Immunomodulation with Romiplostim in Young Adult Primary Immune Thrombocytopenia (ITP) As Second-Line Strategy (iROM-study)

Introduction : To date most treatment strategies of primary immune thrombocytopenia (ITP) are symptomatic, preventing premature platelet destruction and increasing their production. New strategies should focus on targeting the immune dysregulation, rather than the platelet count. Rituximab and dexamethasone have the potential to induce tolerogenic mechanisms, however with moderate long-term results (<30%). Thrombopoietin-receptor agonists (TPO-RAs) obviously have the potential to affect the course of the disease with up to 30% treatment-free remission. Possible mechanisms could be exposure to high-dose antigen and/or the innate immune activity of platelets, especially the release of TGF-ß, which may stimulate or restore regulatory T cells (Tregs). Tregs play a fundamental role in the maintenance of immune tolerance. Previous studies have shown lower and impaired function of Tregs in the peripheral blood of ITP patients. Methods: The iROM study is a national multi-center, open label, single arm pilot study that aims to explore possible immunomodulatory effects of romiplostim administered as second line drug in young adults with ITP. Patients who failed, did not tolerate or relapsed after first-line treatment with steroids and/or intravenous immunoglobulin (IVIG) were included, irrespective of disease duration. Romiplostim was administered subcutaneously for 22 weeks and then stopped. The dose was adjusted every week depending on platelet response, following the product information (target platelet count 50-200x10 9/l). Follow-up was performed until week 52. Immunologic investigations were done at weeks 1, 6, 12, 22 and 52. Tregs (CD4 +, CD25 +, CD127 low) were investigated by flow cytometry and reported as percentage Tregs/CD3. Because of comedication at week 1 (IVIG, steroids), week 6 was defined as the initial immunological state. Confirmatory tests were performed using a paired samples Wilcoxon test at a two-sided alpha of 5%. The p-values are adjusted using the Holm method for all secondary analyses. Results: Between 2016 and 2020, 15 patients were enrolled, including two dropouts. Of the 13 patients analyzed, 9 had newly diagnosed ITP (<3 months), median age 31 years (IQR 8), and 4 chronic ITP (>12 months), median age 31.5 years (IQR 8.75), with a median platelet count at enrollment of 26x10 9/l (IQR 41) and 49.5x10 9/l (IQR 88.5), and at week 52, 168x10 9/l (IQR 88) and 96x10 9/l (IQR 23.5), respectively. All patients were on ITP treatment at enrollment (steroids and/or IVIG). In 6 out of 9 patients with newly diagnosed ITP, discontinuation of romiplostim was successful with sustained treatment-free complete remission (TFR) at 1 year, whereas all patients with chronic ITP relapsed and restarted various treatments. Interestingly, romiplostim dose titration was lower and platelet count response higher and more stable in patients achieving TFR (Fig 1). Platelet counts in patients with relapse showed a very jagged curve over the 22 weeks of treatment. Tregs increased between weeks 6 and 22 (end of treatment), so as between weeks 6 and 52 (end of study) in the whole group of patients with a median change of 0.62 (CI95 (0.14, 1.26)) (p=0.017) at end of study. Tregs variation for patients with sustained TFR versus no remission is shown in Fig 2a, and for the 9 patients with newly diagnosed ITP in Fig 2b. Conclusion : These results support the assumption that early treatment of ITP with TPO-RAs, e.g. romiplostim, could positively influence the natural course of ITP. Induction of tolerance may be more successful in the early stage of an autoimmune disorder because of autoimmune expansion and epitope spreading. We also assume that induction of tolerance may be more successful in younger patients because of potentially reduced immunosenescence. In this small trial only 3 out of 9 patients (33%) with newly diagnosed ITP relapsed after stopping treatment according to the iROM protocol. In contrast, all 4 patients with chronic ITP relapsed after stopping treatment. Our observation of a higher increase of platelets and a more stable increase of Tregs in patients with sustained TFR in comparison to those with relapse corroborate the hypothesis that the tolerogenic stimulus may be supported by the platelet mass. Limitations of the study were the small sample size, the heterogeneity of the patient population regarding ITP duration, and preceding medications overlapping the first study weeks. Figure 1 Figure 1. Disclosures Schifferli: Sobi: Honoraria; Novartis: Honoraria, Research Funding. Rovo: Novartis: Research Funding; AG Alexion: Honoraria; BMS: Honoraria; OrPhaSwiss GmbH: Honoraria; Swedish Orphan Biovitrum AG: Honoraria; Amgen: Other: Financial support for congresses and conference travel; AstraZeneca: Other; BMS: Other; Sanofi: Other; Roche: Other; AstraZeneca: Honoraria; Novartis: Honoraria; CSL Behring: Research Funding; AG Alexion: Research Funding. Kuehne: Novartis: Research Funding; UCB: Honoraria; SOBI: Honoraria; Amgen: Research Funding.

