98 S. Larsen et al. Review criteria Key messages The search on ‘Crohn’s disease’, ‘inﬂammatory Extraintestinal manifestations are common bowel disease’, or ‘ulcerative colitis’ was combined in inﬂammatory bowel disease (IBD). The with ‘adalimumab’, ‘anemia’, ‘arthritis’, ‘bronchitis’, most prevailing extraintestinal manifesta- ‘cutaneous manifestations’, ‘erythema nodosum’, tions are rheumatic (e.g. peripheral arthritis ‘extraintestinal manifestations’, ‘hyperhomocysteine- and axial arthropathies), dermatologic (e.g. mia’, ‘inﬂiximab’, ‘iridocyclitis’, ‘lung disease’, ‘ocu- erythema nodosum and pyoderma gangreno- lar manifestations’, ‘osteomalacia’, ‘pancreatitis’, sum), ophthalmologic (e.g. episcleritis, irido- ‘primary sclerosing cholangitis’, ‘renal stones’, ‘sul- cyclitis, and uveitis) and hematologic (e.g. fasalazine’, ‘thromboembolism’, and ‘treatment’ and anemia and hyperhomocysteinemia). was performed in the PubMed and Embase data- Among the rarer manifestations are primary bases (cut-off date October 2009). English-languageAnn Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 sclerosing cholangitis, pancreatitis, various reviews, practical guidelines, letters, editorials, and lung disorders, osteoporosis, and thromboe- articles were evaluated. Subsequently, articles were mbolic events. selected based on their clinical relevance, and addi- All those manifestations are cumbersome tional papers were found in their reference lists. for both patients and their physicians because Other sources of information were the Cochrane the diagnostic process may be long and Library and the web sites of the European Agency complex. for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA). Rheumatic manifestations extraintestinal manifestations is often empirical, and For personal use only. the lack of randomized, controlled trials makes it Epidemiology difﬁcult to obtain valid evidence of therapeutic efﬁ- Inﬂammatory arthropathies are among the most com- cacy. However, for many of the more frequent manif- mon extraintestinal manifestations in IBD with a prev- estations, newer biopharmaceuticals have been alence of 10%–35% and are found more commonly shown recently to be effective, e.g. in IBD-associated in patients with Crohn’s disease (CD) (5,6). Asymp- peripheral arthritis, pyoderma gangrenosum, and tomatic sacroiliitis indeed may be seen in up to three- episcleritis. quarters of IBD patients. Careful questioning may also The aim of the present review is to summarize the reveal many patients with a history of swollen joints latest data on epidemiology, clinical features, and treat- and other musculoskeletal symptoms, often preceding ment of extraintestinal manifestations and to serve as the diagnosis of IBD by several years (7). The preva- a guideline for clinical use. lence of axial arthritis varies from 3% to 25% of patients with IBD and may or may not be associated with peripheral arthropathy (7,8). In contrast to the Table I. Extraintestinal manifestations of inﬂammatory bowel disease male predominance in ankylosing spondylitis (AS), (IBD). both sexes are equally represented among patients with IBD-associated spondyloarthropathy (SpA) Rheumatic: Peripheral arthritis Axial arthropathies (Figure 1). In some cases, joint manifestations may Metabolic: Osteopenia/osteoporosis also become apparent years after colectomy in patients Osteomalacia with ulcerative colitis (UC). It is uncertain, however, Dermatologic: Erythema nodosum whether this can be ascribed to memory lymphocytes Pyoderma gangrenosum primed in a previously inﬂamed bowel or, rather, to Aphthous stomatitis Sweet’s syndrome development of a rheumatic disease sui generis. Ophthalmologic: Uveitis Episcleritis Scleritis Symptoms Hepatobiliary: Primary sclerosing cholangitis Both axial and peripheral arthropathies with symp- Cholelithiasis Hematologic: Anemia toms of arthralgia and swollen joints are viewed by Thromboembolic: Hyperhomocysteinemia many as reactive arthritides secondary to intestinal Urinary tract: Nephrourolithiasis infections at least in some IBD patients. The list of pos- Pulmonary: Chronic bronchitis sible etiologic agents includes intracellular bacteria Bronchiectasis (either obligatory or facultative aerobic) and invasive Pancreatic: Pancreatitis Gram-negative bacteria such as Shigella, Salmonella,
