The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to understand it?

Inflammatory bowel disease (IBD) associated arthritis is a subgroup of spondyloarthritis (SpA) that has suffered from lack of recognition in rheumatology clinical and research circles for over 100 years.

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The initial description of a potential cause and effect relationship between arthritis and inflammatory bowel disease (IBD) likely goes back to well over 100 years ago in 1895 where William H White wrote, ‘among twenty-three cases of ulcerative colitis… two had urate of soda in their joints’.1 Almost 30 years later and into the next century, in 1922, Rea Smith, a surgeon based in Los Angeles, noted alleviation of swelling, pain and joint immobility in multiple patients with chronic arthritis on the conclusion of various bowel operations. Although he made mention of ‘ileocaecal coil’ changes on some of his patient’s X-rays, it is difficult to tell if his patients had true IBD or another intestinal affliction; the full characterisation of the various features of IBD phenotypes were not generally appreciated throughout the USA at that time. He then stated, quite prophetically, that ‘no study of a case of arthritis is complete without a careful investigation of the gastro-intestinal tract’.2

A decade later at the Mayo Clinic, where quite a few patients with ulcerative colitis (UC) had assembled for patient care, Arnold Bargen in 1929 and Philip Hench in 1935, in separate publications, drew the attention to peripheral arthritis manifestations in their patients with UC.3 4 They had observed and studied 1500 patients with chronic UC; 60 had arthritis which they felt was the most common complication of the colitis except for polyposis. They went further in their review and expanded the descriptions which became the beginning of an appreciation of the heterogeneric nature of arthritis in IBD. Bargen and Hench described four types of arthritis: (1) Arthritis preceding UC for a fairly long time, resembling the atrophic variety (‘atrophic arthritis’ was the prior description of rheumatoid arthritis (RA)), and considered unrelated to colitis, (2) Atrophic arthritis and colitis occurring at the same time but progressing independently, (3) Arthritis resembling atrophic arthritis that occurs during colitis remission and not during exacerbation of the bowel disease, and (4) The more common type, a subacute arthritis that flares with colitis exacerbations and experiences relief with colitis remission; all of this latter type showing a striking conformity with remissions and exacerbations of both occurring simultaneously. They considered the first three types as the unrelated coincident associations between RA and IBD, and these investigators concluded the fourth and more common type was a specific complication of the colitis itself rather than a coincident association of another disease.

The rheumatism reviews published in 1936 commented that the foregoing data from Bargen and Hench were admittedly incomplete to establish a new condition, referring to a specific colitis-arthritis entity.5 However, the review authors did comment about certain points that did distinguish this entity from garden variety atrophic arthritis (which was clearly progressive and relentless) and these included facts that the clinical relationships among the appearance, activity and recovery from the colitis and arthritis were similar, and most importantly, there was a greater tendency to periodicity as well as to complete remissions in the arthritis compared with what is typically seen in usual atrophic (rheumatoid) arthritis.

The rheumatism reviews’ authors clearly were wrestling with this newly recognised association between the gut and the joints. They were sceptical of those colleagues who were ‘glibly incriminating more or less symptomless intestines as the cause of atrophic arthritis’. They stated that “Those who blame the bowels may find some comfort in the evidence which shows that arthritis and intestinal diseases can be causally related by the hematogenous route, but the rarity of a proved relationship should give one pause”. The authors of the reviews stated quite specifically (and possibly presciently in the editorial comments section of the reviews) that there is a need for complete open-mindedness on this difficult problem of a symptomless gastrointestinal infection playing a role either as a primary or an underlying predisposing cause of arthritis.5

In retrospect, it is highly likely that the type of arthritis of large joints that occurs during colitis remission and not during exacerbation (Hench and Bargen type 3) reflects the now known association between colitis and the peripheral arthritis of ankylosing spondylitis (AS). This issue is examined in detail below; however, since AS was not recognised by Hench and Bauer (and particularly, by Bauer) as a separate entity from RA, it is very likely that it was assumed to be just another part of RA that, on occasion, was called rheumatoid spondylitis.6

There is a distinct literature gap from the late 1930s until the 1950s for arthritis-IBD associations. Why did this happen?

We are unable to find IBD-arthritis descriptions in the literature for the next decade or during the World War II postwar years; neither was a connection mentioned or referenced in the standard nomenclature of diseases approved by the American Rheumatism Association of 1952. For example, the first two editions in 1950 and in 1954 of the textbook Harrison’s Principles of Internal Medicine did not contain text, reference or discussion of IBD-related arthritis.6 Investigators who observed and commented on this information gap later in the century opined that the gap could be in part due to the attribution of these disease manifestations to be simply the coincidence of an association with RA.7 8

