Ankylosing spondylitis and ulcerative colitis

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The Link between Ankylosing Spondylitis, Crohn’s Disease, Klebsiella, and Starch Consumption

Both ankylosing spondylitis (AS) and Crohn’s disease (CD) are chronic and potentially disabling interrelated conditions, which have been included under the group of spondyloarthropathies. The results of a large number of studies support the idea that an enteropathic pathogen, Klebsiella pneumoniae, is the most likely triggering factor involved in the initiation and development of these diseases. Increased starch consumptions by genetically susceptible individuals such as those possessing HLA-B27 allelotypes could trigger the disease in both AS and CD by enhancing the growth and perpetuation of the Klebsiella microbes in the bowel. Exposure to increased levels of these microbes will lead to the production of elevated levels of anti-Klebsiella antibodies as well as autoantibodies against cross-reactive self-antigens with resultant pathological lesions in the bowel and joints. Hence, a decrease of starch-containing products in the daily dietary intake could have a beneficial therapeutic effect on the disease especially when used in conjunction with the currently available medical therapies in the treatment of patients with AS and CD.

1. Introduction

Ankylosing spondylitis (AS) is regarded as the prototype of seronegative spondyloarthropathies (SpAs) that comprise a group of spondylitis-associated conditions. Other disease entities of SpA include reactive arthritis, psoriatic arthritis, undifferentiated SpA, and arthritis associated with inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC) . SpAs are interrelated conditions which share certain associated clinical, laboratory, radiological, and genetic manifestations such as inflammatory back pain caused by spondylitis/sacroiliitis, as well as asymmetric oligoarthritis, enthesopathy, anterior uveitis, positive family history, and association with HLA-B27 genes, but without positivity for the rheumatoid factors.

Although patients with CD usually present with clinical features of bowel involvement, the characteristic presentation in those with AS and spondylitis-associated CD is progressive inflammatory backache with or without other SpA-associated features .

Both AS and CD affect early age groups and have a world-wide distribution. There are at least one million individuals in the United Kingdom who suffer from some features of AS. The negative impact of AS on the employment and the psychological status of patients with this disease has been well established. The disease in CD can also have an impact on the social status and work abilities of patients, especially in women . Because of these negative impacts on the general health and welfare status of patients with AS and CD, with certain drawbacks of the currently used medical treatments, a search for the causative factor and an alternative therapeutic measure involving eradication of the cause could be helpful in the management of patients with these diseases.

2. Genetic Background of AS and CD

A positive family history is one of the key points in defining the characteristics of patients with SpA. In a family study of AS probands and healthy controls in an Icelandic population, it has been shown that there is evidence which might support the existence of common genetic components for AS and IBD. The study demonstrated a risk ratio of 3.0 and 2.1 in the first and second-degree relatives, respectively, for the occurrence of AS in families of probands with IBD, and with the occurrence of IBD in families of patients with AS . In a more recent study, it has been shown that there is genetic overlap across the autoimmune diseases including also AS and IBD . It appears, therefore, that certain common genetic factors might act in the development of both diseases in AS and CD.

The frequency of association of HLA-B27 allelotypes in patients with AS is considered as the strongest genetic link with any disease which have been encountered in the field of rheumatology . This genetic bond was discovered in the early 1970s, where more than 95% of patients with AS have been found to possess HLA-B27, whilst the frequency of this gene in the general population was below 10% . Other diseases in the SpA group have lower but different degrees of associations with this allelotype. For example, the frequency of this allelotype in patients with IBD/CD without associated arthritis is comparable to those of the normal population but increases to 40%–60% in those patients with spondylitis/sacroiliitis . These data show that a spondyloarthropathic patient presenting with spinal involvement has a higher chance of possessing HLA-B27 genes than those presenting with peripheral joints involvement only. Apart from HLA-B27, other genes, whether located within or outside the major histocompatibility complex region, have also been implicated in the aetiopathogenesis of both AS and CD .

3. The Link between AS and CD

There are certain characteristics linking AS and spondylitis-associated CD together based on sharing some of the genetic, clinical, immunological, and microbial features . Furthermore, most if not all SpA conditions are thought to have a fundamental link with the gut lesions and enterobacterial microbes . For example, around 10 percent of patients with AS have overt IBD, whilst 70% of AS patients have subclinical terminal ileitis . Axial and peripheral arthritis can occur in up to 30% of patients with CD , and the prevalence of AS might increase to up to 6% in patients having CD . Moreover, HLA-B27 positive patients with IBD were shown to have higher chance of developing AS compared to those without IBD . Rats transgenic for HLA-B27 spontaneously develop a chronic inflammatory disease that resembles, both clinically and histologically, the human SpA, while control rats transgenic for HLA-A2 do not develop such an illness . These results support the role of gut and intestinal flora in the development of SpAs mainly in genetically susceptible individuals such as those possessing the HLA-B27 genes. Nevertheless, up to 30 percent of patients with unclassified HLA-B27-positive inflammatory rheumatic diseases develop into one form of definite SpA group such as AS, IBD, or reactive arthritis . It has also been reported that more than half of patients with undifferentiated SpA will develop AS over certain period of time .

It would appear from these results that both HLA-B27 and gut inflammation play a pivotal role in the development of SpAs, especially AS and CD, and that the main aetiopathogenetic process is triggered by genetic and environmental (mainly microbial) factors.

4. Evidence of Subclinical Microbial Infections in AS and CD

The first evidence of the epidemiological link between infection and SpA was detected in the early twentieth century where a triad of symptoms consisting of urethritis, conjunctivitis, and arthritis, being termed as Reiter’s syndrome, was detected in a group of soldiers living under unhygienic condition during the First World War following several bouts of infections . This condition, however, was later recognized as a form of reactive arthritis, which is known to be preceded by infections with enterogenic or urogenital bacteria .

Previous review analyses have shown that the results of molecular, immunological, and microbiological studies could establish the link between subclinical Klebsiella infections and the aetiopathogenesis of both AS and CD . Evidence for these links is summarized as follows.

