enteropathic arthritis

Rheum Dis Clin N Am 29 (2003) 513–530

Enteropathic arthritis

Wendy Holden, MB, MRCPa,Tim Orchard, MA, MD, MRCPb,

Paul Wordsworth, MA, MB, FRCPa,*aDepartment of Rheumatology, University of Oxford, Nuffield Orthopaedic Centre,

Oxford OX3 7LD, UKbSt Mary’s Hospital, Praed Street, London W1, UK

Enteropathic arthritis is a form of arthritis associated with the chronic inflam-

matory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD).

This form of arthritis is classified as one of the group of seronegative spondylo-

arthropathies, which also includes psoriatic arthritis, reactive arthritis, and

idiopathic ankylosing spondylitis (AS). Joint involvement also occurs with other

gastrointestinal diseases such as Whipple’s disease, celiac disease, and following

intestinal bypass surgery for morbid obesity. In these conditions, abnormal bowel

permeability and immunologic and genetic influences are probably involved in the

pathogenesis of the joint disease, although the exact mechanisms remain uncertain.

Articular involvement is the most common extraintestinal manifestation of

IBD, with a prevalence of between 2% and 26% in both retrospective [1,2] and

prospective studies [3]. The relationship between peripheral arthritis and UC was

first described in 1929 [4], but it was not until the late 1950s that the peripheral

arthritis associated with IBD was distinguished from rheumatoid arthritis [5–7].

Joint involvement in enteropathic arthritis has been divided historically into

two main patterns: (1) peripheral arthritis, and (2) axial involvement, including

sacroiliitis with or without spondylitis similar to idiopathic AS. Other periartic-

ular features can occur, including enthesopathy, tendonitis, and a miscellaneous

group including clubbing, periostitis, and granulomatous lesions of joint and

bone [8]. Osteoporosis and osteomalacia secondary to IBD and iatrogenic

complications can also occur.

0889-857X/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0889-857X(03)00043-7

* Corresponding author.

E-mail address: [email protected] (P. Wordsworth).

W. Holden et al / Rheum Dis Clin N Am 29 (2003) 513–530514

Peripheral arthritis associated with inflammatory bowel disease

The peripheral arthropathies associated with IBD occur in between 5% and

20% of patients [2,9,10]. Synovial histology usually reveals nonspecific inflam-

matory changes including villous hypertrophy, edema, and lymphohistiocytic

infiltrates [11], although granulomatous synovitis has also been described [12,13].

In one cohort of patients, peripheral arthritis was identified in 20% of patients who

had CD and 12% of patients who had UC [14].

Until recently, the main pattern of peripheral joint involvement was said to be

pauciarticular and asymmetric, affecting mostly the lower limbs, although other

patterns of articular involvement have been described, including monoarthrop-

athy and small joint symmetrical polyarthropathy. The proportion of each type

varies between studies [2,9,10]. In a recent large retrospective series from Oxford

of 976 patients who had UC and 483 patients who had CD [15], the peripheral

arthritis was subdivided into two groups according to the articular distribution

and natural history (Box 1). Type 1 (pauciarticular) arthropathy affects less than

five joints, generally involves acute self-limiting attacks lasting less than

10 weeks, often coincides with exacerbations of IBD, and is strongly associated

with extraintestinal manifestations of IBD such as erythema nodosum and uveitis

(Table 1). Type 2 (polyarticular) arthropathy affects five or more joints,

symptoms usually persist for months or years, the arthritis is independent of

the activity of IBD, and it is associated with uveitis but not with other

extraintestinal manifestations of IBD (Table 2). In this series, Type 1 arthropathy

occurred in 3.6% of patients who had UC and in 6% of patients who had CD.

