon alfa; symptomatic or life-threatening GIT disease has also been treated with laser therapy or surgery on occasion.64-67 Henoch-Schoenlein purpura The classic definition of Henoch-Schoenlein purpura is a hypersensitivity angiitis in children, which manifests with palpable purpura, musculoskeletal pain, abdominal pain, and which may be associated with hematuria and renal disease.20, 55 According to the 1990 American Rheumatism Association inclusion criteria, however, a patient has Henoch-Schoenlein purpura when at least two of the following four criteria are present: palpable purpura, granulocytes in vascular walls, age less than 20 years at onset, and symptoms and signs of bowel angina. 69 Depending on the diagnostic criteria, then, approximately 50% to 100% of patients with HenochSchoenlein purpura manifest signs and symptoms of gastrointestinal disease, most commonly crampy abdominal pain. 20, 55, 70-72 GIT bleeding, usually occult, occurs in 40% to 60% of these cases. 70-72 Intussusception or perforation may occur. 71 On occasion GIT symptoms precede the cutaneous findings by days to weeks and can mimic other causes of acuteabdominalpain. 7o, 71 Endoscopic findings may show inflammation and purpuric lesions but are relatively nonspecific. 55, 71 The cutaneous signs of Henoch-Schoenlein purpura consist of palpable purpura usually located on the legs and buttocks, which may exhibit vesiculation, necrosis, and ulceration. 72, 73 These often occur in crops accompanied by constitutional symptoms including fever and malaise. Histologic examination reveals a leukocytoclastic vasculitis with fibrinoid degeneration of superficial dermal capillaries and postcapillary venules. 55 Direct immunofluorescence of early lesions will usually reveal C3 in blood vessel

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Gregory and Ho

Fig. 4. Pseudoxanthoma elasticum shows yellow papules in linear array along sides of neck. Patient has episodic gastrointestinal bleeding.

walls, often accompanied by IgM or IgA68; the presence of IgA is considered a specific feature of classic Henoch-Schoenlein purpura. 55 Henoch-Schoenlein purpura usually resolves spontaneously in several weeks to several months; however, recurrences are common during this period. Uncontrolled studies have claimed that systemic corticosteroids are beneficial, particularly for the GIT symptoms of Henoch-Schoenlein purpura, with resolution within 72 hours of the initiation of treatment. 18,74

Malignant atrophic papulosis of Degos Fewer than 100 cases have been reported of this disorder of the skin, GIT, and central nervous system.7 5-77 It is a nonhereditary disorder that usually affects young adults, although it has appeared in infants and children as well as in middle age. In most patients, GIT involvement will occur sometime during the course of the disease, although it may take years to appear. 76 The small bowel is affected most frequently, in 61 % of patients, but any part of the GIT may be involved. 75 , 76 Gastrointestinal manifestations usually begin several months after the onset of cutaneous signs and include bleeding, cramping, and occasionally perforation or peritonitis. 55 , 77 There is a single case report of a patient who died of ischemic colitis identical pathologically to Degos' disease who did not have any cutaneous lesions. 78 The hallmark cutaneous lesion of Degos' disease

is a firm, pink, dome-shaped papule less than 6 mm in diameter with an atrophic porcelain-white center. These asymptomatic discrete lesions occur in crops and thus appear in different stages ofdevelopment. 77 The lesions have a predilection for the trunk and proximal limbs; the head, palms, and soles are usually spared. 73 , 74 Histologic examination shows epidermal atrophy overlying a wedge-shaped area of dermal necrosis and mucinous degeneration; a deep vessel occluded by a thrombus may be seen at the base of the wedge; a lymphocyte-mediated necrotizing vasculitis has been described. 55, 75·77 Central nervous system manifestations occur in approximately 17% of cases76, 77; these usually occur after the cutaneous lesions have appeared and include headache, hemiparesis, aphasia, cranial nerve involvement including visual deficits, and sensory abnormalities. 77 Rarely, serositis and involvement of other internal organs may occur. Approximately half of patients die of the disease within 3 years after diagnosis, secondary to GIT for central nervous system involvement. 77 There is no proven useful therapy for this disorder. Corticosteroids are probably contraindicated, as they have been implicated in intestinal perforations; heparin and the combination of aspirin and dipyridamole have been beneficial in a few case reports. 75

