|CASE BASED REVIEW
|Ahead of print publication
Co-existing ulcerative colitis and takayasu arteritis: A case-based review
Karan Rajgopal Kalani, Anuj Achyut Ban, Sumeet Singla
Department of Medicine, Maulana Azad Medical College and Lok Nayak Hospital, Bahadur Shah Zafar Marg, New Delhi, India
|Date of Submission||30-Dec-2021|
|Date of Acceptance||09-Feb-2022|
|Date of Web Publication||13-Jul-2022|
Department of Medicine, Room No 115, First Floor, B L Taneja Block, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Both Takayasu arteritis (TAK) and ulcerative colitis (UC) are uncommon diseases with diverse pathophysiological and clinical features. Their occurrence in the same patient is highly unusual and interesting. We describe the case of a 32-year-old female with UC who developed TAK, 4 years after the initial diagnosis. She was also found to have the HLA subtype B52 which has been commonly reported in these two conditions. We discuss the similarities and differences in clinico-epidemiological, pathophysiological, and genetic features of TAK and UC. We also performed a literature search and reviewed similar case reports and case series of co-occurrence of TAK and UC, between 2010 and 2021.
Keywords: HLA-B52, inflammatory bowel disease, mycophenolate mofetil, Takayasu arteritis, ulcerative colitis
| Introduction|| |
Ulcerative colitis (UC) is characterized by recurrent episodes of inflammation of the mucosal layer of the colonic epithelium. Most cases involve the rectum, with variable proximal involvement. Takayasu arteritis (TAK) is a large-vessel vasculitis of uncertain etiology predominantly affecting females between 10 and 40 years of age. Although the pathogenetic mechanisms of these diseases have not been completely understood, they seem to involve immune dysregulations in cell mediated immunity, among other factors. HLA subtype B52 has been commonly reported in patients having coexisting UC and TAK. The occurrence of TAK in patients with UC has been reported rarely with about 50 cases in the world literature. Our case is one of the few that have been reported from India.,,
| Case Report|| |
A 32-year-old female presented, in 2014, to another hospital with a chronic, large bowel diarrhea, without any per rectal bleed. A colonoscopy and colonic biopsy done at that time showed distortion of normal glandular architecture, focal cryptitis with a lymphoplasmacytic infiltrate consistent with UC. She was started on prednisolone and delayed release mesalamine. However, she continued to have gastrointestinal symptoms. A repeat colonoscopic biopsy done 2 years later revealed chronic ileitis with activity. She was then started and maintained on Azathioprine 100 mg/day and remained asymptomatic for about 2 years.
She then presented in 2018 to the same hospital with complaints of fever of 3 months duration. This was associated with exertional chest pain, on and off. There were no gastrointestinal or other complaints associated with the fever. All routine investigations done at that point of time were normal. However, a high-resolution CT scan of the chest revealed thickening of the arch, ascending and descending aorta, suggestive of aortitis. Steroids were introduced and subsequently, were gradually tapered. She was since maintained on Azathioprine at a dose of 100 mg/day.
She presented to our hospital in 2019 for rheumatological assessment. Apart from a feeling of fatigue, she had no complaints. Specifically, there was no claudication, neck pain, skin changes, backache, joint pains, oral or genital ulcers, eye complaints, fever, weight loss or any neurological deficit. On examination, she had mild pallor, blood pressure was 170/110 mm Hg in both brachial arteries and 180/120 mm Hg in both popliteal arteries. All pulses were palpable. There were no bruits and fundoscopy was normal. Systemic examination was also normal.
Apart from a hemoglobin of 9.1 g/dl, an erythrocyte sedimentation rate of 112 mm/h and C-reactive protein of 35 mg/L, all other routine investigations, including renal and liver function tests were normal. Chest radiograph, electrocardiography, and echocardiography were normal.
