Adalimumab Maintenance Research Articles

Higher Adalimumab Concentration Is Associated With Complete Fistula Healing in Patients With Perianal Fistulizing Crohn’s Disease

Perianal fistulas can develop in around 30% of patients with Crohn's disease (CD) and are associated with impaired quality of life and worse outcomes including increased rates of hospitalizations and surgeries.1 The cornerstone of pharmacologic treatment for perianal fistulizing CD is anti-tumor necrosis factor therapy, mainly infliximab and adalimumab (ADM).2 Therapeutic drug monitoring (TDM) can be used to identify potential pharmacokinetic and pharmacodynamic issues and avoid or manage unwanted outcomes, such as primary nonresponse and secondary loss of response.3 There are several exposure-response relationship data demonstrating a positive correlation between serum infliximab concentrations and favorable objective therapeutic outcomes in patients with perianal fistulizing CD.4 Nevertheless, there are only limited data, which is mostly from small retrospective studies regarding the association of ADM concentration and outcomes in patients with perianal fistulizing CD.4-8 Furthermore, the optimal ADM concentration for fistula healing still remains to be elucidated. This is clinically important because drug concentration cutoffs are used in reactive and proactive TDM algorithms to define therapeutic drug concentrations. This study investigates the association of maintenance ADM concentrations with complete fistula healing (CFH) and identifies an optimal ADM concentration threshold for CFH.

P570 Efficacy and safety of Adalimumab in Very Early-onset IBD- A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN

Abstract Background Patients with very early onset inflammatory bowel disease (VEOIBD) often present with severe disease course and require escalation to biologics. Exclusion of pediatric patients from clinical trials lead to scarcity of efficacy and safety data on TNFa antagonists therapy in VEOIBD. We aimed to assess safety and efficacy of adalimumab (ADM) induction and maintenance therapy in patients with VEOIBD. Methods This was a retrospective study involving 31 sites affiliated with the IBD Porto Group and IBD Interest Group of ESPGHAN, as well as centers in North America. Demographic, clinical and laboratory data were collected from patients diagnosed with VEOIBD who commenced ADM therapy before 6 years of age between 2014 to 2023. Results We identified 77 VEOIBD patients with a median age at diagnosis of 2.6 years (interquartile range [IQR] 1.3–4.1), of whom 29 (38%) were diagnosed at age <2 years (infantile-onset IBD). Thirty-seven (48%) patients were diagnosed with Crohn’s disease, 25 (32%) with ulcerative colitis and 15 (20%) with IBD-unclassified. Five (9%) from those genetically tested were diagnosed with monogenic disease. Median age at initiation of ADM was 4.2 (IQR 2.8-5.1) years. Forty-four patients (57%) were Infliximab experienced, discontinued mainly due to pharmacokinetic (20 [45%]) and pharmacodynamic (13 [30%]) failures. At initiation of ADM, concomitant corticosteroids and immunomodulators were given in 37 (48%) and 29 (37%) patients, respectively. The median wPCDAI and PUCAI scores at baseline were 45 [37.5-60] and 45 [27.5-57.5], respectively. Median follow-up time was 85.4 (IQR 40.4-139.2) weeks. While patients with CD showed significant clinical improvement after 26 and 52 weeks (PCDAI decreased to 10 [0-33.4], p<0.001, and 10 [0-25], p<0.05, respectively), No significant improvement in PUCAI score was observed among patients with UC (Figure 1). Inflammatory markers and calprotectin showed a gradual decrease over time (Figure 1). Weight and Height Z scores did not differ significantly throughout the follow-up period. ADM discontinuation rates after 1 and 3 years were 40% and 65%, respectively, mainly due to primary non-response (14, 29.8%) and loss of response (19, 40.4%). Drug discontinuation rates were not dependent on concomitant immunomodulator treatment or ADM initiation or on age (less or above 3 years). Four patients (5.2%) developed severe infections, including a patient with TTC7A mutation who died following septic shock. Conclusion Adalimumab therapy was relatively safe and seemed more effective in young patients with Crohn’s disease, but not in those with ulcerative colitis. Durability was relatively low due to high rates of primary non-response and secondary loss of response.

Efficacy of Switching to Adalimumab for Maintenance of Remission Following Induction Therapy with Tacrolimus in Patients with Ulcerative Colitis.

