Administration Of Azathioprine Research Articles

P1086 Re-administration of infliximab in patients with extremely refractory perianal Crohn’s disease

Abstract Background This study aims to evaluate the efficacy of infliximab re-administration to a cohort of patients with extremely refractory perianal Crohn's Disease (CD). Methods Retrospective analysis of prospectively collected data in CD patients with perianal disease, who despite being treated with infliximab, had to change treatment either because of primary non-response, secondary loss of response, or due to the occurrence of an allergic reaction. They then became resistant to the other therapies tested, resulting in Infliximab being given again. We then evaluated the clinical response to fistula management (Perianal Disease Activity Index PDAI ≤ 4), as well as the occurrence of adverse reactions in these patients. Results We included 14 patients (8 women), with a mean age (SD) of 38.2 (9.5) years. According to the Montreal classification our patients had L1 (n=2), L2 (n=2) and L3 (n=10) disease. After the initial Infliximab failure (even after dose escalation), patients received vedolizumab, ustekinumab and adalimumab without response or with secondary loss of response. Therefore, it was decided to re-administer infliximab with concomitant administration of azathioprine. After 1 year of follow up clinical response (PDAI ≤ 4) was seen in 4 patients (28.5%). Re-administration of infliximab was discontinued in 2 patients due to severe allergic reaction; however, the remaining patients did not experience side effects. Conclusion Re-administration of Infliximab may be able to help a small percentage of treatment resistant patients with perianal CD.

Use of non-steroidal anti-inflammatory drugs in renal transplant patients: A retrospective study.

Renal transplanted patients are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for analgesic purposes. Considering the dearth of data, we carried out the present study to evaluate the use of various NSAIDs and the incidence of acute kidney injury (AKI) in transplant patients. A retrospective study amongst renal transplant patients prescribed at least one dose of NSAID was carried between January and December 2020 at the Department of Nephrology, Salmaniya Medical Complex, Kingdom of Bahrain. The patients' demographic details, serum creatinine values, and drug-related details were obtained. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used for defining AKI. Eighty-seven patients were included. Forty-three patients were prescribed diclofenac, 60 received ibuprofen, six received indomethacin, 10 were administered mefenamic acid, and 11 received naproxen. Due to multiple courses of NSAID prescription, a total of 70 prescriptions were identified for diclofenac, 80 for ibuprofen, six for indomethacin, 11 for mefenamic acid, and 16 for naproxen. No significant differences were observed in the absolute (p =0.08) and percent changes in serum creatinine (p =0.1) between the NSAIDs. Twenty-eight (15.2%) courses of NSAID therapy met the KDIGO criteria for AKI. Age (OR: 1.1, 95% CI: 1.007, 1.2; p =0.02), concomitant everolimus (OR: 483, 95% CI: 4.3, 54407; p =0.01), and mycophenolate + cyclosporine + azathioprine (OR: 63.4E+006, 95% CI: 203.2157 to 19.8E+012; p =0.005) administration were observed with significant risk of NSAID-induced AKI. We observed possible NSAID-induced AKI to an extent of around 15.2% in our renal transplant patients. No significant differences were observed in the incidence of AKI between various NSAIDs and none of them had either graft failure or death.

Diagnosis and management of Neuro-Behçet disease with isolated intracranial hypertension: a case report and literature review

BackgroundNeuro-Behçet's disease (NBD), characterized by isolated intracranial hypertension, is a rarely encountered condition, especially in children. In this study, we describe the treatment of a pediatric patient with NBD, who exhibited isolated intracranial pressure elevation as indicated by the initial manifestation of diplopia and physical examination finding of papilledema.Case presentationAn 8-year-old boy was admitted to the hospital with a confirmed diagnosis of Behçet's disease (BD) over eight months. The patient also presented with the symptom of diplopia for three days. The evaluation of the patient’s nervous system did not reveal any apparent abnormalities. The measurement of cerebrospinal fluid pressure yielded a reading of 470 mm H2O. The examination of the fundus indicated papilledema, and imaging scans revealed evidence of focal demyelination. The symptoms of the child showed alleviation after the administration of mannitol, methylprednisolone, and azathioprine. Furthermore, this study involved a comprehensive analysis of 18 cases of NBD with isolated intracranial hypertension, comprising one case reported herein and 17 cases from the literature review. Three cases were children, and an equal distribution of males and females 9:9 was noted. The average age at the onset of symptoms was 24.7 years (8-38 years). Headache (90%) was the most commonly reported clinical manifestation, followed by blurred vision or diplopia (80%). The ocular manifestations included papilledema (100%), abducent nerve paralysis (20%) and local eye hemorrhages in the retina (30%). Notably, 88.9% of these ocular manifestations were relieved or cured after treatment.ConclusionThis study presents the first reported case of NBD with isolated intracranial hypertension in the pediatric population of China. In a child with Bechet's disease presenting with features of raised intracranial pressure, it is important to be aware of neuro Bechet's presenting with intracranial hypertension without other neurological abnormalities. This will help make early diagnosis, institute treatment and prevent sequelae resulting from untreated raised intracranial pressure.