Extraintestinal manifestations of IBD 99Ann Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 Figure 1. X-ray showing sacroiliitis. Yersinia, and Campylobacter species. In most cases, often seen parallelism between ﬂare-up of CD and however, there is no evident microbial culprit. peripheral arthritis. Other, albeit indirect, evidence For personal use only. Axial involvement may vary from asymptomatic for a bacterial role in CD-related peripheral arthritis symmetric sacroiliitis to clinically evident inﬂamma- comes from the fact that germ-free B27 transgenic tory low back pain with decreased spinal mobility, rats develop colitis and arthritis only after restoration extending to SpA fulﬁlling AS classiﬁcation criteria of the gut ﬂora (12). and modiﬁcations thereof (9). There are several genetic markers that may be involved, directly or indirectly, as components of extrain- testinal joint and musculoskeletal manifestations in Diagnosis IBD. The human leukocyte antigen (HLA) system, for The arthritides in IBD usually are divided into per- example, is considered one of the major genetic markers ipheral or axial arthropathies. associated with many immunoinﬂammatory diseases, The peripheral arthropathies are characteristically including IBD, and HLA-B27-positive IBD patients seronegative, pauciarticular, asymmetric, migrating, have a signiﬁcantly higher risk of developing axial arthri- and transitory, and they rarely result in joint destruc- tis, including AS. In contrast, B27 is less often associ- tion. However, joint manifestations often are associated ated with peripheral arthropathy in IBD. Indeed, this with enthesopathy, tenosynovitis, and/or dactylitis, complication seems to segregate into at least two phe- which may cause pain and compromise daily activities notypes, each of which with immunogenetically distinct (10). Clubbing, periostitis, and granulomatous lesions features (13). Thus, type 1 arthropathies are associated of joints and bone have been described as well. with HLA-DRB10103, B35, and B27, and type 2 It is thought that reactive arthritis may arise as a arthropathies are associated with B44, suggesting that result of T cell-mediated immune responses to bac- the two types of arthritic complications in IBD may terial antigens and degradation products circulating have different etiopathogenesis. It has also been reported from gut to joint. Although there is no direct evidence that UC patients with the HLA-DRB10103 pheno- to support the theory that viable bacteria colonize type have a higher risk of arthritis (8). the joint, bacterial antigens, including lipopolysac- Altered bacterial handling and gut permeabil- charides, have been detected in blood leukocytes and ity may also be of pathogenic importance for the synovial ﬂuid of patients with reactive arthritis and extraintestinal manifestations of IBD. For example, AS (11). Since T cells reactive to bacterial antigens the CD-susceptibility gene caspase activation and have also been found in the joints of these patients, recruitment domain–containing protein 15 (CARD15)/ it is speculated that naive T cells may have been nucleotide-binding oligomerization domain 2 (NOD2) primed by bacterial antigens in inﬂamed gut mucosa encodes an intracellular pattern recognition recep- in IBD and subsequently recirculate and home to tor with binding afﬁnity for peptidoglycan, a com- joints, causing arthritis (7). This is supported by the ponent of muramyl dipeptide, which is an important
100 S. Larsen et al. bacterial pathogen-associated component (14). Poly- Treatment of axial arthropathies in IBD is also morphisms in CARD15 are known risk factors in CD, focused on reducing the activity of the underlying and these genetic variants also appear to be strongly bowel disease. Therapy is otherwise similar to that used associated with IBD and the presence of SpA (15). in classic AS, i.e. to reduce the inﬂammatory activity Interestingly, the CARD15 mutants associated with and to prevent deformity. NSAIDs are effective in CD are loss-of-function mutants, i.e. they fail to acti- reducing inﬂammation and pain but may not affect vate the inﬂammatory pathway mediated by nuclear progressive spine destruction and may aggravate the factor-kappa B (NFB) (16). Thus the CARD15 intestinal disease. While sulfasalazine has been shown mutations governing IBD and its extraintestinal in several studies to be effective in AS, its effect in manifestations may function through a decreased IBD-associated