Tacrolimus (TAC) effectively induces remission in refractory ulcerative colitis (UC). However, TAC therapy usually lasts for 3 months. Although azathioprine (AZA) is often used in maintenance therapy, the relapse rate remains high. Herein, we evaluated the efficacy of adalimumab (ADA) for remission maintenance in patients with UC after induction therapy with TAC. We prospectively enrolled patients with moderate-to-severe UC who achieved clinical remission after 3 months of TAC therapy with endoscopic non-mucosal healing (Cohort A). After TAC discontinuation, the remission maintenance rate up to 1 year after starting ADA therapy was examined. We retrospectively enrolled patients with UC treated with TAC (Cohort B). Among patients in clinical remission after TAC treatment for 3 months, those who received AZA as remission maintenance therapy after TAC discontinuation constituted the AZA group. Patients in Cohort A who received ADA and AZA as remission maintenance therapy after TAC discontinuation constituted the ADA + AZA group. We compared the remission maintenance rates in the AZA and ADA + AZA groups for up to 5 years after TAC discontinuation. In Cohort A, of the 46 patients with UC treated with TAC, 17 were eligible for analysis after receiving ADA as remission maintenance therapy. A notable 88.2% (15/17) were still in remission 1 year after starting ADA. The ADA + AZA group (n = 16) exhibited a significantly higher relapse-free rate than the AZA group (n = 26) (p < 0.05; log-rank test). switching to ADA for remission maintenance in patients with refractory UC who achieved clinical remission with TAC is clinically useful.

Adalimumab Clearance, Rather Than Trough Level, May Have Greatest Relevance to Crohn's Disease Therapeutic Outcomes Assessed Clinically and Endoscopically.

We postulated that adalimumab [ADA] drug clearance [CL] may be a more critical determinant of therapeutic outcome than ADA concentration. This was tested in Crohn's disease [CD] patients undergoing ADA maintenance treatment. CD patients from four cohorts received ADA induction and started maintenance therapy. Therapeutic outcomes consisted of endoscopic remission [ER], sustained C-reactive protein [CRP] based clinical remission [defined as CRP levels below 3 mg/L in the absence of symptoms], and faecal calprotectin [FC] level below 100 µg/g. Serum albumin, ADA concentration, and anti-drug antibody status were determined using immunochemistry and homogeneous mobility shift assay, respectively. CL was determined using a nonlinear mixed effect model with Bayesian priors. Statistical analysis consisted of Mann-Whitney test and logistic regression with calculation of odds ratio. Repeated event analysis was conducted using a nonlinear mixed effect model. In 237 enrolled patients [median age 40 years, 45% females], median CL was lower in patients achieving ER as compared with those with persistent active endoscopic disease [median 0.247 L/day vs 0.326 L/day, respectively] [p <0.01]. There was no significant difference in ADA concentration between patients in endoscopic remission compared with those with recurrence [median 9.3 µg/mL vs 11.7 µg/mL, respectively]. Sustained CRP-based clinical remission and FC levels below 100 µg/g were generally associated with lower CL and higher ADA concentration. Repeated event analysis confirmed those findings with better performances of CL than concentration in associating with ER and other outcomes. Lower ADA clearance is associated with an improved clinical outcome for patients with Crohn's disease and may be a superior pharmacokinetic measure than concentration.

Successful Treatment of Generalized Pustular Psoriasis with Adalimumab in a Pediatric Patient: a case report

Introduction: Generalized pustular psoriasis (GPP) is a rare life-threatening subtype of psoriasis and continues to be a therapeutic challenge. We herein describe a 3-year-old girl with a body weight of 14.2 kg in whom adalimumab was used to successfully treat GPP. Case presentation: A 3-year-old girl with a 10-day history of systemic symptoms of fever, malaise, and the onset of studded painful pustules overlying an erythematous base on the scalp, face, neck, trunk, and bilateral extremities, affecting a body surface area of 90%. Laboratory examination results were notable for leukocytosis and elevated inflammatory markers. Biopsy confirmed the diagnosis of GPP. After failure of conventional therapies including cyclosporine and methotrexate, the patient began off-label treatment with adalimumab and achieved complete lesion clearance. At the time of this writing, she remains in remission on maintenance adalimumab therapy. Discussion: No consensus on the standard treatment regimen for GPP has been reached. Unfortunately, all drugs that have been reported to be effective for GPP are off-label. These treatments include systemic immunomodulators such as cyclosporine and methotrexate, systemic retinoids such as acitretin and isotretinoin, and various biologics. The FDA has approved adalimumab, an anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody, for the treatment of plaque psoriasis. Our findings lend weight to the scant evidence describing the effective use of adalimumab in the treatment of pediatric GPP. Conclusion: Off-label use of adalimumab may be an effective and safe therapeutic option for GPP.