Azathioprine monotherapy withdrawal in inflammatory bowel diseases: A retrospective mono-centric study.

There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation. To describe the events following AZA cessation. Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups. A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1st year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years. AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.

Eosinophilic granulomatosis with polyangiitis developed after dupilumab administration in patients with eosinophilic chronic rhinosinusitis and asthma: a case report

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a form of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small-to-medium vessel vasculitis associated with asthma, rhinosinusitis, and eosinophilia. EGPA is often difficult to distinguish from severe asthma and eosinophilic chronic rhinosinusitis (ECRS) in cases when there are no findings that suggest vasculitis. Dupilumab, an anti-IL-4Rα monoclonal antibody, is expected to be effective in eosinophilic airway inflammatory diseases, such as refractory asthma and chronic rhinosinusitis (CRS). Although transient eosinophilia and eosinophilic pneumoniae have been reported in patients with refractory asthma and CRS associated with dupilumab, few studies have examined the development of EGPA.Case presentationWe report a case of a 61-year-old woman treated with dupilumab for refractory ECRS and eosinophilic otitis media (EOM) complicated by severe asthma. Although she had a previous history of eosinophilic pneumoniae and myeloperoxidase (MPO) ANCA positivity, there were no apparent findings of vasculitis before the initiation of dupilumab. After the second administration of dupilumab, several adverse events developed, including worsening of ECRS, EOM and asthma, and neuropathy. A blood test showed an eosoinophilia and re-elevation of MPO-ANCA levels after the administration of dupilumab. Therefore, dupilumab was discontinued owing to the development of EGPA, and prednisolone and azathioprine administration was initiated for a remission induction therapy.ConclusionTo the best of our knowledge, this is the first case report that suggests that dupilumab may directly trigger the manifestation of vasculitis in patients who were previously MPO-ANCA-positive. Although the precise mechanism of how dupilumab could trigger the development of EGPA requires further elucidation, measuring MPO-ANCA in patients with multiple eosinophilic disorders before the initiation of dupilumab might be helpful when considering the possibility of a latent EGPA. When administering dupilumab to patients with a previous history of MPO-ANCA positivity, clinicians must carefully monitor and collaborate with other specialists in the pertinent fields of study for appropriate usage.

Role of transduodenal endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) for diagnosis of retroperitoneal fibrosis (Ormond's disease).

Retroperitoneal fibrosis (RPF), often referred to as Ormond's disease when it is of idiopathic origin, is a rare disease characterized by the presence of inflammatory infiltrates and periaortic masses in the retroperitoneum. For a definite diagnosis, a biopsy and subsequent pathological examination is required. Currently accepted methods for retroperitoneal biopsy include open, laparoscopic, or CT-guided approaches. However, transduodenal endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) for diagnosis of RPF has attracted only little attention in the literature. We report two male patient cases who presented with leukocytosis, elevated C-reactive protein, and a suspicious retroperitoneal mass of unknown origin on computed tomography. One patient also reported left lower quadrant pain, whereas the other patient suffered from back pain and weight loss. In both patients, idiopathic RPF was successfully diagnosed by using transduodenal EUS-FNA/FNB with 22- and 20-gauge aspiration needles. Histopathology revealed dense lymphocytic infiltrates and fibrosis. The procedures lasted approximately 25 and 20 minutes, respectively, and in both patients no serious adverse events occurred. Treatment included steroid therapy and administration of Azathioprine. We demonstrate that using EUS-FNA/FNB to diagnose RPF is a feasible, fast, and safe method, which should always be considered as a first-line diagnostic modality. Hence, this case report emphasizes that gastrointestinal endoscopists are likely to play an important role in the setting of suspected RPF.

Prevalence of hepatotoxicity and myelosuppression with alternate day use of azathioprine and glucocorticoids for treatment of dermatological conditions in dogs.