Because of the elevated inflammatory markers, hypertension, and previous report computed tomography (CT) report of aortitis, a CT angiogram was advised, also suspecting renal arterial involvement. It revealed diffuse concentric intramural thickening of the entire length of the ascending aorta, the arch, descending aorta, arch branches, abdominal aorta, celiac axis, superior mesenteric artery along with 70% stenosis in bilateral renal arteries suggestive of TAK (Type 5 as per angiographic classification) [Figure 1], [Figure 2], [Figure 3]. Positron emission tomography-CT scan was suggestive of mild fluorodeoxyglucose (FDG) avid circumferential mural thickening of the ascending aorta, arch of aorta, proximal left subclavian artery, left common carotid, brachiocephalic, the descending thoracic and abdominal aorta, and proximal renal arteries [Figure 4]. Other findings of note were diffuse osteopenia in the visualized bones, diffuse FDG uptake in the long segment of large bowel loops, and patchy ground-glass haziness in bilateral lungs.
|Figure 1: Computed tomography angiogram showing bilateral stenosis at the origin of the renal arteries (orange arrows)|
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|Figure 2: Computed tomography angiogram showing diffuse circumferential intramural thickening in the arch of aorta (yellow arrow)|
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|Figure 3: COMPUTED tomography angiogram showing loss of haustrations in the descending colon (yellow arrow) leading to a lead-pipe appearance, consistent with ulcerative colitis|
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|Figure 4: Positron emission tomography computed tomography showing mildly fluorodeoxyglucose avid circumferential mural thickening of the descending aorta, the branches of the arch of aorta and diffuse uptake in the long segment of the large bowel loops|
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ANA, rheumatoid factor, and HLA-B51 were negative. Total immunoglobulin G4 (IgG4) levels were normal, p-ANCA was mildly positive and HLA-B52 was positive.
In our case, the arteritis manifested despite the patient being on azathioprine. Furthermore, long-term corticosteroid intake had already contributed to the diffuse osteopenia, hypertension, and weight gain, among other manifestations. Our patient was unwilling to receive further corticosteroids. In view of the above findings and after a thorough discussion with the patient, we started her on Mycophenolate Mofetil at 1 g/day and subsequently increased to 2 g/day after 2 weeks. She was advised of regular follow-up. We planned to start her on biological therapies like the interleukin 6 (IL-6) inhibitor, Tocilizumab, or the tumor necrosis factor alpha (TNF-α) inhibitor, Infliximab if she does not respond to mycophenolate. Bilateral renal artery ballooning and/or stenting was also planned, once the disease activity comes under control.
| Discussion|| |
We describe a young lady with an uncommon association of 2 diseases. She was diagnosed with UC at the age of 32 years, and treated with mesalazine, steroids, and azathioprine. 4 years later she was diagnosed with TAK, while her UC was inactive. She was also found to carry the HLAB52 gene. Mycophenolate mofetil was started and the patient is currently in remission.
The ACR 1990 criteria are used for the classification of TAK which consists of 6 manifestations out of which 3 are required for diagnosis. In our case, only 2 criteria were found and thus, the ACR criteria for TAK were not fulfilled. However, the aforementioned “classification criteria,” were primarily intended for clinical trials to have uniform cohorts for research. Hence, taking into account the clinical scenario, the laboratory and imaging tests, other differential diagnoses of large vessel vasculitis were ruled out. These included Giant Cell Arteritis, Rheumatoid Arthritis, Spondyloarthropathy, Tuberculosis, Syphilis, IgG4 disease, Behcet's disease among others. She was already a biopsy-proven case of UC. Hence, a diagnosis of co-occurrence of TAK and UC was made, where UC preceded TAK by 4 years but was clinically quiescent at the time of diagnosis of TAK. [Table 1] highlights the spectrum of gastrointestinal manifestations that have been reported in TAK patients. It also lists the vasculitic associations of inflammatory bowel disease (IBD).,
|Table 1: Overlap in clinical presentations between takayasu arteritis and inflammatory bowel disease|
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We will now discuss the association of TAK and UC in terms of their epidemiology, pathogenesis (with emphasis on UC), common genetic susceptibilities (again emphasizing UC), and clinical and endoscopic features.