4.1. Klebsiella and AS

(A)Rabbits immunised with HLA-B27-positive lymphocytes showed increased haemagglutinating activity against sheep red cells coated with Klebsiella lipolysaccharide and these elevations were statistically significant when compared to serum samples obtained from the same rabbits before immunisation . It has also been shown that HLA-B27 positive allogeneic human tissue typing sera were binding more significantly to Klebsiella microbes in comparison to sera containing other HLA-tissue specific antibodies .(B)Anti-HLA-B27 monoclonal antibodies bind to Klebsiella, Shigella, and Yersinia, enterobacterial agents , indicating the existence of some shared or cross-reactive antigens among these microbes. Other anti-B27 monoclonal antibodies were found to bind more preferentially to Klebsiella than to Shigella and Yersinia microbial antigens .(C)A homologous amino acid sequence, QTDRED, present in HLA-B27 was found to have molecular similarity to another sequence within Klebsiella pneumonia nitrogenase reductase enzyme . More homologous amino acid sequences were found to exist between Klebsiella secretion products and self-antigens. A quadrimeric DRDE sequence present in Klebsiella pullulanase pul-D enzymes shares homology with a DRED sequence present in HLA-B27 molecules. Another homologous sequence was found to exist between Klebsiella pullulanase pul-A enzymes, which have the tripeptide “Gly-X-Pro” sequence, and the same antigen is present in collagen types I, III, and IV .(D)Various immunological studies carried out by independent groups from 16 different countries have shown that antibodies against K. pneumonia and/or cross-reactive self-antigens but not against other microorganisms are significantly elevated among patients with AS when compared to patients with other diseases or to healthy individuals .(E)Levels of anti-Klebsiella antibodies were found to be significantly higher in the serum than in the synovial fluid samples taken from AS patients . The sources of these antibodies are from extra-articular regions such as the lymph nodes draining the gut .(F)Serum samples taken from active AS patients were found to possess significant in vitro cytotoxic activities when compared to sera taken from patients with RA or healthy controls. Increased percentage of lysis is present in sheep red blood cells which have been coated with Klebsiella cross-reactive antigens such as HLA-B27 synthetic peptides, QTDRED .(G)Antibodies to Klebsiella nitrogenase reductase peptides, QTDRED, were shown to bind preferentially to the synovial tissues of AS patients when compared to those from patients with other rheumatic diseases .(H)Klebsiella bacteria have been isolated by different independent groups more significantly from the bowel of active AS patients when compared to controls . These findings, however, were not confirmed by other groups . The discrepancies in these results could be explained by the differences in the methods of collections and cultures of the faecal specimens and the disease activity status. Furthermore, in a study by a group from Finland it was shown that elevated levels of IgA anti-Klebsiella antibodies in patients with AS correlated with the degree of gut inflammation .

It is well documented that there is a strong link between gut inflammation and/or AS . The level of total and secretory IgA immunoglobulins increased in the majority of patients with AS. Moreover, there is evidence for elevated levels of IgA, particularly secretory IgA antibody against Klebsiella antigens or Klebsiella cross-reactive antigens in active patients with AS. The results of these studies linking Klebsiella, collagen, and HLA-B27 to AS could explain some of the predominant characteristic clinical, genetic, and immunological features present in the patients with this disease (Table 1).

“AS” associated features Suggested explanation
Fluctuation in the course of the disease and low concordance rates in identical twins Involvement of nongenetic, environmental, factors in the disease pathogenesis
High association with HLA-B27 Cross-reactivity of these antigens with Klebsiella
Predilection for involvement of the sacroiliac and vertebral joints Lymphatic drainage plexus of the bowel (containing Klebsiella antibodies) is in close proximity to the sacro-iliac joints
Polyarticular joint involvement
Cross-reactivity between collagen I, III, and IV fibres and Klebsiella
Associated uveitis Cross-reactivity of uveal tract tissues with Klebsiella
Associated enthesitis A site of inflammation in the early cases of AS
Increased total IgA and secretory IgA in sera of AS patients Enhanced mucosal immune response due to subclinical bowel infections by Klebsiella
Higher onset of AS among young people Increased intake of starch diet among young age groups

Table 1 Possible explanations for some of the predominantly associated features in “AS.”

4.2. Klebsiella and CD

(A)Previous studies showed that Klebsiella microbes have been isolated from the large bowel specimens in more than 25% of patients with CD , and that relapses of the disease in patients with CD were found to be associated with Klebsiella colitis .(B)Serological and immunological studies on the link between Klebsiella and patients with IBD/CD were carried out by various groups from six different gastroenterology centres. (a) Elevated levels of anti-Klebsiella and anti-Yersinia antibodies were observed in patients with CD and UC from Birmingham when compared to corresponding healthy control subjects . (b) Both groups of patients with IBD and AS from Glasgow and Edinburgh were shown to have significantly elevated levels of anti-Klebsiella IgA antibodies when compared with corresponding healthy controls. (c) Three consecutive studies from London and Winchester in the UK have shown similar results. In one study, anti-Klebsiella antibody levels were found to be significantly elevated in patients with AS, CD, and UC when compared to healthy or diseases controls, whilst no such elevation in antibodies was observed against Escherichia or anaerobic intestinal microbes (Figure 1) . In a second study, elevated levels of class-specific antibodies against many capsular serotypes of Klebsiella bacteria have been observed in patients with CD and AS when compared to patients with coeliac disease or to healthy control subjects . In the third study, class-specific antibodies against Klebsiella microbes and cross-reactive collagen types I, III, IV and V were found to be significantly elevated in patients with AS, as well as in early and advanced cases with CD when compared to healthy subjects. In the same study, serum samples from CD patients had shown a positive correlation between antibody levels to Klebsiella and types I, III, and IV of collagen .


Figure 1

Furthermore, experimental studies from Nagakute in Japan have shown that collagen-induced enterocolitis and arthritis were both observed in animals when immunised with homologous colonic extracts and collagens together with Klebsiella lipopolysaccharides.

