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Extraintestinal manifestations (EIM) are associated with diminished quality of life. The efficacy of Ustekinumab and vedolizumab for EIM treatment is not well established. The aim was to compare the effectiveness of ustekinumab and vedolizumab for treatment of EIM in IBD.
Methods
We included IBD patients treated with vedolizumab or ustekinumab in the Gastroenterology department, Sheba Medical Center, for up to 52 weeks between 2015 and 2021. Patients with active EIM before treatment initiation were included.
Results
111 patients were included. 53 patients (48%) were treated with ustekinumab; 88% (n-99) had CD. The most common EIM was arthralgia (95/111, 84%). Patients treated with ustekinumab were more likely to be anti-TNF experienced (n-51/53 [96%] compared with vedolizumab n = 36/58 [62%], p < 0.001).
Clinical response of EIM at week 52 was achieved in 36% of patients treated with ustekinumab (n-18/50) and 34% of patients (n-19/54) treated with vedolizumab, with no statistically significant difference (p = 0.9). No statistical significance was achieved for patients presented with arthralgia. Clinical response of arthralgia at week 52 was seen in 34% (n-19/55) and 36% (n-18/46) of the patients treated with vedolizumab and ustekinumab, respectively, (p = 0.3).
Conclusion
In this study, no difference was found between vedolizumab and ustekinumab regarding their effect on EIM in IBD patients for up to 52 weeks.
Extraintestinal manifestations (EIM) are common among inflammatory bowel disease (IBD) patients, their frequency is variable and estimated to be up to 50%, depending on the effected organ [
]. EIM most commonly involve the musculoskeletal system, causing arthritis and arthralgia, both axial and peripheral. The latter is estimated to occur in 20–40% of Crohn's disease (CD) patients and in 5–10% of ulcerative colitis (UC) patients [
]. While less common, EIM can also affect other organs, such as skin in up to 15% of the patients (erythema nodosum [EN], pyoderma gangrenosum [PG], aphthous stomatitis), eyes in 2–5% of the patients (uveitis, episcleritis and iritis) and the hepatobiliary system in 5% of the patients (primary sclerosing cholangitis [PSC], autoimmune liver and pancreas disease) [
Some EIM correlate with activity of the intestinal disease, that include peripheral arthralgia (type 1), EN and aphthous stomatitis. Others, such as ankylosing spondylitis and uveitis, are independent and can flare without a clear correlation to the existing IBD [
]. The pathophysiology of EIM is unclear. Theories suggested include shared epitopes of joint and skin antigen and intestinal bacteria causing an immune response at different extraintestinal sites. Another hypothesis argues that leakage of antigen from the gut may trigger an immune response resulting in EIM [
Tumor necrosis factor alpha antagonists (anti-TNFα) are considered as the primary treatment and first line option in EIM management. Recent studies have tried to estimate the effect of alternative treatment options such as ustekinumab and vedolizumab. Ustekinumab showed high response rates in patients suffering from arthralgia, with a gradual resolution of arthralgia complaints, from 63% (n = 29) of the patients still suffering from arthralgia at week 8 to only 17.4% (n = 8) at week 52 of follow-up [
]. Although the number of the studies is limited and rely on a small number of patients, ustekinumab also showed promising results in treating skin associated EIM such as PG (100% complete remission [n = 3/3]) and EN (50% of the patients [1/2] achieved clinical remission) along with good response rates in patients suffering from uveitis [
]. While, potentially, its selectivity has an advantage with regard to systemic side effects and adverse reactions, it may also be a disadvantage in its effect on extraintestinal symptoms. Post hoc analyses of GEMINI 2 revealed that patients treated with vedolizumab were less likely to develop new onset or worsening arthralgia/arthritis complaints compared with placebo [
Efficacy of vedolizumab induction and maintenance therapy in patients with ulcerative colitis, regardless of prior exposure to tumor necrosis factor antagonists.
Our aim is to compare EIM rate in vedolizumab versus ustekinumab therapy IBD patients.
2. Material and methods
This was a retrospective cohort study. We included adult patients with an established CD or UC diagnosis that were treated either vedolizumab or ustekinumab at Sheba Medical Center between the years 2015–2021. We included all patients with EIM before treatment initiation. Patients without EIM documentation at the initiation of the treatment were excluded.