Type 2 arthropathy occurred in 2.5% of patients who had UC and in 4% of

patients who had CD. The peripheral arthritis associated with IBD is seronegative

and is typically nondeforming and nonerosive [14], although erosive disease

affecting the hip, elbows, metacarpophalangeal joints, metatarsophalangeal

Box 1. Classification of peripheral neuropathy

Type 1 (pauciarticular)

Less than 5 jointsAcute, self-limiting attacks (< 10 weeks)Often coincides with relapses of IBD

Type 2 (polyarticular)

Five or more jointsSymptoms usually persist for months to yearsRuns a course independent of IBDAssociated with uveitis but not with other extraintestinal

manifestations

Table 1

Clinical features of erythema nodosum and uveitis in inflammatory bowel disease

Erythema nodosum

(n = 39)

Ocular inflammation

(n = 50)

Female:male ratio 33.6 (5.5:1) 35:15 (2:3.1)

Present at or before diagnosis (%) 20 (51) 11 (22)

Related to IBD activity (%) 36 (92) 39 (78)

Recurrent episodes (%) 8 (21) 18 (32)

W. Holden et al / Rheum Dis Clin N Am 29 (2003) 513–530 515

joints, and an erosive polyarthritis have been described [16–19]. In the meta-

carpophalangeal and metatarsophalangeal joints, the arthropathy differs from

rheumatoid arthritis, because it is predominantly asymmetric and pauciarticular

with evidence of reactive bone formation but little bony fusion [18–20]. In a

prospective study of 100 patients who had CD, 2% developed a destructive

arthritis of the hip similar to that seen in rheumatoid arthritis [21]. In children

who have CD, symmetrical finger involvement with boutonniere deformities and

sacroiliac erosions are well recognized [22].

Relationship between intestinal symptoms and peripheral arthritis

The arthritis associated with IBD can occur before the onset of bowel disease

[15], although it usually occurs concurrent with or after the onset of IBD. The

initial presentation of arthritis is as likely to occur in patients who have bowel

disease of less than 6 months duration as it is to occur in patients who have

disease duration of more than 10 years [10]. Peripheral arthritis is most frequently

seen in patients who have extensive UC [7] or CD affecting the colon rather than

the small intestine [2,14,19,23]. In one cohort of patients who had strictly defined

CD, peripheral arthritis was found in 16% of patients who had colonic

involvement, in 4% of patients who had small intestinal involvement, and in

3.6% of patients who had ileocolonic involvement [23]. This pattern has also

been found in the arthritis associated with IBD in children. In a series of 102

children who had IBD, 19% with Crohn’s colitis had arthritis and 35% had

arthralgia compared with 12% who had arthritis and 8% who had arthralgia in

children who had CD without colonic involvement [24]. In UC in particular there

is a relationship between flares and the severity of bowel disease and episodes of

Table 2

HLA associations of peripheral arthropathy in inflammatory bowel disease

HLA type

Type 1 arthropathy

% (n = 57)

Type 2 arthropathy

% (n = 45)

Controls

% (n = 603)

IBD controls

% (n = 92)

HLA-B*27 26a 4 7 5

HLA-B*35 33a 7 15 14

HLA-B*44 12 62a 31 11

HLA-DRB1*0103 35a 0 3 4

a Significant increase.


arthritis [2], although the onset of joint disease can occur at the same time as the

onset of bowel disease or precede it by many years [14,25]. Surgical removal of

the diseased part of the colon or total proctocolectomy for UC usually induces

remission in the peripheral arthritis [22], and restorative proctocolectomy with

creation of an ileal pouch has been associated with the development of an acute

symmetrical polyarthropathy, although this might be more like intestinal bypass

arthritis rather than that associated with UC [26]. In CD, although colonic disease

increases the likelihood of peripheral arthritis, surgical removal of the diseased

part does not appear to affect the course of the arthritis [27]. In a series of patients

who had spondyloarthropathy who underwent serial ileocolonoscopy, patients

whose peripheral arthritis went into remission also had resolution of their

intestinal lesions, and in cases in which there was persistent joint involvement,

the intestinal inflammation often persisted [28]. Clinical remission of the joint

inflammation coincided with an improvement in gut histology after treatment

with sulfasalazine [29,30]. In children, arthritis is usually associated with the

presence of active bowel disease, but it is less frequently related to flares of IBD

than in adults. In one series of children who had CD, 62% of episodes of arthritis

were associated with episodes of active bowel disease, but most exacerbations of

IBD were not associated with joint involvement. This also applies to children

who have UC and arthritis [31].

