Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease.

BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker. METHODS: In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography-tandem mass spectrometry. RESULTS: From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG1 (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PGtotal was MTX-PG5. MTX-PG6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.

Therapeutic drug monitoring of methotrexate in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD). AIM: To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation. RESULTS: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 µg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (ß -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 µg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity. CONCLUSIONS: Higher MTX-PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG3 could be used for TDM if a target concentration can be established.

Smoking and colorectal neoplasia in patients with inflammatory bowel disease: Dose-effect relationship.

BACKGROUND AND AIMS: Prior studies on the effect of smoking on the risk of colitis-associated colorectal neoplasia (CRN) have reported conflicting results. We aimed to further elucidate the association between smoking, including possible dose-effects, and the development of colorectal neoplasia in patients with inflammatory bowel disease (IBD). METHODS: We performed a prospective multicenter cohort study including patients with colonic IBD enrolled in a surveillance program in four academic hospitals between 2011 and 2021. The effects of smoking status and pack-years at study entry on subsequent recurrent events of CRN (including indefinite, low- and high-grade dysplasia, and colorectal cancer [CRC]) were evaluated using uni- and multivariable Prentice, Williams, and Peterson total-time Cox proportional hazard models. Adjustment was performed for extensive disease, prior/index dysplasia, sex, age, first-degree relative with CRC, primary sclerosing cholangitis, and endoscopic inflammation. RESULTS: In 501 of the enrolled 576 patients, at least one follow-up surveillance was performed after the study index (median follow-up 5 years). CRN occurred at least once in 105 patients. Ever smoking was not associated with recurrent CRN risk (adjusted hazard ratio [aHR] 1.04, 95% confidence interval [CI] 0.75-1.44), but an increasing number of pack-years was associated with an increased risk of recurrent CRN (aHR per 10 pack-years 1.17, 95% CI 1.03-1.32; p < 0.05). Separate analyses per IBD type did not reveal differences. CONCLUSIONS: This study found that an increase in pack-years is associated with a higher risk of recurrent CRN in patients with IBD, independent of established CRN risk factors (NCT01464151).

Potential of Mesalazine Therapeutic Drug Monitoring by Measuring Fecal Excretion in Patients With Ulcerative Colitis.

BACKGROUND: Therapeutic drug monitoring of mesalazine (5-ASA) in patients with ulcerative colitis is unavailable. Mucosal 5-ASA concentrations are assumed to be higher during remission, but biopsy is not practical. Therefore, we investigated the feasibility of measuring mesalazine levels in feces. To explore the potential role of fecal mesalazine measurements in therapeutic drug monitoring, we compared the dry fecal concentration and daily fecal excretion of 5-ASA and its metabolite N-acetyl-5-ASA in patients with ulcerative colitis with active and quiescent disease. METHODS: Adults with ulcerative colitis on oral mesalazine and scheduled for colonoscopy were eligible for inclusion in this cross-sectional study. Stool and urine samples were collected for 48 and 24 hours, respectively, and rectal biopsies were performed. (N-acetyl-)5-ASA was measured using mass spectrometry. Biochemically active disease was defined as a fecal calprotectin level above 100 mcg/g and endoscopically active disease as any activity following the endoscopic Mayo score (≥1). RESULTS: Approximately 28 patients were included in the study. Daily fecal excretion of (N-acetyl-)5-ASA did not differ between patients with (n = 13) and without (n = 15) endoscopically active disease [median 572 mg/d versus 597 mg/d ( P = 0.86) for 5-ASA and 572 mg/d versus 554 mg/d ( P = 0.86) for N-acetyl-5-ASA]. The same applied to the fecal concentration [median 9.7 mcg/mg dry weight versus 10.3 ( P = 0.53) and 12.0 versus 9.9 ( P = 0.89)]. The results were comparable when the biochemical disease activity definition was used. The mucosal concentrations and urinary excretion of (N-acetyl-)5-ASA did not differentiate between quiescent and active activity. CONCLUSIONS: Fecal (N-acetyl-)5-ASA measurements do not correlate with disease activity, which renders it an unsuitable tool for therapeutic drug monitoring of mesalazine.

Thioguanine is Effective as Maintenance Therapy for Inflammatory Bowel Disease: A Prospective Multicentre Registry Study.