Treatment With Adalimumab 80 mg Every Other Week in Inflammatory Bowel Disease: Results of Treatment Intensification in Clinical Practice.

Loss of response to anti-tumor necrosis factor drugs in patients with inflammatory bowel disease (IBD) is frequent and, in case of low drug levels, treatment intensification is recommended. In addition, in cases in which clinical response without attainment of remission (clinical, endoscopic, or radiological), intensification could be justified since higher drug levels are associated with better outcomes. For adalimumab (ADA), the standard intensification regimen is 40 mg every week (ew). Availability of ADA 80 mg prefilled pens has enabled every other week (eow) intensification. We assessed the clinical efficacy of intensification with ADA 80 mg eow. This retrospective study was conducted at a tertiary hospital in Spain. Patients with IBD receiving maintenance ADA 80 mg eow with clinical, biomarker, and drug-level assessments were included. Demographics and clinical, biological, and endoscopic evaluation of the disease before and after ADA intensification, and pharmacokinetic assessments, were collected. Eighty-seven patients (72 Crohn's disease, 15 ulcerative colitis; average age 50 years) were included. Reasons for ADA intensification were: low ADA levels-<5 µg mL-1-(17%), low ADA levels-<5 µg mL-1-without clinical response (63%), clinical response without clinical remission (15%) and active disease on objective evaluation (including colonoscopy, magnetic resonance imaging, capsule endoscopy, and/or intestinal ultrasound; 5%). Following treatment intensification to ADA 80 mg eow, 75 patients (86%) were in clinical remission and 69 (79.3%) were in biologic remission (clinical remission and normalization of biomarkers). After a median follow-up of 19 months (interquartile range 13-25), 63 patients (72%) remained on treatment and in clinical remission. There were no serious infections, hospitalizations, or deaths. Drug costs did not increase with the 80 mg eow regimen versus a standard intensification regimen. ADA intensification to 80 mg eow was safe, effective, and did not increase drug costs versus standard intensification to 40 mg ew in our experience.

Non-medical switch from the originator to biosimilar and between biosimilars of adalimumab in inflammatory bowel disease – a prospective, multicentre study

IntroductionClinical data on the efficacy and safety of non-medical switch between adalimumab(ADA) biosimilars are limited. AimsThe aim of this study was to evaluate medium-term clinical efficacy, drug sustainability and safety comparing non-medical switches from the originator to biosimilar ADA, and between ADA biosimilars. Methods276 consecutive patients on maintenance ADA therapy (n = 205 Crohn's disease, n = 71 ulcerative colitis) were included. Data on clinical efficacy, biomarkers and adverse events were collected at four time points: 8–12 weeks prior switch, at baseline/switch, 8–12 weeks and 20–24 weeks after switch. Drug survival was evaluated after a median 40(IQR:35–42) weeks follow-up. ResultsA total 174 patients underwent a non-medical switch from the originator to a biosimilar, and 102 patients had a biosimilar-to-biosimilar switch. No significant difference was found in clinical remission rates at any time point in patients switching from originator to biosimilar(87.3%/88.5%/86.5%/85.7%) or biosimilar to biosimilar(74.5%/78.4%/85.3%/79.8%). Mean C-reactive protein levels remained unchanged in both cohorts(p = 0.856 and p = 0.525). Drug survival was similar between the two cohorts with a probability of 91.6%(SE: 2.2) and 87.0%(SE:3.4) to stay on drug after 40 weeks(log-rank:0.96; p = 0.327). Five cases of injection related adverse events were reported. ConclusionClinical benefit was sustained following non-medical switch from originator to biosimilar, or between biosimilars in adalimumab treated IBD patients.

Efficacy and safety of biologic therapy in microscopic colitis: systematic review and meta-analysis.

