Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies: A case report of infantile-onset inflammatory bowel disease.

BACKGROUND: Treatment of infantile-onset inflammatory bowel disease (IO-IBD) is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics. Secondary loss of response is frequently caused by the production of anti-drug antibodies, a well-known problem in IBD patients on biologic treatment. We present a case of IO-IBD treated with therapeutic drug monitoring (TDM)-guided high-dose anti-tumor necrosis factor therapy, in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies. CASE SUMMARY: A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life, as well as relapsing perianal abscess and growth failure. Hypoalbuminemia, anemia, and elevated inflammatory markers were also present. Endoscopic assessment revealed skip lesions with deep colic ulcerations, inflammatory anal sub-stenosis, and deep fissures with persistent abscess. A diagnosis of IO-IBD Crohn-like was made. The patient was initially treated with oral steroids and fistulotomy. After the perianal abscess healed, adalimumab (ADA) was administered with concomitant gradual tapering of steroids. Clinical and biochemical steroid-free remission was achieved with good trough levels. After 3 mo, antibodies to ADA (ATA) were found with undetectable trough levels; therefore, we optimized the therapy schedule, first administering 10 mg weekly and subsequently up to 20 mg weekly (2.8 mg/kg/dose). After 2 mo of high-dose treatment, ATA disappeared, with concomitant high trough levels and stable clinical and biochemical remission of the disease. CONCLUSION: TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production. This strategy could be a good alternative to combination therapy, especially in very young patients.

Auditory cortex hypoperfusion: a metabolic hallmark in Beta Thalassemia.

BACKGROUND: Sensorineural hearing loss in beta-thalassemia is common and it is generally associated with iron chelation therapy. However, data are scarce, especially on adult populations, and a possible involvement of the central auditory areas has not been investigated yet. We performed a multicenter cross-sectional audiological and single-center 3Tesla brain perfusion MRI study enrolling 77 transfusion-dependent/non transfusion-dependent adult patients and 56 healthy controls. Pure tone audiometry, demographics, clinical/laboratory and cognitive functioning data were recorded. RESULTS: Half of patients (52%) presented with high-frequency hearing deficit, with overt hypoacusia (Pure Tone Average (PTA) > 25 dB) in 35%, irrespective of iron chelation or clinical phenotype. Bilateral voxel clusters of significant relative hypoperfusion were found in the auditory cortex of beta-thalassemia patients, regardless of clinical phenotype. In controls and transfusion-dependent (but not in non-transfusion-dependent) patients, the relative auditory cortex perfusion values increased linearly with age (p < 0.04). Relative auditory cortex perfusion values showed a significant U-shaped correlation with PTA values among hearing loss patients, and a linear correlation with the full scale intelligence quotient (right side p = 0.01, left side p = 0.02) with its domain related to communication skills (right side p = 0.04, left side p = 0.07) in controls but not in beta-thalassemia patients. Audiometric test results did not correlate to cognitive test scores in any subgroup. CONCLUSIONS: In conclusion, primary auditory cortex perfusion changes are a metabolic hallmark of adult beta-thalassemia, thus suggesting complex remodeling of the hearing function, that occurs regardless of chelation therapy and before clinically manifest hearing loss. The cognitive impact of perfusion changes is intriguing but requires further investigations.

Hearing Loss in Beta-Thalassemia: Systematic Review.

In the last half century, the life expectancy of beta-thalassemia patients has strikingly increased mostly due to regular blood transfusions and chelation treatments. The improved survival, however, has allowed for the emergence of comorbidities, such as hearing loss, with a non-negligible impact on the patients' quality of life. This thorough review analyzes the acquired knowledge regarding hearing impairment in this hereditary hemoglobinopathy, aiming at defining its prevalence, features, course, and possible disease- or treatment-related pathogenic factors. Following PRISMA criteria, we retrieved 60 studies published between 1979 and 2021. Diagnostic tools and criteria, forms of hearing impairment, correlations with beta-thalassemia phenotypes, age and sex, chelation treatment and laboratory findings including iron overload, were carefully searched, analyzed and summarized. In spite of the relatively high number of studies in the last 40 years, our knowledge is rather limited, and large prospective studies with homogeneous diagnostic tools and criteria are required to define all the aforementioned issues. According to the literature, the overall prevalence rate of hearing impairment is 32.3%; age, sex, and laboratory findings do not seem to correlate with hearing deficits, while the weak relationship with clinical phenotype and chelation treatment seems to highlight the presence of further yet to be identified pathogenic factors.