BACKGROUND AND AIMS: Thioguanine is a well-tolerated and effective therapy for inflammatory bowel disease [IBD] patients. Prospective effectiveness data are needed to substantiate the role of thioguanine as a maintenance therapy for IBD. METHODS: IBD patients who previously failed azathioprine or mercaptopurine and initiated thioguanine were prospectively followed for 12 months starting when corticosteroid-free clinical remission was achieved (Harvey-Bradshaw Index [HBI] ≤ 4 or Simple Clinical Colitis Activity Index [SCCAI] ≤ 2). The primary endpoint was corticosteroid-free clinical remission throughout 12 months. Loss of clinical remission was defined as SCCAI > 2 or HBI > 4, need of surgery, escalation of therapy, initiation of corticosteroids or study discontinuation. Additional endpoints were adverse events, drug survival, physician global assessment [PGA] and quality of life [QoL]. RESULTS: Sustained corticosteroid-free clinical remission at 3, 6 or 12 months was observed in 75 [69%], 66 [61%] and 49 [45%] of 108 patients, respectively. Thioguanine was continued in 86 patients [80%] for at least 12 months. Loss of response [55%] included escalation to biologicals in 15%, corticosteroids in 10% and surgery in 3%. According to PGA scores, 82% of patients were still in remission after 12 months and QoL scores remained stable. Adverse events leading to discontinuation were reported in 11%, infections in 10%, myelo- and hepatotoxicity each in 6%, and portal hypertension in 1% of patients. CONCLUSION: Sustained corticosteroid-free clinical remission over 12 months was achieved in 45% of IBD patients on monotherapy with thioguanine. A drug continuation rate of 80%, together with favourable PGA and QoL scores, underlines the tolerability and effectiveness of thioguanine for IBD.

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis.

AIMS: In immune-mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first-line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta-analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX-PG) in erythrocytes and efficacy as well as toxicity across IMIDs. METHODS: Studies analysing MTX-PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta-analyses were performed resulting in several summary effect measures: regression coefficient (ß), correlation coefficient and mean difference (of MTX-PG in responders vs. nonresponders) for IMIDs separately and collectively. RESULTS: Twenty-five studies were included. In RA and JIA, higher MTX-PG was significantly associated with lower disease activity at 3 months (ß: -0.002; 95% confidence interval [CI]: -0.004 to -0.001) and after 4 months of MTX use (ß: -0.003; 95% CI: -0.005 to -0.002). Similarly, higher MTX-PG correlated with lower disease activity in psoriasis (R: -0.82; 95% CI: -0.976 to -0.102). Higher MTX-PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2 nmol/L MTX-PGtotal ; P < .01). CONCLUSION: We showed that higher concentrations of erythrocyte MTX-PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs.

Immunomodulator Withdrawal From Anti-TNF Therapy Is Not Associated With Loss of Response in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The benefit of concomitant immunomodulators (thiopurines or methotrexate) in patients with inflammatory bowel disease (IBD) on anti-tumor necrosis factor α (anti-TNF) (infliximab or adalimumab) maintenance therapy is debated. We compared outcomes after immunomodulator withdrawal vs continuation of combination therapy. METHODS: This was a retrospective cohort study in a general hospital and a tertiary referral center. We included adult IBD patients, receiving anti-TNF therapy for ≥4 months, plus an immunomodulator at baseline, between January 1, 2011, and January 1, 2019. The primary endpoints were loss of response (LOR) (ie, anti-TNF discontinuation because of disease activity) and anti-drug antibodies. Adjusted hazard ratios (aHRs) were calculated by mixed-effects Cox regression analysis. RESULTS: We included 614 treatment episodes of combination therapy in 543 individuals, yielding 1664 patient-years of follow-up. The immunomodulator was withdrawn in 296 (48.2%) episodes after 0.9 (interquartile range, 0.6-2.1) years, which was not associated with a higher risk of LOR (aHR, 1.08; 95% confidence interval [CI], 0.72-1.61), although anti-drug antibodies were detected more frequently (aHR, 2.14; 95% CI, 1.17-3.94), compared with continuation. Clinical remission at the time of withdrawal reduced the risk of LOR (aHR, 0.48; 95% CI, 0.25-0.93), while longer duration of combination therapy before withdrawal decreased the risk of anti-drug antibodies (HR per year, 0.56; 95% CI, 0.32-0.91). Higher prewithdrawal infliximab trough levels reduced the subsequent risks of anti-drug antibodies and LOR. Infliximab trough levels were lower after immunomodulator withdrawal (P = .01). CONCLUSIONS: Patients who withdrew the immunomodulator in this retrospective cohort were not at increased risk of LOR within the following 1-2 years, but an increase in anti-drug antibodies was observed. Our findings require prospective validation, preferably in adequately powered randomized controlled trials.