SpA is less clear, and it may be effec- production of antibacterial polypeptides that, in tive only on peripheral joint involvement (5). While turn, alters the enteric ﬂora and, consequently, gut methotrexate may be effective in AS, concrete evi- permeability and mucosal inﬂammation. dence for effect in IBD-associated AS is scarce (5).Ann Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 A diagnosis of inﬂammatory lower back pain Anti-TNF- drugs, particularly inﬂiximab and adali- should include pain during the night and at rest that mumab, are effective in most IBD patients with SpA, improves with movement, in addition to lack of and these agents are often recommended if patients radiologic abnormalities. A diagnosis of IBD-associ- fail to respond adequately to NSAIDs (19). Physical ated AS includes low back pain and morning stiff- therapies and exercise are as important in these patients ness for more than 3 months associated with a as in other forms of SpA. decreased mobility of the lumbar spine and limita- tion in chest expansion combined with radiologically Metabolic manifestations evident sacroiliitis. HLA-B27 also is heavily associ- ated with AS in cases linked to IBD. Osteopenia and osteoporosis For personal use only. Epidemiology. IBD is associated with an increased Treatment risk of developing osteoporosis (20) (Figure 2). The prevalence rates range from 2% to 30% and, for Treatment of peripheral arthritis in IBD primarily osteopenia, from 40% to 50% (20–22). The T score involves treatment of the underlying intestinal disease. is proposed by the World Health Organization (WHO) This usually improves the joint symptoms, and further as the strongest determinant of fracture risk. T score therapies are unnecessary in mild cases. If arthropathy is deﬁned as the number of standard deviations (SDs) persists seemingly independently of the bowel disease, by which a given bone mineral density (BMD) mea- therapies are similar to those of the primary articular surement exceeds or falls below the normal mean diseases. Hence non-steroidal anti-inﬂammatory BMD of healthy 30-year-old individuals (peak bone drugs (NSAIDs), including cyclooxygenase-2 (COX-2) mass). A BMD that is up to 1 SD below peak bone mass inhibitors, may be used as in patients with rheumatoid is considered normal; at 1–2.4 SDs below peak, BMD arthritis (RA). Caution is advocated, however, because is considered to indicate osteopenia and mild or mod- the gastrointestinal side-effects of NSAIDs may agg- erate bone deﬁciency; at 2.5 SDs or more below peak, ravate the underlying bowel disease, although the evi- BMD is labeled osteoporotic with marked bone deﬁ- dence is weak (7). Today there is insufﬁcient evidence ciency (20). to warrant NSAID avoidance among those IBD patients who really need them for joint symptoms, and Symptoms. Osteoporosis might be without symptoms it is not yet clariﬁed if COX-2 inhibitors are safer than for decades until fractures suddenly occur. Some classical NSAIDs in IBD (17). However, a careful fol- osteoporosis fractures, especially of the back, may even low-up of IBD patients, mainly those in remission, is be without initial symptoms and are ﬁrst diagnosed recommended in the ﬁrst weeks of treatment with at a later stage when pain arises related to the location NSAIDs. At present, further randomized, double- of the fractures. Hip fractures typically occur as a result blinded trials are needed to address this issue further of a trivial accident. Osteopenia is without symptoms, (18). Glucocorticoids, often part of the basic treatment but as this condition progresses, the diagnosis changes regimen, are also highly effective on the arthritic mani- to osteoporosis. festations. In patients with oligoarthritis, local injection The role of glucocorticoids is complex. Some stu- of glucocorticoids is effective as well. Biologic response dies show an important relationship between dosage, modiﬁers, particularly antibody constructs targeted duration, and pattern of glucocorticoid therapy, and against the cytokine tumor necrosis factor (TNF-), these factors are related to the incidence of patho- are effective in about two-thirds of RA patients and will logic fractures (20,23). Other studies report that the also improve peripheral arthritis in most IBD patients IBD and not the use of glucocorticoids relates to the who are responders to biologics. reduced BMD (24,25).