Demographic data and data of IBD phenotype, duration of the disease and previous treatments were obtained from Sheba medical records. Data regarding use of combination therapy such as immunomodulator therapy and corticosteroids was obtained. C-reactive protein (CRP) levels and calprotectin values along with Harvey-Bradshaw Index (HBI) and Simple Clinical Colitis Activity Index (SCCAI) were noted if they were taken up to one month before treatment initiation and during the follow-up.
EIM was defined as one of the following: arthralgia or arthritis, back pain and sacroiliitis, EN, PG, aphthous stomatitis, uveitis or episcleritis.
Clinical response was defined as either improvement or remission of EIM complaints, as subjectively described by the patient or taken from the treating physician's assessment.
The primary outcome of the study was clinical response at week 26–52 (defined by the patient and treating physician estimation).
Secondary outcomes included steroid free clinical response at week 26–52 and clinical response of arthralgia at week 26–52.
The study was approved by the Sheba Medical Center ethics committee.
2.1 Statistical analysis
Continuous variables were articulated as the median and interquartile range (IQR). Categorical variables were analyzed using Chi-squared/Fisher's exact tests and continuous variables by the t-test/Mann–Whitney test as needed. A p-value < 0.05 was considered statistically significant. We constructed a multivariate logistic regression model to identify the independent predictors of week 16–22 response and remission, as well as treatment continuation after induction. Variables with a significance level <0.1 based on univariate analysis were included in the multivariate model. To investigate the effect of the variables on treatment discontinuation, we planned a survival analysis using a Kaplan Meyer survival curve or Cox proportional hazard analysis. The analysis was performed using IBM SPSS (version 22.0; Armonk, NY, USA)
3. Results
3.1 Patients’ characteristics
262 patients and 565 patients with EIM documentation were treated with ustekinumab and vedolizumab, respectively, between the years 2015–2021. Of those patients only 53 (20%, n-53/262) patients that received ustekinumab and 58 (10%, n-58/565) patients that received vedolizumab had documented EIMs pre-treatment initiation. Patients’ characteristics are provided in Table 1 as per the two biological treatments. Patients treated with ustekinumab were more often anti-TNF experienced compared to patients treated with vedolizumab (n-51/53 [96%] compared with n-36/58 [58%], p < 0.0001). There were more Ulcerative Colitis (UC) patients in the vedolizumab group compared with the ustekinumab group (n-12/58 [20%] compared with n-1/53 [2%], p < 0.002).
Table 1Patients characteristics according to biological treatment.
Out of 53 patients treated with ustekinumab, 7 patients (13%) underwent primary treatment failure and had their treatment altered; two of the patients underwent a surgical procedure due to an IBD exacerbation; 1 patient (2%) developed colorectal carcinoma; 1 patient (2%) died from an unrelated non-IBD cause; Two patients stopped their treatment at their own discretion.
Out of 58 patients treated with vedolizumab, 7 patients (12%) did not respond to the treatment and were considered as primary failure; 2 patients (3%) developed adverse effects (myalgia and paresthesia); 1 patient (2%) was lost to follow-up and 2 patients (3%) stopped the treatment at their own discretion (Fig. 1).
Fig. 1Flow chart demonstrating patients inclusion into the study.
Clinical response of the intestinal disease was similar between the two groups during the 52 weeks of follow-up. After 6 weeks of treatment, clinical response was noticed in 66% of the patients in both groups (n-37/56 in the vedolizumab group and n-26/39 in the ustekinumab group). After 14 weeks of treatment, clinical response was noted in 59% of the patients in the vedolizumab group (n-32/54) compared with 48% (n-16/33) in the ustekinumab group. On week 26 clinical response rates were also similar between the two groups with 50% (n-28/55) in the vedolizumab group and 41% (n-15/36) in the ustekinumab group. 42% (n-21/50) in the vedolizumab group and 44% (n-19/43) in the ustekinumab group had a clinical response during week 52 of treatment. No significant difference between the two groups was noticed in any of the timepoints (week 6, 14, 26, 52; p = 0.9, p = 0.3, p = 0.4, p = 0.9, respectively). Clinical response rates according to the different timepoints are illustrated on Fig. 2. Of the patients treated with ustekinumab, 13% (n-7/53) had a primary treatment failure compared with 12% of the patients (n-7/58) treated with vedolizumab without a significant difference between them (p = 0.9). Two patients from the ustekinumab group (n-2/53, [3%]) had to stop their treatment due to their worsening arthralgia compared with one patient (n-1/58, [2%]) from the vedolizumab group p = 0.6).
