Author: Paschalis, Eleftherios I ; Vavvas, Demetrios ; Papaliodis, George ; Dohlman, Thomas H ; Sharma, Jyoti ; Lei, Fengyang ; Kim, Sarah ; Dohlman, Claes H ; Chodosh, James ; Urtti, Arto ; Zhou, Chengxin

AbstractBackground and PurposeLate secondary glaucoma is an often‐severe complication after acute events like anterior segment surgery, trauma and infection. TNF‐α is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti‐TNF‐α antibodies are in animals very effective in protecting the retinal cells and the optic nerve—and might therefore be useful prophylactically against secondary glaucoma in future such patients. Here we evaluate (1) toxicity and (2) efficacy of two TNF‐α inhibitors (adalimumab and infliximab), in rabbits by subconjunctival administration.MethodsFor drug toxicity, animals with normal, unburned corneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drug efficacy, other animals were subjected to alkali burn before such injection, or steroids (for control). The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. A sub‐set of eyes were stained ex vivo after 3 days for retinal cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated by paraphenylenediamine staining after 50 or 90 days. Loss of retinal cells and optic nerve degeneration were quantified.ResultsSubconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated. Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab and of 100 mg infliximab. For efficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mL provided practically full protection against retinal cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following burn injury, control optic nerves showed about 50% axon loss as compared to 8% in the adalimumab treatment group.ConclusionsSubconjunctival injection of 4.0 mg adalimumab in rabbits shows no eye toxicity and provides excellent neuroprotection, both short (3 days) and long‐term (90 days). Our total. accumulated data from several of our studies, combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti‐TNF‐α biologics to reduce inflammation and future secondary glaucoma.

01 Apr 2024·Minerva Gastroenterology

Therapy in elderly IBD patients

Article

Author: Castiglione, Fabiana ; Imperatore, Nicola ; Zingone, Fabiana ; D'Incà, Renata

INTRODUCTIONAppropriate treatment is critical in elderly inflammatory bowel disease (IBD) subjects since they are at higher risk of complications such as infections, malignancies and mortality.EVIDENCE ACQUISITIONWe conducted an extensive PubMed search for guidelines, systematic reviews and primary studies to perform a critical analysis of the existing literature on the efficacy and safety of conventional and biological therapies for elderly IBD patients.EVIDENCE SYNTHESISDue to the exclusion of elderly population from clinical trials, most evidences comes from real-life studies. While aminosalicylates remain a cornerstone treatment of elderly patients with ulcerative colitis (UC), for their effectiveness and safety, their use in Crohn's disease (CD) should not be further supported. Corticosteroid use should be limited for the induction of remission, while as maintenance treatment it should be avoided, due to the low safety profile. Although as efficacious as in the younger population, immunosuppressant use has been associated with higher risk of infective/malignant issues and further use should be carefully evaluated. Biologics have demonstrated high effectiveness in the elderly. However, due to increased morbidity and mortality described in elderly subjects treated with anti-TNF alpha agents, vedolizumab and ustekinumab should be favoured over anti-TNF alpha agents.CONCLUSIONSTreatment of elderly IBD patients remains challenging, since comorbidities and the risk of adverse events can complicate the effectiveness and safety of therapy. Close monitoring of such patients in a multidisciplinary team is advocated to reduce the risk of infections and optimize the treatment, choosing a suitable agent.

01 Sep 2023·The Pharmacogenomics Journal

One year of experience with combined pharmacokinetic/pharmacogenetic monitoring of anti-TNF alpha agents: a retrospective study

Article

Author: Dilillo, Dario ; De Silvestri, Annalisa ; Zuin, Giovanna ; Penagini, Francesca ; Cattaneo, Dario ; Norsa, Lorenzo ; Sansotta, Naire ; Cheli, Stefania ; Clementi, Emilio ; Savino, Diego ; Panceri, Roberto

Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (-308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammatory Bowel Diseases	Preclinical	IT	Cosmo Pharmaceuticals SA	-

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