Spondyloarthropathy and axial involvement associated with inflammatory

bowel disease

The clinical spectrum of the spondyloarthropathies is wide and encompasses

axial symptoms, sacroiliitis, spondylitis, peripheral synovitis, dactylitis, and en-

thesopathy. Axial involvement in IBD manifests as either AS identical to

idiopathic AS or asymptomatic sacroiliitis. Axial involvement is generally more

common in CD (5%–22%) than in ulcerative colitis (2%–6%) [32]. AS in IBD

can occur at any age, whereas in idiopathic AS, onset after the age of 40 is rare. In

idiopathic AS, men are more commonly affected (2.5:1), whereas in AS related to

IBD, the sex ratio is 1:1 [8]. Clinically, AS secondary to IBD manifests as

inflammatory spinal pain and alternating buttock pain or chest pain, and clinical

indices reflect progressive bony ankylosis generally moving from the lumbar

toward the cervical spine.

The European Spondyloarthropathy Study Group (ESSG) has developed

classification criteria for the spondyloarthropathies [33] that have also been

validated as diagnostic criteria [34,35]. The ESSG criteria enable the inclusion of

previously neglected cases of undifferentiated spondyloarthropathy such as

patients who have isolated dactylitis or enthesopathy as the only manifestation

of their disease. Patients who have IBD and inflammatory back pain or peripheral

synovitis might now also fulfill the classification criteria for spondyloarthropathy,

but the precise prevalence of spondyloarthropathy in patients who have IBD has

been difficult to ascertain with certainty because of methodological differences in


the studies. Population-based studies have been rarely performed, and in some

studies only certain aspects of spondyloarthropathy such as classic AS have been

investigated. Most studies were performed before the development of the ESSG

criteria, and some did not use routine radiographic studies to identify asympto-

matic sacroiliitis. Overall, AS occurs in 3% to 12% of patients who have IBD [36],

but radiological evidence of sacroiliitis is much more frequent (14%–20%)

[14,18,22,24,37]. In a prospective study of 79 consecutive hospital patients who

had UC, 43% had axial involvement with 25% satisfying the Modified New York

criteria for AS [38] and 18% manifested inflammatory spinal pain [25]. In another

prospective study of 103 patients who had IBD, 39% had objective clinical

articular manifestations, 30% had inflammatory spinal pain, 10% had synovitis,

and 7% had a peripheral enthesopathy. Overall, 10% fulfilled the New York

criteria for AS and a further 18% had radiologic evidence of sacroiliitis [39]. These

figures from a tertiary referral center confirm the findings of others [15], but they

are higher than those in the population-based studies [40,41] and might reflect

referral bias. Somewhat surprisingly, in a population-based inception cohort of

160 patients who had IBD, fewer patients who had CD (2%) than UC (5.1%)

fulfilled the modified New York criteria for AS. Overall, 18.1% of these IBD

patients fulfilled the ESSG criteria for spondyloarthropathy [40], but a further

14.4% of patients had one or more spondyloarthropathy-related manifestations

such as Achilles tendonitis or plantar fasciitis without fulfilling ESSG criteria for

spondyloarthropathy. This finding suggests that the ESSG criteria might still

exclude a proportion of patients who have rheumatological manifestations related

to IBD. In a longitudinal population-based study of 654 patients who had newly

diagnosed IBD followed-up for 6 years from diagnosis, the prevalence of AS was

2.6% in UC and 6% in CD (overall prevalence 3.7%) [41]. The overall prevalence

of spondyloarthropathy was 22%, and a further 19% had inflammatory type spinal

pain. There was a much lower frequency of asymptomatic radiological sacroiliitis

(2%) compared with the 10% to 18% found in hospital-based studies [37,39],

probably reflecting the shorter duration of disease, although differences in

radiologic scoring techniques might also have contributed.

In the authors’ series of patients who had CD for at least 5 years, 15 of 42

(36%) had evidence of sacroiliitis on MRI and 10 of these patients had frank AS.

All the CD patients who were HLA-B27+ developed AS [42].