We conducted a literature search for case reports [Table 2] and case series [Table 3] of patients in whom TAK co-existed with IBD. The search string used was: (”Takayasu Arteritis” OR ”Takayasu's arteritis” OR ”aortitis'' OR ”aortoarteritis” OR “large vessel vasculitis”) AND (”Inflammatory Bowel Disease” OR “Ulcerative Colitis” OR “Crohn's Disease”). This string was run through the Pubmed (MEDLINE) and Scopus databases on the January 6, 2022. The search revealed 68 results on Pubmed and 118 results on Scopus database, respectively. Articles before 2010 were excluded. Articles on giant cell arteritis were also excluded. Relevant articles between 2010 and 2021 were selected. References of relevant articles were manually checked for other relevant articles. We found 40 relevant case reports of association of TAK and IBD and 10 case series/association studies of these 2 diseases. The search strategy we followed is shown in [Figure 5].
|Table 2: Individual case reports showing co-existence of takayasu arteritis with inflammatory bowel disease|
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|Table 3: Case series showing patients with co-existing takayasu arteritis and inflammatory bowel disease|
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|Figure 5: Search strategy for articles on Medline (Pubmed) and Scopus databases. The search was run on January 6, 2022|
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| Epidemiology|| |
As shown in [Table 1], both TAK and IBD can have a wide spectrum of overlap. In 2002, Bansal et al. identified 41 cases of co-occurrence of UC and TAK in the world literature, since 1979. By 2013, Galizia et al. had identified 40 cases of co-occurrence of CD with TAK in the world literature, since 1976. Hence, the co-occurrence of these diseases is uncommon, but not unknown.
In our literature search of the last 10 years alone, we identified 41 cases of co-occurrence of TAK and IBD (including our case). Among these 41 cases, shown in [Table 2], IBD preceded TAK in 29 cases, while TAK preceded IBD in only 6 cases. 6 patients developed UC and TAK simultaneously, i.e., at presentation or within 1 year. Among the cases of IBD preceding TAK, 17 were of UC,11 were cases of CD and 1 was IBD (unclassified). The average age of the patients at diagnosis of UC among these 17 cases was 19.1 years (youngest being 9 years and eldest being 34 years). The mean interval between the development of UC and TAK among these 17 cases was 8.1 years (range of 2 to 24 years). Most of these cases were treated with Mesalazine and steroids for UC while steroids were employed for the treatment of TAK. All patients of TAK were in remission.
In a large case series from Japan, UC was found in 6.4% of patients of TAK. Also, TAK developed at a younger age among these patients than in those without UC. In a case series cum literature review from North America, Sy et al. reported 12 patients with IBD who also had TAK. Eight of these had CD while 4 had UC. IBD preceded TAK in 10 (92%) cases and there was the simultaneous onset of both in 2 cases. Another 133 cases of TAK associated with IBD were identified by them in a literature search from 1964 to early 2014. Among these, almost half were UC and the other half were CD cases. In 69% of these cases, IBD preceded TAK. Also, most patients with IBD and TAK were of Asian ethnicity, were younger when TAK was diagnosed and had more headaches, constitutional and gastrointestinal symptoms. Most patients of TAK achieved remission.
Another notable study from Japan, by Akiyama et al. studied demographic, endoscopic, and genetic features of TAK patients who had IBD versus those who did not have IBD. They found that, among 142 patients of TAK, 13 (9.2%) developed IBD. Among these 13 patients, the most common type of TAK was type 1. IBD preceded TAK in 69% of cases while TAK preceded IBD in 31% of patients. The median time between diagnosis, when IBD preceded TAK, was 4 years, while the median time between diagnosis, when TAK preceded IBD, was 7.5 years. The indications for performing colonoscopy among TAK patients were hematochezia/melena (69%), diarrhea (15%), and positive fecal occult blood test (8%).