Extraintestinal manifestations of IBD 101Ann Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 Figure 2. The decalciﬁed osteoporotic bone. Disease duration has not been established as a Treatment. It is well known that supplementation signiﬁcant factor for low BMD because some studies with calcium and vitamin D is essential for bone report no effects, whereas others indicate a positive For personal use only. metabolism. Several studies have shown that relationship between length of disease (i.e. duration) calcium and/or vitamin D or its analogs have a and a lower BMD (22,26–30). Furthermore, the dis- small beneﬁt in BMD as well as a small controver- ease activity has no effect on BMD according to sial age-dependent trend (though not totally clear) ﬁndings from some studies, whereas other studies in the reduction of bone fractures, especially of the report that BMD is higher with an increasing dura- spine in postmenopausal women (20,32). All tion of quiescent disease (22,26,31). patients receiving glucocorticoid treatment should Diagnosis. Diagnosis is based on dual X-ray absorp- have supplements of calcium and vitamin D as daily tiometry (DEXA) scanning and the T score. prophylaxis. Both the American College of Gastroenterology Bisphosphonates, an antiresorptive analog of and the American Gastroenterological Association pyrophosphate, have proven effective in increasing recommend selective screening of IBD patients with BMD and reducing fractures of the spine, hip, and DEXA scans. The criteria include a postmenopausal wrist in the treatment of osteoporosis in postmeno- state, on-going glucocorticoid treatment, cumulative pausal women (20,33–35). Estrogens increase the prior use of glucocorticoids exceeding 3 months, BMD in patients under glucocorticoid treatment, history of low-trauma fractures, and an age greater but the effect on prevention of bone fractures than 60 years (20). remains unclear. Estrogens are not recommended The pathogenesis is multifactorial, and the bone for this purpose, and they are known to increase the loss depends signiﬁcantly on the age (above 60 years), risk of breast cancer (20,36). Raloxifene is a selec- gender, use of glucocorticoids, and grade of systemic tive estrogen receptor modulator that has been inﬂammation (i.e. intestinal disease activity correlates approved for the prevention and treatment of post- with the risk of fracture) (8). Recent research has menopausal spinal osteoporosis. However, no stud- shown that interleukin 6 (IL-6) is a pathogenic factor ies with raloxifene have yet been performed in IBD that results from loss of estrogen and has implicated patients. Teriparatide (a genetically engineered frag- this cytokine in the physiopathology of several other ment of human parathyroid hormone) stimulates diseases caused by an increased osteoclastic bone resor- new bone formation, leading to increased BMD. No ption, including diseases such as RA (20). Genetic studies have been performed in IBD-associated variations in the IL-6 and IL-1 receptor antagonist osteoporosis (20). Some clinicians suggest that teri- genes identify IBD patients at risk for increased bone paratide should be considered for the treatment loss. Other genes, including LRP5 and the vitamin D of patients with an established glucocorticoid- receptor (VDR) gene, are seen in association with induced osteoporosis who require long-term steroid increased risk of bone loss (20). treatment (37).