Relationship between intestinal symptoms and axial involvement

The course of IBD and the onset of axial involvement are usually independent,

and axial symptoms frequently precede bowel disease by many years [32]. In a

prospective study of the development of bowel pathology in patients who had

spondyloarthropathy, 7.7% of patients who had AS in whom IBD was excluded

on preliminary ileocolonoscopy developed IBD 2 to 9 years later [43]. All of

these patients had abnormal bowel biopsies on first examination with nonspecific

inflammatory features. Furthermore, four of 71 spondyloarthropathy patients who


did not have AS or IBD also developed AS and IBD after 2 to 9 years. The

extent, location, duration of IBD, and the development of complications such as

strictures or fistulae and amelioration of the bowel complications by surgery do

not affect the progress of spondylitis or sacroiliitis.

Gut inflammation in patients who have spondyloarthropathy

Most patients who have spondyloarthropathy do not have symptoms or signs

of intestinal inflammation, but histologic studies have demonstrated that a

proportion of these patients might have subclinical intestinal inflammation,

usually affecting the ileum. Retrospective studies of patients who have spondylo-

arthropathy (excluding those with psoriatic arthritis or spondyloarthropathy

associated with IBD), show that up to 67% have features of macro- and mi-

croscopic gut inflammation on ileocolonoscopy and some will go on to develop

overt IBD [29,44,45]. These intestinal lesions can be divided into two types:

acute inflammation resembling infectious enterocolitis, and chronic inflammatory

changes more suggestive of early CD [46]. Acute inflammatory changes include

normal mucosal structure with infiltration of the epithelium with neutrophils and

eosinophils, crypt abscess formation, and infiltration of the lamina propria with

polymorphonuclear cells. Chronic histologic changes include crypt distortion

and villous blunting, mixed lamina propria cellularity, and basal lymphoid ag-

gregates [47].

In a prospective study of 123 of 354 patients who had spondyloarthropathy

who underwent ileocolonoscopy, gut lesions were found in 72% of the patients

who had non-AS spondyloarthropathy, and chronic lesions were slightly more

prevalent than acute lesions [43,47,48]. Chronic lesions were more common in

patients who had a family history of AS, spondyloarthropathy, or CD. Inflam-

matory gut lesions were found in 61.5% of patients who had classic AS. Chronic

lesions were significantly more common than acute lesions (52% versus 10%).

At follow-up ileocolonoscopy, remission rates in the groups that had normal

histology, acute lesions, or chronic lesions, were identical (approximately 44%).

None of the patients who had initially normal histology subsequently developed

IBD. Eight (7%) of the patients and another three of 94 patients (3%) followed

up by telephone eventually developed IBD after 2 to 9 years of follow-up (nine

CD and two UC). All 11 of these patients were eventually diagnosed as having

AS, although only two were HLA-B27+. Ten of the 11 patients had ‘‘chronic’’-

type lesions compared with 45% of the whole sample. Risk factors for the

development of IBD included regular diarrhea early in the disease, raised

inflammatory markers, chronic inflammatory gut lesions, and HLA-B27 nega-

tivity in the presence of bilateral sacroiliitis or AS. This study is consistent with

the theory that HLA-B27� patients who have AS are at higher risk of de-

veloping IBD [37]. It also suggests that ileocolonoscopy might be useful,

particularly in HLA-B27� patients, in identifying some patients who have

early, asymptomatic CD. A distinction needs to be drawn, however, between


subclinical Crohn’s-like lesions and the preclinical lesions found in the spondylo-

arthropathy that will eventually be associated with CD. This is potentially

clinically relevant because most patients who have spondyloarthropathy will be

prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), which are associated

with inflammatory lesions in the small and large bowel [49–51]. Gut inflamma-

tion has been found in patients who have spondyloarthropathy but who are not

taking NSAIDS [29], and resolution of intestinal lesions occurs in some patients

who have spondyloarthropathy who continue to take NSAIDs [47]. Subclinical

gut inflammation has also been found in 16% of patients who have psoriatic

arthropathy [52].