Loss of response to anti-TNFα agents depends on treatment duration in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is often managed with anti-tumour necrosis factor-α therapy (anti-TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%-21% per patient-year). AIMS: To assess whether the incidence of loss of response decreases with longer treatment duration METHODS: This was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti-TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti-TNFα discontinuation and dose escalation. RESULTS: We included 844 anti-TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti-drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three-fold higher than after four years of treatment (17.2% vs 4.8% per patient-year, P < 0.001). The incidence of anti-TNFα discontinuation (28.6% vs 14.0% per patient-year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient-year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10-2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15-2.46) and male sex (aHR 0.55, 95% CI 0.38-0.78). Immunomodulators were protective against loss of response with anti-drug antibodies (aHR 0.42, 95% CI 0.24-0.74). CONCLUSIONS: Patients with sustained benefit to anti-TNFα after 2 years are at low risk of subsequent loss of response.

Quality of life in patients with IBD during the COVID-19 pandemic in the Netherlands.

OBJECTIVE: COVID-19 has put a strain on regular healthcare worldwide. For inflammatory bowel disease (IBD), gastrointestinal surgeries were postponed and changes in treatment and diagnostic procedures were made. As abrupt changes in treatment regimens may result in an increased morbidity and consequent well-being of patients with IBD, the aim of this study was to determine the effect of the COVID-19 pandemic on health-related quality of life (HRQoL) in patients with IBD. DESIGN: All patients with IBD who completed both Inflammatory Bowel Disease Questionnaire (IBDQ) and 36-Item Short Form Health Survey (SF-36) questionnaire between 31 August and 13 September 2020 were included in our cohort study. The primary end point was to determine the HRQoL in patients with IBD, measured by the IBDQ and SF-36 questionnaire. The secondary end point was determining which factors influence the HRQoL in patients with IBD. RESULTS: 582 patients with IBD filled in the IBDQ and SF-36 questionnaire. The HRQoL in our study population was low according to the questionnaires on both physical and mental subscales. In addition, multivariate analysis showed that increased age, female sex and patients who underwent surgery had a significantly lower HRQoL, most frequently on the physical domains in both questionnaires. CONCLUSION: Patients with IBD had an overall low HRQoL during the COVID-19 pandemic. Furthermore, older patients, women and patients who underwent surgical procedures had the lowest physical HRQoL.

Outcome of Reverse Switching From CT-P13 to Originator Infliximab in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients suffering from inflammatory bowel diseases (IBD) and treated with originator infliximab are increasingly being switched to biosimilars. Some patients, however, are "reverse switched" to treatment with the originator. Here we assess the prevalence of reverse switching, including its indication and outcomes. METHODS: In this retrospective multicenter cohort study, data on patients with IBD from 9 hospitals in the Netherlands were collected. All adult patients with IBD were included if they previously had been switched from originator infliximab to the biosimilar CT-P13 and had a follow-up time of at least 52 weeks after the initial switch. The reasons for reverse switching were categorized into worsening gastrointestinal symptoms, adverse effects, or loss of response to CT-P13. Drug persistence was analyzed through survival analyses. RESULTS: A total of 758 patients with IBD were identified. Reverse switching was observed in 75 patients (9.9%). Patients with reverse switching were predominantly female (70.7%). Gastrointestinal symptoms (25.5%) and dermatological symptoms (21.8%) were the most commonly reported reasons for reverse switching. In 9 patients (12.0%), loss of response to CT-P13 was the reason for reverse switching. Improvement of reported symptoms was seen in 73.3% of patients after reverse switching and 7 out of 9 patients (77.8%) with loss of response regained response. Infliximab persistence was equal between patients who were reverse-switched and those who were maintained on CT-P13. CONCLUSIONS: Reverse switching occurred in 9.9% of patients, predominantly for biosimilar-attributed adverse effects. Switching back to originator infliximab seems effective in patients who experience adverse effects, worsening gastrointestinal symptoms, or loss of response after switching from originator infliximab to CT-P13.

Adherence to Adalimumab Was Not Improved by a Reminder-Based Intervention with an Electronic Needle Container.

BACKGROUND: Adherence to adalimumab in inflammatory bowel disease (IBD) patients is reported to be below par. Non-adherence may result in loss-of-response and increased hospitalization. We analyzed the effect of an electronic needle container (ENC) on adherence to adalimumab. METHODS: In this multicenter, 12-months observational study, we included adalimumab treated IBD patients. All patients were invited to receive an ENC. Patients who declined or did not complete the registration for an ENC served as controls. Primary endpoint was whether an ENC increased adherence, calculated from pharmacy refills as proportion of days covered (PDC). Secondary endpoints were clinical outcomes, including loss-of-response, identification of predictors of adherence and correlation between different modalities for measuring adherence. Loss-of-response was defined as a disease flare, dose-escalation or IBD-related hospitalization or surgery. RESULTS: The pharmacies' records identified 198 eligible patients, of whom 32 were excluded. The ENC was supplied to 69 patients, the remaining 97 patient formed the control group. Median baseline PDC (98.4% vs. 96.1%, p = 0.047) and the proportion of adherent (PDC ≥ 86%) patients (87.0% vs. 74.2%, p = 0.045) was higher for the ENC group. The ENC did not improve the adherence of patients during follow-up (odds ratio 1.26, 95% CI 0.55-2.86). During follow-up, five (7.2%) patients in the ENC group and 13 (13.4%) in the control group discontinued adalimumab (log-rank p = 0.22). Loss-of-response occurred in 12 (17.4%) and 14 (14.4%) patients, respectively (log-rank p = 0.66). CONCLUSIONS: Our results show no beneficial effect of a reminder-based intervention on adherence or treatment outcomes.

A Systematic Review With Meta-Analysis of the Efficacy of Cannabis and Cannabinoids for Inflammatory Bowel Disease: What Can We Learn From Randomized and Nonrandomized Studies?

GOAL AND BACKGROUND: A number of studies have investigated the effectiveness of cannabis or cannabinoids for treatment of inflammatory bowel diseases (IBD). We aimed to systematically analyze their effect in in the treatment of IBD patients. STUDY: We included randomized controlled trials and nonrandomized studies analyzing IBD patients of any age using cannabi(noid)s. Two reviewers searched 3 databases until August 13, 2019. Primary outcome was clinical remission and secondary outcomes included inflammatory biomarkers, symptom improvement, quality of life (QoL) scores, and hospital outcomes. Risk of bias was assessed according to study type. The meta-analyses were performed using a random-effects model with subgroup analyses based on study type. RESULTS: The search identified 682 records of which 15 nonrandomized studies and 5 randomized controlled trials were eligible for inclusion. The meta-analysis of the primary outcome included 146 randomized participants, all 18 years of age or older. Risk of bias was moderate. Cannabi(noid)s were not effective at inducing remission (risk ratio=1.56, 95% confidence interval=0.99-2.46). No effect on inflammatory biomarkers was observed. However, clinical symptoms (abdominal pain, general well-being, nausea, diarrhea, and poor appetite) all improved with cannabi(noid)s on Likert-scales. Baseline QoL scores were lower in patients using cannabis among cohort studies but improved significantly with cannabi(noid)s. Although length of hospital stay was shorter and risk of parenteral nutrition was lower in patients using cannabis, there was no effect on other IBD complications. CONCLUSIONS: Cannabi(noid)s do not induce clinical remission or affect inflammation in IBD patients. However, cannabi(noid)s significantly improve patient-reported symptoms and QoL.

Anti-tumor necrosis factor therapy in patients with inflammatory bowel disease; comorbidity, not patient age, is a predictor of severe adverse events.

PURPOSE: To assess safety and effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in IBD patients ≥ 60 years. METHODS: Ninety IBD patients ≥ 60 years at initiation of anti-TNF therapy, 145 IBD patients ≥ 60 years without anti-TNF therapy and 257 IBD patients < 60 years at initiation of anti-TNF therapy were retrospectively included in this multicentre study. Primary outcome was the occurrence of severe adverse events (SAEs), serious infections and malignancies. Secondary outcome was effectiveness of therapy. Cox regression analyses were used to assess differences in safety and effectiveness. In safety analyses, first older patients with and without anti-TNF therapy and then older and younger patients with anti-TNF therapy were assessed. RESULTS: In older IBD patients, the use of anti-TNF therapy was associated with serious infections (aHR 3.920, 95% CI 1.185-12.973, p = .025). In anti-TNF-exposed patients, cardiovascular disease associated with serious infections (aHR 3.279, 95% CI 1.098-9.790, p = .033) and the presence of multiple comorbidities (aHR 9.138 (1.248-66.935), p = .029) with malignancies, while patient age did not associate with safety outcomes. Effectiveness of therapy was not affected by age or comorbidity. CONCLUSION: Older patients receiving anti-TNF therapy have a higher risk of serious infections compared with older IBD patients without anti-TNF therapy, but not compared with younger patients receiving anti-TNF therapy. However, in anti-TNF-exposed patients, comorbidity was found to be an indicator with regards to SAEs. Effectiveness was comparable between older and younger patients.