102 S. Larsen et al. Osteomalacia However, larger doses (4000–50,000 units/day) may be necessary in some patients with malabsorption (42). Epidemiology. Osteomalacia is a rare complication in The goal in treating patients with vitamin D should IBD (38,39), and the prevalence is 30%–40% among be to maintain serum 25-hydroxy vitamin D those with a small intestinal resection (40). It is (25-OHD) levels higher than 25 ng/mL (38). characterized by a decreased bone matrix mineral- ization and is a common clinical ﬁnding associated with calcium and vitamin D deﬁciency. It may occur Dermatologic (mucocutaneous) in IBD patients with signiﬁcant small bowel resec- manifestations tions in the absence of vitamin D supplementation. Patients with an altered bile salt resorption, such as Erythema nodosum those with involvement of the terminal ileum or ileal Epidemiology. Erythema nodosum (EN) (Figure 3) is resections or those who receive bile acid-sequestering the most common cutaneous manifestation associatedAnn Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 agents, are at greatest risk of developing vitamin D with IBD (44,45). EN affects 2%–20% of the IBD malabsorption (41). population (2,46,47). Women are affected more com- Symptoms. Osteomalacia manifests as progressive, monly than men (44,48). EN is believed to be a delayed generalized bone pain, muscle weakness, hypocalce- hypersensitivity reaction, the antigen being identiﬁed mia, and pseudofractures and in its late stages as a in approximately 40% of patients (44). However, in ‘waddling gait’ (42). most patients, the manifestation is without apparent cause (idiopathic) (44). Diagnosis. Biochemical abnormalities include low serum calcium, phosphorus, and vitamin D concen- Symptoms. The primary lesions are raised, deep-red, trations, as well as elevated alkaline phosphatase tender, warm, and round nodules, 1–5 cm in diame- and parathyroid hormone concentrations. Classic ter, distributed symmetrically over the anterior lower legs. Occasionally, they also appear on the trunk, upper For personal use only. radiologic features include pseudofractures, bicon- cave vertebrae, and a triradiate pelvis (42). extremities, and face (44,49). Neither ulceration nor Although osteoporosis and osteomalacia both result scarring occurs in EN. EN typically is associated with in low BMD, apart from elevated bone alkaline phos- exacerbation of the IBD but not with the severity or phatase levels, osteomalacia can be distinguished from extent (44,48). osteoporosis only through a bone biopsy, but this is Diagnosis. Biopsies that show focal panniculitis gener- rarely pursued (38). ally are not necessary because the diagnosis may be Treatment. For patients with vitamin D deﬁciency, secured on the characteristic clinical appearance (45,49). vitamin D doses at 1000 units/day are sufﬁcient (43). The differential diagnosis of EN includes other types Figure 3. Erythema nodosum localized on the anterior crus.
Extraintestinal manifestations of IBD 103 of panniculitis, cutaneous infections, and subcutane- bowel disease. Local wound therapy should be ous lymphomas (44). guided by a wound care specialist and include strin- gent wound care, analgesia, and treatment of sec- Treatment. The disease is self-limited with an ondary infections. Local wound care consists of excellent prognosis. The time to remission is, on lavage with sterile saline, topical antibacterial creams, average, 5 weeks. Supportive treatment with com- and hydrocolloid dressings. Oral prednisolone in pression stockings, leg elevation, and rest may be doses up to 1 mg/kg (and no more than 40 mg/day) sufﬁcient. For severe cases, glucocorticoids may be are usually effective in rapidly controlling PG applied (44). Dapsone and inﬂiximab have been (50,52,53). In mild cases, a combination of gluco- reported to be successful in treating severe or corticoids and dapsone has been used successfully refractory lesions (49). with an initial dosage of dapsone of 100 mg/day orally, gradually increasing to 200–300 mg/day (50,54). Steroid-dependent patients require immu-Ann Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 Pyoderma gangrenosum nosuppressive treatment with azathioprine/6-mer- Epidemiology. Together with Sweet’s syndrome captopurine, which has a delayed onset of efﬁcacy of (see below), pyoderma gangrenosum (PG) belongs a minimum of 8–10 weeks. Anti-TNF- treatment to a group of diseases called the neutrophilic derma- has been reported to be effective, and anti-TNF- toses. These immune-mediated inﬂammatory condi- has become the drug of choice in steroid-refractory tions of the dermis are characterized by the PG; initial doses of 5 mg/kg, with repeat treatments unpredictable development of chronic ulcerated depending on response, have been recommended skin lesions, up to 70% of which are distributed to (50,52,55–57). the lower extremities. Another common lesion site is peristomal; in fact, this is a pathergic phenome- non that occurs in about one-quarter of patients Aphthous stomatitis For personal use only. with PG (50). Epidemiology. Aphthous stomatitis is the most com- PG affects 0.5%–2% of the IBD population (2,46, mon oral lesion in IBD (Figure 4). The incidence is 50). Conversely, about one-third of patients with PG 4%–20% (53). This manifestation, however, also suffer from IBD (51). appears in 15% of the background population. This Symptoms and diagnosis. PG is characterized by a complication generally occurs during active stages of painful deep ulcer with a violaceous undermined the intestinal disease, and it responds favorably to border and a necrotic purulent center. It typically treatment. affects the legs but may occur in any area of the skin, Recurrent aphthous ulcerations are more frequent sometimes even as peristomal ulcers (44). in IBD patients with other extraintestinal manifesta- There are no absolute diagnostic tests for PG, and tions (53). the disease has no absolute histologic appearance. Symptoms. Aphthous stomatitis consists of shallow The diagnosis ultimately is based on a combination round ulcers with a central ﬁbrinous membrane and of clinical and histologic features (50). The differential an erythematous halo (48). diagnosis of PG includes cutaneous infections, Sweet’s syndrome (see below), cutaneous malignancies, vascu- Diagnosis. This manifestation is associated with IBD lopathies, collagen-vascular diseases, and halogeno- and cannot be differentiated clinically from common dermas (44). A skin biopsy will conﬁrm the clinical aphthous stomatitis (48). The differential diagnoses suspicion, and it helps to exclude other disorders include oral herpes simplex, Behçet’s disease (58), that mimic PG. The histologic ﬁndings vary depend- and coxsackievirus infection. Oral herpes simplex ing on the area biopsied as well as on the age of the and coxsackievirus lesions begin as vesicles that lesion (44,50).Typical features include a diffuse inﬂam- later ulcerate. Aphthous stomatitis does not have a matory inﬁltrate within the dermis, evidence of surface vesicular stage. ulceration, features of an acute folliculitis, and ﬁbri- noid changes within blood vessels (50). Ulcerations Treatment. Treatment of the underlying bowel disease appear in the later stages (44). is often curative. For symptomatic pain relief, 2% viscous lidocaine is frequently used. Treatment with Treatment. There is a lack of randomized clinical tri- topical corticosteroids such as triamcinolone 0.1% als concerning the treatment of PG, and the litera- paste once to three times per day is effective in pro- ture is largely founded on small case series and moting healing. In addition, 5% amlexanox paste may personal experience. The essence of the treatment of be beneﬁcial (48,59). Systemic glucocorticoids should PG is cleansing and appropriate dressings for the be used only in refractory cases or in persistent or severe ulcers and appropriate therapy for the underlying aphthous stomatitis (48).
104 S. Larsen et al.Ann Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 For personal use only. Figure 4. Aphthous stomatitis. Sweet’s syndrome Uveitis Epidemiology. Sweet’s syndrome is a rare disease; only Epidemiology. Anterior uveitis (iridocyclitis) (Figure 5) about 35 cases associated with IBD have been reported occurs in up to 17% of the IBD population (65,67). in the literature (60). It is also named acute febrile The incidence of uveitis of the posterior segment in neutrophilic dermatosis. The syndrome predominantly some studies is reported as rare ( 1%); other studies affects women (61). report frequencies of up to 10% (65,66). Uveitis is often associated with coexisting joint and skin mani- Symptoms and diagnosis. Sweet’s syndrome is a cuta- festations. This condition is characterized by inﬂam- neous lesion characterized by a constellation of mation of the vascular coat of the anterior eye, i.e. the clinical symptoms including pyrexia, tender erythe- iris and the ciliary body (iritis), and the posterior eye, matous skin lesions (papules, nodules, and plaques), i.e. the vitreous (vitritis), choroid, or retina (68). and a diffuse inﬁltrate consisting predominantly of mature neutrophils typically located in the upper Symptoms. Anterior uveitis often presents as a painful dermis, often in the face, neck, and upper limbs. eye with visual blurring and photophobia. A seri- The histologic ﬁndings are characterized by a neu- ously affected eye will be miotic and may have an trophilic inﬁltrate with leukocytoclasis (62). abnormal papillary response to light (68). Treatment. Most cases respond to systemic treat- Diagnosis. The eye redness associated with uveitis is ment with glucocorticoids (63). Treatment with unique in that it exhibits a ‘ciliary ﬂush’ with redness anti-TNF- antibodies has also been successful most intense at the limbus and radiating outward (61,64). for a short distance. Deﬁnitive diagnosis is made by slit-lamp examination (68). Treatment. Topical glucocorticoids are the primary Ophthalmologic manifestations treatment for uveitis, and they successfully prevent The incidence of ocular involvement in IBD varies blindness or corneal perforation (69). A number of from 2%–29% according to the published literature studies describe anti-TNF- antibodies (inﬂiximab) (65–67). as a successful treatment (5,47,69,70).