Inflammatory bowel disease and arthritis in children

The frequency of arthritis associated with IBD in children is probably similar

to that in adults, occurring in between 7.5% and 21% of patients. There have been

large differences in the reported frequencies of arthritis associated with IBD, and

there has been no consensus on whether arthritis is more commonly associated

with CD or UC in children. In the largest series of 522 patients who had CD,

arthritis was found in 7.5% of patients [53], but in another smaller study, 19% of

children who had CD had arthritis [54]. In UC, arthritis has been reported to

occur in between 9% and 21% of children [31,54]. The widely differing

frequencies might reflect difficulties in the diagnosis of IBD or the definition

of arthritis. Arthritis in IBD manifests as either peripheral or axial disease.

Peripheral arthritis occurs equally in boys and girls and tends to be pauciarticular

and confined to the lower limb joints, although mono- and polyarthropathy can

also occur [24,31]. The majority of episodes of peripheral arthritis last less than

8 weeks and resolve with treatment of the underlying bowel condition, although

erosive arthropathy has been described [22]. The arthritis usually occurs

concurrently with the onset of IBD, but it precedes IBD in a minority of cases.

Peripheral arthritis usually occurs at the same time as active bowel disease, but it

is not related to flares of the bowel disease. Sacroiliitis associated with enthesitis

and peripheral oligoarthritis can also occur, but much less frequently than

peripheral arthritis [55]. Spondylitis identical to AS has been found in children

who have IBD, and in a series of 136 children who had IBD and arthritis, all five

children who had spondylitis were boys [31]. The comparative rarity of axial

disease in children is illustrated by another series of 102 children who had IBD in

which no axial involvement was demonstrated [24]. Sacroiliitis and spondylitis in

IBD are associated with HLA-B27 [56] and might be progressive despite

treatment for the IBD. No HLA associations have been demonstrated for the

peripheral arthritis associated with IBD, although children who have IBD

frequently have a first-degree relative who has IBD [54]. As in adults, nonspe-

cific inflammatory changes have been found in the bowel in children who have

juvenile-onset spondyloarthropathy, and in these patients there is a high risk of

erosive arthritis and progression to AS [57,58]. Management of peripheral


arthritis is generally dependent on management of the IBD and consists of

symptomatic treatment with NSAIDs plus sulfasalazine to control bowel inflam-

mation. Physiotherapy is the mainstay of treatment for axial disease.

Communication between the gut and joints (gut iteropathy concept)

Animal models of spondyloarthropathy and clinical cases of polyarthritis

following intestinal bypass surgery suggest that pathogenic bacteria might be

involved in the development of spondyloarthropathy and that gut and joint

manifestations are linked. Although the exact mechanisms linking the gut and

the joints in spondyloarthropathy are unknown, the recirculation of antigen-

specific memory T cells from the gut to the joints might be critical and has been

termed the gut iteropathy concept [59]. In rats transgenic for HLA-B27 and human

b2 microglobulin, about half develop inflammatory lesions of the gut, peripheral

arthritis, and inflammatory lesions of intervertebral discs similar to AS; however,

in HLA-B27 transgenic rats bred in a pathogen-free environment, gut and joint

inflammation do not develop until normal bacterial flora is introduced [60]. Certain

anaerobic bacteria have been linked to the pathogenesis of arthritis. Metronidazole

prevents arthritis from developing in a rat model of blind-loop arthritis coincident

with the elimination of gut anaerobic Bacteroides species [61]. Following

jejunoileal bypass surgery for morbid obesity, a symmetric polyarthritis develops

in 20% to 80% of patients. Surgical reanastomosis results in complete resolution of

the symptoms [62]. Symmetric polyarthritis has also been describes in patients

after restorative proctocolectomywith an ileal pouch anal anastomosis for UC [26].

In these clinical situations, bacterial overgrowth in the blind loop with increased

absorption of immune complexes might have a pathogenic role because circulating

complexes of secretory IgA [62] and bacterial antigens [63] have been isolated

from the serum in these patients. Immune complexes have also been identified in

the serum of patients who have acute arthritis and AS, although immune complexes

have not been found within the synovium of inflamed joints in IBD, casting doubt

on the causal role of these immune complexes in peripheral arthritis. Increased

mucosal permeability of the gut has been demonstrated using several experimental

techniques in AS, IBD, juvenile chronic arthritis, and psoriatic arthritis, even in the

absence of bowel pathology [64–66]. Many proinflammatory mediators such as

tumor necrosis factor (TNF)-a and interleukin-6 (IL-6) have been demonstrated in

active IBD [66], and antibodies to TNF-a can completely inhibit arthritis in rats

that have experimentally induced bacterial overgrowth [61]. A unifying theory

linking intestinal inflammation with joint pathology has been proposed [67].

