Ustekinumab In Crohn's Disease Research Articles

Trends in Public Drug Plan Expenditures for Patients With Crohn Disease and Ulcerative Colitis Initiating Targeted Immune Modulator Therapy

The objective of this analysis was to examine the changes in drug expenditures with the initiation of targeted immune modulator (TIM) treatment in patients diagnosed with Crohn disease (CD) and ulcerative colitis (UC). Patient cohorts for CD and UC were identified from hospitalizations in Canada. Expenditure data for TIMs with a Health Canada–approved indication for the treatment of CD or UC were extracted from all provincial drug plans (except Quebec) and Yukon from 2016 to 2021, and a descriptive analysis was performed to assess the expenditure patterns. Annual expenditures on TIMs for patients with CD increased each year from 2016 to 2019 before decreasing in 2020 and 2021, whereas expenditures on TIMs in UC increased each year, generally by a greater percentage than was observed in CD (peak percentage growth of 92.5% for UC versus 15.9% for CD in 2018). Expenditures associated with TIM initiation among patients with CD and UC were driven by infliximab and adalimumab, with the 2 drugs accounting for nearly all expenditures in both indications in 2016 and most expenditures in 2021. In both CD and UC, vedolizumab expenditures increased over time, as did the proportions of TIM expenditures on ustekinumab in CD and tofacitinib in UC, albeit to a lesser extent than vedolizumab.

Meta-analysis: Persistence of advanced therapies in the treatment of inflammatory bowel disease.

The expanding options in advanced therapies for ulcerative colitis (UC) and Crohn's disease (CD) present challenges in treatment selection. Persistence analysis assesses drug durability in real-world settings, acting as a surrogate marker for medication efficacy and tolerance. Unlike traditional comparative studies, persistence analysis provides insights extending beyond the initial year of treatment. To provide real-world evidence on treatment effectiveness, tolerability and preferences of physicians and patients regarding various advanced therapies for IBD. We conducted a systematic review of observational studies up to March 2023 assessing advanced therapies' persistence in UC and CD. Advanced therapies under examination included infliximab, adalimumab, vedolizumab, ustekinumab, golimumab, certolizumab and tofacitinib. We pooled the persistence of each agent and conducted a meta-analysis to compare the persistence of newer agents with traditional TNF inhibitors (TNFi)-specifically infliximab and adalimumab. Among 63 observational studies, vedolizumab had the highest 1-year persistence in UC (73.8%, 95% CI: 70.0%-77.6%) and ustekinumab in CD (77.5%, 95% CI: 72.9%-82.1%). Compared to TNFi, vedolizumab demonstrated increased persistence with a relative risk (RR) of 1.30 (95% CI: 1.19-1.41) for UC and 1.14 (95% CI: 1.09-1.20) for CD at 1 year, while ustekinumab demonstrated a RR of 1.15 (95% CI: 1.07-1.23) for CD at 1 year. Vedolizumab exhibited sustained increased persistence in UC over 2 years compared to TNFi (RR: 1.33, 95% CI 1.14-1.54). This meta-analysis highlights the superior persistence of ustekinumab and vedolizumab over TNFi, and offers valuable insights for clinicians navigating the challenging landscape of UC and CD therapeutic choices.

10 years of biologic use patterns in patients with inflammatory bowel disease: treatment persistence, switching and dose intensification - a nationwide population-based study.

