Dig Dis 1992:10:274-294
Department of Rheumatology, Central Hospital of Aust-Agder. Arcndal. and Department of Rheumatology. Tromso University Hospital. Norway
Keyw ords
Inflammatory bowel disease Immunology Ulcerative colitis Arthritis Crohn’s disease Ankylosing spondylitis
Joint Manifestations in Gastrointestinal Diseases 1. Pathophysiological Aspects, Ulcerative Colitis and Crohn's Disease
Abstract The many unique structural and functional features of the intestine may offer explanations to the well-established asso ciation between arthritis and inflammatory bowel diseases (IBD). In ulcerative colitis (UC) and Crohn's disease (CD) some 6-8% of cases develop peripheral joint disease which frequently correlates with the activity and extent of the underlying bowel disorder. Ankylosing spondylitis is also found rather frequently in UC and CD. but is apparently not related to the severity of colitis. The occurrence of rheumatic manifestations in these two IBD is reviewed in detail.
There are few chronic diseases that are more annoying or more severe in their course than the inflammatory bowel disorders (IBD). When ulcerative colitis (UC) and Crohn's dis ease (CD) are accompanied by manifestations of the locomotor system, the condition may lead to a serious problem for both patients and physicians. In addition. IBD as well as the inflammatory rheumatic diseases often have severe socioeconomic consequences [I-3] and a particular problem of IBD is that the disability often occurs in younger patients than what is experienced in other diseases [ I ]. As these intestinal disorders [4-6] as well as
the rheumatological conditions [7] are rather frequently observed in the general popula tion, they have significant impact on health economy. The syndromes of arthritis with intestinal disease seem therefore worthy of description for their effect on patients and health services. From a more academic point of view, the link between arthritis and the gut needs to be explored to achieve a greater insight into the pathophysiology of these diseases. The recog nition of the association between IBD and arthritic conditions in the middle of this cen tury, and the introduction of the unifying con-
Jan Tore Gran. MD Department of Rheumatology Central Hospital of Aust-Agder N-4800 Arcndal (Norway)
© 1992 S. Karger AG. Basel 0257-2753/92/ 0105-027452.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
Jan Tore Gran Gunnar Husby
Immunological Aspects of the Gastrointestinal Tract
The intestinal mucosa may be regarded as a barrier between the external environment and the internal human organism, providing a mechanical and functional defence against the continuous ingestion of foreign antigens. Even in normal subjects, this barrier is an incomplete one allowing small quantities of molecules of different sizes to cross the intact epithelium either through passive niecha-
nisms or by active pinocytosis. Changes in the anatomy of the intestine or the invasiveness of infective organisms may therefore signifi cantly alter the absorption of putative diseasepromoting antigens and allow them access to the circulation [15]. The detergent effects of bile acids and the proteolytic properties of pancreatic and epithelial brush border en zymes together with gut peristaltics and intes tinal mucous also represent mechanical bar riers to antigens [16]. If. however, antigens succeed in penetrating the epithelial barrier they are met by a second line of protection, represented by the gut-associated lymphoid tissue (GALT) [17], The GALT constitutes an impressive 25% of the mucosa and consists of organized lym phoid follicles (Peyer’s patches), cells within the lamina propria, intraepithelial lympho cytes and mesenteric lymph nodes [ 16]. Peyer’s patches increase in number in the more distal parts of the ileum and consist of the dome containing absorptive cells and some specialized cells called M-cells [18]. the T-cell-rich thymic dependent area and the Bcell-rich follicles. The M-cclls facilitate con trolled uptake of antigens for induction of mucosal immunity. The antigens are trans ported and processed by the M-cclls to adja cent lymphocytes and macrophages [16]. which are found in increased frequency in the dome and follicles of the Peyer’s patches. These lymphoblasts then migrate to draining mesenteric lymph nodesand lymph ducts and further to the general circulation. By a unique process (horning) these immunocytes then re turn to mucosal surfaces. It has been shown [ 19.20] that the lympho cytes bind specifically to unique endothelial cells of the high endothelium venules of Peyer’s patches, mesenteric lymph nodes and peripheral lymph nodes depending on their site of origin. The high endothelium venules are normally not present in the lamina pro
275
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
cept of the seronegative spondarthrilides in the middle of the 70s [8] certainly formed the foundations for further studies in this field. The idea of a possible connection between the gut and arthritis is, however, far from new. In the 1920s several reports of colectomies on patients with rheumatoid arthritis in order to alleviate the disease emerged [9. 10]. The indications for performing such surgical inter ventions were based on the ideas of specific bowel infections or altered bacterial flora among patients with polyarthritis. It was be lieved that colonic stasis, be it anatomic or functional in origin, fostered bacterial 'fer mentation' which produced the arthritis [11], The concept of an altered bacterial flora pro ducing arthritis soon fell into disrepute but interestingly current opinion favours the con cept of enteric organisms acting as bowel trig gers in disease-susceptible individuals [12]. To explain the associations between in flammatory rheumatic diseases and IBD, the intestine offers many unique structural and functional features which are inherent in host defense and antigenic processing [13, 14], A brief description of some immunological as pects of the gastrointestinal tract thus seems warranted before addressing the specific rheumatological conditions connected to various intestinal diseases.
276
Gran/Husbv
Peycr’s patches are rich sources of IgA pre cursor B-cells [32] which receive additional differentiation signals as they migrate to mes enteric lymph nodes [33] possibly also by the spleen [34]. By the homing process, the primed B-cells arrive at their mucosal sites to complete their differentiation into IgA pro ducing plasma cells when antigcnctically stimulated. Thus, the raised scrum concentra tion of IgA in some rheumatic diseases [26. 27] may point to a pathogenetically crucial role for the gastrointestinal canal in the devel opment of these disorders. In conclusion, transient or permanent de fects in either the mechanical mucosal barrier processes or the immunological protection system of the gut may lead to passage of potentially pathogenic antigens from the in testine to the peripheral circulation and fur ther to other organ systems such as the joints.
Definition and Description of Some Inflammatory Rheumatic Diseases
The seronegative spondylarthropathy complex encompasses a variety of disorders linked together by common clinical, labora tory and genetic features (table 1). Character istically. serum rheumatoid factors are not found more often than what is expected among healthy controls, hence the term 'se ronegative’. Similarly, other serum autoanti bodies such as antinuclear antibodies rather frequently observed in connective tissue dis eases are regularly absent in this group of dis eases. Moreover, in contrast to rheumatoid arthritis subcutaneous nodules do not appear and the arthritis is most frequently asymmet rically distributed, affecting large and me dium-sized joints. In most of the seronegative disorders, the brunt of the arthritic attacks falls on rather large joints such as the knees and ankles [8]. Furthermore, the majority of
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
pria but are found in inflamed tissues of CD [19]. They may be found normally in lymph nodes [12]. The antigen-stimulated lympho cytes not only return to the intestinal surfaces, but also to sites that arc normally immunologically privileged, such as synovium and the eye [ 12], These immunological pathways may have important significance regarding the as sociations between bowel diseases and disease manifestations such as arthritis and acute an terior uveitis. According to the cross-tolerance theory pa tients possessing the histocompatibility anti gen HLA B27 carry a particular antigen on their cells which cross-reacts with a similar antigen on the surface of certain grain-nega tive microorganisms [21]. As both ankylosing spondylitis and acute anterior uveitis [22, 23] are highly associated with HLA B27. intesti nal antigens may well trigger the development of inflammatory diseases in joints as well as the eye [24. 25], This does not. however, explain the apparent lack of association be tween peripheral arthritis in IBD and particu lar genetic host factors, such as HLA anti gens. Being found in increased serum concentra tions in several rheumatic disorders [26. 27], immunoglobulin A (IgA) also connects the i m mu nocompetence of the intestinal tissues to inflammation in such remote sites as the joints. It has long been recognized that IgA repre sents a major barrier to bacterial invasion of the host via the gut mucosa. Secretory IgA is capable of agglutinating a wide variety of intestinal organisms [28], and agglutinated bacteria are known to be transported more rapidly through the intestinal tract [28] thus preventing absorption through the gut muco sa. Also important is the ability of secretory IgA to inhibit bacterial motility [29] and to block the adherence of bacteria to the muco sal surface [30. 31].