Enhanced mucosal permeability and abnormally high levels of anaerobic bacteria

colonizing inflammatory lesions in active IBD might lead to the absorption of

proinflammatory bacterial components, stimulating a pathologic immune re-

sponse. Spontaneous remission of gut pathology or medical or surgical therapy

allows mucosal permeability to decrease, hence reducing the perpetuating stimuli

and allowing peripheral arthritis to resolve. This model does not, however, explain


the development of axial involvement in IBD, which is independent of gut

pathology. The observation of bacterial components and DNA in the joints of

patients who have enteropathic arthritis lends credence to this hypothesis [68].

Subsequently, the identification of the NOD2 (CARD15) gene as an important

influence in the development of CD [69] provides a potentially important link

between the gut and joint inflammation. CARD15 is an important component of

the innate immune system because of its role in activating nuclear factor NFKB in

response to bacterial lipopolysaccharide in mononuclear cells. Although a role for

CARD15 (NOD2) has been excluded in spondyloarthropathies [70] and rheuma-

toid arthritis [71], other members of the Toll-like receptor family could be

implicated and further studies are needed to evaluate it.

Genetics and HLA associations in enteropathic arthritis

Idiopathic AS is characterized by inflammation of the axial skeleton with bony

ankylosis, although peripheral joint involvement also occurs in about 20% of

patients. Idiopathic AS is associated with possession of HLA-B27 in more than

90% of cases [72]. AS and sacroiliitis associated with IBD apparently exhibit a

lower frequency of HLA-B27 (50%–70%) of cases [73,74], but no association

with HLA-B27 has been described with isolated sacroiliitis in IBD [15]; however,

this might depend on the method of ascertainment of cases. Thus in one series of

197 patients who had AS and IBD who were primarily ascertained through having

AS, 77% were HLA-B27+ [70]. The peripheral arthropathies associated with IBD

are often classified as part of the HLA-B27–related spondyloarthropathies

according to the ESSG [33], and type 1 peripheral arthritis is certainly clinically

similar to postenteric reactive arthritis, which is associated with HLA-B27 in up to

80% of cases [75]. In contrast to reactive arthritis, early studies of type 1

arthropathy with small numbers of patients failed to demonstrate an association

with HLA-B27 [76,77]. More recently, two types of peripheral arthritis have been

described [15], and further convincing evidence of the distinctiveness of the types

1 and 2 arthropathies in IBD comes from their different HLA associations (Table 2)

[78]. Type 1 peripheral arthritis is significantly associated with HLA-B27 (in 26%

of patients), although to a much lesser degree than reactive arthritis. A rare DR1

antigen, DRB1*103, is significantly more common in type 1 than type 2 peripheral

arthritis. HLA-B35 is also increased in type 1 arthropathy, whereas in type 2

peripheral arthritis there is a significant association with HLA-B44, strongly

suggesting that the two forms of peripheral arthritis in IBD are not only clinically

different but also immunogenetically and etiologically distinct.

Management of enteropathic arthritis

The natural history of spondyloarthropathy is characterized by periods of flares

and remissions or by persisting disability in some patients who have type 2


peripheral arthritis and AS. The episodic nature of the arthropathy in some patients

can make therapeutic efficacy difficult to establish. Many patients are managed

with simple measures such as rest, splints, physiotherapy, and intra-articular steroid

injections. Most patients who have spondyloarthropathy will respond to NSAIDs,

although these should be prescribed with caution because they might exacerbate

IBD [79] and have been associated with ulcerations throughout the small and large

intestine [49–51]. For peripheral arthritis, because the activity of the arthritis often

parallels the activity of bowel disease, control of the bowel inflammation is the

