|
Rheumatic Manifestations of Gastrointestinal Diseases
Ibrahim S. Alghafeer, MD
Fellow, Division of Rheumatology
University of Medicine and Dentistry of New Jersey
New Brunswick, NJ
Leonard H. Sigal, MD
Professor and Chief, Division of Rheumatology
University of Medicine and Dentistry of New Jersey
New Brunswick, NJ
Summary Points
- Impairment of the gastrointestinal barrier function may play
a role in the pathogenesis of arthropathies.
- Arthritis is the most common extracolonic manifestation of
chronic ulcerative colitis.
- Reactive arthritis is one of the most common arthritides
affecting young adults.
Introduction
Pathologic changes in the gastrointestinal tract may be associated with clinical
complaints in multiple organs including the musculoskeletal system. Impaired barrier
function and immunogenetic mechanisms are implicated (1). In some instances, the
association between gastrointestinal pathology and extraintestinal disease is so strong
that treatment of gastrointestinal disease resolves many of the patient’s
extraintestinal complaints. This article will focus primarily on the rheumatic
manifestations of the gastrointestinal diseases and the available treatment modalities.
Gastrointestinal Pathophysiology
The gut has multiple mechanisms to regulate the efficient absorption of nutrients
while excluding bacterial and dietary antigens. Impairment of the gastrointestinal barrier
function can be observed in several diseases including inflammatory bowel disease (IBD)
and other spondyloarthropathies, and this defect may play a role in the pathogenesis of
arthropathies.
Illeocolonoscopy and multiple biopsies were carried out in
96 patients with seronegative spondyloarthropathy, 17 patients with osteoarthritis taking
nonsteroidal anti-inflammatory drugs (NSAIDs), and 19 patients with chronic abdominal
discomfort. Inflammatory gut lesions were detected in two thirds of the patients with
spondyloarthropathy, 12.5% of patients with osteoarthritis, and 16% of patients with
abdominal discomfort. More recently, an Italian study confirmed microscopical mucosal
inflammation on biopsy in 15 people with psoriatic arthritis but without bowel symptoms, 6
of whom had normal appearing mucosa by colonoscopy (2).
Altered gut permeability may also play a role in the
pathogenesis of arthropathies. Permeability may be measured by oral feeding of different
tracers (eg, 51Cr-labeled EDTA, lactoglobulin, lactalbumin, polyethylene glycol particles,
lactulose, or mannitol) followed by urine analysis of excretion. Increased intestinal
permeability was found in all subtypes of juvenile chronic arthritis with correlation
between abnormalities in lactulose/mannitol test and the histopathological features of the
gut mucosa (3). Another study showed an increase in the 24-hour urine excretion of
51Cr-EDTA in 34 patients with Behcet’s syndrome and 10 patients with ankylosing
spondylitis (AS), when compared with 15 healthy controls (4).
Because the results obtained from such studies are entirely
dependent on normal gastric emptying, normal renal function, and an accurate urine
collection, they should be interpreted carefully. Also, the results may be altered by
possible effect of the NSAIDs on prostaglandin synthesis and gut permeability.
Most recently, Salmi et al concluded that different
leukocyte populations derived from inflamed gut of patients with IBD bind avidly to
synovial vessels using a distinct repertoire of adhesion molecules, suggesting that their
recirculation may contribute to the development of reactive arthritis in inflammatory
bowel diseases (5). This study is the first experimental support of the homing of
lymphocytes from the gut mucosa to joint tissue in enteropathic arthritis.
Inflammatory Bowel Disease (IBD)
Crohn’s disease and ulcerative colitis (UC) are both associated with a number of
extra-intestinal chronic inflammatory diseases. Arthritis is the most common extracolonic
manifestation of chronic UC (6). Patients with Crohn’s disease also have an increased
prevalence of inflammatory joint disease although arthritis is more common in patients
with colitic disease than small bowel inflammation alone (7).
The type of arthritis associated with IBD may be either
axial or peripheral (Table 1). Peripheral joint disease occurs in 10% to 20% of patients
with IBD and is not usually associated with HLA-B27. The onset of arthritis either
accompanies or follows the onset of the colitis and the activity of the joint disease
generally parallels the activity of the IBD. Patients can present with an oligoarthritis
but no bowel symptoms and yet have IBD as the cause of their arthritis. The course is
usually asymmetric oligoarthritis lasting 2 to 6 weeks and radiographic changes in the
joints are rare (8).