The use of azathioprine (AZA) in dogs is limited by the potential for hepatotoxicity and myelosuppression. To determine the prevalence of AZA-associated hepatotoxicity in dogs with dermatological conditions receiving alternate-day AZA. The hypothesis was that dogs receiving AZA every other day (EOD) would have a lower prevalence of hepatotoxicity compared to published data for dogs receiving daily AZA. A secondary aim was to determine the prevalence of AZA-associated myelosuppression over the same time period and population. Forty-one client-owned dogs with dermatological conditions treated with AZA EOD and glucocorticoids with clinical and haematological follow-up available for a minimum of two months of AZA therapy. Retrospective analysis of data from April 1994 to July 2020. Hepatotoxicity was defined as elevation of alanine aminotransferase (ALT) at least twofold above the reference range. Azathioprine-associated hepatotoxicity was observed in two of 41 dogs (4.9%), with onset at 18 and 40 days, respectively. One dog receiving AZA at 1.9mg/kg EOD had a fourfold increase in ALT. The other dog (AZA dose 2.3mg/kg EOD) had a 30-fold increase in ALT. Azathioprine was not associated with thrombocytopenia, anaemia or neutropenia in any dogs. Lymphopenia developed in one dog (2.4%) with onset at 105 days. Alternate-day AZA administration with tapering glucocorticoids was well-tolerated in dogs with dermatological conditions.

Intestinal microbiota-mediated biotransformations alter the pharmacokinetics of the major metabolites of azathioprine in rats after oral administration

Adverse reactions to azathioprine (AZA) vary greatly among individuals, which is associated with the variable levels of its major metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). The intestinal microbiota has been proven to contain AZA-metabolizing enzymes, although the explicit role of the intestinal microbiota in AZA metabolism in vivo remains poorly comprehended. In this study, the pharmacokinetic behaviours of 6-TGN and 6-MMP were assessed in the pseudo germ-free (PGF) group and control group following oral administration of AZA. The AUC0-t and Cmax of 6-TGN in the PGF group were significantly decreased by 34.0% and 35.0% (P < 0.05) compared with those in the control group. Additionally, the AUC0-t and Cmax of 6-MMP were reduced by 27.9% and 34.2% in the PGF group, although the differences were not significant. The TPMT and NUDT15 genotypes of rats in the two groups were genetically identical. The expression levels of key AZA-metabolizing enzymes in liver were not different between two groups. Furthermore, the major metabolites of AZA in the incubation system with intestinal microbial enzymes were identified. In summary, shifts in the composition of the intestinal microbiota may regulate the exposure of 6-TGN in vivo by altering the gut microbial metabolism of AZA.

P368 Safety issues of azathioprine in patients with inflammatory bowel disease: clinical experience from a referral center

Abstract Background Despite the development new agents for inflammatory bowel disease (IBD) therapy, azathioprine (AZA) is widely used as both as monotherapy and as combination therapy for induction and maintenance of remission both Crohn’s disease (CD) and ulcerative colitis (UC). Aim of this study is to investigate the long-term safety of AZA, to document the prevalence of adverse events of AZA in patients with IBD. Methods In this retrospective study, we included, 222 patients with IBD, who were monitored at University hospital of Ioannina from, 2003 to, 2019. The diagnosis of IBD was made based on endoscopic and histologic findings after ileocolonoscopy with biopsies. Inclusion criteria of study were diagnosis of IBD and regular follow-up intervals at least every six month after start of AZA administration. Results The average age of patients was, 46.9 years (Std. Dev., 17,9) at start of AZA administration., 65.6% of IBD patients (146/222) had CD and, 34.4% had UC (76/222). The mean duration of AZA administration was, 51 months (range:, 0–135 months). The most frequent location of CD was ileocolonic (38.4%, 56/146), while the most patients with UC had left sided colitis (54%, 41/76). Furthermore, the main indication for AZA treatment was the maintenance of remission both in UC and CD. The most common dose of AZA was, 100mg/day (range:, 50-200mg). The most common adverse events were gastrointestinal symptoms (8.6%, 18/222), leucopenia (2.7%, 6/222), hepatotoxicity (5.4%, 12/222) and pancreatitis (1.8%, 4/222). Two patients were diagnosed with basal cell cancer. Infections were recorded in, 19 patients (8.6%) of whom, 6 needed hospitalization. Conclusion According to this retrospective observational study, approximately one-third of IBD patients receiving AZA presented clinical significant adverse event during follow-up. Azathioprine withdrawal or dose reduction was needed in, 47 (21%) patients.