Pseudoxanthoma elasticum This disorder is characterized by diffuse calcification and degeneration of elastic fibers. Major features include skin lesions, angioid streaks and other degenerative changes of the retina, arterial calcification and hypertension, and gastrointestinal hemorrhage. Both autosomal recessive and dominant forms have been described. 79-81 The disease has been subdivided into four groups: type I dominant and recessive and type II dominant and recessive. The classic form of pseudoxanthoma elasticum, type I recessive, has the highest incidence of GIT disease, whereas type II dominant and type II recessive forms generally do not have visceral involvement. The estimated incidence of pseudoxanthoma elasticum is 0.6 per 100,000 population. 8o GIT involvement usually manifests as upper GIT bleeding. Lower GIT bleeding occurs less often. GIT bleeding typically begins in persons from 20 to 30 years of age55 , 80 but may start earlier and may be the first manifestation of the disease. 8o Radiography

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Skin manifestations ofgastrointestinal disorders. II. 379

is not usually helpful in diagnosis but endoscopy reveals yellow cobblestone-like lesions similar to those seen in the mouth and skin. 55 Cutaneous changes are distinctive. Small yellow papules aggregate to give a "plucked chicken" appearance on the neck and in flexures (Fig. 4). Similar changes are seen on the lips, buccal mucosa, and soft palate. Affected skin is generally soft and lax. 80,81 These changes are usually present by 30 years of age and may rarely be seen in infancy; they are persistent and may be gradually progressive. 80,81 Elastosis perforans serpiginosa occurs in some patients with pseudoxanthoma elasticum. 79 Histologic examination oflesions reveals fragmentation, clumping, and calcification of elastic fibers in the mid and reticular dermis. 79 Eye and arterial involvement are also important features ofpseudoxanthoma elasticum. Ocular manifestations include angioid streaks due to crazing of Bruch's membrane, hemorrhages, choroiditis, and loss of central vision. Involvement of large arteries may lead to hypertension and vessel obstruction. The course of pseudoxanthoma elasticum is gradually progressive. Unfortunately, treatment options are limited and generally restricted to supportive or symptomatic management of complications of the disease. 79-81

Ehlers-Danlos syndrome Ehlers-Danlos syndrome is a group of inherited disorders of collagen that has been classified into many types according to the biochemical abnormality, mode of inheritance, and clinical presentation. The main clinical features are fragility of the skin and blood vessels, hyperelasticity of the skin, and hyperextensibility of the joints. 80 Only type IV, the ecchymotic or arterial form, is strongly associated with gastrointestinal bleeding. 55 Type IV Ehlers-Danlos syndrome is a rare and severe form of the disorder, with both recessive and dominant inheritance patterns. 80 The skin of these patients is thin and translucent. Cutaneous extensibility and joint mobility, however, are minimally increased over that of normal subjects. 55, 80 Fragility of blood vessels is the major problem. Hemorrhage from colon or uterus or rupture of large artery aneurysms are the major causes of death, which usually occurs at an early age. No treatment has been shown to be effective in

type IV Ehlers-Danlos syndrome. Patients and their families should have genetic counseling. CUTANEOUS MANIFESTATIONS OF MISCELLANEOUS DISORDERS OF THE GIT

Celiac disease and dermatitis herpetiformis The relation between these two disorders has been well established since the first observation by Marks et al. 82 in 1966 of proximal small bowel villus atrophy in association with dermatitis herpetiformis. Approximately 1% of patients with celiac disease have dermatitis herpetiformis. Twenty percent of patients with dermatitis herpetiformis have clinically overt celiac disease, whereas another 80% show endoscopic or histologic changes in the jejunum consistent with celiac disease, although no clinical or biochemical abnormalities are found. 82 Celiac disease (celiac sprue, gluten-sensitive enteropathy) is a chronic intestinal malabsorption disorder characterized by intolerance to gluten and a flat jejunal mucosa that improves on a gluten-free diet. Gluten is a protein component found in wheat, rye, barley, and oats; the gliadin fraction of gluten is thought to act as an antigen. Mucosal antibodies bind to the gliadin to form immune complexes that activate an immune response that causes inflammation of and damage to the jejunal mucosa. Gliadin may also act directly as a toxin in persons who genetically lack the ability to metabolize and detoxify the protein. Celiac disease occurs in genetically predisposed persons. 83 Increased frequency of both HLA-B8 and HLA-Dw3 is noted in both celiac disease and dermatitis herpetiformis. 83 The gastrointestinal manifestations of celiac disease include diarrhea, steatorrhea, weight loss, bloating, and other features of malabsorption. Various biochemical tests are available to confirm the diagnosis of malabsorption, such as fecal fat determination and serum levels of carotene and albumin. A jejunal biopsy specimen demonstrates blunting and flattening of the villi and changes in the surface epithelium. 83 IgA antiendomysial antibodies to primate smooth muscle cells are found in the serum of almost 100% of patients with clinically active celiac disease; these may be used diagnostically or to monitor treatment as levels appear to correspond with the severity of the intestinal disease. 84, 85 Dermatitis herpetiformis is a chronic, intensely pruritic dermatosis typically characterized by a

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Fig. 5. Vesiculopustular lesions in patient with bowelassociated dermatosis-arthritis syndrome. Syndrome developed in patient after bowel-bypass surgery. (Courtesy Dr. O. Schlappner, Vancouver, Canada.)

symmetric eruption of grouped vesicles, papulovesides, and excoriations on the elbows and extensor forearms, knees, scalp, and scapular and lumbosacral regions. It most often begins in the third decade. Histologic features of papillary tip microabscesses that progress to form subepidermal blisters are characteristic. Direct immunofluorescence of clinically uninvolved skin almost invariably shows granular deposition of IgA at the dermoepidermal junction. 86 Circulating IgA antiendomysial antibodies have been demonstrated in approximately 70% of patients with dermatitis herpetiformis.84 A dramatic response to the therapeutic administration of dapsone or sulfapyridine may also be considered a useful diagnostic criterion. 18 Concern has been expressed about the relation between celiac disease and intestinal lymphoma. An overall incidence of intestinal lymphoma of 6.9% in patients with celiac disease was observed in one series; intestinal lymphoma occurs rarely in the general population. 86 The lymphoma is most often of large-cell type and located in the jejunal area. It has been suggested that strict adherence to a gluten-free diet may lessen this risk but this has not been clearly established. 86 , 87 The risk of development of intestinal lymphoma in patients with dermatitis herpetiformis is also increased over that of the general population; several reports of this combination have been published. 87-94 Most often these patients have overt celiac disease. Treatment of the gastrointestinal disease, when

Journal of the American Academy of Dermatology

clinically active, requires adherence to a gluten-free diet, usually for life. Adjunctive therapy with systemic corticosteroids, parenteral hyperalimentation, or both may be required. 83 Dermatitis herpetiformis may be treated with dapsone or sulfapyridine; it may also respond to withdrawal of dietary gluten, although this is slower to take effect and has a greater chance of treatment failure, perhaps because of noncompliance. 86 Whether or not dermatitis herpetiformis patients who have dermatitis herpetiformis with subclinical celiac disease should be given a gluten-free diet remains controversia1. 83 , 84 Theoretically, maintenance of a gluten-free diet may lessen the risk of intestinal lymphoma, but as Marks and Shuster95 point out it is difficult to insist on such a measure when the benefits are uncertain, the risks of noncompliance may be slight, and strict adherence to the diet may be arduous.

Bowel-associated dermatosis-arthritis syndrome Up to 20% of patients who have ileojejunal bypass surgery for morbid obesity have a recurrent episodic serum sickness-like illness with a prominent purpuric and pustular eruption; this complex is known as bowel-bypass syndrome.96-I02 Systemic signs and symptoms include arthralgias and arthritis, myalgias, fever and chills, malaise, nephritis, and Raynaud's phenomenon. 99 An identical syndrome has been described in patients who had other GIT diseases including post-Billroth II gastroenterostomy and IBD; for this reason the term bowelassociated dermatosis-arthritis syndrome has been proposed. 98 , 100 This syndrome may be caused by circulating immune complexes that form in response to systemically absorbed bacterial peptidoglycans. 96 ,97 The typical cutaneous lesion is a vesiculopustule (Fig. 5). Lesions occur in recurrent crops at 4- to 6-week intervals; each crop takes about 1 week to resolve. 96-102 Histologic examination reveals papillary edema and subepidermal vesicle formation in early lesions. More established lesions show a dense neutrophilic dermal infiltrate, which may be accompanied by necrotizing vasculitis. Direct immunofluorescence studies have demonstrated deposits of immunoglobulins and complement at the dermoepidermal junction and around vessels. Similarity between these lesions and those of Behget's syndrome, as well as those of the vesicula-

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pustular eruption of ulcerative colitis, has been noted by various authors. 96,97 Treatment ofbowel-associateddermatosis-arthritis syndrome consists of the administration of systemic antibiotics to suppress bacterial overgrowth or surgical restoration of normal bowel anatomy in the case of postileojejunal bypass syndrome. 96 - lOO When bowel-associated dermatosis-arthritis syndrome occurs in relation to bowel disease other than bypass surgery, antibiotic therapy or treatment of the underlying condition may be effective. 98 , 100 REFERENCES 1. Paller AS. Cutaneous changes associated with inflammatory bowel disease. Pediatr Dermatol 1986;3:439-45. 2. Hendrix TR, Bayless TM. Diarrhea and constipation. In: Harvey AM, Johns RJ, McKusick VA, et ai, eds. The principles and practice of medicine. New York: AppletonCrofts, 1980:672-7. 3. Glickman RM. Inflammatory bowel disease: ulcerative colitis and Crohn's disease. In: Braunwald E, Isselbacher KJ, Petersdorf RG, et ai, eds. Harrison's principles of internalmedicine. New York: McGraw-Hill, 1987:1277-87. 4. Samitz MH, Greenberg MS. Skin lesions in association with ulcerative colitis. Gastroenterology 1951;19:476-9. 5. Basler RSW, Dubin HV. Ulcerative colitis and the skin. Arch Dermatol 1976;112:531-4. 6. Edwards FC, Truelove sc. The course and prognosis of ulcerative colitis. Gut 1964;5:1-15. 7. Greenstein AJ, Janowitz HD, Sachar DB. Medicine 1976;55:401-12. 8. Hendricks KM, Walker WA. Zinc deficiency in inflammatory bowel disease. Nutr Rev 1988;46:401-8. 9. Lembcke B. Malabsorption syndromes. Baillieres Clin GastroenteroI1988;2:329-51. 10. Bianchi CA. Cutaneous manifestations of the malabsorption syndrome. Moo Cutan Ibero Lat Am 1984;12:27785. 11. Diongi R. Diagnosing malnutrition. Gut 1986;27(suppl): 5-8. 12. Bhattacharyya AK. Nutritional aspects in pediatric dermatology. Indian J DermatoI1983;28:149-62. 13. Delahoussaye AR. Cutaneous manifestations of nutritional diseases. Dermatol Clin 1989;7:559-70. 14. Rankin GB, Watts HD, Melnyck CS, et al. National cooperative Crohn's disease study: extraintestinal manifestations and perianal complications. Gastroenterology 1979;77:914-20. 15. Bernstein ML, McDonald JS. Oral lesions in Crohn's disease. Report of two cases and update of the literature. Oral Surg 1978;46:234-45. 16. LevineN, BangertJ. Cutaneous granulomatosis in Crohn's disease. Arch DermatolI982;1l8:1006-9. 17. Warren S, Sommers S. Pathogenesis of ulcerative colitis. Am J Pathol 1949;25:657-9. 18. Samitz MH. Dermatologic manifestations of gastrointestinal disease. In: Berk EJ, ed. Gastroenterology. Philadelphia: WB Saunders, 1985:285-315. 19. McCallum Dr, Kinmont PDC. Dermatological manifestations of Crohn's disease. Br J Dermatol 1968;80:1-8.

20. Loeffel ED, Koya D. Cutaneous manifestations of gastrointestinal disease. Cutis 1978;21 :852-61. 21. Powell FC, Perry HO. Pyoderma gangrenosum in childhood. Arch Dermatol 1984;120:757-61. 22. Fenske NA, Gem JE, Pierce D, et al. Vesiculopustular eruption of ulcerative colitis. Arch Dermatol 1983; 119:664-9. 23. Callen JP, Woo TY. Vesiculopustular eruption in a patient with ulcerative colitis. Arch Dermatol 1985; 121:399-404. 24. O'Loughlin S, Perry HO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol 1978; 114:1961-4. 25. Forman L. The skin and the colon. Trans St John's Hosp Dermatol Soc 1966;52:139-62. 26. Johnson ML, Wilson HTH. Skin lesions in ulcerative colitis. Gut 1969;10:255-63. 27. Basler R WS. Ulcerative colitis and the skin. Med Clin North Am 1980;64:941-54. 28. Kahn EI, Daum F, Aiges Hw, et al. Cutaneous polyarteritis nodosa associated with Crahn's disease. Dis Colon Rectum 1980;23:258-62. 29. Chalvardjian A, Nethercott JR. Cutaneous granulomatous vasculitis associated with Crohn's disease. Cutis 1982;30:645-55. 30. Dyer NH, Dawson AM, Verbov JL, et al. Cutaneous polyarteritis nodosa associated with Crohn's disease. Lancet 1970;1:648-50. 31. Feurle GE. Regional enteritis and polyarteritis nodasa. Gastroenterology 1977;72:560-1. 32. Solley GO, Winkelmann RK, Rovelstad RA. Correlation between regional enteritis and cutaneous polyarteritis nodosa: two cases and review of the literature. Gastroenterology 1975;69:235-9. 33. Goslen JB, Graham W, Lazarus GS. Cutaneous polyarteritis nodosa: report of a case associated with Crohn's disease. Arch Dermatol 1983;119:326-9. 34. Verbov J, Stansfeld AG. Cutaneous polyarteritis nodosa and Crahn's disease. Trans St John's Hosp Dermatol Soc 1972;58:261-8. 35. Roenigk HH Jr, Ryan JG, Bergfeld WE Epidermolysis bullosa acquisita: report of three cases and review of all published cases. Arch DermatolI971;103:1-1O. 36. Pegum JS, Wright JT. Epidermolysis bullosa acquisita and Crohn's disease. Proc R Soc Med 1973;66:234. 37. Livden JK, Nilsen R, Thunold S, et al. Epidermolysis bullosa acquisita and Crohn's disease. Acta Derm Venereol (Stockh) 1978;58 :241-4. 38. Ray TL, Levine JB, Weiss W, et al. Epidermolysis bullosa acquisita and inflammatory bowel disease. J AM ACAD DERMATOL 1982;6:242-52. 39. Stapleton SR, Curley RK, Simpson W A. Cutaneous gangrene secondary to focal thrombosis-an important cutaneous manifestation of ulcerative colitis. Clin Exp DermatolI989;14:387-9. 40. YatesVM, Watkinson G, Kelman A. Further evidence for an association between psoriasis, Crohn's disease and ulcerative colitis. Br J Dermatol 1982;106:323-30. 41. Burgdorf W. Cutaneous manifestations of Crahn's disease. JAM ACAD DERMATOL 1981;5:689-95. 42. Fielding JF, Cooke WT. Finger clubbing and regional enteritis. Gut 1971;12:442-4. 43. McPoland PR, Moss RL. CutaneousCrohn's disease and progressive vitiligo. J AM ACAD DERMATOL 1988; 19:421-5.

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44. Lichtiger S, Present DH. Preliminary report: cyc1osporin in treatment of severe active ulcerative colitis. Lancet 1990;336:16-9. 45. Gupta S, Keshavarzian A, Hodgson HJF. Cyclosporin in ulcerative colitis. Lancet 1984;2:1277-8. 46. Allison MC, Pounder RE. Cyclosporine A for Crohn's disease. Aliment Pharmacol Ther 1987;1:39-43. 47. Brynskoff J, Freund L, Rasmussen SN, et al. A placebocontrolled double-blind randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321 :845-50. 48. Matis WL, Ellis CN, Griffiths CEM, et al. Treatment of pyoderma gangrenosum with cyclosporine [Abstract]. 1 Invest DermatoI1991;96:54. 49. Klein S, Mayer L, Present D, et al. Extraintestinal manifestations in patients with diverticulitis. Ann Intern Med 1988;108:700-2. 50. Mosher DB, Fitzpatrick TB, Ortonne J, et al. Disorders of pigmentation. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. Dermatology in general medicine. N ew York: McGraw-Hill, 1987:794-876. 51. Sherman A, Genuth L, Hazzi CG, et al. Perirectal abscess in the Hermansky-Pudlak syndrome. Am J Gastroenterol 1989;84:552-6. 52. Schinella RA, Greco MA, Cobert BL, et al. HermanskyPudlak syndrome with granulomatous colitis. Ann Intern Med 1980;92:20-3. 53. Peery WHo Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). Am J Med 1987;82:989-97. 54. Vase P, Grove O. Gastrointestinal lesions in hereditary hemorrhagic telangiectasia. Gastroenterology 1986; 91 :1079-83. 55. Lamberts RJ. Gastrointestinal hemorrhage and the skin. Dermatol Clin 1989;7:403-18. 56. Champion RH. Disorders affecting small blood vessels: erythema and telangiectasia. In: Rook A, Wilkinson DS, Ebling FlG, et aI, eds. Textbook of dermatology. Oxford: Blackwell, 1986:1081-97. 57. Fritzler MJ, Arlette JP, Behm AR, et al. Hereditary hemorrhagic telangiectasia versus CREST syndrome: Can serology aid diagnosis? J AM ACAD DERMATOL 1984;10:192-6. 58. Allende HD, Ona FV, Noronha AI. Bleeding gastric telangiectasia: complication of Raynaud's phenomenon, esophageal motor dysfunction, sclerodactyly and telangiectasia (REST) syndrome. Am J Gastroenterol 1981; 75:354-6. 59. Snyder LH, Doan CA. Clinical and experimental studies in human inheritance: Is the homozygous form of multiple telangiectasia lethal? J Lab Clin Meel 1944;29:1211-6. 60. Bean WB. Vascular spiders and related lesions ofthe skin. Springfield, Ill: Charles C Thomas, 1958:178-85. 61. Oranje AP. Blue rubber bleb nevus syndrome. Peeliatr DermatoI1986;3:304-10. 62. Guarda LA, Luna MA, Smith JL, et al. Acquired immunodeficiency syndrome: postmortem findings. Am J Clin Pathol 1986;81 :549-57. 63. Nieelt GW, Schinella RA. Acquired immunodeficiency syndrome: clinico-pathological study of 56 autopsies. Arch Pathol Lab Meel 1985;109:727-34. 64. Saltz RK, Kurtz RC, Lightdale CJ, et al. Gastrointestinal involvement in Kaposi's sarcoma [Abstract]. Gastroenterology 1982;82:1168. 65. Lemlich G Schwam L, Lebwohl M. Kaposi's sarcoma j

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in adult celiac disease and idiopathic steatorrhea. Am J Moo 1967;42:899-912. Jenkins D, Lynde CW, Stewart WD. Histiocytic lymphoma occurring in a patient with dermatitis herpetiformis. J AM ACAD DERMATOL 1983;9:252-6. Gjone E, Nordog A. Dermatitis herpetiformis, steatorrhea and malignancy. Br Med J 1970;1:610-2. Anderson H, Dotevall G, Mobacken H. Malignant mesenteric lymphoma in a patient with dermatitis herpetiformis, hypochlorhydria and small-bowel abnormalities. Scand J GastroenteroI1971;6:397-9. Goodwin P, Fry L. Reticulum cell sarcoma complicating dermatitis herpetiformis. Proc R Soc Med 1973;66:625-6. Connon JJ, McFarland J, Kelly A, et al. Acute abdominal complications of coeliac disease. Scand J GastroenteroI1975;10:843-6. Fowler JM, Thomas DJB. Lymphoma in dermatitis herpetiforrnis [Letter]. Br Med J 1976;2:757. Freeman HJ, Weinstein WM, Shnitka TK, et al. Primary abdominal lymphoma as presenting manifestation of celiac sprue or complicating dermatitis herpetiforrnis. Am J Moo 1977;63:585-94. Silk DBA, Mowat NAG, Riddell RH, et al. Intestinal lymphoma complicating dermatitis herpetiforrnis. Br J DermatoI1977;96:555-60.

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95. Marks J, Shuster S. The skin and disorders of the alimentary tract. In: Fitzpatrick TB, Eisen A, WolffK, et aI, eds. Dermatology in general medicine. New York: McGrawHill, 1987:1965-76. 96. Jorizzo JL. Pustular vasculitis: an emerging disease concept [Editorial]. JAM ACAD DERMATOL 1983;9:160-2. 97. Ely PH. The bowel bypass syndrome: a response to bacterial peptidoglycans. JAM ACAD DERMATOL 1980;2:47387. 98. Jorizzo JL, Apisarnthanarax P, Subrt P, et al. Bowelbypass syndrome without bowel bypass: bowel associated dermatosis-arthritis syndrome. Arch Intern Med 1983; 143:457-61. 99. Person JR, Bernhard JD. Autointoxication revisited. J AM ACAD DERMATOL 1986;15:559-63. 100. Dicken CR. Bowel-associated dermatosis-arthritis syndrome: bowel bypass syndrome without bowel bypass. J AM ACAD DERMATOL 1986;14:792-6. 101. Ely PH, Utsinger PD. Clinical observations and immunologic abnormalities following bowel bypass surgery [Editorial]. J AM ACAD DERMATOL 1980;2:529-30. 102. Presser SE, Blank H, Ziboh VA. Essential fatty acid deficiencyafter iIitestinal bypass [Letter]. JAM ACAD DERMATOL 1983;8:127-8.