In the case of UC, colectomy results in complete remission
of the peripheral arthritis, whereas surgical therapy for Crohn’s disease results in
remission of arthritis in only 50% of cases. In contrast, spondylitis and sacroiliitis
occur in 2% to 7% of patients with IBD and are generally associated with HLA-B27. Isolated
subclinical sacroiliitis has been reported in 24% of patients with IBD, suggesting that
axial involvement may be more common than reported previously (9). The axial disease
frequently precedes the onset of GI symptoms, and follows a chronic course which is
independent of the activity of the IBD. Surgery has no effect on this axial arthropathy
(8).
Orchard et al (10) retrospectively assessed 976 patients
with UC and 483 with Crohn’s disease and found two types of enteropathic peripheral
arthropathy. Type 1 is a self limited disease with presentation similar to post-dysenteric
reactive arthritis, different from the polyarticular disease with a course independent of
the IBD, type 2 (Table 2).
The same investigators have studied the association of
peripheral arthropathies with certain HLA phenotypes (11). Fifty-seven patients with type
1 arthritis and 45 with type 2, who were identified by case note review and questionnaire,
underwent genotyping by sequence-specific primer polymerase chain reaction. HLA-B27 was
prevalent in 27% of type 1 patients, however, DR1 antigen was present in 33% of type 1
compared with none of type 2 and 3% of 603 controls (P<0.0001). In contrast, type 2 was
associated with HLA-B44 in 62% (P=0.01). These data suggest that the clinical
classification into type 1 and type 2 arthropathies is consistent with immunogenetically
distinct entities and establishes that in polygenic disorders, genes may determine
clinical phenotype without conferring overall disease susceptibility.
Management of arthritis in IBD patients relies on good
control of the underlying gastrointestinal pathology. Sulfasalazine, azathioprine,
glucocorticoids, and methotrexate are widely used; experience with cyclosporine is
limited. The Food and Drug Administration has approved tumor necrosis factor-alpha
antibody (infliximab) for the treatment of Crohn’s disease, which has resulted in a
significant improvement of axial and peripheral arthritis related to this disease in early
studies (12).
Low bone mineral density is a recognized complication of
IBD. In a cross-sectional study by Abitbol et al (13), 34 patients with Crohn’s
disease and 50 with UC (49 women and 35 men) underwent a metabolic bone assessment,
including serum levels of osteocalcin, phosphate, calcium, parathyroid hormone,
25-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3. Bone mineral densities were measured
by dual energy X-ray absorptiometry of the lumbar spine and femoral neck. Osteopenia was
present in 36 patients (43%), 27 of whom were on glucocorticoid therapy. Although no
patient complained of muscular or bone pain, 6 patients (7%) had vertebral crush
fractures. Risk factors for the development of osteopenia were identified as age,
cumulative glucocorticoid doses, increased erythrocyte sedimentation rate, and low
osteocalcin level.
Another study (14) conducted on 119 patients with Crohn’s
disease (ages 5 to 25 years) showed similar results with hypoalbuminemia, total
glucocorticoid exposure, requirement for total parenteral nutrition, and prior use of
6-mercaptopurine being the most powerful risk factors for low bone mineral density (BMD).
Patients with IBD should be advised to consume adequate vitamin D and calcium and to
participate in a regular weight-bearing exercise program. Therapy with disphosphonates may
be necessary as well.
Treatment with alendronate (10 mg daily) in 32 patients
with Crohn’s disease and a bone mass T score of -1 or more significantly increased
the bone mineral density of the lumbar spine by 5%, compared with a decrease of 0.9% in
patients receiving placebo (P < 0.01) (15). Alendronate was safe, well tolerated, and
there was no difference in adverse events among treatment groups. Bone densitometry should
be performed, where possible, to identify those in need of treatment, to avoid unnecessary
treatment, and to monitor the effect of treatment designed to prevent bone loss. The dose
of glucocorticoids should be kept to a minimum, and vitamin D deficiency should be
corrected.
Celiac Sprue
Also known as gluten enteropathy, celiac sprue is characterized by diffuse damage to
the proximal small intestinal mucosa that results in villous atrophy and altered gut
permeability. It is strongly associated with the HLA class II antigens: DR3 and DQw2.