5. Aetiopathogenic Mechanism Linking Klebsiella to AS and CD

Molecular mimicry or cross-reactivity hypothesis is suggested to be the main mechanism that can link Klebsiella with the initiation and development of AS and spondylitis-associated CD . Evidence obtained from other diseases such as rheumatic fever and primary biliary cirrhosis indicates that molecular mimicry is more than an epiphenomenon, whereby humoral and/or cellular immune responses are consistently detected against targeted tissues at the pathological sites in patients with these conditions.

The types of cross-reactive antibodies produced following Klebsiella infections will determine the anatomical location of the pathological lesions, especially in AS. Some antibodies are reacting with HLA-B27, an antigen which is expressed in most articular tissues inside the synovial joints, whilst other antibodies are reacting with types I, III, and IV of collagen, which form an important component of the spinal tissues where the pathological lesions are located. The binding of these Klebsiella cross-reactive antibodies, when present in high titres, triggers inflammatory cascades such as the complement system together with the production of various cytokines resulting in the pathological changes with consequent fibrosis, calcification, and new bone formation leading to the development of classical AS. Moreover, the raised level of HLA-B27 antigen expressions on the targeted tissues in patients with AS will make these molecules more accessible and hence will increase the chance of their binding to anti-Klebsiella cross-reactive antibodies.

6. Starch and Gut Microbes

The main substrate that is necessary for the growth of colonic microbial agents includes starch and complex carbohydrates which are usually available in considerable amounts in the bowel. In a study, carried out by a group from Minnesota, using hydrogen breath tests as an index of carbohydrate absorption in healthy individuals, up to 20% of a test meal of starch was found to be available for metabolism by the colonic microflora . It has been found also that up to 10%, of consumed starch can escape the absorption in the small bowel , indicating that a considerable proportion of dietary starch reaches the large intestine. In another experimental study it has been shown that a significant increase in the total bacterial population of enterobacterial microbial agents was noticed in the faeces of rats which have been fed diets containing resistant potato starch when compared to those taking rapidly digestible waxy maize starch .

7. Klebsiella and Starch-Debranching Enzymes

Starch or macromolecular polysaccharides must initially be hydrolyzed to smaller substrates in order to be transported into cells. To accomplish this hydrolytic and transportation process, bacteria usually use their carbohydrate-degrading enzymes, such as pullulanases and isoamylases .

The starch molecules, which consist of approximately 20% amylose and 80% amylopectin glucose polymers (Figure 2), are catalyzed by amylases, cyclodextrinases, glucosidases, and other starch debranching enzymes such as bacterial pullulanases . Amylose is a linear polymer consisting of α-(1→4) links between glucose residues and these can be readily hydrolysed by amylases present in digestive enzymes. Amylopectin, however, is a branched polymer consisting of linear sequences of amylose like chains linked by α-(1→6) side chain giving rise to a branched structure (Figure 3), which can be broken down by Klebsiella pullulanase but not by digestive enzymes. Hence, the digestion of starch in the small bowel is limited by inability of luminal digestive enzymes in the gut to break α-(1→6) bonds of amylopectin and thereby giving rise to formation of “hard starch” which accumulates in the colon.


Figure 2
Structure of amylopectin showing a branched carbohydrate polymer and the site of β-amylase action yielding free maltose molecules (with permission).

Figure 3
Amylopectin chemical structure showing the point of action by Klebsiella pullulanase enzyme on the α-(1→6) links (with permission).

Klebsiella can survive in harsh environments exploiting some of its enzymatic degrading products, which are required for the protection, maintenance and survival of these microbes. Apart from other enzymatic products such as nitrogenase reductase, Klebsiella can also produce starch-hydrolysing and debranching pullulanase enzymes. Klebsiella can utilize starch as the sole carbon and energy source via two metabolic routes. The first one involves the extracellular degradation into linear maltodextrins by hydrolysis of the glycosidic bonds via the cell surface-associated pullulanase and then the subsequent cleavage of the glycosidic linkages by the action of the extracellular glycosyltransferase . A fraction of the total dietary starch consumed daily in humans resists digestion by pancreatic amylase in the small intestine, thereby, reaching the colon . This form of undigested or resistant starch is usually fermented by human gut microflora, providing a source of energy and carbon for more than 400 species of bacteria present in colon .

A group from Los Angeles had shown that the mean number of faecal Klebsiella concentrations in individuals taking high carbohydrate/low protein diet was forty times higher than in those having low carbohydrate/high protein diet . Similarly, the mean number of Klebsiella was found to be ten times higher when incubated with simple carbohydrate products such as sucrose, lactose, and glucose than with eleven different amino acids . These results indicate that complex carbohydrates such as starch-containing products are necessary for the growth, replication, and persistence of many enterobacterial agents including Klebsiella microbes in the large bowel.

8. Potential for the Use of Low Starch Diet in AS and CD Patients

The current medical therapeutic agents used in patients with AS and CD include nonsteroidal anti-inflammatory and immunosuppressive drugs, as well as biological agents. These treatments, however, cannot reverse the existing destructive spinal lesions and might be associated with deleterious side effects . Therefore, implementation of other therapeutic measures especially those involving the means for effective eradication of the causative agents by using a low starch diet intake and possibly antibiotics together with the currently used medical treatments could have a beneficial effect in the management of patients with AS and CD.

These data support the causative effect of high starch consumption and the beneficial effect of low starch intake in patients with SpAs, especially those with AS or IBD. For example, in a previous study on a group of UC patients, analyses of the contents of surgically removed ileocaecal regions have shown that the ileostomy fluid contained significant amount of monosaccharides and disaccharides . These simple carbohydrate products detected in the ileostomy fluid would appear to be derived from starch. In another prospective longitudinal study, the influence of dietary factors was examined in a group of Italian patients with IBD and a group of healthy controls well matched for age, sex, and location of living. The results showed that patients with CD and UC have an increased consumption of the total carbohydrate and starch with a significantly higher relative risk compared to healthy individuals . In a later review analysis of the literatures on the daily intake of diets and their relation to intestinal microbial flora in patients with IBD, it was shown that a considerably large amount of data show an association between increased intake of westernized carbohydrate food, high intestinal microbial load, and the occurrence of IBD .