Extraintestinal manifestations of IBD 105Ann Med Downloaded from informahealthcare.com by University of California San Francisco on 08/27/10 Figure 5. Red eye as a result of uveitis. Episcleritis dilated surface vessels, whereas the sclerae are white in episcleritis (68). Epidemiology. Episcleritis occurs in up to 29% of IBD patients. It may be diffuse or nodular and may be Treatment. Recurrent scleritis may result in sclero- For personal use only. unilateral or bilateral (65,66). malacia (66). Scleritis can lead to retinal detachment or optic nerve swelling. It therefore requires aggres- Symptoms. Episcleritis is characterized by acute red- sive treatment with systemic glucocorticoids and/or ness, hyperemic patches and complaints of irritation immunosuppressants (68,71,72). Although evidence or burning. Pain or tenderness to palpation is com- is still scarce, biologics such as the B lymphocyte- mon. Episcleritis is not associated with loss of vision, depleting drug rituximab may be beneﬁcial in photophobia, or loss of a normal papillary response the treatment of inﬂammatory ocular diseases in to light. Episcleritis is usually related to the activity IBD (73,74). of the underlying IBD. An ocular examination reveals focal or diffuse patches of redness within which white patches of sclera can be seen between the dilated Hepatobiliary manifestations episcleral vessels (68). Primary sclerosing cholangitis Diagnosis. For diagnosis, see the following section on scleritis. Epidemiology. Primary sclerosing cholangitis (PSC) is a chronic immunoinﬂammatory disorder of the bile Treatment. Application of cool compresses and/or ducts with a multifactorial and polygenic etiology. topical glucocorticoids may be sufﬁcient in conjunc- Thus the preponderance of HLA-A1, -B8, -DR3, tion with appropriate treatment of the underlying -DR6, and -DR2 in PSC, combined with the protec- IBD (68,71). tional haplotype -DR4, suggests that an inappropriate immune response may play a pathogenic role (75). Scleritis There is a strong but incompletely understood asso- ciation between PSC and IBD, and PSC is more Epidemiology. Scleritis occurs in up to 18% of all IBD frequent in UC than in CD. Thus a Swedish study patients (65). has shown that 82% of all PSC patients also had IBD (76), whereas only 35% of southern Europeans (77) Symptoms. Scleritis may impair the vision, and and only 20% of Japanese IBD patients have this asso- patients often complain of severe eye pain associated ciation (78). On the other hand, between 3% and with tenderness to palpation. The deep scleral vessels 7% of patients who have UC also have PSC (79). are hyperemic along with the episcleral and conjunc- PSC is predominantly a disease of younger men, tival vessels. This may cause the inﬂamed area to with a male:female ratio of 2:1. appear violet when viewed in natural light (68). A German study has shown that the estimated Diagnosis. Scleritis can be distinguished from episc- time from diagnosis to either death or orthotopic leritis in that the sclerae appear pink between the liver transplantation is 9.6 years, with 40% of all