Table 2. The prevalence of HLA B27 in various seronegative spondylarthropathies
T a b le l. The seronegative spondvlarthropathy complex: diseases and common clinical features
Diseases
Ankylosing spondylitis Reiter’s disease Psoriatic arthritis Reactive arthritis Arthritides associated with inflammatory bowel diseases (Behcet’s disease) Manifestations
Scronegativitv for rheumatoid factors Absence of antinuclear antibodies Absence of subcutaneous nodules Arthritis: often asymmetric large and medium-sized joints propensity for lower limbs non-erosivc (nondestructive) Radiological sacroiliitis Genitourinary: urethritis, vaginitis, balanitis Mucocutaneous: stomatitis, keratoderma blenorrhagica. dermatitis Intestinal: enteric infections or chronic inflammation Genetic: association with HLA B27 familial aggregation
Disease
Prevalence of HLA B27. %
Reference
Ankylosing spondylitis Associated with UC Associated with CD Associated w'ith Whipple’s disease Reiter’s syndrome Reactive arthritis (enteric) After salmonella infection After shigella infection After Campylobacter infection After yersinia infection Psoriatic arthritis Peripheral joint affection Ankylosing spondylitis
95 50-75 57 7-10 85 36-100 80-83 45 91
22. 23. 35 36. 37 38-48 49. 50 51.52 51.52 53. 54 55. 56 57 58
normal 54
59 60
277
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
the disorders in this group shows a highly sig nificant association with the tissue antigen HLA B27 (table 2), also in contrast to rheu matoid arthritis which is associated with HLA DR4 [61.62], The prototype of the seronegative spondylarthropathics is ankylosing spondylitis. Ankylosing spondylitis is an inflammatory rheumatic disease predominantly affecting the sacroiliac joints and the spine, but often also the peripheral joints particularly hips and knees [2], About 95% of the patients afflicted by ankylosing spondylitis possess HLA B27 [22. 23. 35] as compared to a prevalence in the general population of about 7-16% [63. 64], Extraspinal manifestations of ankylosing spondylitis include cardiac conduction distur bances. acute anterior uveitis [2] and rather infrequently renal amyloidosis [65]. Another disorder classified as a seronega tive spondvlarthropathv is Reiter’s disease traditionally characterized as a triad of symp toms consisting of arthritis, urethritis and conjunctivitis occurring concomitantly or se-
Joint Manifestations in Ulcerative Colitis
There are two distinct patterns of rheu matic disease manifestations observed in as sociation with UC: a peripheral arthritis often termed ‘enteropathic synovitis' and SI with or without ankylosing spondylitis [21]. Peripheral Arthritis The first author to report an association between arthritis and UC was probably White in 1895 who on post mortem examination found UC in an arthritic patient [67], Since then a number of studies on this topic have emerged (table 3) [36. 68-94]. Frequency o f Peripheral Arthritis in UC. At first sight (table 3), there seems to be a signifi cant variation among the reported occurrence
278
Gran/Husby
rates of peripheral arthritis in UC. with preva lences ranging from 0.9% [91] to 34.6% [93]. However, out of 28 surveys. 19 studies con cluded with a frequency of peripheral of ar thritis of less than 11 %. Most probably, the true prevalence of peripheral arthritis in UC lies between 5 and 8%. Perhaps the preva lence is even lower, as the material presented in table 3 should be regarded as rather se lected patients groups of UC mainly deriving from specialized departments of medicine or surgery. According to Berkson's [95] bias, such hospitalized patients will tend to reveal a higher degree of association between the two disorders than the general population. In deed. the recent study by Odes et al. [96] con cluded that as many as 80% of UC patients in fact never required hospitalization, and that only 2.4% were treated surgically. Another example of selection is the study by David [70] in which exclusively patients not re sponding to medical therapy were studied. Moreover, as the author pointed out [70], the patients lost on follow-up in such studies are those most likely to suffer from a milder dis ease and less frequent complications. In some of the early studies it is also difficult to distin guish between arthritis and arthralgia. The latter symptom does not necessarily bear any relation to the bowel disease but is shared by a significant proportion of the general popula tion [97], In another report [80], peripheral arthritis also comprised infectious arthritis, rheumatoid arthritis and spondylitis. In spite of these cautionary notes, periph eral arthritis represents one of the most fre quent complications of UC. although its true prevalence should be estimated by prospec tively conducted population surveys. It is fur ther noted that arthritis in UC is slightly more prevalent among women than among men [73, 88],
Joint Manifestations in Gastrointestinal Diseases. 1.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
quentiallv. Mucus and skin features are not infrequently observed in Reiter’s disease or more correctly Reiter's syndrome. A similar clinical picture is rather frequently seen devel oping after genitourinary and gastrointestinal infections and is termed reactive arthritis. In reactive arthritis, however, arthritis of the pe ripheral joints clearly dominate. This condi tion must be separated from infectious arthri tis (septic arthritis) in which microorganisms are present and can be cultivated from in volved joints. In reactive arthritis, bacterial viral or fungal cultures of synovial fluid or synovium are always repeatedly negative. Both reactive arthritis and full-blown Reiter’s disease are associated with HLA B27 [51. 52], Other diseases belonging to the seronega tive spondylarthropathy complex are pso riatic arthritis [66], some forms of juvenile chronic arthritis and the arthritides associ ated with the bowel diseases UC, CD and Whipple's disease.
Table 3. Peripheral arth ritis in UC
Year
Selection of patients
Bargen [68] Hurst [69] David [70] Willard ctal. [71] Feder[72] Bargen et al. [73] Jankelson et al. [74] Ricketts and Palmer [75] Kirsner et al. [76] Fischcl [77] Rice-Oxley and Truelove [78] Bone et al. [79] Sloan et al. [80] Brown et al. [81 ] Dennis and Karlson [82] Flood et al. [84] Bockus et al. [85] Kirsner et al. [86] Hamilton [87] Bywaters and Anseil [88] Fernandez-Herliby [89] Cornes and Stecher [90] Rotstein étal. [91] Wright and Watkinson [92] Palumbo et al. [93] Grcenstcin et al. [94] Dekker-Sayes et al. [36]
1930 1935 1935 1938 1938 1938 1942 1946 1948 1949 1950 1950 1950 1951 1952 1956 1956 1957 1957 1958 1959 1961 1963 1965 1973 1976 1978
dept. med. hospital priv. pract. dept. med. dept. med. dept. med. hospital dept. med. hospital -
M
_
—
-
-
19 32 33 491 -
hospital dept. med. hospital hospital hospital hospital hospital hospital
Time Relation o f Peripheral Arthritis and UC. Bargen [68] in 1930 noted three types of arthritis in UC; arthritis which followed re currences and improvements of UC. arthritis which preceded colitis and finally arthritis which apparently occurred without relation to the bowel disease. Table 4 shows the results of some surveys in which the time relation between onset of colitis and arthritis was properly described. In the majority of cases, colitis preceded the development of arthritis whereas in 0-25% of
31 34 55 380 -
-
-
48
52
-
-
hospital dept. med. dept. med. 1.113 dept. med. 83 dept. surg. hospital+out-pat. cl. 69 hospital dept. med. 93 -
F
-
41 265 84 160 117 -
-
887 64 -
79 -
87 -
68 290 116 173 152 -
-
-
24
34
T
693 40 50 66 88 871 145 206 100 85 129 112 2.000 147 267 148 125 180 138 109 555 200 333 269 121 202 58
Arthritis % 4.3 2.5 >9.1 7.5 2.3 6.3 8.3 5.8 8.0 22.0 5.4 9.0 7.7 7.5 7.1 11.5 22.0 22.2 2.2 14.7 1.8 9.5 0.9 11.5 34.6 22.8 6.9
cases, the onset of arthritis antedated that of UC. A simultaneous occurrence of joint dis ease and UC is seen in no more than about 20% of cases. In recent years [ 101 ] it has been shown that a significant number of patients with undifferentiated seronegative polyarthri tis have indeed subclinical IBD. On the other hand, according to the results shown in ta ble 4. there seems to be little reason to exam ine a patient with seronegative arthritis in order to detect bowel disorders requiring treatment.
279
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
Study
Table 4. O nset o f arthritis am ong patients with UC
Study
Year
Number
Arthritis preceding colitis. %
Arthritis following colitis. %
Simultaneous arthritis and colitis, %
Sloan et al. [80] Bywaters and Anscll [88] Fernandez-Herliby [89] Ford and Vallis [98] McEwen el al. [99] Wright and Watkinson [92] Clark et al. [100]
1950 1958 1959 1959 1962 1965 1971
155 28 18 15 84 31 15
20.6 25.0 5.6 0.0 10.0 0.0 6.7
57.4 60.7
21.9 14.3
280
Gran/Husbv
20.0 90.0 100.0
73.3
20.0
Relationship between Arthritis and the Se verity and Occurence o f Complications in UC. Rice-Oxley and Truelove [78] studied 129 pa tients with UC. Arthritis occurred in 41.7%of cases who also had skin manifestations (5 out of 12 patients) in contrast to only 1.7% (2 out of 117 cases) among those without dermato logical problems. The most striking associa tion reported has been that between erythema nodosum and arthritis [88, 92, 98. 99. 102). Others have found arthritis to be associated with perianal disease, pseudopolyps, massive hemorrhage, recurrent ulceration of the buc cal mucosa, uveitis and cutaneous manifesta tions such as pyoderma gangrenosum and leg ulceration [92]. Interestingly, in a review [103] of patients presenting with pyoderma gangrenosum at the Mayo Clinic, a high inci dence of arthritis and UC was observed. As will be discussed later in this review, further investigation of the frequently occurring com bination of intestinal disease, joint manifesta tions and dermatological features may reveal important findings regarding general patho physiological mechanisms. Characteristics o f Arthritis in UC. The ar thritis of UC mostly conforms to the concept of the seronegative arthritides, characterized
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
There appears to be a clear relationship between the activity of the bowel disease and the joint manifestations [88]. In the study of McEwen et al. [99] simultaneous flares of coli tis and peripheral arthritis were observed in 60% of the patients. According to Ford and Vallis [98], arthritis was associated with re lapse of UC in 14 out of 15 patients [93.3%). It should be emphasized, however, that al though arthritis tends to wax and wane with the activity of the underlying bowel disorder not every relapse of colitis will be followed by joint disease [98]. Relationship between Arthritis and the Ex tent o f Colitis. In the extensive survey of arthritis in UC reported in 1965 by Wright and Watkinson [92] a correlation between the incidence of inflammatory joint disease and the extent of bowel affection in UC was ob served. If the rectum was affected exclusively, only 4.9% had arthritis which sharply con trasted with the 14.4% incidence of arthritis among patients whose entire colon was af fected. According to these authors [92] such a correlation was, however, not observed in the male subgroup, possibly due to the low num ber of men studied.