Treatments for inflammatory bowel diseases (IBD) have evolved in the era of biologics. However, the real-world data on their usage patterns and sequencing are still limited. We aimed to investigate treatment persistence and dose intensification of first- and second-line biologics in patients with IBD. In this retrospective, cohort study using nationwide claims data, 13,087 patients with IBD initiating biologic therapy between 2010 and 2020 were identified. Treatment persistence and dose intensification during the first 2 years and switching patterns of biologics were analysed while identifying predictors of non-persistence. As a first-line treatment of Crohn's disease (CD), ustekinumab had a lower risk for non-persistence compared to infliximab [adjusted hazard ratio (aHR), 0.69, p = 0.048]. Second-line ustekinumab and vedolizumab showed the highest and lowest persistence (79.2% and 54.9%), respectively. As a first-line treatment of ulcerative colitis (UC), golimumab had a higher risk for non-persistence compared to infliximab (aHR, 1.68, p < 0.001). Second-line golimumab also showed a significantly lower persistence rate than adalimumab and vedolizumab. The risk of non-persistence was higher in UC than in CD (first line: aHR, 1.97; second line: aHR, 1.39; p < 0.001), and in the second-line treatment than in the first-line treatment for CD (aHR, 1.55; p < 0.001). The cumulative rate of dose intensification was highest with ustekinumab for CD (first line, 43.3%, second line, 69.1%) and adalimumab for second-line UC (40.7%). It was significantly increased in second-line therapy in CD, but not in UC. Among switchers of first-line anti-tumour necrosis factor-α inhibitor therapy, after all biologics were approved, 69% of CD patients and 78.4% of UC patients switched to other classes of second-line treatment. Ustekinumab had higher persistence in the first-line treatment of CD, while golimumab had lower persistence for first- and second-line treatments of UC. Dose intensification rates varied, with the highest cumulative rates observed for ustekinumab in CD and adalimumab in second-line UC.

Superior treatment persistence with ustekinumab in Crohn's disease and vedolizumab in ulcerative colitis compared with anti-TNF biological agents: real-world registry data from the Persistence Australian National IBD Cohort (PANIC) study.

Medication persistence contributes real-world evidence about treatment effectiveness, tolerability and prescriber and patient acceptability. To evaluate persistence of biological agents in Crohn's disease (CD) and ulcerative colitis (UC) and the effects of immunomodulator use and treatment lines. Retrospective national population-based data on treatment persistence for adalimumab, infliximab vedolizumab and ustekinumab for CD and UC were analysed from the Australian Pharmaceutical Benefits Scheme using Kaplan-Meier analysis and Cox proportional hazards models. There were 2499 patients included with 8219 person-years of follow-up. In CD patients ustekinumab had increased persistence compared to anti-TNF agents (HR: 1.79, 95%CI: 1.32-2.38, P<0.01). Twelve-month CD persistence rates were ustekinumab 80.0%, vedolizumab 73.5%, infliximab 68.1% and adalimumab 64.2% (P=0.01). In moderate-severe UC vedolizumab had increased persistence compared to anti-TNF agents (HR: 1.67, 95% CI: 1.27-2.18 P<0.001). Twelve-month UC persistence rates were vedolizumab 73.4%, infliximab 61.1% and adalimumab 45.5% (P<0.001). Immunomodulator co-therapy did not significantly increase persistence in non-anti-TNF therapy (P>0.05). Thiopurines increased persistence of anti-TNF agents in CD (P<0.001) and UC (P=0.03). Methotrexate co-therapy increased persistence of anti-TNF agents in CD (P=0.001) only. First-line therapy was superior to non-first line in persistence (P<0.001). In fistulising CD, the persistence of infliximab and adalimumab was not significantly different (P=0.11). Persistence was highest in ustekinumab in CD and vedolizumab in UC. Factors which increased the persistence of biological agents are first-line therapy, and immunomodulator co-therapy in anti-TNF agent use.

S0733 Factors Associated With Ustekinumab Dose Escalation in Patients With Crohn's Disease

INTRODUCTION: Ustekinumab (UST) is a monoclonal antibody which inhibits both IL-12 and IL-23 activity and was approved for treatment of Crohn's disease (CD) in 2016. The current approved dosing is an initial intravenous weight-based loading dose followed by 90 mg subcutaneous maintenance injections every 8 weeks. Yet, patients frequently require dose escalation, most commonly to every 4 or 6 weeks. However, reasons for UST dose escalation and to which interval are poorly understood. METHODS: Retrospective cohort study of adult patients with CD who were treated with UST and underwent dose escalation between 1/1/2016 and 1/31/2019 at a tertiary referral center. Electronic health records were manually reviewed for demographic data, CD history, UST serum concentrations within 3 months prior to escalation and to identify primary reason for dose escalation. RESULTS: We identified 238 patients on UST for CD. Among these patients, 123 (51.7%) underwent escalation to every 4 (n = 64), 5 (n = 1), 6 (n = 55) or 7 (n = 3) weeks. UST serum concentrations were measured in 18/238 (14.6%) patients within 3 months prior to dose escalation with mean of 2.0 ug/ml and 1.3 ug/ml in patients escalated to 4 or 6 weeks, respectively (P = 0.54). Of the 123 patients, a total of 85 patients (69.1%) were escalated due to persistent clinical disease activity with Harvey Bradshaw Index (HBI) of 5 or greater. Among the 38 patients with HBI <5, primary reasons for escalation were as follows; early symptom recurrence (n = 10), concurrent corticosteroid use (n = 8), evidence of inflammation on endoscopy (n = 8), low UST drug concentrations (n = 3), elevated fecal calprotectin (n = 3), radiographic evidence of inflammation (n = 3), active perianal disease (n = 3) and patient preference (n = 1) (Figure 1). CONCLUSION: Among patients with CD who undergo UST dose escalation, nearly one fourth are escalated despite achieving remission as defined by HBI <5 without concurrent use of corticosteroids on standard UST dosing. The most common reasons for dose escalation among these patients are early recurrence of symptoms prior to next maintenance dose and evidence of inflammation on endoscopy. UST serum concentrations are uncommonly utilized to guide dose escalation and its utility remains unclear. Larger, prospective studies are needed to determine the long-term benefits and cost effectiveness of dose escalation of UST, as well as to further elucidate effectiveness of dose escalation primarily based on endoscopic findings in the absence of clinical symptoms.Figure 1.: Reasons for Ustekinumab Dose Escalation Among Patients with HBI <5 (n = 38).

Устекинумаб при болезни Крона с перианальными проявлениями и псориазоподобными изменениями кожи, индуцированными анти-ФНО-терапией

Устекинумаб при болезни Крона с перианальными проявлениями и псориазоподобными изменениями кожи, индуцированными анти-ФНО-терапией

Anti-IL-12/23p40 antibodies for maintenance of remission in Crohn's disease.

Anti-IL-12/23p40 antibodies for maintenance of remission in Crohn's disease.

692 Low Levels of Ustekinumab Despite Dose Escalation Is a Risk Factor for Surgery

INTRODUCTION: Ustekinumab is an IL-12/23 inhibitor used for the treatment of Crohn's disease (CD). Previous studies have suggested that dose escalation to every 4-week intervals can be beneficial in patients who do not achieve a clinical response on every 8-week maintenance dosing. However, safety and efficacy is unknown in CD patients escalated to more frequently than every 4-week intervals in patients who continue to have low trough drug levels. METHODS: We performed a retrospective chart review of patients on ustekinumab for CD who had dosing escalation to every two weeks (Q2) due to persistent low drug levels (&lt;5 µg/mL) despite being on q4 weeks (Q4) maintenance dosing and clinically losing response. RESULTS: Out of 200 CD patients on ustekinumab 90 mg subcutaneous (SQ) maintenance in our IBD program, 112 underwent reactive therapeutic drug monitoring for loss of response or incomplete response to therapy. Of the 112 with drug levels, none had anti-drug antibodies, but 80 patients had levels &lt;5 mcg/mL. All 80 patients were frequency escalated to q4 week dosing. Of these, 12 patients continued to have low ustekinumab trough levels at week 4 (&lt;5 mcg/mL) and thus were escalated to Q2 week dosing. Eight of the 12 patients had IV reinduction dosing prior to dose escalation to Q2 frequency. Of the 12 patients, 6 (50%) required surgery for their active Crohn's disease. These patients were on Q2 week dosing for median of 16 weeks (range 1-68) prior to surgery. All 6 (100%) were able to be de-escalate to less frequent dosing after surgery. Two patients that were unable to de-escalate their dosing frequency are planning for surgery in the near future. The remaining four patients were able to de-escalate to Q4 dosing after clinical response. See full details in Table 1. No adverse events unrelated to their Crohn's disease, including infections or other safety markers were noted. CONCLUSION: Low levels of ustekinumab despite escalation of dosing to every 2 weeks may suggest a need for Crohn's disease related surgery. In our study, all patients who underwent surgery were able to de-escalate to lower dosing frequency suggesting that high inflammatory disease burden contributed to the low levels of ustekinumab. Further studies are needed to assess the safety and efficacy of high frequency dosing of ustekinumab.

697 Safety of Ustekinumab in Inflammatory Bowel Diseases: Integrated Safety Analysis of Results From Phase 2 and 3 Studies in Crohn's Disease and Ulcerative Colitis

INTRODUCTION: Ustekinumab (UST) is a well-established therapy in Crohn's disease (CD) and psoriatic diseases. UST was safe and effective in phase 3 ulcerative colitis (UC) studies. Pivotal studies of UST in CD (UNITI, IMUNITI) and UC (UNIFI) had similar designs, which allows for integrated analysis across both indications. We present an integrated safety analysis of UST in inflammatory bowel disease (IBD). METHODS: Data from 6 phase 2/3 studies were pooled, and safety was evaluated through 1 year of follow-up. In phase 3, pts received a single IV placebo (PBO) or UST (130 mg or ∼6 mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90 mg q8w or q12w). Concomitant immunomodulators (IMM) and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes through 1 year are presented as the number of pts with events per 100 patient-years (PY) of follow-up. RESULTS: At induction baseline (2370 pts in pooled phase 3 IBD studies), median age was 38.0 years, 46.9% were receiving corticosteroids, 30.8% were receiving IMM, 53.0% had failed biologics, and 37.1% were naïve to biologics. In phase 3 IBD studies, through Wk8 of PBO-controlled induction, the frequency of key safety events was similar between UST and PBO (Table 1). In addition, through 1 year across phase 2/3 IBD studies (Table 2), numbers of pts per 100 PY with key safety events were similar between treatment groups. The most frequently occurring AEs (excluding diseases under study) were arthralgia (PBO 16.93 vs UST 16.56), headache (16.43 vs 16.50), nausea (13.25 vs 11.94), and abdominal pain (14.59 vs 11.54); infections were nasopharyngitis (16.26 vs 18.11) and upper respiratory tract infection (11.40 vs 11.36). For serious infections, the CD-specific event of anal abscess occurred in PBO 2.02 and UST 0.90 pts per 100 PY. When CD-specific events were excluded, overall rates of serious infections were similar between UC and CD. The only malignancy (excluding NMSC) reported in &gt;1 UST-treated patient was prostate cancer; no lymphomas were reported through 1 year. Two pts receiving UST (0.12 per 100 PY; both had UC) died from events that investigators considered to be unrelated to study agent (esophageal varices hemorrhage and acute respiratory failure during thyroid surgery). CONCLUSION: The safety profile of UST in pts with UC and across integrated IBD indications through 1 year was favorable and consistent with the established safety profile in pts with CD and psoriatic disease.

P039 Efficacy and safety of ustekinumab in patients with refractory Crohn's disease: data from a real world study in Brazil

BACKGROUND: Ustekinumab (UST) is a fully human monoclonal antibody against IL-12/23. UST induced a clinical response and maintained a higher rate of response than placebo in patients with Crohn's disease (CD). UST was approved in Brazil in November 2017. Real world data regarding efficacy and safety to UST in CD is lacking in our country. We report our experience of UST use in patients with CD refractory to anti-TNF therapy. METHODS: An open-label prospective not controlled study was performed including patients from 4 academic medical centers with severely active, refractory CD starting on UST (IV infusions followed by scheduled subcutaneous [SC] injections) between November 2017 and August 2018. We evaluated clinical response and remission (based on Harvey-Bradshaw index [HBI]), C-reactive protein (CRP) and faecal calproprotectin (FC) levels. Clinical response and clinical remission were defined by HBI decrease ≥3 and HBI ≤3, respectively. Patients were evaluated by HBI from baseline until week 32. CRP and FC were evaluated from baseline and at week 16. RESULTS: Thirty-seven patients were treated with UST during the study period. The mean age was 37.5 years (IQR: 22–68), disease duration 10.7 years (IQR: 1–29), 75.6% had previous surgeries, 54% had perianal disease, 68.5% had anaemia. Mean HBI at baseline was 10.5 (IQR: 5–19). At baseline mean CRP was 25.9 mg/L and mean FC was 1,134.6 mg/kg (IQR: 150–3,157). At week 8, 81.1% achieved clinical response and 40.5% achieved clinical remission. At second SC injection (week 16 or 20), 63.3% of individuals achieved clinical remission (19/30). After the third SC injection (week 24 or 32), 66.7% of patients presented clinical remission (14/21). CRP decreased to 15.9 mg/L at week 8 and to 10.8 mg/L at week 16. Mean FC at week 16 was 996.2 mg/Kg (IQR: 5–2,362), exhibiting a decrease of 138.4 mg/Kg from baseline. One patient stopped UST due to non-response. No new safety signals were observed. CONCLUSION(S): UST therapy was successful for inducing clinical remission and improving laboratory biomarkers of disease activity in patients with refractory CD. Both UST induction and maintenance regimens until week 32 were well tolerated. This result support a favorable safety profile.

Successful treatment of hidradenitis suppurativa in the setting of Crohn disease with combination adalimumab and ustekinumab

Herein we report the combination of adalimumab and ustekinumab to successfully treat a 39-year-old woman who presented for evaluation of hidradenitis suppurativa in the setting of Crohn disease of both the small and large intestine. The patient reported previous control of her hidradenitis when she was using adalimumab for her Crohn disease. She had recently been started on ustekinumab for Crohn disease and had flaring of her hidradenitis. The patient re-started on adalimumab weekly and ustekinumab every 8 weeks. After one month, the patient reported clear improvement in her hidradenitis and Crohn disease with the combined therapy.

Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease.

Increased knowledge of pathways involved in the pathogenesis of IBD has led to the development of new treatment options for Crohn's disease (CD) and ulcerative colitis (UC). Two new biological agents have been recently approved for IBD: vedolizumab and ustekinumab. They have different therapeutic targets (α4 β7 integrin for vedolizumab and interleukin-12/23 pathways for ustekinumab) than the primary biological class, anti-tumour necrosis factor alpha (anti-TNF) agents. As the armamentarium for IBD increases in coming years, it will become important to understand factors associated with response in order to best position and personalise therapy. To summarise the current data on predictors of response to vedolizumab and ustekinumab in IBD patients. We conducted a comprehensive literature review. A PubMed search was performed using pre-defined key words and terms to identify relevant studies on predictors of response. Patients with severe disease (by clinical activity and inflammatory biomarkers), or prior anti-TNF exposure are less likely to respond to vedolizumab. Ileocolonic disease, no prior surgery and uncomplicated phenotype were associated with better responses to ustekinumab in CD. Initial response seems to predict a better long-term maintenance in both therapies (P < 0.001). Contrary to anti-TNF therapies, immunogenicity appears to play less of a role in response. As the number of new biological therapies increase in IBD, identifying patients who are most likely to benefit from specific agents is of paramount importance to help best position IBD therapies.

Ustekinumab Does Not Increase Risk of Serious Adverse Events: A Meta-Analysis of Randomized Controlled Trials

Introduction: Inflammatory bowel disease (IBD) therapy is continuously evolving with novel drugs targeting various inflammatory pathways. Ustekinumab (USK), a monoclonal antibody inhibiting the IL-12/23 pathway, was approved in September 2016 to treat moderate-to-severe Crohn's disease (CD). While safety data in IBD is limited, USK has been used to treat other autoimmune diseases with favorable safety profiles. We aimed to establish rates of adverse events (AE) and demonstrate non-inferiority of AE of USK compared to placebo and other biologics. Methods: MEDLINE, PubMed and Embase databases were searched in May 2017 using terms “ustekinumab” and “clinical trials.” Two authors independently performed quality assessment and dual extraction. Randomized control trials comparing USK to placebo or other biologics regardless of disease were included. The primary outcome was the odds ratio (OR) of AE of USK vs placebo, expressed as pooled OR and 95% confidence interval (CI). Secondary outcomes included OR of mild/moderate and serious AE (SAE) in USK vs placebo, USK vs biologics, and low vs high-dose USK, respectively (Table 2). A sub-analysis of outcomes in CD trials was performed. Random effects meta-analysis was performed for all outcomes.Table: Table. Odds ratio for Adverse Events in USK groupResults: 16 papers with 6756 subjects (44% female) were included (Fig 1). Infections were the most common AE (Table 1). The OR of serious AE in USK vs placebo was 0.76 (95% CI 0.56-1.03, Fig 2). The OR of mild-to-moderate AE in the USK vs placebo was 1.12 (95% CI 1.01-1.24), suggesting increased risk of mild/moderate AE with USK (Fig 3). However, this was no longer significant after sub-analysis of the three CD trials. Analysis of 5 trials comparing low vs high-dose USK revealed an OR of 0.96 (95% CI 0.46-2.04) for SAE and 1.17 (95% CI 0.98-1.39) for mild-to-moderate AE. Use of USK was not associated with increased AE compared to other biologics, with OR of 0.91 (95% CI 0.61-1.35) for SAE and 0.98 (95% CI 0.85-1.13) for mild/moderate AE. Heterogeneity was low for all calculations.Figure: Prisma diagram for study identification and inclusion.Figure: Forest Plot of Serious Adverse Events, Ustekinumab vs Placebo.Figure: Forest Plot of Mild/Moderate Adverse Events, Ustekinumab vs Placebo.Table: Table. Rates of Adverse EventsConclusion: USK has a comparable safety profile to placebo and other biologics in the treatment of various diseases, although we did find a mildly elevated risk of mild/moderate AE with USK; however, this was not seen in CD trials. The favorable safety profile of USK is of clinical importance with the advent of USK in CD and ongoing clinical trials for ulcerative colitis. More data on long-term safety data in the IBD population is needed.

Investigación clínica en 2016: artículos destacados

Many high quality articles were published in 2016 regarding Crohn's disease (CD) and ulcerative colitis (UC). The importance of diet and microbes in inflammatory bowel disease (IBD), the burden of IBD on patient quality of life are some of the relevant topics. The role of calprotectin or the possibility of using PET for follow-up is also highlighted.IBD treatment has been the focus of numerous clinical trials, which have consolidated infliximab (suggesting levels in week 2), adalimumab, and golimumab as front-line treatment. The use of ustekinumab in CD is supported, with methotrexate being left as a last resort, except in the case of arthropathy. Other treatments investigated that are worth mentioning were stem cells, other biosimilar, and new drugs.

Ustekinumab for the Treatment of Crohn‘s Disease

Crohn's disease (CD) results from a pathological immune response to luminal antigens in genetically predisposed individuals. Since the causes of CD are complex and only partially understood, treatment is based on the empiric use of anti-inflammatory drugs. Although multiple therapies for CD currently exist, a substantial proportion of patients are unresponsive to conventional agents. Approximately a third of patients fail treatment with TNF antagonists, and up to 40% of patients who initially benefit subsequently lose response. Accordingly, new approaches are required. Ustekinumab, a fully human IgG1-κ monoclonal antibody to the p40 subunit shared by IL-12 and IL-23, has emerged as a promising new treatment for both psoriasis and CD. This article reviews the available data regarding the mechanism of action, pharmacokinetics, efficacy and safety of ustekinumab in CD.

Ustekinumab en la artritis psoriásica y la enfermedad de Crohn

Although ustekinumab is currently licensed for the treatment of psoriasis, in view of the innovative mechanism of action of this biologic agent, it is reasonable to hypothesize that it will, in the near future, be approved for other indications, such as the treatment of psoriatic arthritis and Crohn disease.Interactions between genetic, environmental, and immunological factors play a key role in the pathogenesis of both psoriasis and psoriatic arthritis. The IL-23/TH17 axis is one of the main pathogenic pathways in these diseases, and there is ample evidence to support the use of pharmacologic agents targeting this pathway. Ustekinumab, a human monoclonal antibody that binds to the p40 subunit shared by IL-12 and IL-23, is currently the only agent capable of modulating the IL-23/TH17 pathway. While there is some evidence supporting the use of ustekinumab in the treatment of psoriatic arthritis, more data on safety and efficacy are required.Crohn disease is a chronic inflammatory disease of unknown etiology that affects the digestive tract. It is treated with corticosteroids, immunosuppressants, and anti-TNF agents. Alternative treatments, such as ustekinumab, however, are needed for patients who do not respond to conventional therapy. The results of 2 recent phase IIb studies showed that ustekinumab induced and maintained clinical response in patients with Crohn disease; most of those who responded well had previously been unsuccessfully treated with infliximab and had elevated C reactive protein levels at the time of treatment. Many issues remain to be resolved, including the establishment of an optimal dose and administration route. Further studies are needed to evaluate the efficacy of ustekinumab in Crohn disease and to determine the best treatment regimen.The present chapter reviews the current evidence on the potential usefulness of ustekinumab in the treatment of psoriatic arthritis and Crohn disease.