Kilic et al., from Turkey studied 52 patients of TAK. 3 patients had IBD along with TAK. In all 3, IBD was diagnosed before TAK; the time interval between diagnosis of IBD and TAK was 9, 30, and 60 months, respectively. In addition, the age at diagnosis of TAK among the 3 patients with IBD was lesser as compared to patients of TAK, without IBD. TAK was suspected due to elevated acute-phase proteins, hypertension, and weight loss among IBD patients. Esatoglu et al. studied the presence of other inflammatory diseases among TAK patients (mainly IBD, Behcet's syndrome, and ankylosing spondylitis). They found that among 198 patients of TAK, 12 (6%) had IBD out of which 7 had CD and 5 had UC. 9 out of these 12 patients (75%) were diagnosed with both diseases simultaneously. Majority of these patients were treated with glucocorticoids and azathioprine. Despite being on treatment, out of these 12 patients, 2 developed perianal fistulae, 1 developed pulmonary arterial hypertension, 1 developed recurrent myocardial infarctions and 1 had a stroke. Another study done recently from Turkey in 2021 studied 27 TAK patients of which 2 (7.4%) had IBD. Both were diagnosed to have CD. In one patient CD preceded TAK while both diseases were diagnosed simultaneously in the other patient. Both patients went into remission after being treated with infliximab and azathioprine.
Two studies were done in 2021 among patients of IBD to look for the presence of TAK. Guarino et al., recruited 3800 patients of IBD and found 3 patients (0.08%) with TAK among them. All 3 patients had CD and in all of them, development of CD preceded TAK. All were given glucocorticoids and sulfasalazine. One patient was also given infliximab but she eventually died while the other 2 went into remission, out of which one patient also received adalimumab and ustekinumab. Martins et al., studied 5601 patients of IBD. Among them, 7 (0.12%) were found to have TAK. 5 out of these 7 patients had CD and 2, had UC. All patients developed IBD first with mean age of diagnosis of IBD being 21.9 years and mean age for diagnosis of TAK being 26.6 years. They received treatments varying from infliximab monotherapy to combination therapy consisting of steroids, azathioprine, 6-MP, tocilizumab, and infliximab. All of them were reported to be in clinical remission after therapy.
The above case series suggest that the prevalence of IBD among patients of previously diagnosed TAK is significantly higher than the prevalence of TAK amongst patients of previously diagnosed IBD.
Although not precisely known, the pathophysiology of TAK likely involves a persistent, predominantly cell-mediated inflammatory response in a genetically susceptible individual. A triggering antigen (e.g., HSP-65) that mimics normal cellular antigens initiates an inflammatory cascade that involves a release of cytokines and activation of adaptive immunity, resulting in granuloma formation and tissue fibrosis which form the hallmark of TAK pathology. TNF-alpha, interferon-gamma, IL-1, IL-6 appear to play an important role in the pathogenesis. Similar cytokines are thought to play a role in the causation of IBD. IBD patients have antibodies against HSP-60, which is antigenically similar to the HSP-65 antigen implicated in TAK. The antigen that initiates the inflammatory cascade in TAK may well be exposed due to the tissue damage or bacterial translocation seen in IBD. The gut microbiota composition plays an important role in IBD. Interestingly, recent studies have found that the gut microbiota composition in Kawasaki vasculitis strongly correlates with the severity of the disease. Similar associations have also been found for Behcet's disease. Akiyama et al. reported that HLA-B52-positive TAK patients might have changes in the intestinal microbiome triggering IBD. Thus, the gut microbiota also appears to play an important role in the pathogenesis of vasculitis. Raised fecal S100A12 was found among TAK patients with intestinal ischemia or IBD as reported in a study by Cem et al. This novel fecal biomarker shows promise in screening for gastrointestinal involvement among TAK patients.
This association points toward a common pathophysiological pathway in the causation of TAK and IBD. Indeed, given their prevalence in the general population, the probability of the two coexisting purely by chance is 1 in 10. The actual rate of association is more than ten thousand times higher, suggesting that some common pathophysiological background may exist.