Arthritis is a well-known complication in children and adults. It was present in 52 of 200
adult celiac disease patients attending a routine gastroenterology follow-up clinic (16).
The distribution of arthritis was peripheral in 19 patients, axial in 15, and an overlap
in 18 subjects. The prevalence of joint disease was less common among patients on gluten
free diet.
Recently, Usai et al found axial joint inflammation in 63%
of patients with celiac disease (17); 22 patients with celiac sprue underwent bone
scintigraphy using 99mTc methylene diphosphonate. Changes compatible with sacroiliitis
were found in 14 cases, 11 of whom had low back pain. Five patients with low back pain had
negative scintigraphy. Sacroiliac radiographs were obtained in only four patients, and all
had bilateral sacroilitis. One patient had rheumatoid arthritis but all studied
individuals were HLA-B27 negative.
Arthritis and other rheumatic complaints have been the
presenting symptom in patients with gluten enteropathy with improvement in the clinical
abnormalities on a gluten-free diet (18,19,20). An increased level of antigliadin
antibodies was seen in 9 of 74 patients with spondyloarthropathies, 1 of whom had elevated
antiendomysium antibodies and biopsy proven celiac disease (21). Thus, antiendomysial
antibody testing is recommended as a screening tool in patients with suspected gluten
enteropathy. Another study found that 3.3% of sprue patients had Sjogren’s syndrome
(22).
Serial bone mineral density measurements of 55 patients
with celiac disease detected osteoporosis (defined as a Z score equal or below 2) in 50%
of the men and 47% of the women (23). Celiac disease was an independent risk factor for
the development of osteoporosis.
Whipple’s Disease
Whipple’s disease is a rare multisystemic illness caused by infection with the
bacillus Tropheryma whippelii. It can involve any organ system, but the small
intestine is affected in the majority of patients. The source of infection is unknown, but
no cases of human-to-human spread have been documented. It may occur at any age but most
commonly affects white men in the fourth to sixth decades.
The most common complaints are diarrhea, abdominal pain,
weight loss, fever, and arthritis. Axillary and cervical lymphadenopathy and generalized
hyperpigmentation also are common features. Protein-losing enteropathy due to intestinal
or lymphatic involvement may result in hypoalbuminemia and edema. Extraintestinal
manifestations are common and often start prior to the onset of gut symptoms. Arthritis or
arthralgia may be the only presenting symptoms predating other manifestations by years
(24).
In a retrospective clinical study of 52 patients with
Whipple’s disease, 35 patients (67%) had articular manifestations as presenting
features of the disease, while 8 patients (15%) presented with gastrointestinal complaints
(25). At a later stage of the disease, 44 patients (85%) developed diarrhea and
malabsorption while 8 (15%) did not show any intestinal symptoms throughout the course of
the disease. The classic setting is long-term, unexplained, seronegative oligoarthritis or
polyarthritis with a palindromic or relapsing course, although chronic destructive
polyarthritis and spondyloarthropathy have been reported (26).
The diagnosis of Whipple’s disease is established by
duodenal or lymph node biopsy, which demonstrates infiltration of the lamina propia with
PAS-positive macrophages that contain Gram-positive bacilli. A recent important diagnostic
test is polymerase chain reaction of the 16S ribosomal RNA of Tropheryma whippelii.
O’Duffy et al reported 2 patients presenting with polyarthritis and negative
bowel mucosal biopsies for Whipple’s disease in whom the synovial fluid of 1 and the
synovial tissue of the other were positive for Tropheryma whippelii when examined
by polymerase chain reaction (PCR) and DNA sequencing (27).
Antibiotic therapy is mandatory. The recommended regimen is
trimethoprim combined with sulfamethoxazole for one year, which usually results in
clinical remission and an excellent prognosis (28). Joint symptoms and fever subside in a
few days, while diarrhea and malabsorption disappear within 2 to 4 weeks (29).
Enteric Reactive Arthritis
Reactive arthritis (ReA), formerly known as Reiter’s syndrome, is one of the most
common arthritides affecting young adults. In most cases ReA follows urogenital or
intestinal bacterial infection, in cases of enteric infection, the longer the duration of
diarrhea, the greater likelihood of developing ReA. There is a third important group of
patients, those who develop clinical features of ReA with no evidence of precipitating
infection. These patients should have further investigation for the presence of covert
infection, possibly in the respiratory tract or eyes, in addition to work-up for possible
other features of ReA.