94.6 80.0
2SI
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
by nondestructive migratory mild synovitis who underwent colectomy and ileostomy the and lack of serum rheumatoid factors. joint disease continued unabated postoperaAlthough the joints most commonly in tively [89]. More studies are warranted to volved are the knees and ankles [83. 88, 92] evaluate a possible effect on arthritis by medi most joints may become affected. The onset cal treatment of the bowel disease. of arthritis is rather acute in about 70% of Ankylosing Spondylitis and Sacroiliitis cases, and is monoarticular in 65% of patients Interpretation of the incidence of ankylos again most commonly in a knee or an ankle [99], The joint distribution is most often ing spondylitis in UC is difficult mainly due asymmetric [92], but a symmetric pattern is to the infrequent use of appropriate diagnos also quite frequent [99]. An attack of arthritis tic criteria for ankylosing spondylitis in the usually involves from 1-3 joints, and less than actual surveys. The majority of studies were 10% of cases have more than 6 joints in in fact reported prior to the promulgation of volved [75]. The arthritis subsides within 6-8 such criteria [105, 106], Another pitfall has weeks in more than half of the cases [92. 99] been that very few studies have used routine and in less than 10% it lasts for up to 1 vear x-rays of the sacroiliac joints of their UC patients to detect the possible presence of [99]. Changes in working capacity of UC pa ankylosing spondylitis. This is important as tients arc mainly caused by problems con radiological sacroiliitis is a conditio sine qua nected to the bowel affection [101]. However, non for the diagnosis of this rheumatic disor general malaise and arthritis appear to cause der [107], In a number of surveys published from such problems in about 28% of the patients 1920 to 1949. ankylosing spondylitis was not [104], Effect o f Therapy on Arthritis. In 1952. mentioned as a complication of UC [1 OSDennis and Karlson [82] showed that out of 112]. Perhaps the first author to report an 19 patients with UC and arthritis, all but 1 association between UC and ankylosing spon improved following removal of the colon, and dylitis was Romanus [ 113] in 1953. Frequency o f Ankylosing Spondylitis in UC. most patients enjoyed complete loss of symp toms. The same experience was gained in a Reported prevalences of ankylosing spondyli subsequent report [83] in which 13 out of 14 tis in UC vary between 0.8 and 6.0% (table 5). patients responded to surgical treatment. Most studies conclude with a prevalence of Among the 14 patients with UC and periph ankylosing spondylitis in UC between 3 and eral joint disease who had colectomy studied 6% which is 3-10 times higher than that of by Bywaters and Ansell [88], however. 2 had the general population [35], Time Relation between Ankylosing Spon occasional arthralgia. I had a brief recurrence of arthritis. 1 experienced no joint remission, dylitis and UC. As is shown in table 6. no clear and 1 patient developed severe generalized pattern regarding a possible relation between the onset of ankylosing spondylitis and UC arthritis for the first time after colectomy. Thus, the overwhelming majority of pa has emerged. Some observers [114] have tients with arthritis seems to benefit from sur found ankylosing spondylitis to be most fre gical treatment of the bowel disease but if quently diagnosed first while others conclude rheumatoid arthritis is present the beneficial that the bowel disease is the initial manifesta tion [89. 99. 102). Ankylosing spondylitis may effect of surgery is lost. In 10 out of II patients with rheumatoid arthritis and UC antedate the onset of UC by as much as over
Table 5. Prevalence o f ankylosing spondylitis (AS) and radiological sacroiliitis (SI) am ong patients with UC
Author
Brooke [83] Flood ct al. [84] Femandcz-Hcrlihy [89] Ford and Vallis [98] Zwaiflerand Martel [102] Achcson [114] Comes and Stecher [90] Rotstein et al. [91 ] Wright and Watkinson [92] McEwen et al. [ 115] Macrae and Wright [116] Palumbo et al. [93] Grecnstein et al. [94] Dekker-Sayes et al. [36]
Year
1956 1956 1959 1959 I960 1960 1961 1963 1965 1971 1973 1973 1976 1978
Patients with UC
Prevalence, %
males
females
all
AS
SI
47 65 265
84 79 290
131 148 555 3711 100 1.154 200 333 269 1.200 87 121 202 58
0.8 1.4 5.0 l.l 6.0 2.6 1.0 2.7 3.8 1.6 12.6 25.6 4.0 3.4
_
-
-
51 1.154 84 160 117
49 0 116 173 152
-
-
35
52
-
-
-
-
24
34
-
18 -
8.6
1 CD also included.
282
Gran/Husby
time relationship to the IBD. the association of IBD with sacroiliitis or ankylosing spondy litis is not the result of one being causally related to the other [8] but is rather based on disease susceptibility genes for one condition predisposing to the other disorder. Relation between Disease Activity o f UC and Ankylosing Spondylitis. In contrast to pe ripheral arthritis, the activity of ankylosing spondylitis does not seem to parallel the activ ity of the bowel disease [89], Among the anky losing spondylitis cases with UC evaluated by McEwen et al. [99], simultaneous flares of colitis and spondylitis were seen in only 26% [99]. In their review, Neumann and Wright [21] concluded that in UC, spondylitis seems to progress independently of the activity of the bowel disease. However, prospectively conducted surveys of the course of ankylosing spondylitis in IBD are largely lacking.
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
20 years [114], but on the other hand colitis may precede the spinal disease by up to 8 years [118], The discrepancy between the various re ports could be partly ascribed to insufficient use of diagnostic criteria, scarce patient mate rial, uncertainty regarding the date of onset of the two diseases and variations in study de signs. Another explanation for the apparent disagreement could be different disease dura tion among the patient groups investigated. In one study, sacroiliitis was found in 14.4% of those patients with a duration of colitis of less than 4 years, as contrasted by a prevalence of 22% among patients with UC of more than 4 years' duration [118]. Accordingly, the longer the duration of colitis among patients studied, the greater the chance of detecting ankylosing spondylitis. However, as it has been re peatedly observed that the clinical picture of spondylitis develops without any consistent
Table 6. The onset of ankylosing spondylitis (AS) and U C in patients with both disorders
Year
AS+UC
AS first %
Fcrnandez-Herlihy [89] Zwaiflerand Martel [102] Acheson [114] McEwen et al. |99] McBride clal. [117] Wright and Watkinson [118]
1959 1960 1960 1962 1963 1965
28 5 30
17.9 20 63.3 26.0 37.5 38.5
-
24 13
Severity ami Extent o f Colitis and Ankylos ing Spondylitis. There are very few reports on the association between the development of ankylosing spondylitis and the extent of bowel involvement in UC. According to Wright and Watkinson [118] sacroiliitis was found in 13% of those patients who had only rectal involvement as compared to 23.2% among cases in whom the entire colon was affected. In cases with the distal parts of the colon involved, sacroiliitis was observed in 16.7% [118]. These figures seem to be in agreement with studies reporting significantly more complications in patients with extensive and total colitis (25.9%) as opposed to those with distal colon involvement only (11.4%) [96]. Thus, there seems to be a correlation between the occurrence of radiological sa croiliitis and extent of colitis, but further studies are needed before establishing a simi lar association with regard to ankylosing spondylitis. We will discuss later the differ ence between radiological sacroiliitis and an kylosing spondylitis in UC. Wright and Watkinson [118] also found sacroiliitis to be more prevalent (25%) in those cases with an acute fulminant course of UC. Sacroiliitis was observed in 11.8% among cases with procto-colitis only and in
Colitis first %
Simultaneous onset. %
82.1 20 23.3
60 13.3 74 45.8 38.5
16.7 23.0
21 % of those with a chronic course of bowel disease. Effect o f Therapy upon Ankylosing Spondy litis and UC. In one study [89] 15 patients with UC and spondylitis underwent colec tomy and ileostomy but progressive symp toms of spondylitis continued postoperatively in 12. The impression of other workers [ 12] is that all exlraintestinal manifestations of UC except spondylitis and sclerosing cholangitis with cirrhosis remit concomitantly with im provement of bowel disease. Unfortunately, there are few reports on the course of ankylos ing spondylitis after institution of therapeutic modalities such as surgery' and use of salazopyrin. particularly regarding the possible pro gression of radiological changes in the sacroil iac joints and the spine. Ankylosing Spondylitis and Other Compli cations ofUC. Uveitis has been found in 0.52.5 % of patients with UC [68. 69. 73. 75. 119, 120]. Among patients with spondylitis and UC, the prevalence of uveitis is reportedly 5.6-16.1 % [99. I 14], most likely reflecting the increased prevalence of HLA B27. More in teresting than these absolute figures is the lack of relation between radiological sacroiliitis and uveitis, which contrasts the clear associa tion between this ocular manifestation and
283
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
Author
284
Gran/IIusbv
[122], A cautionary note should be added, however, because ankylosing spondylitis has for a long time been greatly underestimated among females [122], Uveitis is seen in about 25% of ankylosing spondylitis [2] and independently of this dis ease it is associated with HLA B27 [125], Thus, the finding in UC of an association between uveitis and ankylosing spondylitis and not between uveitis and radiological sa croiliitis [118] further suggests that the latter finding is not a manifestation of idiopathic ankylosing spondylitis. Further evidence strongly indicating etiopathogenetic differ ences between asymptomatic radiological sa croiliitis and ankylosing spondylitis in UC has been provided by the family study of UC conducted by Macrae and Wright [116], In the study, it was shown that the prevalence of ankylosing spondylitis in the relatives of pro bands with UC and ankylosing spondylitis was higher than among relatives of probands with UC exclusively. On the other hand, ra diological sacroiliitis was equally frequent among the two groups of relatives. Then, what about the manifestations of ankylosing spondylitis seen in UC compared to what is found in idiopathic ankylosing spondylitis? The 4 cases with ankylosing spondylitis and UC reported by Steinberg and Storey [126] in 1957 appeared to be no differ ent from idiopathicankylosingspondylitisde scribed in classical textbooks [8]. Three out of 4 cases had ankylosis of sacroiliac joints, and all 4 patients demonstrated calcifications of the spinal ligaments. Naturally, these cases represent selected patients of ankylosing spondylitis and UC similar to those reported by Zwaifler and Martel [102]. These studies, nevertheless, clearly show the development of classical ankylosing spondylitis in UC. The 28 ankylosing spondylitis/UC patients reported by Fernandez-Herlihy [89] in 1959 also fit with a clinical picture of idiopathic ankylos