Common pathogenetic mechanisms between TAK and UC are also supported because treatment with TNF alpha inhibitors is efficacious in both diseases. Further, in CD, but not UC, granuloma formation in the gut mucosa is seen, as is also in the arterial walls in TAK. The neo-antigen theory hypothesizes that IBD is a chronic inflammatory process in the terminal ileum and the colon, which can expose antigens due to tissue damage and/or bacterial translocation and subsequently lead to generation of autoantibodies. Cross-reaction of these auto-antibodies against other organs may then lead to extra-intestinal features such as arthritis, uveitis, cholangitis, and even aortitis. The proximity of the aorta and ileum/colon may help translocation of these antigens/bacteria.
Most early reports of co-occurring TAK and UC in literature showed an association with HLA-B52 and HLA-DR2, specifically with the haplotype A24-B52-DR2.,
Genome-wide association studies (GWAS) from Japanese TAK patients, have shown that HLAB52 and IL-12B are susceptibility genes for TAK. Others have also shown that these 2 genes are also associated with UC., Among the recent studies focusing on HLA Class I molecules, HLA-B52 stands out as an important genetic marker associated with TAK. Our patient, too, was positive for HLA-B52, but typing for other HLA loci could not be done. It is noteworthy that the HLAB51 gene, which is strongly associated with Behcet's disease (that involves the gastrointestinal tract frequently) differs from HLAB52 gene by only 2 amino acids.
In the study by Terao et al., the prevalence of HLAB52 was significantly higher (92.6% vs. 50.7%), with an odds ratio of 12, in TAK patients with UC versus those without UC. Also, the IL-12B risk allele (rs6871626) was seen at a higher frequency (88.5% vs. 75.6%) with an odds ratio of 2.5, although the difference was non-significant. Akiyama et al. also found that patients with IBD-TAK co-occurrence had a significant association with HLA-B52 and HLA-C12 as compared to patients with TAK without IBD (100% versus 49%). HLA-A24 was also more frequently found among patients with this co-occurrence than in patients with isolated TAK (90% versus 61%). HLA class II molecules found having a significant relation to IBD-TAK patients were HLA-DRB15, DQA01, DQB06, and DPB09. They did not find a significant association of TAK-IBD patients with the IL-12B (rs6871626) risk allele. Genetic associations of polymorphisms in PTK2B and IL12B and a locus on chr21q22 were found in patients of both TAK and IBD.
There may be other HLA subtypes and non-HLA genes predisposing to co-occurrence of TAK and UC. Terao et al. found that 70 non-HLA single nucleotide polymorphisms, which conferred susceptibility to UC, also conferred susceptibility to TAK, with a significant size of correlation. All of this evidence lends considerable support for a common underlying genetic predisposition for TAK and UC.
Majority (up to 70%) of the cases of such co-occurrence of TAK and IBD (including our case) displayed a clear chronology, with IBD predating TAK. The proportion of female patients tended to be lower among TAK cases with UC than those without UC. Sy et al. reported that patients with co-occurrence of TAK and IBD had more headaches, constitutional features of fever, and gastrointestinal symptoms. However, both Akiyama et al. and Sy et al. reported that there was no association between the clinical disease activity of TAK and IBD, as both occurred at different time points in the overwhelming majority of cases. TAK patients with UC did not have an excess of complications such as aortic regurgitation, ischemic heart disease, stroke, and renal artery stenosis, as compared to TAK patients without UC. Also, the rate of colectomy was not found to be higher in patients with both TAK and UC, as compared to patients with only TAK. But there was a suggestion of increased use of biological drugs in the former group of patients.
An interesting finding reported by Akiyama et al. was that among patients with TAK, the endoscopy findings of IBD may be atypical. The major colonoscopic finding in these patients was focal mucosal inflammation with discontinuous aphthous ulcers. Such findings may evolve into typical CD or UC later or may remain the same, on follow-up. This study tells us that the diagnosis of IBD must not be discarded in the absence of typical findings on endoscopy, in this group of patients. Follow-up endoscopies are warranted.
In a study by Eshed et al. among 34 TAK patients, 4 (11.7%) had sacroiliitis. Among these 4 patients, 3 (75%) were diagnosed to have IBD. This suggests that sacroiliitis and IBD screening may be carried out in patients of TAK as it may influence therapeutic decisions towards earlier use of TNF alpha inhibitors.