The actual incidence of ReA after enteritis varies
according to the causative organism: approximately 2% to 3% percent of all patients with
shigella, salmonella, and campylobacter infections but a much higher proportion of those
with yersiniosis (30). In enteric ReA the sudden onset of an asymmetric oligoarticular or
polyarticular inflammatory arthritis that usually involves the knees, ankles, or small
joints of the feet may occur (31). A much smaller group presents with monoarthritis.
Arthritis occurs typically 2 to 4 weeks after the onset of diarrhea and may follow an
acute or chronic course. Low back pain is noted in 30% to 90% of patients with typical ReA
(30). In a 4-year follow-up study of 31 patients with post yersinia arthritis, 4 patients
(13%) gave a history of low back pain during the enteritis; 6 (19%) had definite
sacroiliitis at follow-up, 3 (10%) of these having classic AS (32).
Over two thirds of Caucasian patients with enteric ReA are
HLA-B27 positive, compared with less than 10 percent of healthy Caucasian controls (33).
The mechanism by which HLA-B27 mediates susceptibility to post-enteric ReA remains
unclear. Scofield et al found peptides from enteric organisms share a sequence with the
binding site of the B27 molecule, which may suggest a mechanism for autoimmunity that may
operate in the B27 associated spondyloarthropathies involving peptides bound to and
derived from histocompatibility alleles (34).
Symptomatic treatment with analgesics and NSAIDs is the
mainstay of therapy. There have been reports of the presence of Chlamydia particles,
salmonella DNA, and yersinia antigens in the synovial fluid of patients with ReA which
raised the question of whether long-term antimicrobial therapy could modify the course of
the disease (35).
In a randomized, double-blind, placebo-controlled trial,
Anneli et al looked at the use of lymecycline, a form of tetracycline, in the management
of ReA (36). A 3-month course of treatment shortened the disease duration by approximately
24 weeks in 50% of patients with Chlamydia-triggered ReA than in those treated with
placebo, but a similar difference was not observed in other patients with ReA. Despite
evidence for persisting antigen presence, antimicrobial therapy seems of no proven value
in enteropathic ReA. Patients with persistent symptoms may respond to high dose
sulfasalazine (37).
Summary
The term “enteropathic arthritis” describes joint manifestations that occur
in conjunction with gastrointestinal disease. The clinical picture of this entity is still
evolving and has gained importance from advances in knowledge regarding gut
pathophysiology and cell trafficking. It is very important to keep enteropathic arthritis
in the differential diagnosis of patients with unexplained arthritis and to obtain
detailed history, complete physical examination, and appropriate testing. These arthritic
syndromes can be treated symptomatically, but long-term therapy should be directed at the
underlying cause.
References
1. Wollheim FA. Enteropathic arthritis: how do the joints
talk with the Gut? Curr Opin Rheumatol 2001;13:305-9.
2. Scarpa R. Microscopic inflammatory changes in colon of
patients with both active psoriasis and psoriatic arthritis without bowel syndrome. J
Rheumatol 2000;27:1241-6.
3. Picco P, Gattorno M, Marchese N, Vignola S, Sormani MP,
Barabino A, Buoncompagni A. Increased gut permeability in juvenile chronic arthritides: a
multivariate analysis of the diagnostic parameters. Clin Exp Rheumatol 2000;18:773-8.
4. Fresko I, Hamuryudan V, et al. Intestinal permeability
in Behcet’s syndrome. Ann Rheum Dis 2001;60:65-6.
5. Salmi M, Jalkanen S. Human leukocyte subpopulations from
inflamed gut bind to joint vasculature using distinct sets of adhesion molecules. J
Immunol 2001;66:4650-7.
6. Bargen JA. Complications and sequelae of chronic
ulcerative colitis, Ann Intern Med 1929;3:335-52.
7. Greenstein AJ, Janowitz HD, Sachar DB. The
extra-intestinal complications of Crohn’s disease and ulcerative colitis: a study of
700 patients. Medicine (Baltimore)1976;55:401-12.
8. Inman RD. Arthritis and enteritis - an interface of
protean manifestations. J Rheumatol 1987;14:406-10.
9. Queiro R, et al. Subclinical sacroiliitis in
inflammatory bowel disease: a clinical and follow-up study. Clin Rheumatol 2000;19:445-9.