This systematic review and meta-analysis sought to evaluate the effectiveness and safety of biologic therapy in the treatment of steroid-refractory microscopic colitis (MC). We searched MEDLINE, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on biologic use (infliximab, adalimumab, certolizumab, golimumab, vedolizumab, ustekinumab, and tofacitinib) for induction and maintenance of remission in MC. We assessed clinical remission and response rates and all reported adverse events (AEs). A total of 376 studies were screened yielding 13 articles (including four abstracts) with a combined information on 78 patients for efficacy and safety outcomes. Most studies were case series. Vedolizumab was used in five studies, adalimumab in three, and a combination of infliximab and adalimumab in five studies. The rates of remission were 66.08% (95% CI, 36.79-95.37%; I2 , 71%) at weeks 3-6 and 54.20% (95% CI, 39.39-69.01%; I2 , 0%) at weeks 12-16. Clinical response rates were 100% (95% CI, 88.04-100%; I2 , 0%) at weeks 3-6 and 67.20% (95% CI, 47.72-86.69%; I2 , 52%) at weeks 12-16. Most frequent AE was medication discontinuation with a pooled incidence of 16.1% (95% CI, 5.9-37.5%). No deaths attributable to biologic use were reported. The overall quality of evidence was very low due to the high risk of biases. Low-quality evidence supports the short-term efficacy of biologics in budesonide refractory MC. While our findings represent the most comprehensive evaluation of biologic therapy in severe MC, further research including randomized clinical trials is needed to better define the role of specific agents and long-term therapy.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease.

BACKGROUNDTumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing.AIMTo determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODSIn this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test.RESULTSOne hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083].CONCLUSIONHigher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results

SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P= .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P= .069). In the integrated (main+ Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achievedclinical remission at week 52 (nominal P= .045). Safety profiles were comparable between dosing regimens. Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. gov, Number: NCT002209456.

Real‐world experience of adalimumab therapy for patients with ulcerative colitis: A single tertiary medical center experience in Central Taiwan

AbstractThere are few studies on the treatment outcomes of adalimumab therapy in Taiwanese patients with ulcerative colitis (UC). A total of 102 patients with ulcerative colitis were identified from the electronic clinical database of the Changhua Christian Hospital. The demographic data and clinical features of the disease pattern of the UC patients receiving adalimumab therapy were retrospectively reviewed. Between January 2015 and June 2020, 18 patients with UC received adalimumab therapy. Due to the absence of a response, 5 of the 18 patients (27.7%) only received the induction therapy. Of the 13 patients who received maintenance adalimumab therapy, four discontinued the therapy: three (23.1%) stopped due to a loss of response, and one (7.7%) stopped due to a cutaneous reaction to adalimumab. Because of Taiwan's 1‐year limit on the use of adalimumab, seven patients relapsed and required a second course of therapy. The median period between course completion and relapse was 31 weeks. Two (20%) of the ten patients who finished the first course of therapy did not experience a relapse. The treatment response of patients with UC to adalimumab therapy appears to be comparable to those in previously published Western studies. The majority of patients who responded to adalimumab will relapse following a limited duration of adalimumab therapy in Taiwan.

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

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. 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. 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). 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.

P578 Non-medical switch between adalimumab biosimilars and from the originator adalimumab to biosimilars in inflammatory bowel disease patients – a multicentre study on efficacy and drug sustainability

Abstract Background The use of biosimilar adalimumab (ADA) is effective and safe in inflammatory bowel disease (IBD), although clinical data on switching between ADA biosimilars is still rare. At the end of 2020, a non-medical switch to biosimilar ADA became mandatory in Hungary due to reimbursement policy changes of the National Health Insurance Fund of Hungary (NEAK). The aim of the present study was to evaluate short- and medium term clinical efficacy, drug sustainability and safety comparing non-medical switches from the originator to biosimilar ADA, and between ADA biosimilars. Methods 246 consecutive patients on maintenance ADA therapy (n=181 Crohn’s disease [CD] and n=65 ulcerative colitis [UC], male/female: 44%/56%, median disease duration: 10years(y) (IQR: 10–16)) were included from 4 IBD centers between September 2019 and December 2020. Data on clinical efficacy, using Crohn’s Disease Activity Index (CDAI) and partial Mayo Score (pMayo), laboratory parameters (C-reactive protein – CRP) and adverse events were collected at 8–12 weeks prior switch, at baseline, and 8–12 weeks, 20–24 weeks after switch. Drug sustainability following the switch was evaluated after a median of 41 weeks (IQR: 35–42) follow-up time. Results A total of 246 IBD patients (n=153 patients [115CD/38UC, median age: 38y(IQR: 27–45)] and n=93 patients [66CD/27UC, 32y(IQR: 26–40.5)] underwent a non-medical switch from the originator to a biosimilar, and biosimilar to biosimilar. Clinical disease activity based on CDAI and pMayo scores are presented in Figures 1 and 2. No significant difference was found in the proportion of patients in clinical remission at week 8–12 prior switch / switch / week 8–12 and week 20–24 in either patients switched from originator to biosimilar (86.8% / 88.2% / 86.0% / 85.0%; p=0.87 among groups) or biosimilar to biosimilar (72.0% / 77.4% / 84.9% / 77.6%; p=0.21). 89.2% and 83.1% of patients who were in clinical remission at switch/baseline sustained clinical remission up to week 20–24 in the first and second cohorts. Mean CRP levels were also unchanged during follow-up in both cohorts (p=0.71 and p=0.94). Drug survival was similar between originator to biosimilar and biosimilar to biosimilar switch cohorts, with a probability of 90.6% (SE: 2.4) and 85.8% (SE:3.7) to stay on drug after 40 weeks (log-rank: p=0.271). Figure 3. Two cases of skin reactions were registered as adverse events, one leading to treatment discontinuation. Conclusion Clinical remission was sustained following non-medical switch from originator or biosimilar adalimumab to a biosimilar in IBD patients. Medium-term drug sustainability following the switch was high, and comparable between patients with an originator to biosimilar and a biosimilar to biosimilar switch.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

Higher adalimumab maintenance regimen is more effective than standard dose in anti-TNF experienced Crohn's disease patients.

Many Crohn's disease patients treated with anti-tumor necrosis factor (TNF) therapies suffer from loss of response over time and require dose escalation. The aim of this study was to evaluate the efficacy and safety of treating anti-TNF experienced Crohn's disease patients with higher maintenance regimens of adalimumab. In a retrospective observational study, Crohn's disease patients receiving adalimumab were categorized according to their maintenance regimen; 40 mg weekly, 80 mg every other week or greater were defined as a high-dose maintenance regimen and 40 mg every other week was defined as a standard maintenance regimen. The primary outcome was time to treatment failure. Thirty-nine patients were started on high-dose regimens following induction and 40 patients received the standard regimen. According to a Kaplan-Meier survival curve analysis, time to treatment failure was significantly longer in patients in the high-dose group (P = 0.0015). Patients on high-dose adalimumab had a lower treatment failure rate (hazard ratio 0.21; P = 0.0005) when compared to patients on the standard regimen, after adjusting for induction dose and concomitant immunomodulator use. No difference in adverse events was identified between the groups (31 vs. 30%; P = 0.94). High-dose maintenance regimens were more effective than the standard adalimumab maintenance protocol with better short and long-term clinical outcomes.

Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis. The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557. 93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p<0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period. Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis. AbbVie.

Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis.

Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40mg subcutaneous (sc) weekly or 80mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6years (interquartile range [IQR] 4.0-9.6) and 3.0years (IQR 0.9-9.4) in the SD group (log-rank test P=0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P=0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P=1.0). Results were similar in the propensity score-matched cohort. High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.

P271 Evolving Targets in Ulcerative colitis: Defining Disease Clearance in the VARSITY Study