Role of Oral Tranexamic Acid in Treating Patients of Melasma in A Charity Hospital of Lahore

Objective: To evaluate the efficacy and safety of oral tranexamic acid (TA) in the treatment of melasma Method: This was a descriptive, cross sectional study which was performed in department of dermatology in Akhtar Saeed Trust Hospital, Lahore from April till December 2019. 70 patients of moderate to severe melasma were enrolled regardless of gender, > 18 years of age. 250 mg oral TA was given BD for 3 months along with broad spectrum topical sunscreen. Follow up done on monthly basis, 2 months after stopping the treatment. Photographs were taken at first visit & MASI (melasma area severity index) scoring done at start & after 3 months of treatment. Side effects were noted down if present. Results were recorded & analysed using SPSS. Results: A total of 70 patients were enrolled, 44 females and 26 males. Mean age of patients was 30.7. There was a significant decrease mean 3.4 in MASI scoring at 12 wks of treatment. 25 patients had good, 22 had fair, 7 had fair response to TA. No serious side effects were noted at end of treatment. No reversal of melasma was recorded at 2 months after stopping treatment. Conclusion: Oral tranexamic acid is a quick & effective treatment of patients of melasma. Key words: Melasma, tranexamic acid, treatment.

D-Serine: A Cross Species Review of Safety

Background:D-Serine, a direct, full agonist at the D-serine/glycine modulatory site of the N-methyl-D-aspartate-type glutamate receptors (NMDAR), has been assessed as a treatment for multiple psychiatric and neurological conditions. Based on studies in rats, concerns of nephrotoxicity have limited D-serine research in humans, particularly using high doses. A review of D-serine's safety is timely and pertinent, as D-serine remains under active study for schizophrenia, both directly (R61 MH116093) and indirectly through D-amino acid oxidase (DAAO) inhibitors. The principal focus is on nephrotoxicity, but safety in other physiologic and pathophysiologic systems are also reviewed.Methods: Using the search terms “D-serine,” “D-serine and schizophrenia,” “D-serine and safety,” “D-serine and nephrotoxicity” in PubMed, we conducted a systematic review on D-serine safety. D-serine physiology, dose-response and efficacy in clinical studies and dAAO inhibitor safety is also discussed.Results: When D-serine doses >500 mg/kg are used in rats, nephrotoxicity, manifesting as an acute tubular necrosis syndrome, seen within hours of administration is highly common, if not universal. In other species, however, D-serine induced nephrotoxicity has not been reported, even in other rodent species such as mice and rabbits. Even in rats, D--serine related toxicity is dose dependent and reversible; and does not appear to be present in rats at doses producing an acute Cmax of <2,000 nmol/mL. For comparison, the Cmax of D-serine 120 mg/kg, the highest dose tested in humans, is ~500 nmol/mL in acute dosing. Across all published human studies, only one subject has been reported to have abnormal renal values related to D-serine treatment. This abnormality did not clearly map on to the acute tubular necrosis syndrome seen in rats, and fully resolved within a few days of stopping treatment. DAAO inhibitors may be nephroprotective. D-Serine may have a physiologic role in metabolic, extra-pyramidal, cardiac and other systems, but no other clinically significant safety concerns are revealed in the literature.Conclusions: Even before considering human to rat differences in renal physiology, using current FDA guided monitoring paradigms, D-serine appears safe at currently studied maximal doses, with potential safety in combination with DAAO inhibitors.

Letter to the Editor from Colle et al

In their article, Fucà et al highlight that early tumor shrinkage and depth of response predict the prognosis of patients with metastatic colorectal cancer (mCRC) microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) treated by immune checkpoint inhibitors (ICI). We are surprised that no cases of pseudoprogression (PSPD) were reported in their study. PSPDs were described under ICI in patients treated for MSI/dMMR mCRC. In a cohort of 123 patients treated with anti-PD1±antiCTL-4 for MSI/dMMR mCRC, we reported 12 patients with PSPD, representing 10% of the cohort. Of 12 patients with PSPD, 8 secondary achieved an objective response and were alive and free of progression at the data lock. Conversely, in Fucà’s article, no PSDP was observed and the patients with primary radiological progression (21.7%) had a poor overall survival. These differences between the two series could be probably explained by the following points. First, Fucà et al use RECIST 1.1 criteria for radiological evaluation. Second, the first imaging was done after 8–9 weeks of treatment in Fucà’s article, which may be late to detect PSPD. In conclusion, if the first evaluation is made during the first 3 months of treatment, using iRECIST criteria seems mandatory to avoid stopping treatment prematurely, especially in patients receiving anti-PD1 alone.