main goal of treatment. Sulfasalazine has been shown to be effective in treating

both the underlying disease and flares of UC [80,81], but the situation is less clear-

cut for CD. Some trials have shown sulfasalazine to be effective in CD [82], but

others have not shown a benefit [83,84]. The varying efficacy of sulfasalazine in

axial and peripheral AS is controversial. Some trials have shown a benefit in both

axial and peripheral disease [85–87] whereas some have shown a benefit in

peripheral disease only [88] or more benefit in those with peripheral disease [89]. In

a series of 123 patients who had spondyloarthropathy who underwent initial

ileocolonoscopy and were followed for 2 to 9 years, 49 underwent a second

ileocolonoscopy [90]. Patients were given sulfasalazine if they had active joint or

axial disease after 3 months, then sulfasalazine was stopped if symptoms and signs

of inflammatory arthritis had been absent for 6months.Withdrawal of sulfasalazine

because of clinical remission was significantly more common in non-AS spondy-

loarthropathy patients compared with AS patients, suggesting that sulfasalazine

has more effect on peripheral than axial disease. One trial showed no benefit of

sulfasalazine in AS [91], although these patients had a median disease duration

of 12.3 years, hence might have had irreversible joint damage. Individual trials of

sulfasalazine in AS have been flawed by the varying study designs, small numbers

of patients, and short duration of therapy, but in a meta-analysis of five placebo-

controlled, randomized trials, sulfasalazine was found to be significantly more

effective than placebo in reducing morning stiffness and improving well-being in

patients who had AS [92]. There was no evidence of a difference in response of

peripheral and axial disease. More recently, therapy for enteropathic arthritis has

been influenced by the advent of targeted biological therapies. Biological blockade

with the TNFa antagonists infliximab and etanercept is effective in refractory AS

[93], psoriatic arthritis [94,95], and enthesopathy associated with spondyloar-

thropathy [96]. Infliximab (but not etanercept) is also effective in controlling bowel

inflammation in CD and the associated spondyloarthropathy [97]; however,

anecdotal evidence suggests that etanercept might be effective in spondyloarthritis

associated with CD—including resolution of spondylitis demonstrated by MRI—

even though the drug had no effect on the bowel disease [98].

Whipple’s disease

Whipple’s disease is a rare multisystem disease caused by the bacteria

Tropheryma whippelii. It is classically said to affect predominantly middle-aged


white men [99], but in a recent review of 52 cases, men constituted 73% of the

cases and the mean age at diagnosis was 55 years, with an age range of 20 to

82 years [100]. Pathologic changes characteristically occur in the small intestine

and include dilatation and thickening of the intestine with villi distended with

foamy macrophages, variable villous atrophy, intestinal lipodystrophy, and

periodic acid-Schiff (PAS)-positive macrophages with cytoplasmic granules

consisting of clumps of T whippelii. Clinical features include weight loss,

abdominal pain, diarrhea, polyarthralgia, low-grade fever, lymphadenopathy,

dementia, and neuropsychiatric features. In 67% of patients arthralgia and

arthritis are the only symptoms and can precede the other symptoms by many

years [100]. In a series of 52 cases, peripheral joint involvement occurred in 67%

of patients. The arthritis was oligo- or polyarticular, it mainly affected the limb

and girdle joints, and it tended to be migratory and episodic with acute episodes

followed by periods of remission. No joint damage or deformity was seen,

although one case involving destructive arthritis of the hip has previously been

described [101]. In another series of 25 patients who had arthropathy related to

Whipple’s disease, the most common pattern was found to be a symmetric

migratory polyarthritis affecting mainly the knees, ankles, and wrists [102]. Axial

involvement with sacroiliac and lumbar tenderness has been described in up to

40% of patients [103], and radiologic signs similar to those found in AS (eg,

sacroiliitis, syndesmophytes, and apophyseal joint ankylosis) have also been seen