Fig. 2Clinical response of the intestinal disease VEDO vs. UST at different timepoints.
Improvement of EIM on week 6 was 44% (n-25/56) in the vedolizumab group compared with 35% (n-14/40) in the ustekinumab group with no significant difference between them (p = 0.4). At week 14 clinical response rates were 43% (n-24/55) and 33% (n-12/36) in the vedolizumab group and the ustekinumab, respectively (p = 0.39). No significant difference was noticed after 26 and 52 weeks of treatment between the two groups (39%, n-22/55 vs. 33%, n-13/39; p = 0.5 and 34%, n-19/54 vs. 36%, n-18/50; p = 0.9, respectively). Clinical response of EIM according to the different timepoints is illustrated on Fig. 3.
Fig. 3VEDO vs. UST, clinical response of EIM regarding the different timepoints.
A significant positive correlation between improvement of the intestinal disease and clinical improvement of EIM was seen in each of the time points (week 6,14. 26, 52) (r = 0.002, r = 0.0001, r = 0.0001, r = 0.0001, respectively).
3.4 Steroid and immunomodulators treatments
There was no difference between the two groups regarding exposure to steroids or immunomodulators treatment at any of the time points (Table 2). Of those that achieved clinical response, steroid free clinical response rates were 31% (n-18/56) in the vedolizumab group compared with 27% (n-11/40) from the ustekinumab group (p = 0.7). After 14 weeks of treatment 34% (n-19/55) of the patients treated with vedolizumab compared with 25% (n-9/36) of the patients treated with ustekinumab achieved steroid free clinical response with no significant difference between the two groups (p = 0.3). On week 26 of the treatment, 37.5% of the patients (n = 21/55) treated with vedolizumab were steroid-free and achieved clinical response vs. 23% of the patients treated with ustekinumab (n-9/39), with no significant difference (p = 0.1). After 52 weeks of follow-up, 30% (n-17/54) vs. 28% (n = 14/50) achieved steroid-free clinical response with no significant difference between the vedolizumab and ustekinumab, respectively (p = 0.8).
Table 2VEDO vs. UST steroid and immunomodulators treatment regarding the different timepoints.
There was no significant difference between vedolizumab versus ustekinumab with regard to immunomodulators treatment in patients that achieved clinical response.
3.5 Arthralgia
Eight patients (15%) from the vedolizumab group suffered from a non IBD associated arthralgia such as fibromyalgia compared to 7 patients (13%) from the ustekinumab group (p = 0.7). Clinical response of arthralgia after 52 weeks of treatment was seen in 34% (n-19/54) and 41% (n-18/46) of the patients treated with vedolizumab and ustekinumab respectively with no significant difference (p = 0.3). No significant difference was achieved at earlier timepoints; (weeks 6, 14, 26) (n-23/53, [43%] vs. n-11/37, [29%]; p = 0.2, n-24/54, [44%] vs. n-12/36, [33%]; p = 0.4, n-22/55, [39%] vs. n-15/37, [40%]; p = 0.9) (Fig. 4).
Fig. 4VEDO vs. UST, clinical response of arthralgia regarding the different timepoints.
Arthralgia developed during treatment in two patients from the ustekinumab group. One of the two patients had suffered in the past from arthralgia and had a known sacroiliitis related complaints at the time of treatment initiation. During the time of the follow-up, she suffered from recurrence of arthralgia in addition to her back pain complaints without any improvement. The second patient developed de novo arthralgia during the time of the follow-up.
In the vedolizumab group 2 patients were presented with EIM not arthralgia related, and none of them developed arthralgia during the time of the follow-up.
A significant positive correlation between clinical response of the intestinal disease and clinical response of arthralgia was seen in each of the time points (week 6,14. 26, 52) (r = 0.001, r = 0.0001, r = 0.0001, r = 0.0001, respectively)
3.6 Sacroiliitis
Only 2 patients treated with ustekinumab (4%, n-2/53) and 1 patient treated with vedolizumab (2%, n-1/58) were initially presented with sacroiliitis. All three patients did not improve with either of the treatments. Two of the patients had to alter their treatment due to lack of response.
