Objectives: Patients with organic growth hormone deficiency (GHD) or with structural hypothalamicpituitary abnormalities may have additional anterior pituitary hormone deficits, and are at risk of developing complete or partial corticotropin (ACTH) deficiency. Evaluation of the integrity of the hypothalamic -pituitary -adrenal axis (HPA) is essential in these patients because, although clinically asymptomatic, their HPA cannot appropriately react to stressful stimuli with potentially life-threatening consequences. Design and methods: In this study we evaluated the integrity of the HPA in 24 patients (age 4.2 -31 years at the time of the study) with an established diagnosis of GHD and compared the reliability of the insulin tolerance test (ITT), short synacthen test (SST), low-dose SST (LDSST), and corticotropin releasing hormone (CRH) test in the diagnosis of adrenal insufficiency. Results: At a cortisol cut-off for a normal response of 550 nmol/l (20 mg/dl), the response to ITT was subnormal in 11 subjects, 6 with congenital and 5 with acquired GHD. Four patients had overt adrenal insufficiency, with morning cortisol concentrations ranging between 66.2 -135.2 nmol/l (2.4-4.9 mg/dl) and typical clinical symptoms and laboratory findings. In all these patients, a subnormal cortisol response to ITT was confirmed by LDSST and by CRH tests. SST failed to identify one of the patients as adrenal insufficient. In the seven asymptomatic patients with a subnormal cortisol response to ITT, the diagnosis of adrenal insufficiency was confirmed in one by LDSST, in none by SST, and in five by CRH tests. The five patients with a normal cortisol response to ITT exhibited a normal response also after LDSST and SST. Only two of them had a normal response after a CRH test. In the seven patients with asymptomatic adrenal insufficiency mean morning cortisol concentration was significantly higher than in the patients with overt adrenal insufficiency. ITT was contraindicated in eight patients, and none of them had clinical symptoms of overt adrenal insufficiency. One of these patients had a subnormal cortisol response to LDSST, SST, and CRH, and three exhibited a subnormal response to CRH but normal responses to LDSST and to SST. Conclusion: We conclude that none of these tests can be considered completely reliable for establishing or excluding the presence of secondary or tertiary adrenal insufficiency. Consequently, clinical judgment remains one of the most important issues for deciding which patients need assessment or re -assessment of adrenal function. European Journal of Endocrinology 152 735-741

Background Since infliximab (IFX) patent expiry in 2015, several IFX biosimilars have been licensed in EU for all indications, including inflammatory bowel diseases (IBD). IFX biosimilars currently available in Italy include CT-P13 and SB2, both of which demonstrated comparable efficacy, safety and immunogenicity with IFX originator in IBD patients. Safety and clinical efficacy of single switch from originator IFX to CT-P13 have also been confirmed in a prospective clinical trial. On the contrary, data regarding multiple therapeutic switching of IFX originator with CT-P13 and SB2 are currently lacking. Methods This study was aimed to evaluate the safety and efficacy of double switch from IFX originator to CT-P13 and subsequently to SB2 in patients with IBD. From November 2018 to May 2019, patients undergoing IFX double switch in 8 Centres in Lombardy were retrospectively analysed. The overall rate of IFX discontinuation, incidence and type of adverse events (AE) and proportion of patients on clinical remission over time were recorded. Data were compared with a control group of 66 IBD patients single switched from IFX originator to CT-P13. Results Fifty-two double-switched IBD patients were enrolled (63% M, mean age 41 years, 75% Crohn’s disease, 25% ulcerative colitis). Main indications for IFX therapy were moderate to severe disease (50%) and steroid-dependent disease (25%). The overall 24- and 48-week IFX discontinuation rates following second switch (CTP13->SB2) were 2% (95% CI 0–6%) and 14% (95% CI 3–25%), respectively. During a median follow-up of 40 weeks (18–48), 4 patients (12%) experienced a total of 6 AE (2 cutaneous, 2 infectious, 1 articular and 1 immunological), leading to IFX discontinuation in 3 cases (6%). No infusion reactions were observed. At week 24 following second switch, 49 (94%) patients were in clinical remission, the remaining 3 patients not being in remission already at the time of second switch. Only one patient lost response after week 24, 48 (92%) of patients being in clinical remission at the end of follow-up. No differences in IFX discontinuation, AE and clinical remission rates were found between double-switched and single-switched patients. No clinical parameters were found to predict safety and efficacy outcomes. Conclusion The study supports both safety and efficacy of the double switch from IFX originator to CT-P13 and SB2 in patients with IBD, and demonstrates its non-inferiority to a single switch strategy, with potential cost implications.