Effect of NUDT15 polymorphisms on early hematological safety of low-dose azathioprine in Chinese patients with pemphigus vulgaris: A prospective cohort study.

Azathioprine (AZA) is the preferred immunosuppressant for treating pemphigus vulgaris (PV), with discontinuation mainly attributed to hematological adverse events (AE). Reportedly, nucleoside diphosphate‐linked moiety X‐type motif 15 (NUDT15) polymorphisms have been strongly associated with thiopurine‐induced leukopenia. To investigate hematological AE of low‐dose AZA based on NUDT15 genotypes among patients with PV, a prospective cohort study was conducted in patients with PV, followed‐up for the first 8 weeks after AZA administration. All patients were divided into wild homozygous and heterozygous NUDT15 groups. Both groups initiated AZA at low dose (50 mg/day) and continued with different dose‐escalating approaches. Bone marrow suppression was considered the principal outcome. Overall, 62 patients with PV were enrolled (48 in the wild homozygous NUDT15 group vs. 14 in the heterozygous NUDT15 group). Except for median maintenance doses of AZA, no statistically significant differences were observed between the two groups in terms of age, sex, white blood cells, neutrophil count, platelet count, hemoglobin level, median final doses of corticosteroids (mg prednisone equivalent), pemphigus disease area index, and anti‐desmoglein 1/3 autoantibodies. In both groups, patients presented similar hematological AE and treatment responses after administration of different low‐dose AZA treatment strategies. Low‐dose AZA based on NUDT15 genotypes can reduce the risk of early hematological AE among patients with PV.

Genotyping before azathioprine administration in dermatology.

Click https://wileyhealthlearning.com/#/online-courses/7d0b59ae-5b45-4a42-a0a4-d0cea56c92e0 for the corresponding questions to this CME article.

Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies.

Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of corticosteroids, azathioprine and other immunosuppressants like calcineurin inhibitors and mycophenolate mofetil. Withdrawal of immunosuppression often results in disease relapse, and, in some cases, therapy is ineffective or associated with serious side effects. Understanding the mechanisms underlying AIH pathogenesis is therefore of paramount importance to develop more effective and well tolerated agents capable of restoring immunotolerance to liver autoantigens. Imbalance between effector and regulatory cells permits liver damage perpetuation and progression in AIH. Impaired expression and regulation of CD39, an ectoenzyme key to immunotolerance maintenance, have been reported in Tregs and effector Th17-cells derived from AIH patients. Interference with these altered immunoregulatory pathways may open new therapeutic avenues that, in addition to limiting aberrant inflammatory responses, would also reconstitute immune homeostasis. In this review, we highlight the most recent findings in AIH immunopathogenesis and discuss how these could inform and direct the development of novel therapeutic tools.

The Examination of a TPMT Gene Before Administration of Azathioprine in Rheumatology Practice and Identification of a Novel Variant p.W29R.

Two-hundred patients were assessed for the presence of genetic allelic variants using PCR amplification and direct sequencing. In 19 patients, we detected genetic allelic variants affecting TPMT activity; in 1 case, it was an unpublished heterozygous variant c.85T>C (p.W29R); of those, 15 patients were switched from AZA to a different medication, and 1 patient was prescribed a reduced dose of AZA. Our findings show the importance of testing for variants of the TPMT gene before the administration of AZA in clinical rheumatology practice. Patients with documented episodes of leukopenia or elevated liver biochemical tests while on AZA should undergo TPMT genotype testing and/or TPMT enzyme activity testing.

Clinical features and management of coexisting anti-N-methyl-D-aspartate receptor encephalitis and myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis: a case report and review of the literature.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune encephalitis caused by antibodies targeting the GluN1 subunit of NMDA receptors. Myelin oligodendrocyte glycoprotein (MOG) antibody disorders are now widely accepted as peculiar neuroimmunological diseases with specific clinical and pathological features. Some rare cases of overlapping anti-NMDA receptor encephalitis and MOG antibody-associated diseases have been reported, presenting complex clinical symptoms that make the disease more difficult to recognize. In accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, the terms "NMDAR" and "MOG," "NMDAR" and "demyelination," and "MOG" and "encephalitis" were searched in PubMed. Clinical cases with dual-positive anti-NMDA cerebrospinal fluid receptors and MOG serum antibodies during the disease course were included in this study. A total of 25 patients were analyzed in this study. The age at onset ranged from 3 to 54years. The median number of relapses was 2.8. Administration of intravenous methylprednisolone and immunoglobulin was the most widely used treatment strategy (19/25 patients). Second-line treatments such as administration of mycophenolate mofetil, rituximab, interferon-β, azathioprine, cyclophosphamide, and temozolomide were also reported, followed by good outcomes. The rates of coexisting anti-NMDA receptor encephalitis and MOG antibody-associated encephalomyelitis may be underestimated. Clinical symptoms such as seizures and cognitive decline accompanied by atypical central nervous system demyelination serve as warning signs of possible coexisting anti-NMDA receptor encephalitis and MOG antibody-associated encephalomyelitis. These patients could achieve good outcomes under proper immunotherapies.