Nomegestrol Acetate or Chlormadinone Acetate Progestative Treatment in Women: Meningioma Behavior at Treatment Discontinuation

Background: Associations between progestins and meningiomas is now well established. While the link between cyproterone acetate (CA) and meningioma was thoroughly studied, there is far less available data regarding the link between chlormadinone acetate (CHA) or nomegestrol acetate (NA) and risk of intracranial meningiomaMethods: We are presenting a series of 28 patients diagnosed with single or multiple meningiomas while treated with CHA-NA, in which the clinical and radiological course were analyzed after treatment discontinuation.Results: 28 women, with a mean age of 56 years old, were diagnosed with one or multiple meningioma while being treated with either CHA or NA. After stopping treatment, 89.3% showed either tumor shrinkage or tumor stabilization on follow-up MRIs. Multiple meningiomas were more likely observed in patients with long periods of treatment (>10 years, p 0.03) and seem to have a better clinical course (p 0.01). Most of the lesions were located on the skull base (55.4%). Four patients with multiple meningiomas showed discordant tumors evolution, with some tumors growing while others were decreasing. Most of the growing meningiomas were either convexity or midline lesions and more posteriorly located. Conclusion: Our study demonstrated a significant percentage of tumor diminution or stabilization after NA and CHA discontinuation. Therefore, treatment discontinuation with close monitoring should be the first measure taken if urgent surgery is not indicated. However, our results seem to be less encouraging than previously described in patients treated by CA, with more patients showing tumor growth despite treatment discontinuation. Further studies are needed to differentiate the effect of the different progestins treatment on meningiomas.

P525 Patients’ Perception of Risks of biologic therapy During Covid-19 Pandemic in Israel Orly Lior, Ilia Sergeev, Nahum Ruhimovich, Michal Openheim, Fabiana Benjaminov, Dan Feldman, Yehuda Ringel, Timna Naftali Division of Gastroenterology and Liver Diseases, Meir Medical Center, Kfar Saba, Israel

Background Current inflammatory bowel disease (IBD) therapies are highly effective. However, compliance with treatment is influenced by patients’ perception of benefits versus risks. Understanding these perceptions and their influence on patients’ treatment decision-making is crucial for achieving compliance, especially during Covid-19 pandemic. Aim: to assess patients’ perception of risks of IBD exacerbation and SARS-CoV-2 infection, and their influence on patients’ decisions regarding biologic and immunosuppressive treatments during Covid-19 pandemic in Israel. Methods A prospective internet-based survey among Meir Medical Center, IBD clinic patients. Results 116 patients have responded. Mean age 42 (18–84), 44 (38%) males, 75 (64%) Crohn’s disease, 38 (32%) ulcerative colitis, 34 (29%) with history of abdominal surgery, 47 (40%) were in remission and 9(7.5%) with severe disease. 18 (15%) patients were on Immunosuppressive and 76 (66%) on biologic treatments. Concerns of contracting SARS-CoV-2 infection: 56 (48%) patients considered their risk as equal to that of the general population whereas 53 (46%) considered it to be increased. 55% of the patients related the increase risk of COVID-19 infection to their IBD treatment, whereas 47% related it to having IBD. Patients treated with biologics were more concerned of becoming infected with SARS-CoV-2 then those who were not. There was also a significant association between depression and anxiety levels and the fear of becoming infected (r= 0.3 for depression and 0.4 for anxiety). Adherence to IBD treatment: Only 8 (7.5%) patients considered stopping their IBD treatment, and only 4 (3.7%) patients actually stopped their treatment. Patients with more severe disease were more inclined to stop their treatment compared to those with mild disease. Reasons for not stopping treatment were fear of disease exacerbation in 37 (32%) patients, and reassuring information received from medical providers, in 25 (21.5%) patients. When faced with a theoretical question of trading long-term remission versus risk of SARS-CoV-2infection, 34 (29%) patients were willing to accept a 10% infection risk for a 10-year remission Conclusion Significant portion of the patients with IBD believe that they are at increased risk of contracting SARS-CoV-2 infection, and more than half of them related the increase risk to their IBD treatment. However, despite their fear most patients felt safe enough to continue their treatment. Patients with more severe disease and treated with biologics experienced higher levels of anxiety, depression and fear of COVID-19 infection. Identifying and addressing these fears early might increase patient’s adherence to treatment and prevent the hazardous effects of discontinuation of treatment.