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
ankylosing spondylitis [118. 121. 122]. This discrepancy brings forward the intriguing question regarding the true nature of radiolog ical sacroiliitis in UC. Is it a forme fruste of idiopathic ankylosing spondylitis or should it be regarded as a complication unrelated to the arthritis of the sacroiliac joints in ankylosing spondylitis? Radiological Sacroiliitis and Ankylosing Spondylitis. In their elegant study. Wright and Watkinson [92] clearly distinguished between radiological sacroiliitis and ankylosing spon dylitis. They found radiological sacroiliitis to be a rather frequent feature of UC (18%) in contrast to ankylosing spondylitis which oc curred in 3.3% of their cases. It is. however, difficult to sec how they distinguished sacroil iitis from ankylosing spondylitis, as idio pathic ankylosing spondylitis according to es tablished criteria [106] requires the roentge nological demonstration of sacroiliitis. More over, according to our own results, the degree of sacroiliac arthritis in ankylosing spondyli tis is correlated to the duration of spondylitis [123. 124], but unfortunately, the disease du ration among the two groups were not given in their study [92], Dekker-Saycs ct al. [36] reported 58 pa tients with UC of whom 7 had definite radio logical sacroiliitis. Of these 7 cases. 2 patients were reported to have ankylosing spondylitis according to the New York Criteria [106], Very important to this context is their finding of a low frequency of HLA B27 in radiological sacroiliitis in UC in contrast to the increased frequency of this histocompatibility antigen in ankylosing spondylitis [36]. Such a discrep ancy has also been noted by previous investi gators [37]. Thus, it is very likely that asymp tomatic sacroiliitis demonstrated by x-ray is not a precursor of idiopathic ankylosing spon dylitis. Moreover, the authors found a female preponderance of sacroiliitis in UC which sharply contrasts with ankylosing spondylitis
detail when reactive arthritis in IBD is consid ered later in this review. UC in Ankylosing Spondylitis. There are surprisingly few reports on the occurrence of UC among patients primarily considered to be afflicted by idiopathic ankylosing spondy litis. One of the reasons may be that in pri mary ankylosing spondylitis the diagnosis is clearcut. and further examination could be considered unnecessary. The study of McBride et al. [117] represents an exception in this regard. Sixteen patients with UC were found among 560 ankylosing spondylitis pa tients treated with radiotherapy, a prevalence of 1.8%. This frequency of UC in ankylosing spondylitis was about 20 times higher than that of UC in the general population (0.09%). It is noteworthy, however, that more females had UC (3.6%) than did males (UC or C'D in 1.6%). Among the 222 cases with ankylosing spondylitis reported by Wilkinson and Bvwaters [127], only 4 patients (1.8%) suffered from UC. Also noteworthy is the study of Woodrow and Eastmond [ 128] in which not a single case of UC was observed among 145 subjects afflicted by ankylosing spondylitis. On the other hand. Jayson et al. [129] found UC in 7 out of 47 patients with ankylosing spondylitis (14.9%). A history of diarrhea was obtained in only 5 of these patients. More over. some authors [117] noted that intestinal disease when present in ankylosing spondyli tis was usually mild. Genetic Aspects o f Articular Manifestations oJ UC. Generally, familial aggregation of dis ease occurs in two forms. First, a clustering of the disease amongst close relatives of the affected proband. Secondly, an accumulation of relatives affected by diseases other than that of the proband. Both forms seem to a cer tain extent to occur in UC. The number of rel atives of probands with colitis who them selves also have colitis has been found to exceed by far the expected number based on
285
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
ing spondylitis. In 19 patients (64.3%) the spondylitis was confined to the sacroiliac joints, a figure not far from that found among ankylosing spondylitis patients selected through a population survey as well as from a hospital [ 123]. Spinal abnormalities typical of ankylosing spondylitis were seen in the re maining 10 patients [35.7%). In another sur vey of ankylosing spondylitis in UC, 58.1 % of the patients had radiological changes in the spine typical of ankylosing spondylitis [114], The prevalence of peripheral arthritis of about 32% in ankylosing spondylitis accom panying UC [89] is similar to that reported among hospitalized ankylosing spondylitis patients [98] but somewhat thigher than what is observed when unselected ankylosing spon dylitis patients are investigated [121]. We are not aware of any extensive survey of ankylosing spondylitis in UC exploring the incidence of such extra-articular complica tions of ankylosing spondylitis as cardiac con duction disturbances and amyloidosis. To conclude, radiological sacroiliitis when observed in UC should not be interpreted as a manifestation of ankylosing spondylitis un less the patient conforms to signs and symp toms of ankylosing spondylitis as described according to the New York criteria for the diagnosis of this disease [ 106], The finding of a negative HLA B27 test will strengthen the assumption that the sacroiliitis found is merely a coincidental finding and not repre senting idiopathic ankylosing spondylitis. An kylosing spondylitis when developing in UC should, however, be expected to run the same disease course as that of idiopathic ankylosing spondylitis with a similar risk of contracting disease manifestations of the spine. Thus, im mediate therapeutic action should be taken when diagnosing ankylosing spondylitis in UC. The relationship between HLA B27 and ankylosing spondylitis will be discussed in
286
Gran/Husby
Joint Manifestations in Crohn's Disease
The first report of an occurrence of joint disease in CD may have been the patient described by Abercrombie [12] in 1930. The patient suffered rheumatic problems and was found on postmortem to have a vesicoileal fis tula. Since then a number of surveys have emerged, strongly supporting an association between CD and disease manifestations of the locomotor system. Peripheral Arthritis in CD. The prevalence of arthritis of the peripheral joints among patients afflicted by CD varies from 0.4 to 23.0% [90, 135-146] (table 7). The peripheral arthritis of this IBD resembles that of UC [21 ] and is characterized by subacute episodes in volving a few joints [146] in an asymmetric distribution. The joint manifestations are most frequently located in the lower extremi ties [98] and the joints most commonly in volved are the knees and ankles [141], The wrist and small joints of fingers and feet also seem to be prone to develop arthritis [141]. The attacks of arthritis are usually of short duration (3-8 weeks) and self-limited, but they may recur [147], As with the arthritis of UC, complete recovery is, however, the rule [147] and destructions of the affected joints are very rarely encountered [ 140]. Strikingly similar to UC. the severity of the arthritis seems to parallel the activity of the intestinal disease [136, 137]. Moreover, in periods of quiescence the recrudescence of arthritis often heralds a recurrence of enteritis [147], Females appear more prone to develop arthritis than males [146]. In the majority of patients with CD and peripheral arthritis, the bowel involvement tends to precede that of the joints [98. 141], Among the 8 patients with peripheral arthritis and CD studied by Gilvarry et al. [146]. the arthritis postdated the bowel symptoms in 7 patients.
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
prevalence alone [ 130. 131]. Furthermore, an kylosing spondylitis has been reported in in creased prevalence among relatives of pro bands with both UC and CD [116, 132], These results may point to a crucial role of genetic factors in UC and moreover to a com mon genetic link between UC and ankylosing spondylitis. It should be noted, however, that familial aggregation may also be caused by common environmental factors. Moreover, no common genetic factor for UC and anky losing spondylitis has been detected up to now [133], UC does not seem to be associated with any particular HLA antigen [ 133]. In ankylos ing spondylitis, however, a highly significant association exists with HLA B27. as about 95% of these patients carry the tissue antigen as compared to a prevalence of 8-16% in the general Caucasian population [35. 64]. Anky losing spondylitis in UC also seems to be asso ciated with HLA B27 [36] but no genetic fac tors has been found to explain the increased risk of getting ankylosing spondylitis in UC. The overall prevalence of HLA B27 in anky losing spondylitis associated with IBD is. however, lower than in ankylosing spondylitis in general [128], indicating the presence of one or more HLA B27 independent etiologi cal factors. The risk of getting ankylosing spondylitis among HLA-B27-positive indi viduals is rather low. estimated to be between 2 and 8% [35]. which is in contrast to about 30% in B27-positive UC patients. UC and Systemic Lupus erythematosus. UC has been reported to occur in about 4% of patients with systemic lupus erythematosus (SLE) [134], Furthermore, patients with UC may show positive LE cell phenomenon and may develop SLE features when treated with sulfasalazine [134], Although reported more than 25 years ago. these observations need further investigation.
Table 7. P e rip h era l a rth ritis in C D
Author
Clark etal. [135] van Patter et al. [136] Daffner and Brown [ 137] Crohn and Yarniss [ 138] Groner [139] Cornes and Stecher [90] Anseil and Wiglcy [140] Soren [141] Hämmeret al. [142] I laslock and Wright [39] Greenstein et al. [94] Rankin et al. [ 143] Selby et al. [40] Bourne etal. [144] Münch et al. [145] Modena et al. [38] Gilvarry et al. [146]
Year
1939 1954 1958 1958 1960 1961 1964 1966 1968 1973 1976 1979 1979 1985 1986 1988 1989
M
F
Total
24
20
-
-
53
47
-
-
-
-
53 37
33 54
-
-
-
-
58
58
-
-
-
-
42
80
-
-
63 27 -
104 24 -
44 600 100 674 72 86 91 67 45 116 213 569 122 100 167 51 55
Arthritis, % total
M
F
6.8 4.5 6.0 2.3 0.4 8.1 6.6 7.5 22.0 20.7 12.7 I9.31 8.2 23.0 14.0 19.6 14.5
_
_
-
-
-
-
-
-
-
-
-
-
5.4
7.4
-
-
-
17.2
-
24.1
-
-
-
-
-
-
-
13.0
-
14.0
-
-
-
-
It lias been suggested [21] that the benefi cial effect of intestinal surgery upon arthritis is less pronounced in CD than in UC. Accord ing to other workers [136] exacerbation of joint symptoms in CD subsequent to resec tion invariably heralds a recurrence of the intestinal lesion. Although disputed by some [140]. the ob servation that CD without colonic involve ment has a reduced incidence of peripheral arthritis may support the notion that the dis tal part of the bowel plays a critical role in the development of joint manifestations [12, 146]. In one study [90] of 45 patients with CD of the large intestine, a rather high prevalence (15.5%) of peripheral arthritis was observed. On the other hand, none of 6 patients with ankylosing spondylitis and CD had colonic involvement [148],
Some uncertainty exists regarding the pos sible association between the occurrence of arthritis in CD and other major complica tions of this disease such as fistula formation and malabsorption [21], On the other hand, an association between development of ery thema nodosum and arthritis seems to exist [98] in CD as it does in UC. Ankylosing Spondylitis and Radiological Sacroiliitis in CD. The prevalence of ankylos ing spondylitis in CD varies between 2.0% [ 137] and 9.8% [38], most surveys estimating a prevalence between 2 and 4% (table 8). Thus, there is no striking difference between the occurrence of ankylosing spondylitis in CD and UC (table 5). Male-to-female ratio is about I in spondylitis [146, 148]. Similar to the situation in UC. the prevalence of radio logical sacroiliitis is considerably higher
287
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
1 Arthralgia possibly also induced.
Ankylosing spondyli
Author
Year
Daffner and Brown [ 137] Acheson [114] Comes and Steelier [90] Ansell and Wigley [ 140] Haslock and Wright [39] Mueller et al. [148] Greenstein et al. [94] Dckker-Saycs et al. [36] Selby et al. [40] Bourne et al. [144] Modena et al. [38] Purrmann et al. [41] Gilvarry et al. [146]
[146. 148] approaching 20% in one survev [36]. The overall picture of ankylosing spondyli tis in CD seems to correspond to that seen in UC. with additional spinal abnormalities be ing detected in about 41 % [90], In one study [148], back symptoms preceded recognition of CD in 5 out of 6 cases. There is no association with HLA antigens in CD, and in one study of 47 patients with uncomplicated CD. HLA B27 was not dem onstrated in a single patient [41], There is. however, a significant association between the spondylitis in CD and HLA B27. although none of the 5 ankylosing spondylitis patients with CD and ankylosing spondylitis observed by Modena et al. [38] carried HLA B27. In fact, the association between B37 and Crohn’s spondylitis has been better investigated in this disease than in UC. In one of the largest sur veys, HLA B27 was found in 33.3% [42] which is strikingly less than in idiopathic an kylosing spondylitis (81-95%) [2], However, if taken together the overall prevalence of B27 in ankylosing spondylitis of CD was 56.6% in
288
Gran/Husby
1958 1960 1961 1964 1973 1974 1976 1978 1979 1985 1988 1988 1989
CD
100 733 86 91 116 200 213 51 122 100 51 231 55
Prevalence, % AS
SI
2.0 3.0 2.3 3.3 6.9 3.0 2.8 3.9 0.8 5.0 9.8 7.8 7.3
_ -
9.5 7.0 -
19.6 -
12.7
these surveys thus approaching that of idio pathic ankylosing spondylitis [2. 42] (table 9). In contrast, the prevalence of B27 in asymp tomatic sacroiliitis of CD of 7.1 % (table 9) is similar to the prevalence of this tissue antigen in the general population of whites [2], This further strengthens the impression gained from studies of ankylosing spondylitis in UC that radiological sacroiliitis is not an abortive form or a precursor of ankylosing spondyli tis. In one study, uveitis was found in 18.1 % of ankylosing spondylitis patients affected by CD [114], which is not far from the 22% prev alence of uveitis in idiopathic ankylosing spondylitis [27], Regarding the association between uveitis and CD. a recent observation by Belgian investigators suggested that idio pathic uveitis may be an expression of subclinical CD [150], lleocolonoscopy was per formed in 2 HLA-B27-positive patients with uveitis, neither of whom had articular or intestinal complaints. Microscopic examina tion of the biopsy specimens revealed the presence of chronic inflammatory lesions in
Joint Manifestations in Gastrointestinal Diseases. 1.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
Table 8.
tis in CD
Table 9.
Association between radiological sacroiliitis (SI) and ankylosing spondylitis (AS) and HLA B27
in CD Year
AS + CD
SI + CD
total
with B27
total
with B27
Morris et al. [43] Russel et al. [44] Jacoby and Jayson [45] Duffaut et al. [46] Brcwerton and James [47] Good et al. [48] Deshaycs et al. [ 149] lluaux et al. [42] Purrmann et al. [41] Modena et al. [38]
1974 1974 1974 1974 1975 1976 1976 1978 1988 1988
8 7 3 2 5 7 6 15 18 5
6 7 1 0 4 3 4 5 13 0
_
_
-
-
3
0
-
-
All surveys
-
76
43(56.6%)
the ileum. The findings were, however, based on the examination of only 2 patients who also had been treated with corticosteroids. Consequently, larger materials of patients with uveitis examined by ileocolonoscopy are needed before any firm conclusion regarding the association between uveitis and subclinical CD may be drawn. The prevalence of CD in ankylosing spon dylitis seems to be 40-50 times higher than that of the general population (0.46 versus 0.10%) [117]. In one study [127], only 1 case of CD was diagnosed among 222 patients with ankylosing spondylitis, whereas in another survey [ 129] 1 out of 47 patients with ankylosing spondylitis had CD (2.1%). As in UC. more females than males with ankylosing spondylitis [117] had CD (2.2 versus 0.2%). Other Rheumatic Associations (table 10) Among 10 patients with recurrent knee pain and CD. arthroscopic examinations re vealed inflammatory' changes in 1 patient
Table 10.