Correction of Structural Changes in Thymus by &lt;i&gt;Gentiana algida&lt;/i&gt; Pall Extract at Experimental Azathioprine Immunosuppression

The purpose of the studyis to evaluate the effect ofGentiana algidaPall dry extract on microanatomy of CBA mice thymus at azathioprine immunosuppression.Material and Methods. Experiments were carried out on CBA male mice. Immune deficiency was modeled by intragastrical administration of azathioprine in the dose 50 mg/kg once a day for 5 days. TheG.algidadry extract in the dose 50 mg/kg was administered to animals for 15 days against azathioprine. Morphological studies of the thymus were carried out on day 21 after the azathioprine administration. The area of the thymic lobule, the cortex and the medulla; the width of the cortex; the thickness and length of the medulla; the thickness of the capsule; the density of cells in the subcapsular zone and the deep layers of the cortex were measured using the Axio Vision SE64 Rel.4.8.3 image analysis program. The cellular composition was determined in the subcapsular and central zone of the cortex.Results. TheG.algidaextract limited the development of involutive changes in the thymus caused by cytostatic azathioprine: the cortex area was 16% higher and medulla area 17% lower compared with the control group. The ratio of cortex and medulla in experimental group was 1.4 times higher than that in the control group. TheG.algidaextract increased verage density of cells by 30% in the subcapsular zone. The number of blasts and large lymphocytes increased on average by 2.0 times in the deep layers of the cortex, and in the subcapsular zone - by 4.3 and 2.4 times, respectively, compared with those in control group.Conclusions:G.algidaextract limited the development of pronounced involutive processes in the thymus at azathioprin immunosuppression (increased the mitotic activity of thymocytes, reduced the severity of destructive processes and prevented the growth of adipose tissue).

Azathioprine Hypersensitivity Syndrome in an Asian Woman

Azathioprine Hypersensitivity Syndrome in an Asian Woman

Wound healing in immunocompromised dogs: A comparison between the healing effects of moist exposed burn ointment and honey

Background and Aim:Natural topical products have been used to enhance wound healing, especially in immunocompromised animals. The aims of this study were to evaluate and to compare the effects of moist exposed burn ointment (MEBO) and honey on the healing of full-thickness skin wounds in immunocompromised dogs.Materials and Methods:The study was conducted using 12 adults, apparently healthy mongrel dogs. Immunosuppression was induced in six dogs by oral administration of prednisone (2 mg/kg) and azathioprine (2 mg/kg), once a day for 21 days. On each dog, a total of 9, 1.5 cm in diameter full-thickness skin circular wounds were created aseptically in the thoracolumbar area under general anesthesia using customized skin punch biopsy kit. In a random fashion, three wounds in each dog were treatment using MEBO (contains b-sitosterol, baicalin, and berberine as active ingredients in a base of beeswax and sesame oil), honey or no treatment (control), once per day for 21 days. Wounds were grossly evaluated once a day for signs of inflammation or infection. In addition, biopsy specimens and digital imaging data of each wound were obtained on days 7, 14, and 21 for histopathological evaluation of the healing process.Results:Wounds in immunocompromised dogs appeared to heal significantly in a slower fashion than in non-immunocompromised counterparts. Digital analysis data showed that MEBO-treated wounds expressed better epithelialization area, faster contraction, and smaller wound area percentage when compared with honey-treated wounds. Histopathological analysis showed significantly higher angiogenesis scores in MEBO-treated wounds when compared with other treatments.Conclusion:Results of this study showed that MEBO resulted in significant enhancement of wound healing in both healthy and immunocompromised dogs. However, when compared to honey, the wound healing effect of MEBO was superior to that of honey.

Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis.