In a longitudinal open study carried out in a group of 36 patients with active AS in “London AS Clinic,” most of the patients had shown reductions in their erythrocyte sedimentation rates and total IgA concentrations, as well as a drop in their intake for the anti-inflammatory medicines after a nine-month followup following a decrease the dietary intake of starch . It appears that in both IBD and AS, an interaction between the gut microflora and the mucosa is a possible contributor to the development of these diseases. These data results support the notion that an increase in the bulk of potentially pathogenic organisms such as Klebsiella in the faecal microflora due to high starch consumption could help in the initiation and development of both AS and CD. It seems, therefore, that an exclusion of a diet containing complex carbohydrates such as starch, but not simple carbohydrate-containing foods such as glucose or sucrose, might inhibit the growth of Klebsiella and could ameliorate the disease process and activity in patients with AS and CD.

9. Conclusions

AS and CD are shown to be two interrelated conditions mainly based on the existing genetic and immunological features. The main pathogenetic mechanism which can explain this linkage is “molecular mimicry” or “cross-reactivity” between Klebsiella pneumonia and target tissues. It appears that starch is the main source of Klebsiella growth in the colon. Hence, increased consumption of starch-containing foods by genetically susceptible individuals such as those possessing HLA-B27 genes could result in the initiation and development of AS or spondylitis-associated CD. Dietary manipulation in the form of low starch diet intake can be included in the management of patients with AS or CD, especially when used in conjunction with the current medical therapeutic measures.

Acknowledgments

This study was supported by the Trustees of the Middlesex Hospital and the American Friends of King’s College London.

Co-Managing IBD & Arthritis: A Complex Prescription

Gastroenterologists and rheumatologists discuss patients who have conditions spanning both specialties: those with inflammatory bowel disease and spondyloarthropathy.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a general term for two main bowel diseases: Crohn’s disease and ulcerative colitis. Both are idiopathic inflammatory conditions that affect the gastrointestinal tract, and both cause diarrhea, abdominal pain, blood in the stool, and fatigue. Ulcerations cover affected areas of the bowel and, occasionally in Crohn’s disease, tracts known as fistulas can lead to open communication between the bowel and other body cavities, such as the bladder, or the skin. The natural history of IBD, particularly Crohn’s disease, can be progressive and, as it evolves, it can further complicate over time, needing more intensive medical therapy, and sometimes surgery with loss of significant portions of the bowel. IBD is not rare, with a prevalence of 150-200/100,000 and an incidence of 5-12/100,000.

Spondyloarthropathies

Spondyloarthropathies are inflammatory disorders characterized by chronic low back pain or inflammation of the joints of the (typically) lower extremities. They are comprised of a group of diseases, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, arthritis associated with IBD, and undifferentiated spondyloarthritis. These conditions are often associated with the presence of HLA-B27, a histocompatability molecule involved in regulation of the immune system. Commonly, they exhibit other inflammatory manifestations that are not associated with joints (extra-articular), such as inflammation of the eye (uveitis), inflammation of tendons (enthesitis), psoriasis, dactylitis, and IBD. Although spondyloarthropathies share several characteristics, the natural history varies between them from the acute, self-limited joint inflammation of reactive arthritis to the chronic, progressive, and debilitating spinal arthritis of ankylosing spondylitis. The course of IBD-associated spondyloarthropathy differs depending on which joints are affected; if peripheral joints (those further from the spine) are inflamed, arthritis is usually temporary and leads to minimal destruction of the joint. However, IBD-associated ankylosing spondylitis, which involves the vertebrae and their joints, is usually a chronic, progressive illness that can lead to permanent joint destruction, fusion and osteoporosis of the vertebrae. The spondyloarthropathies are among the most common rheumatologic conditions, with a prevalence of 0.9-1.5%, making them collectively at least as common as rheumatoid arthritis.

Shared Characteristics

IBD and ankylosing spondylitis (AS) commonly involve inflammatory manifestations outside the gut and joints, respectively. Uveitis and psoriasis occur frequently in both. Not only that, AS and peripheral arthritis are common in IBD, and IBD frequently accompanies AS. Around 5-10% of people with IBD fulfill the diagnostic criteria for having AS, and close to the same proportion of those with AS will present with IBD. As well, two thirds of those with a spondyloarthropathy show microscopic inflammation on endoscopy that resembles IBD, and up to one third of those with IBD will have some sort of joint symptoms. However, both AS and IBD are complex to diagnose and even more complex to manage. In both, if those with complicated and progressive disease behaviours are not adequately treated and monitored, permanent disability and low quality of life can result.

A Look at Treatments

There are similarities in how physicians care for these patients. In AS and IBD, the goal is to treat symptoms and minimize complications, yet also minimize the adverse effects and costs of treatment. Therefore, in certain circumstances patients begin treatment on agents with lower effectiveness and fewer side effects. If symptoms are not controlled, then therapy steps up to other, more efficacious treatments. In IBD, medical therapy progresses from 5-ASA (5-aminosalicylic acid) derivatives in ulcerative colitis, such as mesalamine (Asacol®, Mesasal®, Pentasa®, Salofalk®, Mezavant®) and olsalazine sodium (Dipentum®) to oral corticosteroids to immunosuppressives, such as azathioprine (Imuran®) and methotrexate (Rheumatrex™), to biologic agents, such as infliximab (Remicade®) and adalimumab (Humira®). Interestingly, one medication, etanercept (Enbrel®), an anti-TNF agent effective in patients with AS, is ineffective in IBD. Medical therapy of AS progresses from NSAIDs (such as ibuprofen), to sulfasalazine and local steroid injections in peripheral disease, to biologics (such as infliximab, adalimumab, or etanercept) in patients with persistent disease.