Deprescribing Antidepressants in Older People – Breaking Up Can Be Hard to Do

Every drug review for older people should consider which medicines to continue, but equally important, which medicines can be discontinued. As we age, the balance between potential benefits and potential risks of medications often shifts towards more harm. For example, antidepressants are commonly prescribed in general, but in the older person, they carry specific potential harms. Further, there is data indicating that a substantial proportion of users have no evidence-based indications to continue antidepressants and could be candidates to try stopping treatment. We outline first the imperatives and evidence for deprescribing antidepressants and then finally the practical approaches to deprescribing.

Therapeutic drug monitoring of anti-TNF drugs: an overview of applicability in daily clinical practice in the era of treatment with biologics in juvenile idiopathic arthritis (JIA)

Background Anti-tumor necrosis factor (TNF) drugs have improved the prognosis for juvenile idiopathic arthritis (JIA) significantly. However, evidence for individual treatment decisions based on serum anti-TNF drug levels and the presence of anti-drug antibodies (ADAbs) in children is scarce. We aimed to assess if anti-TNF drug levels and/or ADAbs influenced physician’s treatment decisions in children with JIA. Methods Patients’ records in our center were retrospectively screened for measurements of anti-TNF drug levels and ADAbs in children with JIA using etanercept, adalimumab or infliximab. Clinical characteristics and disease activity were retrieved from patient charts. Results We analyzed 142 measurements of anti-TNF drug levels in 65 children with JIA. Of these, ninety-seven (68.3%) were trough concentrations. N = 14/97 (14.4%) of these showed trough concentrations within the therapeutic drug range known for adults with RA and IBD. ADAbs against adalimumab were detected in seven patients and against infliximab in one patient. Seven (87,5%) of these ADAb-positive patients had non-detectable drug levels. A flowchart was made on decisions including rational dose escalation, stopping treatment in the presence of ADAbs and undetectable drug levels, showing that 45% of measurements influenced treatment decisions, which concerned 65% of patients (n = 42/65). Conclusions In the majority of patients, measurement of anti-TNF drug levels led to changes in treatment. A wide variation of anti-TNF drug levels was found possibly due to differences in drug clearance in different age groups. There is need for determination of therapeutic drug ranges and pharmacokinetic curves for anti-TNF and other biologics in children with JIA.

Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.

Toxicity and inconvenience associated with the use of injectable drug-containing regimens for tuberculosis (TB) have made all-oral regimens a preferred alternative. Widespread resistance to fluoroquinolones and pyrazinamide makes it essential to identify new drug candidates and study their effects on current regimens for TB. TB47 is a pyrazolo[1,5-a]pyridine-3-carboxamide with powerful synergistic in vitro and in vivo activities against mycobacteria, especially with clofazimine. Here, we investigated the bactericidal and sterilizing activities of novel oral regimens containing TB47 + clofazimine + linezolid, and the potential roles of levofloxacin and/or pyrazinamide in such drug combinations. Using a well-established mouse model, we assessed the effect of these regimens on bacterial burden in the lung during treatment and relapse (4 months after stopping treatment + immunosuppression). Our findings indicate that the TB47 + clofazimine + linezolid + pyrazinamide, with/without levofloxacin, regimens had fast-acting (4 months) sterilizing activity and no relapse was observed. When pyrazinamide was excluded from the regimen, treatment times were longer (5-6 months) to achieve sterilizing conditions. We propose that TB47 + clofazimine + linezolid can form a highly sterilizing block for use as an alternative pan-TB regimen.

Cotrimoxazole-induced hyperkalaemia in a patient with known hypoaldosteronism

A70-year-old man, with established hypoadrenalism due to a previous bilateral adrenalectomy, was admitted with recurrent episodes of postural dizziness and presyncope. He had been discharged from hospital 3 weeks earlier on a 1-month course of cotrimoxazole following a diagnosis of prostatitis. His electrolytes on admission showed new onset hyponatraemia and hyperkalaemia.His usual glucocorticoid replacement dose was doubled in view of a presumed diagnosis of hypocortisolaemia. However, the hyperkalaemia persisted. On rereviewing his treatment, we suspected a possible diagnosis of cotrimoxazole-induced hyperkalaemia. Cotrimoxazole was stopped and ciprofloxacin started instead. His fludrocortisone replacement was doubled for 3 days after stopping treatment to decrease his postural symptoms. His postural symptoms improved, his serum potassium decreased to normal levels and he was safely discharged.It is essential to remember that cotrimoxazole, a commonly used antibiotic, can induce a potentially fatal hyperkalaemia especially in patients with known hypoadrenalism.