Abstract Background In VARSITY, the first head-to-head randomized controlled trial of biologics, vedolizumab (VDZ) was superior vs adalimumab (ADA) in achieving clinical remission (CR) at Week 52 in patients (pts) with moderate to severe ulcerative colitis (UC).1 Current treatment goals in UC are based on clinical symptoms and endoscopy, with histologic improvement considered an aspirational goal.2-4 In pts with CR in VARSITY, greater treatment differences between VDZ and ADA at Week 52 were seen in endoscopic improvement and histologic response. Here, data from VARSITY were used to define disease clearance: a novel composite outcome in UC comprising clinical and endoscopic remission plus minimal histologic disease activity. Methods VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-control trial of treatment with VDZ (300mg IV Q8W) vs ADA (40mg SC Q2W) maintenance after induction. Pts were randomized in a treat through design, and no dose escalation was allowed. For these analyses, based on pts who completed the study until Week 52, disease clearance was defined as a composite outcome based on 1) CR: partial Mayo score ≤2 and no individual subscore &amp;gt;1 (excluding sigmoidoscopy subscore); 2) endoscopic improvement: endoscopic subscore ≤1; and 3) absence of active histologic disease (minimum histological disease activity [MHDA]): Robarts Histology Index (RHI) &amp;lt;5. Treatment failure was defined as discontinuation from treatment or completion of treatment but failure to achieve any of CR, endoscopic improvement, or MHDA. The rates of disease clearance and failures were compared between treatment groups and stratified by presence of inflammatory burden at baseline: C-reactive protein ≥5 mg/L and fecal calprotectin &amp;gt;100 µg/g. Results More pts in the VDZ treatment group than the ADA group achieved disease clearance at Week 52 (VDZ: 112/383, 29.2%, 95% CI 24.7-34.1 vs ADA: 63/386, 16.3%, 95% CI 12.8-20.4). Compared with treatment failures (VDZ: 92/383, 24.0% vs ADA: 134/386, 34.7%, Table 1), disease clearers had lower C-reactive protein (CRP) baseline mean values (7.4mg/L and 6.4mg/L vs 13.6mg/L and 9.4mg/L for disease clearers vs treatment failures, for VDZ and ADA, respectively). Fewer pts with inflammatory burden at baseline (CRP ≥5 mg/L and fecal calprotectin &amp;gt;100 µg/g) achieved disease clearance (Fig 1). Baseline corticosteroid use was more frequent in ADA disease clearers (42.9%) compared with VDZ disease clearers (32.1%). Conclusion Disease clearance is a novel and achievable composite outcome that is achieved by almost one third of pts in the VDZ treatment group in VARSITY. Analyses are ongoing to further characterize the trajectory leading to disease clearance as well as the role of baseline characteristics.

Disseminated and Central Nervous System Vaccine-Strain Herpes Zoster Infection in a Teenager With Crohn’s Disease on Maintenance Adalimumab Therapy

Patients on immunosuppression, including inflammatory bowel disease patients on anti-tumor necrosis factor therapies, are at increased risk of severe varicella and herpes zoster infections. Although varicella vaccine-related herpes zoster reactivation is a rare complication, physicians must remain vigilant about this diagnosis, particularly in those on immunosuppressive medications. Here, we report a case of a patient with Crohn disease, on only adalimumab immunosuppression, who developed varicella vaccine-related disseminated herpes zoster with meningitis, over 15 years after immunization.

Histological Remission in Ulcerative Colitis in Deep Remission under Treatment with Adalimumab

Background and Aims: Histological remission (HR) has been recently demonstrated as the last therapeutic goal in ulcerative colitis (UC), but it is unknown whether and how it may occur. Our aim was to assess the histology during the follow-up of an UC population in deep remission under treatment with adalimumab (ADA).&#x0D; Methods: We performed a retrospective study on 22 UC patients who were in deep remission and followed-up while receiving therapy with ADA. Colonoscopy in those patients was performed every year. Four-quadrant biopsies every 10 cm were obtained during each colonoscopy and assessed by hematoxylin and eosin stain. Histological activity was classified using the Geboes scale.&#x0D; Results: A total of 22 patients were enrolled in the study. The mean follow-up of those patients was 28±7 months, and 2,592 biopsy specimens in total were taken during 108 colonoscopies performed during the follow-up. At the beginning of the follow-up, histological inflammation was found in 15/22 (68.2%) of patients in deep remissio while receiving maintenance ADA therapy, 8/22 (36.4%) of them with Geboes score ≥3.1. At the end of the follow-up, when patients were still in deep remission while receiving maintenance ADA therapy, only 4 patients (18.2%) had at least one biopsy specimen with evidence of any histological inflammation during the follow-up; only two patients (9.1%) had Geboes score ≥3.1.&#x0D; Conclusions: Our study shows for the first time that UC patients in deep remission under ADA may reach HR, but it seems slower than other clinical or endoscopic goals.