However, an alternate view of this literature gap is possibly related to a distraction caused by the description of a newly recognised arthritis syndrome potentially triggered by an exogenous infectious agent. The tenth rheumatism review published in 1953 describes a recently characterised condition called Reiter’s Syndrome where the statement is made that ‘Numerous reports on this syndrome had appeared’ referring to the American and English literature reports from the preceding years.9 The very first actual description of Reiter’s syndrome was made by the English physician Benjamin Brodie over a century earlier in 1818 where he observed a 45-year-old man with arthritis, urethritis and conjunctivitis.10 In 1916, Reiter in Germany and Fiessinger-Leroy in France described postdysenteric cases of urethritis-arthritis-conjunctivitis combinations occurring in soldiers living in close quarters during World War I.11 The initial characterisation of the syndrome in USA was performed by Walter Bauer and Ephraim Engleman in 1942, describing the Reiter’s triad in a 23-year-old man with no history of preceding diarrhoea or venereal disease; these investigators acknowledged ‘until the aetiology is established, this symptom complex should be referred to as a syndrome rather than a disease’.12

More comprehensive descriptions of this form of acute and subsequent chronic arthritis related to an infectious agent did occur during the intervening World War II years primarily from descriptions by Paronen et al in Finland where prevalent close-quarters living conditions promoted the spread of bacillary dysentery across populations of civilians.13 American publications describing this condition also could have contributed to distracting investigators from further studies characterising IBD-arthritis, although it was prophetically stated in the tenth rheumatism review that postdysenteric arthritis can be clinically indistinguishable from Reiter’s syndrome.9 Further, it is clearly mentioned in this 1953 rheumatism review that a possible relationship to bacillary dysentery should be considered under the discussion of the section called Aetiology of Reiter’s Syndrome.

Bringing the gut-arthritis connection to the forefront of critical thinking was a result of an unintentional experiment of nature, again related to the war effort. A shipboard epidemic of bacillary dysentery took place immediately after an American naval vessel left port from somewhere in Europe in 1962, where Dr Rolf Noer carefully documented the clinical sequelae of this epidemic from the beginning to its conclusion. He found 9 cases of Reiter’s syndrome out of 602 cases of bacillary dysentery, findings which could not be explained by chance. He then stated, “It appeared that our cases of Reiter’s disease were sequelae of bacillary dysentery”.14 Later and well after the genetic association between HLA-B27 and spondyloarthritis (SpA) was discovered, Calin and Fries were able to locate, examine, and clinically and genetically characterise five of the original nine Noer cases; they discovered an 80% positivity rate for HLA-B27 in these former navy enlisted men, all of whom had subsequently experienced severe, progressive destructive SpA. Calin and Fries concluded that B27 had an effect on both the incidence and severity of postdysenteric Reiter’s syndrome.15

Ahvonen et al in 1969 studied various arthritis manifestations associated with Yersinia enterocolitica infection and wrote, ‘transient non-purulent (reactive) arthritis with acute onset has been occasionally reported in association with bacterial infections such as those caused by BrucellaShigella, and Salmonella typhimurium’. They introduced the term ‘reactive arthritis’ for the first time in rheumatology literature.16 A clear and convincing separation between RA and what appeared to be an infectious agent (either from the gut or the genitourinary tract) triggering an acute and then a chronic disease most assuredly required the widespread recognition of the clinical and research importance of what later tuned out to be rheumatoid factor.17 18 The discovery and characterisation of the antibody nature19 of rheumatoid factor (and its absence in the patients with IBD-arthritis) is likely to be a major reason for the subsequent rejuvenated and focused interest in IBD-arthritis20 as a separate and distinguishable entity.

When was RA finally separated from the arthritis of IBD?

Luis Fernandez-Herlihy, an influential practitioner from the Lahey Clinic in Boston, summarised in 1959 his opinion describing (from a database of over 500 cases) the range of articular manifestations in patients with UC. He employed the following five categories: rheumatoid spondylitis, RA, erythema nodosum, arthralgias and acute toxic arthritis. Among these, acute toxic arthritis had the closest relationship with colitis; he noted that this category became clinically evident only with the exacerbation of colitis and relieved on colitis remission without any residual deformity. He then postulated ‘it is possible that acute toxic arthritis constitutes a milder, earlier, or perhaps an atypical form of Rheumatoid Arthritis’.21

However, clarity from Verna Wright and Geoffrey Watkinson whose observations were published in the same year as Fernandez-Herlihy nevertheless made a point of distinguishing ‘colitic arthritis’ from RA; this was based on the negative results from the (newly recognised) agglutination test for RA, and the recognition of asymmetrical joint involvement, lack of joint deformity and the absence of rheumatoid nodules in those with colitic arthritis.22 At around the same time, rheumatologists along with gastroenterologists began emphasising the presence of axial involvement in patients with IBD. Steinberg and Storey in 1957 made what appears to be the first association between AS and Crohn’s disease.23 Eric Bywaters and Barbara Ansell in the following year (1958) reported a case series of 37 patients with UC and arthritis, 6 of whom had sacroiliitis. They distinguished these patients from typical AS without colitis, from reactive arthritis (known at the time as Reiter’s syndrome), and from RA in three ways based on more female patients in the colitis group, absence of urethritis, and negative agglutination tests, respectively.7 The first US scholarly and scientifically controlled observation revealing a relationship between UC and AS was performed by Zvaifler and Martel in 1960; 100 cases of UC were chosen at random from a coded Roentgen database for UC. These investigators observed a 6% prevalence of AS when these imaging studies were reread.24 They stated that the concurrence of spondylitis with UC was too frequent to be explained by chance.

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