3
1
-
-
1 7
0 0
-
-
-
-
14
1 (7.1 %)
Rheumatic manifestation in CD
Peripheral nonspecific arthritis (table 7) Granulomatous non-erosive arthritis [ 151-153] Erosive large joint arthritis [l 00, 154. I55] Septic arthritis of the hip [ 156-158] Calcium pyrophosphate deposition disease (chondrocalcinosis) [I 59] Hypertrophic osteoarthropathy [ 146. 160] Ankylosing spondylitis (table 8) (Radiological sacroiliitis) Granulomatous myositis [ 16 1] Granulomatous osteitis [162] Periosteal new bone formation [ 163] Osteoporosis [94] Avascular necrosis [ 164] Amyloidosis [94]
only [ 159], Four patients had. however, depo sition o f‘glittering’ crystals and additionally 4 cases had positively biréfringent crystals with the appearance of calcium pyrophosphate deposition disease (chondrocalcinosis). Fur-
2S9
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
Author
thermore. hypertrophic osteoarthropathy oc curred in 9% of 55 patients with CD in one study [ 146], but in earlier reports it was found in as many as 40% of cases [160]. In other publications, both granulomatous nonerosivc
synovitis [151-153] and erosive large joint arthritis [100. 154, 155] were detected. Al though fortunately rarely occurring, septic ar thritis of the hip is another important compli cation of CD [ 156-158],
1 Sonncnberg A: Disability from in flammatory bowel disease among employees in West Germany. Gut 1989:30:367-370. 2 Gran .IT: A clinical, radiological and epidemiological survey o f ankylos ing spondylitis: thesis. 1985. 3 Gran JT : The epidemiology of rheu matoid arthritis. Monogr Allergy Immunol 1987:71:162-196. 4 Rose JDR. Roberts GM. Williams G. Mayberry JT. Rhodes J: Cardiff Crohn's disease jubilee: The inci dence over 50 years. Gut 1988:29: 346-351. 5 Mayberry JF. Ballantyne KC. Hardcastle JD. Maugham C. Pye G: Epi demiological study of asymptomatic inflammatory bowel disease: The identification o f cases during a screening programme for colorectal cancer. Gut 1989:30:481-483. 6 Jones HW. Grogono J. Hoare AM: Surveillance in ulcerative colitis: Burdens and benefit. Gut 1988:29: 325-331. 7 Kelsey JL: Epidemiology of muscu loskeletal disorders. Oxford. Oxford University Press. 1982. pp l - l I. 8 Wright V: Relationship between an kylosing spondylitis and other spondarlhritides: in Moll JMH (ed): An kylosing Spondylitis. London. Chur chill Livingstone. 1980. pp 42-51. 9 Mutch N: Alimentary infections in chronic arthritis. Lancet I922:ii: 1107-1109. 10 Smith R: The surgical relief of intes tinal foci of infection in cases of arthritis deformans. Ann Surg 1922: 76:515-548. 11 Katz KD, Hollander D: Intestinal mucosal permeability. Baillierc's Clin Rheum 1989:3:271-284.
12 Isdalc A. Wright V: Seronegative ar thritis and the bowel. Baillicre's Clin Rheum 1989:3:285-301. 13 Doc WF: The intestinal immune system. Gut 1989:30:1679-1685. 14 Brandtzxg P. Halstensen TS. Kelt K. Krajci P. Kvale D. Rognum TO. Scott H. Sollid LM: Immunobiology and immunopathology of human gut mucosa: Humoral immunity and intraepithelial lymphocytes. Gastroenterology 1989:97:1562— 1584. 15 Rooney PJ. Jenkins RT. Buchanan WW: A short review of the relation ship between intestinal permeability and inflammatory joint disease. Clin Exp Rheum 1990:8:75-83. 16 Sartor RB: Importance of intestinal mucosal immunity and luminal bac terial cell wall polymers in the aeti ology of inflammatory joint dis eases. Bailliére's Clin Rheum 1989: 3:223-245. 17 Utsinger PD. Spalding DM. Weiner SR. Clarke J: Intestinal immunology and rheumatic disease: Inflamma tory bowel disease and intestinal by pass arthropathies: in Espinoza L. Goldenberg D. Arnett F. Alarcon G (eds). Infections in the Rheumatic Diseases. London. Gruñe & Strat ton. 1988, pp 317-342. 18 Owen RL. Jones AL: Epithelial cell specialization with human Pever’s patches: An ultrastructural study of intestinal lymphoid follicles. Gas troenterology 1974:66:189-203. 19 Butcher EC: Lymphocyte migration and mucosal immunity; in Heyworth MF, Jones AL (eds): Immu nology of the Gastrointestinal Tract and Liver. New York. Raven Press 1988. pp 93-103.
20 Duiveslin AM. Horst E, Pals ST. Rouse BN: Eligh endothelial differ entiation in human lymphoid and inflammatory tissues defined by monoclonal antibody HECA-452. Am J Pathol 1988:130:147-155. 21 Neumann V. Wright V; Arthritis as sociated with bowel disease. Clin Gastroenterol 1983:12:767-795. 22 Brewerton DA. Hart FD. Nicholls A. Caffrey M. James DCO. Sturrock RD: Ankylosing spondylitis and HI.-B27. Lancet 1973;i:904—907. 23 Schlosstein T. Terasaki PL Bluestone R. Pearson CM: High associa tion of an HLA antigen. W27. with ankylosing spondylitis. N Engl J Med 1973:288:704-706. 24 Husby G. Tsuchiya N. Schwimmbeck PL. Keat A. Pahle J A. Oldstone MBA. Williams RC: Cross-reactive epitope with Klebsiella pneumoniae nitrogenase in articular tissue of HLA-B27+ patients w ith ankylosing spondylitis. Arthritis Rheum 1989; 32:437-445. 25 Tsuchiya N. Husby G. Williams RC. Stieglilz H. I.ipsky PE. Inman RD: Autoantibodies to the IILA-B27 se quence cross-react with the hypothe tical peptide from the arthritis-asso ciated Shigella plasmid. J Clin In vest 1990:86:1193-1203. 26 Kinsclla TD. Espinoza I . Vasey FB: Serum complement and immuno globulin levels in sporadic and fa milial ankylosing spondylitis. J Rheumatol 1975:2:308-313. 27 Gran JT. Ostenscn M. Husby G: A clinical comparison between males and females with ankylosing spon dylitis. .1 Rheumatol 1985:12:126— 129.
290
Gran/Husby
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
References
38 Modena V. Amoroso A. Frattasio C. Pera A, Constantini P. Maioceo 1. Ponti V. Centanaro di Vittoria C. Vermc G. Curtoni ES: HLA anti gens and clinical manifestations in Crohn's disease. Clin Exp Rheum 1988;6:221-225. 39 Haslock I. Wright V: The musculo skeletal complications o f Crohn's disease. Medicine 1973:52:217— 225. 40 Selby WS. Kater RHM. Heap TR. Gallagher ND: Crohn’s disease: A rev iew of 122 cases. Aust NZ J Med 1979:9:145-150. 41 Purrmann .1. Zeidler H. Bertrams J. Juli E. Cleveland S. Berges W. Gcmsa R. Spcckcr C. Reis ME: Ill-A antigens in ankylosing spondy litis associated with Crohn's disease. Increased frequency of the HLA phenotype B27. B44. J Rheumatol 1988: 15: 16 5 8 - 1661. 42 Huaux JP. Fiasse R. Bruyère MD. de Deuxchaisncs CN: HLA B27 in regional enteritis with and without ankylosing spondylitis or sacroiliitis. J Rheumatol 1977 (suppl 3):4: 60-63. 43 Morris Rl. Metzger AL. Blcestone R: HLA W27 - A useful discrimina tor in the arthropathies of inflam matory bowel disease. N Engl J Med 1974:290: 1117- 1119. 44 Russel AS. Schlaut J. Percy JS: IILA (transplantation) antigens in an kylosing spondylitis and Crohn's disease. .1 Rheumatol 1974:1:203209. 45 Jacoby RK. Jayson MIV: HL-A27 in Crohn's disease. Ann Rheum Dis 1974;33:422-424. 46 Duffaul M. LcTallec Y. Gudral J: Formes familiales de maladie de Crohn. Cah Med 1974:15:305-310. 47 Brewerton DA. James DCO: The histocompatibility antigen (HLA27) and disease. Semin Arthritis Rheum 1975:4:191-207. 48 Ciood AE. Kawanishi H. Schultz JS: HLA B27 in blacks with ankylosing spondylitis or Reiter’s disease. N Engl J Med 1976:294:16 6 - 167. 49 Weiner SR. Utsinger P: Whipple's disease. Semin Arthritis Rheum 1986;15:157-167. 50 Khan MA: Axial arthropathy in Whipple's disease. J Rheumatol 1982:9:928-929.
51 Nicholls A: Reiter's disease and II LA27. Ann Rheum Dis. 1975: 34(suppl l):27. 52 Calin A: Reiter's syndrome: Epide miology and immunogenetics. Scand J Rheumatol I980:suppl. 32: 178-183. 53 llannu I J. Leirisalo-Repo M: Clini cal picture of reactive salmonella ar thritis. J Rheumatol 1988:15:1668— 1671. 54 Inman RD. Johnston MEA. Hodge M, Falk J. Helewa A: Postdysenteric reactive arthritis. Arthritis Rheum 1988:31:1377-1383. 55 Simon DG. Kaslow RA. Rosen baum J: Reiter's syndrome follow ing epidemic shigellosis. J Rheuma tol 1981:8:969-973. 56 Calin A. Fries JF: An 'experimental' epidemic of Reiter's syndrome revi sited. Ann Intern Med 1976:84: 564-566. 57 Gran JT, Mushy G: Joint manifesta tions in gastrointestinal diseases. Part II. Dig Dis 1992:10:295-312. 58 Aho K. Ahvonen P. Lassus A. Sievers K. Tiilikaincn A: HLA antigen 27 and reactive arthritis. Lancet 1973:ii: 157. 59 Suarcz-Almazor ME. Russell AS: Saeroiliitis in Psoriasis: Relation ship to peripheral arthritis and HI.A-B27. J Rheumatol 1990:17: 804-808. 60 l ope/.-Larrea C. Torre Alonso JC, Perez AR. Coto E: HLA antigens in psoriatic arthritis subtypes of a Spanish population. Ann Rheum Dis 1990:49:318-319. 61 Stastny P: Association of the B-ccll alloantigcn DRw4 with rheumatoid arthritis. N Engl J Med 1978:298: 869-871. 62 Gran JT. Husby G. Thorsby E: The association between the HLA anti gen DR4 and rheumatoid arthritis. Ann Rheum Dis 1983:42:292-296. 63 Gofton .IP: Epidemiology, tissue type antigens and Bechterew’s syn drome (ankylosing spondylitis) in various ethnical populations. Scand .1 Rheumatol 1980;suppl 32:166168. 64 Gran JT. Mellby AS. Husby G: The prevalence of HLA-B27 in Northern Norway. Scand .1 Rheumatol 1984: 13:173-176.
291
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
28 Shearman DJC. Parkin DM, McClelland DBL: The demonstra tion and function of antibodies in the gastrointestinal tract. Gut 1972: 13:483. 29 Mcstecky J. McGee JR. Kulhavy R: Synthesis of IgA and the induction of local immunity; in Pceters H (ed): Symposium on IgA. Protidcs Biol Fluids. Oxford. Pcrgamon Press. 1987. pp 811-818. .30 Williams RC. Gibbons RJ: Inhibi tion o f bacterial adherence by secre tory immunoglobulin A: A mecha nism for antigen disposal. Science 1972:177:697. 3 1 Porter P. I.ingood MA: Novel muco sal antimicrobial functions interfer ing with the plasma-mediated viru lence determinants of adherence and drug resistance. Ann NY Acad Sci 1983:409:564. 32 Frangakis MV. Koopman WJ. Kiyono H: An enzymatic method for preparation of dissociated mu rine Pcyer's patch cells enriched for macrophages. J Immunol Methods 1982:48:33-44. 33 Guy-Grand D. Griscelli C. Vassali P: The gut-associated lymphoid sys tem: Nature and properties of large dividing cells. Eur J Immunol 1974: 4:435. 34 Tseng J: Transfer of lymphocytes of Peyer’s patch between allotype congenic mice. Repopulation of the IgA plasma cells in gut lamina pro pria. J Immunol 1981:127:2039. 35 Gran JT. Husbv G. Hordvik M: Prevalence of ankylosing spondylitis in males and females in a young middle-aged population of Tromso. northern Norway. Ann Rheum Dis 1985:44:359-367. 36 Dckker-Saycs BJ. Mcuwisscn SGM. van den Bcrg-loonen F.M. de Maas WHD. Agenant D. Tytgat GNJ: Prevalence of peripheral arthritis, saeroiliitis and ankylosing spondyli tis in patients suffering from inflam matory bowel disease. Ann Rheum Dis 1978:37:33-35. 37 Hyla JF. Frank WA. Davis JS: Lack o f association of UFA B27 with ra diographic saeroiliitis in inflamma tory bowel disease. J Rheumatol 1976:3:196-200.
82 Dennis C. Karlson KE: Surgical measures as supplements to the management of idiopathic ulcer ative colitis: Cancer, cirrhosis, and arthritis as frequent complications. Rec Adv Surg 1952:32:892-912. 83 Brooke BN: Outcome of surgery for ulcerative colitis. Lancet I956;ii: 532-536. 84 Flood CA. Lepore MJ. Hiall RB. Karush A: Prognosis in ulcerative colitis. J C'hron Dis 1956:4:267— 282. 85 Bockus ML. Roth JLA. Buchman E: Life history of nonspecific ulcer ative colitis-relation of prognosis to anatomical and clinical varieties. Gastroenterologica 1956:86:549581. 86 Kirsner JB. Sklar M. Painter WL: The use of ACTH cortisone, hydro cortisone and related compounds in the management of ulcerative coli tis. Am J Med 1957:28:267-274. 87 Hamilton NT: A review of ulcer ative colitis at the Alfred Hospital. Alfred HospClin Rep 1957:7:15. 88 Bywaters EGL. Ansell BM: Arthritis associated with ulcerative colitis. Ann Rheum Dis 1958;17:169-183. 89 Femandez-Herlihy L: The articular manifestations of chronic ulcerative colitis. N Engl J Med 1959:261:259263. 90 Comes JS. Stechcr M: Primary Crohn's disease of the colon end rec tum. Gut 1961:2:189-201. 91 Rotstein J. Entcl 1, Zeviner B: Ar thritis associated with ulcerative co litis. Ann Rheum Dis 1963:22:194— 197. 92 Wright V. Watkinson G: The arthri tis of ulcerative colitis. Br Med J 1965:2:670-675. 93 Palumbo PJ. Ward LE. Sauer WG. Scudamore HH: Musculoskeletal manifestations of inflammatory bowel disease-ulcerative and granu lomatous colitis and ulcerative proc titis. Proc Mayo Clin 1973:48:411416. 94 Greenstein AJ. Janowitz MD. Sachcr DB: The extraintestinal com plications of Crohn's disease and ul cerative colitis. A study of 700 pa tients. Medicine 1976:55:401—412. 95 Bcrkson J: Limitations of the appli cation of fourfold table analysis to hospital data. Biometr Bull 1946:2: 47-53.
Gran/Husby
96 Odes I IS. Fraser D. Krawiec J: Ul cerative colitis in the Jewish popu lation of Southern Israel. 19611985 epidemiological study. Gut 1987;28:1630-1636. 97 Lawrence JS: Rheumatism in pop ulations. London, lleincman 1977. pp 32-67. 98 Ford DK. Vallis DG: The clinical course of arthritis associated with ulcerative colitis and regional en teritis. Arthritis Rheum 1959:2: 526-536. 99 McEwcn C. Lingg C. Kirsner JB: Arthritis accompanying ulcerative colitis. Am J Med 1962:33:923— 941. 100 Clark RL. Muhlctaler CA. Margulies SI: Colitic arthritis. Clinical and radiographic manifestations. Radiology 1971:101:585-594. 101 Miclants H. Vcys EM: The gut in the spondyloarthropathies. .1 Rheumatol 1990:17:7-10. 102 Zwaiflcr NJ. Martel W: Spondyli tis in chronic ulcerative colitis. Ar thritis Rheum 1960:3:76—87. 103 Powell FC. Schroeter AL. Su WPD. Perr>’ HO: Pyoderma gan grenosum: A review of 86 patients. Q J Med 1985:55:173. 104 Wyke RJ. Edwards FC. Allan RN: Employment problems and pros pects for patients with inflamma tory bowel disease. Gut 1988:29: 1229-1235. 105 Kellgren JH. Jeffrey MR. Ball J (eds): The epidemiology of chronic rheumatism. Oxford. Blackwell Scientific Publications, vol I 1963: 326. 106 Bennet PM. Wood PMN: In Bennet PM, Wood PMN (eds): Popu lation Studies of the Rheumatic Diseases. Excerpta Medica Fnd, Int Congr Ser 1966. No 148. p 456. 107 Gran JT: An epidemiological sur vey of the signs and symptoms of ankylosing spondylitis. Clin Rheum 1985;4:161-i 69. 108 Yeomans FC: Chronic ulcerative colitis. JAMA 1921.77:20432047. 109 Buie LA: Chronic ulcerative coli tis. JAMA 1926:87:1271-1274. 110 Hardy TL. Bulmcr E: Ulcerative colitis. Br Med J 1933:2:812-815. 111 Crohn BB. Roscnak BD: A follow up of ulcerative colitis. Am .1 Di gest Dis 1935:2:343-346.
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
65 Husby G: Amyloidosis in ankylos ing spondylitis. Scand J Rheumatol 1980;suppl 32:67-70. 66 Wright V: Arthropathia psoriatica A clinical entity? Scand J Rheuma tol 1980;suppl 32:25-28. 67 White Mil: Colitis. Lancet I985:i: 538-539. 68 Bargcn JA: Complications and se quelae of chronic ulcerative colitis. Medicine 1930:3:335-352. 69 Hurst AF: Prognosis in ulcerative colitis, lancet I935;ii:l 194-1196. 70 David VC: Idiopathic ulcerative co litis. Ann Surg 1935:102:669-670. 71 Willard JH. Pessel JF. Hundley JW. Bockus IIL: Prognosis of ulcerative colitis. JAMA 1938:111:20782086. 72 Feder IA: Chronic ulcerative colitis: An analysts of 88 cases. Am J Digest Dis 1938:5:239-245. 73 Bargcn JA. Jackman RJ. Kerr JG: Studies on the life histories of pa tients with chronic ulcerative colitis (thromboulcerative colitis), with some suggestions for treatment. Ann Intern Med 1938:12:339-352. 74 Jankelson IR. McClure CW. Sweetsir FN: Chronic ulcerative colitis. 2. Complications outside the digestive tract. Rev Gastroenterol 1942:9:99— 104. 75 Ricketts WE. Palmer WL: Compli cations of chronic nonspecific ulcer ative colitis. Gastroenterology 1946: 7:55-66. 76 Kirsner JB. Palmer WL. Maimon SN. Ricketts WE: Clinical course of chronic non-specific ulcerative coli tis. JAMA 1948:137:922-928. 77 Fischel EE: Ulcerative colitis. Am J Med 1949:6:481-494. 78 Rice-Oxley JM. I ruelove S: Com plications of ulcerative colitis. Lan cet 1950;i:607—6 11. 79 Bone FC. Ruffin JM. Baylin GJ. Casscl C: The clinical course of idio pathic ulcerative colitis. South Med J 1950:43:817-823. 80 Sloan WP. Bargen JA, Gage RP: Life histories of patients with chron ic ulcerative colitis: A review of 2.000 cases. Gastroenterology 1950: 16:25-38. 8 1 Brown ML. Kasich AM. Weingarten B: Complications of chronic ulcer ative colitis. Am .1 Dig Dis 1951:1: 52-54.
125 LeClercq SA. Percy JS. Russell AS: Genetic markers for acute anterior uveitis. J Rheumatol 1983:10: 998-1000. 126 Steinberg VL. Storey G: Ankylos ing spondylitis and chronic inflam matory lesions of the intestines. Br Med j ’ 1957;2:1157-1159. 127 Wilkinson M. Bvwaters EGL: Clinical features and course of an kylosing spondylitis. Ann Rheum Dis 1958:17:209-228. 128 Woodrow JC. Eastmond CJ: HLA B27 and the genetics of ankylosing spondylitis. Ann Rheum Dis 1978: 37:504-509. 129 Jayson MIV. Salmon PR. Harrison WJ: Inflammatory bowel disease in ankylosing spondylitis. Gut 1970:11:506-511. 130 Goligher JC. dc Dombal FT. Watts J. Watkinson G: Familial in cidence of ulcerative colitis; in Goligher JC et al (eds): Ulcerative Colitis. London. Baillière. Tindall and Cassell, 1968. p 59. 131 Farmer RG. Michener WM. Mor timer EA: Studies of family history among patients with inflammatory bowel disease. Clin Gastroenterol 1980:9:217-227. 132 llaslock 1: Arthritis and Crohn's disease. A family study. Ann Rheum Dis 1973:32:479. 133 Woodrow JC: Genetics; in Moll JMM (cd): Ankylosing Spondyli tis. Edinburgh. Churchill Living stone. 1980. pp 26-41. 134 Alarcon-Segovia D. Hcrskovic T. Bearing WM. Bartholomew LG. Cain JC. Shorter RG: Lupus ery thematosus cell phenomenon in patients with chronic ulcerative colitis. Gut 1965:6:39-47. 135 Clark RL. Dixon CE. Minn R: Re gional enteritis. Surgery 1939:5: 277-304. 136 Van Palter WN. Bargcn J A. Dockerty MB. Feldman WM. Mayo CW. Waugh JM: Regional enteri tis. Gastroenterology 1954:26: 347-450. 137 Daffncr JE. Brown CH: Regional enteritis. Clinical aspects and diag nosis in 100 patients. Ann Intern Med 1958:49:580-594. 138 Crohn BB. Yarniss H: Regional enteritis. Ed 2. New York. Grunc & Stratton. 1958.
139 Groner U : A review of regional enteritis. J Am Osteopathic Assoc 1960;60:12-15. 140 Anscll BM. Wiglcy RAD: Arthritic manifestations in regional enteri tis. Ann Rheum Dis 1964:23:6472. 141 Soren A: Joint affections in re gional enteritis. Arch Intern Med 1966:117:78-83. 142 Hammer B. Ashurst P. Naish J: Diseases associated with ulcerative colitis and Crohn's disease. Gut 1968:9:17-21. 143 Rankin GB. Watts I ID. Melnyk GS. Kelley ML: National coopera tive Crohn’s disease study: Extraintestinal manifestations and perianal complications. Gastroen terology 1979:77:914-920. 144 Bourne JT. Kumar P. Huskisson EC. Mageed R. Unsworth DJ. Wojtulewski JA: Arthritis in cocliacdisease. Ann Rheum Dis 1985: 44:592-598. 145 Münch I I. Purrmann J. Reis HE. Bertrams J. Zeidler II. Stolze Th. Miller B. Korsten S. Greniers J. Strohmeyer G: Clinical features of inflammatory joint and spine manifestations in Crohn's disease. Hepato-Gastroentcrol 1986:33: 123-127. 146 Gilvarry JM. Keeling F. Fitzgerald O. Fielding JF: Arthritides associ ated with Crohn’s disease. Br J Rheumatol 1989:28(suppl 2): 109. 147 Wilske KR. Decker JL: The articu lar manifestations of intestinal dis ease. Bull Rheum Dis 1965:13: 362-365. 148 Mueller CE. Sceger JF. Martel W: Ankylosing spondylitis and re gional enteritis. Radiology 1974: 112:579-581. 149 Deshayes P. Geffroy Y. Houdenl C: Manifestations rhumatismales dans 80 cas de Crohn. Rev Rheum Mai Osteoart 1976:43:345-355. 150 Mielants H. Veys EM. Verbraekcn II. de Vos M. Cuvelier C: HLA B27 positive idiopathic acute ante rior uveitis: A unique manifesta tion of subclinical gut inflamma tion. J Rheumatol 1990:17:841— 842. 151 Hermans PJ. Fievcz ML. Des camps CL. Aupaix MA: Granulo matous synovitis and Crohn's dis ease. J Rheumatol 1984; 11:710— 712.
293
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
112 Maratka Z. Spcllbcrg MA: Obser vations on the clinical course of non-specific ulcerative colitis. Gastroenterology 1949:12:79-86. 113 Romanus B: Intestinal infections and pelvo-spondylitis ossificans. Acta Med Scand 1953:145:3lb 323. 114 Acheson ED: An association be tween ulcerative colitis, regional enteritis and ankylosing spondyli tis. 0 J Med 1960:29:489-499." 115 McEwen C. DiTata D. Lingg C: A comparative study of ankylosing spondylitis and spondylitis accom panying ulcerative colitis, regional enteritis, psoriasis and Reiter’s dis ease. Arthritis Rheum 1971:14: 291-318. 116 Macrae 1. Wright V: A family study of ulcerative colitis with par ticular reference to ankylosing spondylitis and sacroiliitis. Ann Rheum Dis 1973:32:16-20. 117 McBride J A. King M.I. Baikie AG. Crean GP. Sircus W: Ankylosing spondylitis and chronic inflamma tory diseases of the intestines. Br Med J 1963;2:483-486. 118 Wright V. Watkinson G: Sacro-iliitis and ulcerative colitis. Br Med J 1965:2:675-680. 119 McKittrick LS. Miller RM: Idio pathic ulcerative colitis. Ann Surg 1935:102:656-673. 120 Cullinan ER: Ulcerative colitis: Clinical aspects. Br Med J 1938:2: 1354-1256. 121 Gran JT. Husby G: Ankylosing spondylitis: A comparative study of patients in an epidemiological survey, and those admitted to a department of Rheumatology. J Rheumatol 1984:11:788-793. 122 Gran JT. Ilusby G: Ankylosing spondylitis in women. Semin Ar thritis Rheum 1990:19:303-312. 123 Gran JT. Hordvik M. Husbv G: Roentgenological features of anky losing spondylitis. A comparison between patients attending hospi tal and cases selected through an epidemiological survey. Clin Rheum 1984:3:467-472. 124 Gran JT. Ilusby G. Hordvik M. Stormer J. Romberg-Andcrscn 0 : Radiological changes in men and women with ankylosing spondyli tis. Ann Rheum Dis 1984:43:570575.
156 London D. Fitton JM: Acute septic arthritis complicating Crohn's dis ease. Br J Surg 1970:57:536-537. 157 Jakobsen J. Hellcland H: Baktcriell coxitis som komplikasjon til intestinal infeksjon. Ugeskr l.:cgcr 1986:148:1766-1767. 158 Kyle J: Psoas abscess in Crohn’s disease. Gastroenterology 1971: 61:149-155. 159 Heuman R. Boeryd B. Billquist J. Sjodahl R. Tagesson C: Arthralgia and crystal deposits in Crohn's dis ease. Scand J Rheum 1981:10:
294
Gran/Husby
313-317. 160 Andcrsson DO. Mullinger I1A, Bagoch A: Regional enteritis involv ing the duodenum with clubbing of the fingers and steatorrhea. Gas troenterology 1957:32:917-926.
161 Spiro HM: Clinical gastroenterol ogy. Toronto. Macmillan. 1970. p 631. 162 Nugent FW. Glaser D. FernandezHerlihy L: Crohn's colitis associ ated with granulomatous bone dis ease. N Engl Med 1976:294:262263. 163 Neale G. Kelsall AR. Doyle FIE Crohn's disease, and diffuse sym metrical periosteitis. Gut 1968:9: 383-387. 164 Brown B. Bank S, Marks IW: Peri ostitis. aseptic necrosis and arthri tis occurring in a patient with Crohn's disease. Gastroenterology 1971:60:1106-1109.
Joint Manifestations in Gastrointestinal Diseases. I.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/2/2018 8:31:19 PM
152 Lindstrom C. Wramsby H, 0stberg G: Granulomatous arthritis in Crohn’s disease. Gut 1972:13: 257-259. 153 Al-Hadidi S. Khatib G. Chhatwal P. Ichatib R: Granulomatous ar thritis in Crohn's disease. Clin Exp Rheum 1988;6:221-225. 154 Frayha R. Stevens MB. Baylcss TM: Destructive monarthritis and granulomatous synovitis as the presenting manifestation of Crohn's disease. John Hopk Med J 1975:137:151-155. 155 Tomlingson IW. Jayson Ml V: Ero sive Crohn's arthritis. J R Soc Med 1981:74:540-542.