Finally, the most common angiographic types of TAK, when associated with IBD in a Japanese population, were (in decreasing order of frequency): type I (46.2%), type IIb (30.8%), type V (15.4%), and type IIa (7.7%).
As shown in [Table 2], various agents have been used in the management of this co-occurrence. These include corticosteroids, methotrexate, and azathioprine. Infliximab, Tocilizumab, and Tofacitinib may be used for cases who are refractory to conventional immunosuppressive agents. Most patients of co-occurring TAK and IBD achieve remission using the above drugs.
However, IL-6 inhibitors and TNFi carry a slight risk of lower gastrointestinal perforation, which is higher with the former. Caution is thus warranted in cases with active gastrointestinal symptoms. There are also reports of new-onset TAK or cutaneous vasculitis among patients receiving TNFi. Whether it is the TNFi that trigger TAK in genetically predisposed IBD patients, is a possibility, as yet unproven. Nonetheless, therapeutic response to these agents suggests the important common pathophysiological role of interleukins in both diseases.
Mycophenolate Mofetil has been deemed a useful alternative for the treatment of TAK with effective rates of 80%. It also has a role in the management of IBD intolerant or refractory to conventional medical therapy.
Glucocorticoids remain the mainstay of therapy for TAK. However, there is a lack of a proven first choice agent when it comes to steroid-sparing therapy. A systematic review and meta-analysis were done Misra et al., which reported that leflunomide, TNF alpha inhibitors and tocilizumab showed greater benefit, although the quality of evidence was low. Recently, Janus-Kinase (JAK) inhibitors have shown promise in the treatment of TAK as reported in the systematic review by Rathore et al. UC is conventionally treated using therapies which include aminosalicylates, glucocorticoids, and TNF alpha inhibitor molecules. JAK inhibitors have been shown to be useful in UC patients, especially who have previously received TNF alpha inhibitors as reported in the systematic review by Singh et al. Going forward, JAK inhibitors might be the treatment for both these diseases and may be employed as a single drug treatment for patients having both IBD and TAK.
| Conclusion|| |
TAK and UC are increasingly being reported together; they share certain common pathophysiological mechanisms and genetic predispositions. If these patients fail to respond to conventional corticosteroid and immunosuppressant management, biological and targeted synthetic DMARDs may be deployed for treating these patients. We have listed the learning points from this case report and review below.
- Co-existing TAK and IBD is not uncommon and may be seen in upto 10% of patients of TAK, with IBD usually preceding TAK. However, UC is diagnosed more frequently in such co-occurrences, than CD
- Among cases of TAK, gastrointestinal bleeding must inform the treating physician/cardiologist to suspect IBD, besides mesenteric ischemia
- Screening for IBD in TAK patients can be done using simple, cheap and non-invasive tests like fecal occult blood testing; new fecal biomarkers are arriving on the horizon
- There is no relationship between IBD and TAK, in terms of disease activity
- Among cases of refractory UC or CD, a search should be made for vasculitis, especially TAK by clinical evaluation of pulses and blood pressure in all 4 limbs and non-invasive investigations such as arterial doppler and CT/MR angiography
- Endoscopic findings of IBD among TAK patients can be atypical (discontinuous aphthous ulcers/erosions or focal mucosal inflammation), but can develop into typical UC or CD later on; hence such endoscopy findings must not be labelled as inconclusive.
- HLA-B52, HLA-A24 and HLA-DR2 are strongly associated with co-occurrence of UC and TAK
- The treatment and outcomes of patients with TAK and IBD do not differ from those of patients with primary TAK; most drugs used for TAK are effective in UC also
- There is slightly increased risk of gastrointestinal perforation while using Tocilizumab for TAK and, risk of exacerbation of vasculitis while using TNF alpha inhibitors for IBD
Informed consent statement
Written informed consent was obtained from the patient for the publication of this article.
We would like to acknowledge the help of Ms. Avnika Jain, MBBS student at Maulana Azad Medical College, in performing the literature search on Scopus database.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]