Background Until 2014, infliximab originator (Remicade, IFX-O) was the only biological treatment approved in Italy for ulcerative colitis (UC), followed by the sequential approval of adalimumab (ADA), infliximab biosimilar (CTP-13), golimumab (GOL) and vedolizumab (VDZ). Recently, comparative trials among these drugs provided conflicting results on their reciprocal superiority or equivalence. Methods In a retrospective, real-life, multicenter inception cohort study involving 11 Italian IBD tertiary centres, all consecutive patients with moderate-to-severe active UC, treated with ADA, CTP-13, GOL or VDZ after their post-marketing approval (2014–2018) were followed-up for 1 year or until relapse. All drugs were compared with each other and to patients treated with Remicade in 2013–2014 (reference group). The 80% power calculation of the study required at least 75 patients in each arm. A propensity score analysis was performed. The primary endpoint was the 1 year relapse-free, optimisation-free, steroid-free remission, defined as Mayo partial score ≤2, with bleeding subscore = 0, no relapse after first clinical remission and no optimisation with dose intensification or steroids courses. Multiple further secondary endpoints were analysed (Table 1). Results 492 patients (ADA=90, CTP-13=105, GOL=79, VDZ=142, IFX-O=76) were included. Overall, 65% achieved clinical remission once during the follow-up, with IFX-O performing better than GOL and VDZ. The relapse rate was 24%, with the lowest rates with VDZ. The primary end-point was achieved in similar percentages in all groups, except for lower rates with GOL than IFX-O. IFX-O performed better than each other drug for other clinical outcomes (Table 1). Discontinuation for intolerance was similar among the drugs, but CTP-13 had more frequent adverse events (mainly infusion reactions) than ADA, VDZ and IFX-O. Conclusion Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year, except for GOL vs. IFX originator. IFX-O appears more effective in multiple questionable clinical outcomes. IFX biosimilar had more adverse events than the other drugs. IFX originator should be used as the reference drug in head to head, controlled, comparison trials for current and future biologics in UC.

Background Recently, comparative trials among biologics in ulcerative colitis (UC) provided conflicting results on their reciprocal superiority or equivalence. Therefore, in patients naive to biologics, the first-choice biological drug is uncertain. Methods In a retrospective, real-life, multicentre inception cohort study involving 11 Italian IBD tertiary centres, all consecutive patients, naive to biologics, treated with adalimumab (ADA), infliximab biosimilar (CTP-13), golimumab (GOL) or vedolizumab (VDZ) after their postmarketing approval (2014–2018) for moderate–severe active UC, were followed up for 1 year or until relapse. All drugs were compared with each other and to naive patients treated with IFX-originator (IFX-O, Remicade) in 2013–2014 as a reference group. A propensity score analysis was performed. The primary endpoint was the 1 year relapse-free, optimisation-free, steroid-free remission, defined as Mayo score ≤2, with bleeding subscore = 0, no relapse after first clinical remission and no optimisation with dose intensification or steroids courses. Multiple further secondary endpoints were analysed (Table 1). Results Two hundred ninety-six naive patients (ADA = 56, CTP-13 = 73, GOL = 60, VDZ = 34, IFX-O = 73) were included. The primary end-point was achieved in similar percentages in all groups, irrespective of optimisation. IFX-O and ADA had similar rates of clinical remission achieved once during the follow-up but higher rates than GOL and VDZ. The 1-year relapse rate, however, was lower with VDZ than ADA, GOL and IFX-O. Treatment failure for primary/secondary no response was higher with GOL than IFX-O and ADA. Treatment failures for intolerance were similar among all drugs. CTP-13 performed differently than the originator for some secondary end-points. Conclusion Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year in patients naive to these drugs. IFX originator and ADA appear more effective in the induction phase, while patients responders to VDZ had more prolonged clinical remission. Some differences on secondary questionable outcomes between IFX biosimilar and originator have been observed.