[104]. Diagnosis of Whipple’s disease is usually made by establishing the

presence of PAS-positive inclusions in macrophages in small bowel or lymph

node biopsies, and more recently more accurate diagnosis has been made possible

by polymerase chain reaction of the DNA sequence of the 16S-ribosomal RNA

gene sequence of T whippelii [105] in either synovial fluid [106] or small bowel

biopsy samples [107]. Treatment of Whipple’s disease is by combination therapy

with antibiotics that cross the blood–brain barrier, usually starting with parenteral

treatment followed by oral trimethoprim–sulfamethoxazole for a year. The

condition usually responds rapidly to treatment, although patients who have

central nervous system involvement are more prone to relapses [108]. Whether or

not the recent publication of the complete DNA sequence of T whippelii will lead

to new insights in the etiology and immunopathogenesis of Whipple’s disease is

conjectural, but it is an enticing possibility [109].

Celiac disease

Celiac disease is a gluten-sensitive enteropathy characterized by abnormalities

of the small intestinal mucosa, particularly villous flattening and atrophy leading

to malabsorption. The many clinical manifestations resulting from malabsorption

include diarrhea, weight loss, anemia, and dermatitis herpetiformis. Treatment

with a gluten-free diet (GFD) abolishes symptoms and restores the normal bowel

architecture [110]. Some studies suggest that up to 15% of patients who have

psoriasis also have antigliadin antibodies, although the authors have not been able


to confirm this in their patients [111]. Some patients who have psoriatic arthritis

have shown clinical improvement on a GFD [112]. Celiac disease is also

associated with axial and peripheral arthritis, which in some cases can precede

or occur in the absence of bowel manifestations in adults [113] and in children

[114]. A specific association of celiac disease with inflammatory arthritis was

first described in 1982 [115]. The most common articular pattern described is a

polyarticular symmetrical arthritis affecting large joints such as the knees, hips,

and shoulders [116]. Monoarthritis [117], oligoarthritis [113,118], and a poly-

articular large and small joint arthropathy [119] have also been described. In a

series of 200 patients who had celiac disease compared with 40 controls who had

irritable bowel syndrome [120], arthritis was found to be much more common

than the 3.8% previously described [116], being present in 26% of patients who

had celiac disease and 7.5% of controls. The most common pattern of articular

involvement was a nonerosive, nondeforming oligo- or polyarthritis that often

affected large joints and was associated with axial or sacroiliac involvement. This

pattern is similar to that seen in other enteropathic arthritides. In a series of

Sardinian patients who had celiac disease who underwent bone scintigraphy,

63.6% were found to have evidence of sacroiliitis [121]. Remission of articular

symptoms has been reported on a GFD [112,116,118,122], although it was still

present in 21.6% of patients on a GFD [120]. In another series, articular

symptoms improved in only 2 of 23 patients on a GFD [118]. Imperfect

compliance with a GFD leading to subclinical mucosal damage could explain

the high rates of persisting arthritis and suggests that rheumatologic evaluation

should continue even after the institution of a GFD.

Intestinal bypass arthritis

Operations designed to bypass the small intestine were first developed in the

1950s in an attempt to reduce the absorptive surface of the gut as a treatment

for morbid obesity. Several metabolic consequences and a postoperative

arthritis–dermatitis syndrome develop in 20% to 80% of patients. Jejunocolonic

bypass was replaced by jejunoileal bypass, but similar complications ensued

[123,124]. Clinical features are generally a migratory nonerosive seronegative

polyarthritis involving the fingers, hands, shoulders, wrists, and ankles, al-

though mono- and oligoarthritis have also been described [124]. The arthritis

usually develops within the first 2 to 3 years after the procedure [62] but has

been described after 8 years [125]. Bacterial overgrowth in the blind loop

segment of bowel has been implicated in the pathogenesis of intestinal bypass

arthritis, and immunologic involvement seems likely because immune com-

plexes (including those containing secretory IgA [62] and bacterial antigens)

have been identified in the serum [63]. Further evidence for the link between

bowel and joint pathology comes from the fact that reversal of the bypass

procedure is usually associated with a permanent and complete remission of the

arthritis [124].


The interactions between the gut and joint pathology remain a fascinating area

of study. There is genuine hope that further research in this group of disorders

might eventually yield fundamental insights into the etiology and immunopa-

thology of many forms of inflammatory arthritis.

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