3.7 Uveitis
Only two patients suffered from uveitis pretreatment initiation. Both patients received ustekinumab and showed an early improvement after 6 weeks of treatment. One of the patients had a recurrent episode of uveitis during the time of follow-up. Two additional patients developed uveitis despite of ustekinumab treatment (4%, n-2/53). Another 2 patients developed uveitis on vedolizumab (3%, n-2/58).
3.8 Pyoderma gangrenousum
3 patients (6%, n-3/53) treated with ustekinumab had pyoderma gangrenousum before treatment initiation compared with 1 patient in the vedolizumab group (2%, n-1/58). 2 patients treated with ustekinumab (4%, n-2/53) improved after 6 weeks of treatment, 1 patient improved after 14 weeks of treatment. 2 patients (4%, n-2/53) had recurrent episodes during the 52 weeks follow-up.
The patient treated with vedolizumab improved after 6 weeks of treatment and did not have a recurrence during the follow-up.
3.9 Erythema nodosum
There was only 1 (2%, n-1/59) patient with erythema nodosum pretreatment initiation. Remission achieved after 26 weeks of treatment of vedolizumab. 2 patients from the ustekinumab group (4%, n-2/53) and 2 patients from the vedolizumab group (3%, n-2/58) developed erythema nodosum despite treatment during the time of follow-up.
4. Discussion
During the last decade, emerging new biological treatments have become available and have been proven to be effective in IBD with high response rates. There is still lacking information regarding their effect on extraintestinal manifestation. This study compares vedolizumab with ustekinumab regarding their effect on EIM in real world data, retrospectively.
] found ustekinumab to be effective in IBD related EIM with high response rates reported mostly in patients with arthralgia. Response rates were estimated to be between 30–80% in 52 weeks of follow-up in different studies, retrospective and prospective. These results correlate with our findings, with clinical response rate of 42% after 52 weeks of follow-up.
Vedolizumab, on the other hand, is considered to be restrictive to the intestine with limited systemic effect. Data regarding vedolizumab effect on EIM is limited [
]. In our study, 34% of the patients presented with articular symptoms, either improved or had clinical remission after 52 weeks of treatment. These findings correlate with previous studies. In a recent study, clinical remission of arthralgia was achieved in 44.7% of the patients, however, 13.8% of the patients developed new onset arthralgia during the treatment [
Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort.
There was no difference between ustekinumab and vedolizumab regarding clinical response and remission during the time of the follow-ups. Both treatments had a significant correlation with intestinal disease clinical response. The correlation between the intestinal disease response and arthralgia response might explain the effect of vedolizumab on IBD related arthralgia and has been suggested in previous studies [
]. Thus, ustekinumab is usually preferred in patients presented with EIM. Our finding may raise some questions whether ustekinumab is in fact, a better choice in those specific patients.
No difference was found between the two groups regarding exposure to steroid and immunomodulators treatment, nor there was a difference regarding steroid free clinical response of EIM.
Previous studies did not show an improvement in axial spondylarthritis, including randomized controlled trials reported by Deodhar et al. showing ustekinumab to be ineffective in these specific group of patients [
Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS).
]. Our findings support ustekinumab to be ineffective for this indication. All three patients presented with sacroiliitis did not respond to ustekinumab and two of them (66%) had to change their treatment because lack of response before the end of the follow-up.
The number of patients suffering from EIM other than arthralgia, was quite small in both groups, hence, it's difficult to say whether the treatment had a clear beneficial or non-beneficial effect. Only two patients were presented with uveitis at the baseline with a recurrence and new onset in both groups, with no clear difference between them. Patients presented with PG and EN were also few in both groups with no clear benefit of any of the treatments. Previous studies showed promising results regarding ustekinumab effect on uveitis associated with spondylarthritis [
], other studies showed a good outcome as well with regard to ustekinumab effect on PG. One of the studies examined histological and immunofluorescence analysis that showed an elevation of IL23 in a biopsy. A complete remission was achieved in this patient after ustekinumab initiation [
Ustekinumab–Crohn's disease–neutrophilic dermatosis study group. ustekinumab treatment for neutrophilic dermatoses associated with Crohn's disease: a multicenter retrospective study.