Recent research has shown exciting new frontiers in the treatment strategies of AS and IBD, especially Crohn’s. Both diseases are chronic and progressive and as inflammation proceeds, irreversible damage can be done to the target organ (intestines in IBD, and joints of the spine in AS). The key is to predict which patients will show this type of unrelenting inflammatory damage before it actually occurs, and to treat these individuals with potent agents earlier in the course of the disease. Evidence from recent trials in AS and Crohn’s disease shows that very high rates of remission can be attained by using biologics to treat patients with early disease. The treatment strategy in this case begins with the proven most effective therapy – biologics, instead of less effective ones. This approach is not yet standard practice, due mostly to difficulties in predicting which people will have an aggressive disease course and the high cost associated with TNF inhibitors. However, this and similar research, has spurred gastroenterologists and rheumatologists to determine earlier if less potent therapy has failed, in order to move on to more effective therapies in a timely manner before permanent damage has occurred. Using more potent therapies early on may be particularly relevant in patients with IBD and AS; several studies show that anti-TNF antibody therapy is effective for treating both joint and bowel symptoms.

Diagnosing Clues for the Rheumatologist

AS and IBD can be challenging to diagnose, since many other conditions can show similar symptoms. Dr. Bressler offered some helpful hints to the rheumatologists to help differentiate between IBD and irritable bowel syndrome (IBS):

  • Does diarrhea awaken the patient from sleep? (if yes, then IBD should be considered)
  • How much bloating does the patient have? (bloating is a symptom usually of IBS)
  • Has there been significant weight loss? (weight loss common in IBD)
  • Does the patient have drenching night sweats? (a symptom consistent with IBD)
  • How urgent are the patient’s bowel movements? (more urgent usually in IBD)

Diagnosing Clues for the Gastroenterologist

Dr. Shojania had questions that a gastroenterologist could use to differentiate between mechanical back pain and AS-associated inflammatory back pain:

  • Does morning back stiffness last more than 30 minutes? (if yes, more likely the inflammatory back pain of AS, in contrast to mechanical back pain)
  • Is there pain in the bottom of the feet or heels? (if yes, this might indicate enthesitis, which is associated with AS)
  • Is there a history of eye inflammation requiring eye drops? (typical for AS, especially when only one eye is involved)
  • Is there a history of swollen joints? (peripheral arthritis is common in AS)
  • Is there a family history of AS, psoriasis, or back pain at an early age? (patients with AS often have a family history of the condition)

These questions help to uncover a component of AS in the IBD patient, or vice versa. Since both conditions can frequently manifest in the same patient, gastroenterologists and rheumatologists need a high index of suspicion for concomitant inflammatory bowel disease and spondyloarthropathies. Each specialty had some helpful advice for the other as well.

Suggestions for the Rheumatologist

Below is a list of gastrointestinal perspectives for a rheumatologist treating the AS patient who might have IBD:

  • NSAIDs (such as ibuprofen) and IBD don’t mix – research shows that they can cause the formation of ulcers in the bowel, and lead to IBD flares. There is a particular class of NSAIDs, called COX-II inhibitors, which do not seem to increase the risk of a flare in patients with ulcerative colitis, but these COX-II inhibitors still have the same kidney and cardiovascular risks as traditional NSAIDs.
  • In spondyloarthropathies, a detailed gastrointestinal history can help identify those patients with IBD symptoms.
  • Physicians should choose biologic agents with care when treating AS. For example, etanercept is associated with a numerically but not statistically higher risk of IBD flareups in AS patients who also have IBD.
  • It’s a good idea to use sulfasalazine instead of 5-ASA to manage UC patients who also have a spondyloarthropathy as sulfasalazine is effective in treating peripheral arthritis associated with AS, however, it has not been shown to have any effects on the axial disease.

Suggestions for the Gastroenterologist

Here is a list of rheumatological perspectives for gastroenterologists treating IBD patients who may have a spondyloarthropathy:

  • Be mindful of the risk of osteoporosis when prescribing steroids to patients, especially those with AS who are prone to osteoporosis already. Don’t forget vitamin D, calcium, and bisphosphonates.
  • In IBD patients, a detailed history with a focus on spondyloarthropathy can help identify those who might have co-existing AS.
  • If a patient has bad inflammation in a particular joint, then injections into the joint might be a good idea to avoid the use of NSAIDs.

Outlook

Further valuable discussion followed regarding the co-management of those patients who have both IBD and spondyloarthropathy. The evening was an excellent tool to help raise awareness of concomitant inflammatory conditions, and to provide a framework within which to treat these difficult patients. It is also important for physicians to have a high index of suspicion that there may be more than one inflammatory condition in the person with IBD or AS. Good communication between specialties is vital for effective co-management.

Brian Bressler, MD, MS, FRCP(C), Gastroenterologist, St. Paul’s Hospital, Vancouver, Clinical Instructor, Faculty of Medicine, University of British Columbia
Kam Shojania, MD, FRCP(C), Rheumatologist, Vancouver General Hospital and St. Paul’s Hospital, Vancouver
Head, Rheumatology Division, and Clinical Associate Professor, University of British Columbia
First published in the Inside Tract® newsletter issue 171 – 2009

Ivette Essers1,2, Sofia Ramiro3,4, Carmen Stolwijk1,2, Robert Landewé5,6, Désirée van der Heijde7, Filip van Den Bosch8, Maxime Dougados9 and Astrid Van Tubergen1,2, 1School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, Netherlands, 2Rheumatology, Maastricht University Medical Center, Maastricht, Netherlands, 3Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 4Rheumatology, Hospital Garcia de Orta, Almada, Portugal, 5Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands, 6Rheumatology, Atrium Medical Center, Heerlen, Netherlands, 7Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 8Rheumatology, Department of Rheumatology Ghent University Hospital, Ghent, Belgium, 9Rheumatology B Department, Paris-Descartes University, Cochin Hospital, Paris, France

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Ankylosing spondylitis (AS) and extraarticular manifestations

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Session Information

Session Title: Spondylarthropathies and Psoriatic Arthritis: Clinical Aspects and Treatment III

Session Type: Abstract Submissions (ACR)

Background/Purpose: Ankylosing spondylitis (AS) is associated with extra-articular manifestations (EAMs) such as acute anterior uveitis (AAU), inflammatory bowel disease (IBD), and psoriasis. Little is known about the characteristics of patients who develop any EAM. We aimed to identify characteristics associated with the development of EAMs in a prevalence cohort of patients with AS.

Methods: Twelve year follow-up data from patients included in the Outcome in AS International Study (OASIS) were used. Additionally, medical charts were checked for the presence of AAU, IBD or psoriasis, by two independent extractors. Baseline demographic, clinical and radiographic characteristics of patients with and without uveitis, IBD or psoriasis were compared. Logistic regression was performed to identify characteristics associated with the presence of any EAM. Furthermore, Cox regression and survival analyses were performed to identify characteristics associated with development of any EAM over time. Analysis were performed with baseline characteristics as well as with time-varying characteristics.

Results: 216 patients were included (mean age 43.6 years (SD 12.7), 154 (71%) men, mean symptom duration 20.5 years (SD 11.7), 174 (85%) HLA-B27 positive and mean follow-up period 8.3 years (SD 4.3)). At baseline, 59 (27%) patients had any EAM, of which 39 (18%) AAU, 15 (7%) IBD, and 9 (4%) psoriasis. Four patients (2%) had more than one EAM. At baseline, patients with AAU compared with patients without AAU were older (49.1 vs 42.4 years, pConclusion: At baseline, a substantial number of patients already had an EAM in this prevalence cohort with relatively long symptom duration. Development of new EAMs was infrequently observed. In particular disease activity, but also physical function and patient global assessment, were associated with development of IBD. CRP was associated with the development of AAU. Characteristics associated with the development of psoriasis were not found.

Disclosure:

I. Essers,
None;

S. Ramiro,
None;

C. Stolwijk,
None;

R. Landewé,
None;

D. van der Heijde,
None;

F. van Den Bosch,

Abbott, MSD, Pfizer, UCB,

5,

Abbott, Bristol-Myers Squibb, MSD, UCB,

M. Dougados,
None;

A. Van Tubergen,
None.

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Inflammatory Bowel Disease and Ankylosing Spondylitis

Living with the back pain of ankylosing spondylitis is hard enough. Imagine having to deal with another chronic condition on top of it, one that causes inflammation and irritation in the bowels and triggers abdominal pain, diarrhea, and other intestinal problems. For many, that’s a daily reality.

“Somewhere around 5 to 10 percent of individuals with AS also have inflammatory bowel disease (IBD), either Crohn’s disease or ulcerative colitis,” said Joel Taurog, MD, professor of internal medicine and immunology in the division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas.

Donna Laymon, a 73-year-old retired lab technician from northern California is part of that group. On top of having AS (which went undiagnosed for 50 years), Laymon was diagnosed with ulcerative colitis in 1997. “The first big flare was severe. It took 9 months of prednisone to get it under control. My symptoms were diarrhea and abdominal cramps. I was lucky in that I rarely had any problems with bleeding, a symptom that affects many people with ulcerative colitis,” she said. Another anti-inflammatory medication has since put the colitis in remission.

Laymon said having a flare-up of her inflammatory bowel disease and ankylosing spondylitis at the same time was very hard to handle and is grateful it didn’t happen often.

IBD and Ankylosing Spondylitis: What’s the Link?

An abnormal immune response in the digestive tract appears to play a role in both Crohn’s disease and ulcerative colitis. The immune system is made up of proteins and cells that normally protect against infection. In IBD, the immune system mistakenly attacks harmless or even beneficial cells as if they are harmful invaders. This immune response is believed to cause the chronic inflammation seen in IBD that damages the gastrointestinal tract and causes symptoms.

Why do some people with ankylosing spondylitis develop inflammatory bowel disease? “The association is largely genetic,” said Dr. Taurog. “Over half of the 30-plus genes that have been identified as susceptibility genes for AS are also susceptibility genes for IBD.”

Looking back, Laymon said both inflammatory bowel disease and ankylosing spondylitis run in her family. “My grandmother had both — at least we think she did. She called it spastic colitis, and her arthritis was much worse than mine. They didn’t have much to treat with back then.”

Treating IBD and Ankylosing Spondylitis

“In full-blown AS, some of the anti-TNF therapies that have currently been approved for Crohn’s disease and ulcerative colitis can be used to treat ankylosing spondylitis,” said Ashwin Ananthakrishnan, MBBS, MPH, a gastroenterologist at Massachusetts General Hospital in Boston and an assistant professor of medicine at Harvard Medical School. These drugs help both conditions by targeting the inflammation-causing substance called tumor necrosis factor or TNF, which is produced by the immune system.

Infliximab (Remicade), adalimumab (Humira), and golimumab (Simponi) are approved as both AS treatment and IBD therapy, Dr. Ananthakrishnan said. He added that the dosing can be different in people dealing with both conditions, so a conversation between your rheumatologist and gastroenterologist is needed.

For pain relief, many people with AS rely on non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and others. But when Crohn’s or ulcerative colitis is part of the mix, doctors are very cautious about using NSAIDs because they can cause a flare of the bowel disease. Ananthakrishnan said that taking them once in a great while is probably safe, but long-term or high-dose use of NSAIDs could cause a problem. Getting effective therapy for both AS and IBD can reduce the need for these kinds of pain medication, he added.

Laymon’s AS causes fatigue and pain in her shoulders, elbows, wrists, hands, and knees, but taking an anti-TNF drug seems to be helping.

If you are experiencing symptoms of IBD, don’t wait to talk to your rheumatologist. Your rheumatologist can help you find a reliable gastroenterologist to help better manage your symptoms.

Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study).