Juvenile autoimmune hepatitis (JAIH) is a rare, chronic, inflammatory disease of the liver characterized by a complex interaction between genetic, immunological, and environmental factors leading to loss of immunotolerance to hepatic antigens. It affects both children and adolescents, most commonly females, and its clinical manifestations are quite variable. JAIH is progressive in nature and if left untreated may lead to cirrhosis and terminal liver failure. Although JAIH was first described almost 50 years ago, there have been few significant advances in the clinical management of these patients, both in terms of available diagnostic tools and therapeutic options. Aminotransferase activity, class G immunoglobulins and autoantibodies are the biomarkers used to diagnose AIH and monitor treatment response alongside clinical and histological findings. Despite their utility and cost-effectiveness, these biomarkers are neither an accurate expression of AIH pathogenic mechanism nor a precise measure of treatment response. Current standard of care is mainly based on the administration of steroids and azathioprine. This combination of drugs has been proven effective in inducing remission of disease in the majority of patients dramatically improving their survival; however, it not only fails to restore tolerance to hepatic autoantigens, but it also does not halt disease progression in some patients, it is often needed life-long and finally, it has deleterious side-effects. The ideal therapy should be enough selective to contrast immune-mediated live damage while preserving or potentiating the ability to develop permanent tolerance vs. pathogenic autoantigens. By reviewing the state of the art literature, this article highlights novel diagnostic and therapeutic strategies for managing pediatric AIH with a special focus on new strategies of immunotherapy. These promising tools could improve the diagnostic algorithm, more accurately predict disease prognosis, and provide targeted, individualized treatment.

Application of Economic Evaluation to Assess Feasibility for Reimbursement of Genomic Testing as Part of Personalized Medicine Interventions.

Background: The incorporation of genomic testing into clinical practice constitutes an opportunity to improve patients’ lives, as it makes possible the implementation of innovative, individualized clinical interventions that maximize efficacy and/or minimize the risk of adverse drug reactions. In order to ensure equal access to genomic testing for all patients, the costs associated with these tests should be reimbursed by their respective national healthcare systems. Given that funding for the public health sector is decreasing in real terms, it is of paramount importance that the emerging interventions are thoroughly evaluated both in terms of their clinical effectiveness and their full economic cost. Objective: The aim of this study was to identify those genome-guided interventions that could be adopted and reimbursed by national healthcare systems. Further, we recorded the underlying factors determining the broad adoption of genome-guided interventions in clinical practice, in order to identify potential reimbursement criteria. Methods: We performed a systematic review of published (PubMed-listed) scientific articles on the economic evaluation of those individualized clinical interventions that include genomic tests. Information on genomic tests reimbursed by the US Medicare program was also included. Subsequently, we correlated the regulatory guidance given for the interventions collated in our systematic review with the corresponding economic evaluation results and policies of the Medicare program. Regulatory guidance information was collected from the PharmGKB online knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC). Results: Most of the included studies constitute cost-utility analyses, in which the outcome of the interventions has been measured in quality-adjusted life years (QALYs) whereas an estimate of the total cost has been based upon direct medical cost data. Favorable economic evaluation results, as well as concrete evidence demonstrating the clinical utility of pre-emptive genotyping, are considered as prerequisites for the broad adoption and reimbursement of the costs incurred during genomic testing. Indicatively, pre-emptive HLA-B*5701 and TPMT testing before administration of abacavir and azathioprine, respectively, is reimbursed by Medicare based on both economic and efficacy evidence. Likewise, the medical necessary screening for MMR and BRCA1/2 genes are reimbursed for high-risk populations. Conclusions: Our findings further underline the need for further cost-utility analyses within different national healthcare systems, in order to promote the reimbursement of the cost of innovative genome-guided therapeutic interventions.

Disseminated Exophiala dermatitidis causing septic arthritis and osteomyelitis

BackgroundExophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous or subcutaneous disease. Systemic infections are exceedingly rare and associated with significant morbidity and mortalityCase presentationA 28-year-old female originally from India presented with fevers, chills, weight loss and increasing back pain. She had a recent diffuse maculopapular rash that resulted in skin biopsy and a tentative diagnosis of sarcoidosis, leading to administration of azathioprine and prednisone. An MRI of her spine revealed a large paraspinal abscess requiring surgical intervention and hardware placement. Cultures from the paraspinal abscess grew a colony of dark pigmented mold. Microscopy of the culture revealed a melanized fungus, identified as Exophiala dermatitidis. Voriconazole was initially utilized, but due to relapse of infection involving the right iliac crest and left proximal humerus, she received a prolonged course of amphotericin B and posaconazole in combination and required 7 separate surgical interventions. Prolonged disease stability following discontinuation of therapy was achieved.ConclusionsDescribed is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents.