Joint manifestations in gastrointestinal diseases. 1. Pathophysiological aspects, ulcerative colitis and Crohn's disease.

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

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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


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.


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


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

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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.


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


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



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


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.



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


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



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


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.



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


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.


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


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],

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Diagnosis and management of common gastrointestinal tract infectious diseases in ulcerative colitis and Crohn's disease patients.

Association of oral manifestations with ulcerative colitis.

Immunological studies in ulcerative colitis. VIII. Antibodies to colon antigen in patients with ulcerative colitis, Crohn's disease, and other diseases.

High endothelin-1 immunoreactivity in Crohn's disease and ulcerative colitis.

Interleukin 1 in ulcerative colitis.

Ulcerative colitis and Crohn's disease.

Pathophysiological aspects of Hodgkin's disease.

Ménétrier Disease and Ulcerative Colitis.

Bronchopulmonary disease in ulcerative colitis.

Neurologic manifestations of gastrointestinal and liver diseases.

Immunological Aspects of Gastrointestinal Diseases.

Gastrointestinal endoscopy biopsy derived proteomic patterns predict indeterminate colitis into ulcerative colitis and Crohn's colitis.

ASCRS Joint Symposium: controversies in surgery for ulcerative colitis.

Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases.

Inflammatory disease of the colon: ulcerative colitis and Crohn's colitis.

Atopic disease in ulcerative colitis and Crohn's disease.

Indirect costs of inflammatory bowel diseases: Crohn's disease and ulcerative colitis. A systematic review.

[Is ulcerative colitis an autoimmune disease?].

Extraintestinal manifestations in Crohn's disease and ulcerative colitis: results from a prospective, population-based European inception cohort.

The association of autoimmune diseases with pediatric ulcerative colitis does not influence its disease course.

Perioperative Considerations in Crohn Disease and Ulcerative Colitis.

Letter: Serum lysozyme levels in Crohn's disease and ulcerative colitis.

C3 metabolism in ulcerative colitis and Crohn's disease.

Double contrast barium enema in Crohn's disease and ulcerative colitis.