10. Orchard TR, Wordsworth BP, Jewell DP. Peripheral
arthropathies in inflammatory bowel disease: their articular distribution and natural
history. Gut 1998;42:387-91.
11. Orchard TR. Clinical phenotype is related to HLA
genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology
2000;118:274-8.
12. Van den Bosch F, et al. Crohn’s disease associated
with spondyloarthropathy: effect of TNF-alpha blockade with infliximab on articular
symptoms. Lancet 2000;356:1821-2.
13. Abitbol V, Roux C, Chaussade S, et al. Metabolic bone
assessment in patients with inflammatory bowel disease. Gastroenterology 1995;108:417.
14. Semeao E, Jawad A, Stouffer N, et al. Risk factors for
low bone mineral density in children and young adults with Crohn’s disease. J Pediatr
1999;135:593-600.
15. Haderslev KV, Tjellesen L, Sorensen HA, Staun M.
Alendronate increases lumbar spine bone mineral density in patients with Crohn’s
disease. Gastroenterology 2000;119:639-46.
16. Lubrano E, Ciacci C, Ames PR, et al. The arthritis of
celiac disease: prevalence and pattern in 200 adult patients. Br J Rheumatol
1996;35:1314-8.
17. Usai P. Adult celiac disease is frequently associated
with sacroiliitis. Dig Dis Sci 1995;40:1906-8.
18. Bagnato GF, Quattrocchi E, Gulli S, et al. Unusual
polyarthritis as a unique clinical manifestation of celiac disease. Rheumatol Int
2000;20:29-30.
19. Borg AA, Dawes PT, Swan CH, Hothersall TE. Persistent
monoarthritis and occult celiac disease. Postgrad Med J 1994;70:51-3.
20. Collin P, Korpela M, Hallstrom O, et al. Rheumatic
complaints as a presenting symptom in patients with celiac disease. Scan J Rheumatol
1992;21:20-3.
21. Kallilorm R, Uibo O, Uibo R. Clin Rheumatol
2000;19:118-22.
22. Collin P, Reunala T, Pukkala E, et al. Celiac
disease-associated disorders and survival. Gut 1994;35:1215-8.
23. McFarlane XA. Osteoporosis in treated adult celiac
disease. Gut 1995;36:710-4.
24. Ratnaike RN: Whipple’s disease. Postgrad Med J
2000, 76:760-766
25. Durand DV, Lecomte C, Cathebras P, et al. Whipple
disease. Clinical review of 52 cases. The SNFMI research group on Whipple disease.
Medicine (Baltimore) 1997;76:170-84.
26. Puechal X. Whipple disease and arthritis. Curr Opin
Rheumatol 2001;13:74-9.
27. O’Duffy JD, Griffing WL, Li CY, et al. Whipple’s
arthritis: direct detection of Tropheryma whippelii in synovial fluid and tissue.
Arthritis Rheum 1999;42:812-7.
28. Fantry GT, James SP. Whipple’s disease. Dig Dis
1995;13:108-18.
29. Ramaiah C. Whipple’s disease. Gastroenterol Clin
North Am 1998;27:683-95.
30. Keat A. Reiter’s syndrome and reactive arthritis
in perspective. N Eng J Med 1983;309:1606-12.
31. Finch W. Arthritis and the gut. Postgrad Med J
1986;86:229-34.
32. Marsal L, Winblad S, Wollheim FA. Yersinia
enterocolitica arthritis in southern Sweden: a four-year follow-up study. Br Med J (Clin
Res Ed) 1981;283:101-3.
33. Barth WF, Segal K: Reactive arthritis (Reiter’s
syndrome). Am Fam Physician 1999;60:499-503, 507.
34. Scofield RH, et al. HLA-B27
binding of peptide from its own sequence and similar peptides from bacteria: implications
for spondyloarthropathies. Lancet 1995;345:1542-4.
35. Pacheco-Tena C, et al. Bacterial DNA in synovial fluid
cells of patients with juvenile onset spondyloarthropathies. Rheumatol 2001;40:920-7.
36. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al.
Double-blind, placebo-controlled study of three-month treatment with lymecycline in
reactive arthritis, with special reference to chlamydia arthritis. Arthritis Rheum
1991;34:6-13.
37. Creemers MC, Van Riel PL, Franssen MJ, et al.
Second-line treatment in seronegative Spondyloarthropathies. Semin Arthritis Rheum
1994;24:71-81.
|