J Am Acad Dermatol.2019; 80 (Fahmy M, Ramamoorthy S, Hata T, Sandborn WJ. Ustekinumab for peristomal pyoderma gangrenosum Official journal of the American College of Gastroenterology| ACG. 2012;107:794-795; Nunes G, Patita M, Fernandes V. Refractory pyoderma gangrenosum in a patient with Crohn's disease: complete response to ustekinumab J Crohns Colitis. 2019;13:812-813; Guenova E, Teske A, Fehrenbacher B et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab Archives of dermatology. 2011;147:1203-1205): 781-784
Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort.
Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort.
]. In other studies and case reports, ustekinumab showed good results in patients including anti-TNF experienced patients and patients resistant to vedolizumab. Still, these studies relied on a small number of patients [
]. Further studies should be held in order to better understand ustekinumab and vedolizumab effect on EIM other than arthralgia.
Our study has some limitations. This is a retrospective study, data was obtained from the medical records and depends on patient reports and the treating physician's documentation. The cohort size was rather small. There was missing data on some of the patients treated with ustekinumab during the follow-up. Vedolizumab is given intravenously in the clinic and mandates patients to have a routine checkup every one to two months while ustekinumab can be given at home and does not compel the patients to arrive to the clinic. For that reason, patient data may be missing from several follow-ups. In addition, a bias might have resulted towards the more severe and unresponsive patients arriving to the clinic for a thorough follow-up. Most of the patients had articular complaints with a small presentation of other EIM. Most of the patients had Crohn's disease, with only one UC patient in the ustekinumab group compared with 12 on the vedolizumab group. Lastly, patients treated with ustekinumab were more experienced with anti-TNF treatment compared with the vedolizumab group. This might have also influenced the results with a negative bias towards ustekinumab.
In conclusion, in this retrospective study, there was no difference between vedolizumab and ustekinumab regarding their effect on EIM. Both treatments showed promising good results in patients with EIM, especially with articular complaints with the exception of axial spondylarthritis.
There is need for further studies, prospective and retrospective, to be held in order to examine the effect on EIM specifically ocular and dermatological manifestations.
Declaration of Competing Interest
- Prof. U. Kopylov, MD. has received speaker fees from Abbvie, Janssen, Medtronic, MSD and Takeda, research support from Takeda, Medtronic, and Janssen, and consulting fees from Takeda, Medtronic, and Abbvie.
- Dr. M. Livne-Margolin, MD. discloses no conflicts of interest.
- Dr. S. Attia-Konyo, MD. discloses no conflicts of interest.
- D. Ling discloses no conflicts of interest.
- Prof. S. Ben Horin, MD. has received consulting and advisory board fees and/or research support from Abbvie, MSD, Janssen, Takeda, and Celltrion.
- O. Haj-Natour discloses no conflicts of interest.
- C. Mushka Abitbol discloses no conflicts of interest.
- Dr. B. Ungar, MD. has received consultation fees from Takeda, Neopharm, Janssen, and Abbvie.
References
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Singh A.
Kavanaugh A.
Rubin D.T.
Extraintestinal manifestations of inflammatory bowel disease: current concepts, treatment, and implications for disease management.
Efficacy of vedolizumab induction and maintenance therapy in patients with ulcerative colitis, regardless of prior exposure to tumor necrosis factor antagonists.
Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort.
Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS).
Ustekinumab–Crohn's disease–neutrophilic dermatosis study group. ustekinumab treatment for neutrophilic dermatoses associated with Crohn's disease: a multicenter retrospective study.
J Am Acad Dermatol.2019; 80 (Fahmy M, Ramamoorthy S, Hata T, Sandborn WJ. Ustekinumab for peristomal pyoderma gangrenosum Official journal of the American College of Gastroenterology| ACG. 2012;107:794-795; Nunes G, Patita M, Fernandes V. Refractory pyoderma gangrenosum in a patient with Crohn's disease: complete response to ustekinumab J Crohns Colitis. 2019;13:812-813; Guenova E, Teske A, Fehrenbacher B et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab Archives of dermatology. 2011;147:1203-1205): 781-784
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