Abstract

OBJECTIVE: To study the occurrence of spondyloarthropathies (SpA) in patients with inflammatory bowel disease (IBD) seen 6 years after IBD diagnosis. METHODS: In a population based cohort of 654 patients with IBD, 521 patients (80%) were investigated, which included a complete rheumatological examination. Radiographs of the sacroiliac joints and lumbar spine were performed in 406 of these patients (78%). The development of SpA was analyzed with regard to the presence of HLA-B27, duration of IBD symptoms, and the extent of intestinal inflammation. RESULTS: The occurrence of ankylosing spondylitis (AS) was 2.6% in ulcerative colitis and 6% in Crohn’s disease (p = 0.08), yielding an overall prevalence of 3.7% in IBD. No correlation between localization or extent of the intestinal inflammation and presence of AS was found. HLA-B27 was present in 73% of cases with AS. The overall prevalence of SpA was 22%. Inflammatory back pain without AS (IBP) was found in 18% of the patients. Typical features of SpA were rare, while fibromyalgia was common in IBP, indicating that IBP is not a precursor or manifestation of SpA in patients with IBD. The prevalence of radiological sacroiliitis without clinical features of SpA was 2.0%. CONCLUSION: AS occurred frequently in patients with newly diagnosed IBD. IBP did not seem to predispose to AS or other forms of SpA. The overall prevalence of SpA was 22%, whereas the prevalence of asymptomatic radiological sacroiliitis was low.

Ankylosing spondylitis (AS) is a chronic inflammatory condition. Patients’ symptoms usually progress gradually over time, and may be erratic because the type and severity of the symptoms can improve, worsen or completely stop for periods of time.

Following are some of the common symptoms that a patient with AS may experience.

Sacroiliitis

The main symptom of AS is sacroiliitis or the inflammation of the sacroiliac joints (where the spine joins the pelvis). This can result in pain and stiffness in the lower back, hips, and buttocks, especially in the morning or after long periods of inactivity.

Arthritis

Patients with AS often experience symptoms of arthritis, which causes inflammation at the joints. This commonly occurs at the hip and knee joints and can result in swelling, pain, tenderness, and warmth at the affected sites.

Enthesitis

Enthesitis is an inflammation at the point where the tendons or ligaments connect to the bone (called entheses). This causes pain at the site it occurs. For example, if it occurs at the point where the chest bone meets the ribs, it can manifest as chest pain; if this occurs at the heel, it can make it painful to stand on hard surfaces.

Ankylosis

Advanced AS can cause ankylosis to occur. Ankylosis involves the fusion of bones, such as vertebrae, due to new bone formation. In the spine, for example, this can result in sections becoming rigid, therefore reducing flexibility.

Eye inflammation

Eye inflammation (or uveitis) may occur in patients with AS, which can lead to complications such as cataracts and glaucoma if left untreated. Symptoms of uveitis include bloodshot, watery, or painful eyes. In some cases, the symptoms are not obvious. If blurred vision develops immediate medical care is recommended.

Other symptoms

AS can cause neck pain and fatigue in patients.

In some cases, an AS patient can experience heart problems due to inflammation of the aorta, the largest artery in the body carrying blood out of the heart. The aorta can swell and cause damage to the aortic valve disrupting its function.

AS can cause weakening and thinning of the bones, and if this occurs in the spine, vertebrae may crumble, putting pressure on the spinal cord and potentially causing nerve damage.

Patients with AS also have an increased risk of developing inflammatory bowel syndrome (IBS), symptoms of which include diarrhea lasting longer than two weeks, or bloody or slimy stools.

Note: Ankylosing Spondylitis News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

A Challenging Case of Severe Ulcerative Colitis following the Initiation of Secukinumab for Ankylosing Spondylitis

Secukinumab is an interleukin-17 inhibitor used for the treatment of ankylosing spondylitis (AS), psoriasis, and psoriatic arthritis. The risk of exacerbating underlying inflammatory bowel disease (IBD) in patients being treated with secukinumab for other conditions is controversial. We document a patient with AS and previously undiagnosed IBD, found to be in a severe ulcerative colitis flare shortly after receiving the loading dose of secukinumab. There are no guidelines regarding biologic salvage therapy for IBD in the setting of active treatment with another biologic agent. After waiting one half-life of secukinumab, our patient had an excellent response to initiation of infliximab.

Secukinumab is an interleukin-17 (IL-17) monoclonal antibody inhibitor approved for the treatment of ankylosing spondylitis, psoriatic arthritis, and psoriasis . Data previously showed that secukinumab has no efficacy in Crohn’s Disease ; however, the risk of exacerbating underlying Crohn’s Disease or Ulcerative Colitis in patients being treated with secukinumab for other conditions is controversial.

2. Case

We present the case of a 42-year-old male with a past medical history of ankylosing spondylitis (AS) and anterior uveitis who came to the hospital with nonbloody diarrhea. For the ten days prior to presentation, the patient reported over twenty loose nonbloody bowel movements per day, with associated nocturnal symptoms, tenesmus, fevers, chills, night sweats, and five-pound weight loss. For the two years prior to the onset of these symptoms, he had five bowel movements per day, with intermittent bloody stool, tenesmus, and 20-pound weight loss but never had a workup for inflammatory bowel disease (IBD) including a prior colonoscopy. He was a resident of Los Angeles with no recent travel outside the continental United States and no unusual exposures. He denied relevant family history of inflammatory disorders. He had attributed these chronic gastrointestinal symptoms to a prior diagnosis of external hemorrhoids.

His ankylosing spondylitis (HLA-B27 positive) was active with severe daily stiffness and thoracolumbar back pain but had no symptoms of anterior uveitis for several years. For AS, he was prescribed naproxen and methotrexate. He had previously been trialed on etanercept and then adalimumab, which were both discontinued due to rash. Six weeks prior to admission, he was started on secukinumab and received all five loading doses without change in his AS symptoms. He stopped taking naproxen 10 days prior to admission when the diarrhea began.

On admission, his exam was notable for a temperature of 102.3°F and the absence of any eye, oral, skin, or rectal abnormalities. His abdomen was soft but diffusely tender. Labs were notable for 13.99 (M/uL) white blood cells, hemoglobin 10.6 (g/dL), platelets 501 (k/uL), ESR 78 (mm/hr), CRP 18.9 (mg/dL), albumin 3.2 (g/dL), and fecal calprotectin 359 (mcg/g). He had a normal complete metabolic panel and TSH, with negative HIV, blood cultures, and stool infectious workup, including C. diff toxin. A CT abdomen and pelvis with contrast showed pancolitis. A flexible sigmoidoscopy performed shortly after admission showed severe colitis with deep ulcerations, absent vascular pattern, and friable mucosa in the transverse and sigmoid colon (Figure 1). There was mild colitis in the rectum with patchy erythema. Pathology from the transverse and distal colon showed focal neutrophilic cryptitis, crypt microabscesses, and missing crypts, consistent with inflammatory bowel disease. Histology was negative for CMV colitis. Magnetic resonance enterography showed no evidence of small bowel disease.

Figure 1 Endoscopic evaluation on presentation. Severe colitis seen throughout the colon.

A new diagnosis of an ulcerative colitis (UC) flare (Mayo Score 12) was made. The patient was treated with intravenous solumedrol (60 mg per day) and had a brief period of improvement. However, he did not tolerate a transition to oral prednisone (60 mg per day) and suffered a syncopal event from blood loss. A repeat flexible sigmoidoscopy demonstrated edematous mucosa with loss of vascularity and scattered ulcers from anus to 15 cm and deep large ulcers with friable mucosa and spontaneous bleeding from 15 cm to 40 cm (Figure 2).

Figure 2 Endoscopic evaluation after failed trial on oral steroids. Severe colitis seen up to 40 cm; further evaluation was limited given degree of inflammation.

Surgical consultation was requested after the patient failed the oral steroid trial; however, the patient was hesitant to undergo total proctocolectomy and declined surgical intervention. Biologic salvage therapy was considered, but the timing of initiating a biologic agent was troublesome knowing that he was already on a long acting immunosuppressant (secukinumab) and appreciating the risks of severe immunosuppression. He was put back on intravenous solumedrol; however, his symptoms only mildly improved. After discussion with the patient, the decision was made to start infliximab one month after the last secukinumab infusion along with an oral steroid taper. The patient responded well after two doses of infliximab (10 mg/kg) with improved bloody diarrhea to three times per day and 15-pound weight gain within the first month (Figure 3). The patient has received a total three doses of infliximab. We plan for the patient to receive maintenance infliximab therapy every eight weeks.

Figure 3 Charted weights. Significant weight loss seen on presentation (blue arrow). Red arrows: indication dates of infliximab administration with the corresponding weight gain.

3. Discussion

This case documents the association of initiating secukinumab, an IL-17 inhibitor, with a severe flare of ulcerative colitis in a patient with previously undiagnosed IBD.

The question of whether secukinumab impacts inflammatory bowel disease first arose in 2012 when a study on the treatment of Crohn’s Disease with secukinumab demonstrated poorer outcomes and more adverse events in treated patients than those given a placebo . However, in larger trials on the use of secukinumab in treating AS, there were only six reports of inflammatory bowel disease as adverse events, just two of which were considered serious . Then in October 2016, a review of 14 studies, in which patients were treated with secukinumab for AS, psoriasis, or psoriatic arthritis, made the claim that there was no increased risk of IBD due to secukinumab. The review stated that the incidence of IBD in patients treated with secukinumab was similar to rates of IBD seen in the literature in patients with AS, psoriasis, and psoriatic arthritis .

The acute management of this patient was challenging because of the recent administration of secukinumab which has a half-life of 22–31 days . The addition of another active biologic agent to treat the IBD flare may have subjected the patient to excessive immunosuppression and placed him at increased risk for a negative outcome. There are no guidelines for management of the waiting period between biologic agents in IBD. In the psoriasis literature, there is some consensus on giving the first dose of a new biologic at the time the next dose of the old biologic would be due; however, this is based on expert opinion . In Crohn’s Disease literature, safe administration of adding natalizumab or vedolizumab to infliximab therapy has been described in refractory cases . However, there is no data on using infliximab as an overlapping induction agent in the setting of recent secukinumab use and severe UC. We opted to wait 30 days before starting infliximab (roughly one half-life of secukinumab), which also coincided with the next due dose of secukinumab. Our surgical team was also closely following the patient if his health had declined any further.

An important consideration for this case is that the patient may have had underlying undiagnosed IBD (based on symptom history) and therefore secukinumab may have triggered an IBD flare, rather than a de novo case of IBD. While there is no way to determine whether the patient had previously undiagnosed IBD, even the triggering of an IBD flare by secukinumab has been rarely reported and would be an especially important finding because of the recent literature which specifically refutes this association as a concern for patients with IBD taking secukinumab . Another consideration is that NSAIDs may have triggered the IBD flare; however, the patient had been taking NSAIDs for months to years without issue.

The pathogenesis of UC triggered by secukinumab is largely unknown. Given the delicate balance of the immune response in the setting of inflammatory bowel disease, it is often difficult to predict the effects of cytokine blockade on disease progression. Il-17 antagonists showed promise in preclinical trials. However, not all studies were positive. In 2004, Ogawa et al. reported on a mouse model of colitis that a neutralizing Il-17 monoclonal antibody worsened colitis via increases in CD4-positive helper T cells and CD11b-positive granulocytes-monocytes infiltration and increases in tumor necrosis factor-alpha, interferon-gamma, and IL-6 . It is possible that these mechanisms were at play in our patient. The combination of his potential genetics and secukinumab exposure may have elicited this severe colitis response. Per Hueber et al., in Crohn’s Disease genetic polymorphisms (i.e., TL1A) likely play a role in the response to secukinumab . It is unclear whether our patient had this polymorphism; however, this may be important for future risk stratification of patients.

This case presents an interesting study in the potential side effects evoked by IL-17 antagonists. Given the potential risk of IBD exacerbation with these agents, providers should consider evaluating for underlying IBD prior to their initiation. As more targeted therapies come to the market to treat various inflammatory conditions, it will be important to monitor these side effects and develop strategies to ameliorate the adverse events.

Consent

The patient consented to publication of the case details.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Dean Ehrlich, Nimah Jamaluddin, Joseph Pisegna, and David Padua were all involved in the writing and editing of this manuscript. David Padua is the article guarantor.

This work received grant support from Department of Veterans Affairs RR&D Merit Review (Joseph Pisegna) I01 RX000194 and Human Studies CORE through CURE: Digestive Diseases Research Center supported by NIH Grant P30DK41301 (Joseph Pisegna, David Padua).

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