Application of HLA molecular level mismatching in ethnically diverse kidney transplant recipients receiving a steroid-sparing immunosuppression protocol.

Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across different patient populations are lacking. Using HLA-Matchmaker, HLA-EMMA and PIRCHE-II, this study reports on the association between molecular mismatch (MolMM) and de novo donor-specific antibody (dnDSA) in an ethnically diverse kidney transplant population receiving a steroid-sparing immunosuppression protocol. Of the 419 patients, 51 (12.2%) patients had dnDSA. De novo DSA were seen more frequently with males, primary transplants, patients receiving tacrolimus monotherapy, and unfavorably HLA-matched transplants. There was a strong correlation between MolMM load and antigen mismatch, although significant variation of MolMM load existed at each antigen mismatch. MolMM loads differed significantly by recipient ethnicity, although ethnicity alone was not associated with dnDSA. On multivariate analysis, increasing MolMM loads associated with dnDSA, whereas antigen mismatch did not. De novo DSA against 8 specific epitopes occurred at high frequency; of the 51 patients, 47 (92.1%) patients with dnDSA underwent a pretreatment biopsy, with 21 (44.7%) having evidence of alloimmune injury. MolMM has higher specificity than antigen mismatching at identifying recipients who are at low risk of dnDSA while receiving minimalist immunosuppression. Immunogenicity consideration is important, with more work needed on identification, especially across different ethnic groups.

Patient and health professional views on risk-stratified monitoring of immune-suppressing treatment in adults with inflammatory diseases.

OBJECTIVE: To explore the acceptability of an individualised risk-stratified approach to monitoring for target-organ toxicity in adult patients with immune-mediated inflammatory diseases established on immune-suppressing treatment(s). METHODS: Adults (≥18 years) taking immune-suppressing treatment(s) for at-least six months, and healthcare professionals (HCPs) with experience of either prescribing and/or monitoring immune-suppressing drugs were invited to participate in a single, remote, one-to-one, semi-structured interview. Interviews were conducted by a trained qualitative researcher and explored their views and experiences of current monitoring and acceptability of a proposed risk-stratified monitoring plan. Interviews were transcribed verbatim and inductively analysed using thematic analysis in NVivo. RESULTS: Eighteen patients and 13 HCPs were interviewed. While participants found monitoring of immune-suppressing drugs with frequent blood-tests reassuring, the current frequency of these was considered burdensome by patients and HCPs alike, and to be a superfluous use of healthcare resources. Given abnormalities rarely arose during long-term treatment, most felt that monitoring blood-tests were not needed as often. Patients and HCPs found it acceptable to increase the interval between monitoring blood-tests from three-monthly to six-monthly or annually depending on the patients' risk profiles. Conditions of accepting such a change included: allowing for clinician and patient autonomy in determining an individuals' frequency of monitoring blood-tests, the flexibility to change monitoring frequency if someone's risk profile changed, and endorsement from specialist societies and healthcare providers such as the National Health Service. CONCLUSION: A risk-stratified approach to monitoring was acceptable to patients and HCPs. Guideline groups should consider these findings when recommending blood-test monitoring intervals.

Topical Prescription Management.

With recent advances in topical therapies for atopic dermatitis (AD), steroid-sparing options like calcineurin inhibitors, Janus kinase (JAK) inhibitors, and phosphodiesterase-4 (PDE-4) inhibitors are becoming mainstays in therapy, underscoring the importance of careful selection and usage of topical corticosteroids (TCSs) to minimize side effects. Alongside the necessity of emollient use, these steroid-sparing alternatives offer rapid itch relief and efficacy in improving disease severity. While TCSs still hold a prominent role in AD management, promising novel topical treatments like tapinarof and live biotherapeutics to modulate the skin microbiome are also discussed. Overall, the recent addition of novel topical therapies offers diverse options for AD management and underscores the importance of topical treatments in the management of AD.

Effect of clarithromycin in a case of infantile bullous pemphigoid.

Although rare, cases of infantile or childhood bullous pemphigoid are increasingly being reported in the literature. Treatment challenges, which are amplified in infancy, necessitate balancing efficacy and avoiding long-term risks. In this report, clarithromycin was successfully used to establish and maintain disease remission, offering insights into its immunomodulatory effects, making it a compelling steroid-sparing choice with a favorable side effect profile.

Effectiveness of Palonosetron, 1-Day Dexamethasone, and Aprepitant in Patients Undergoing Carboplatin-Based Chemotherapy.

INTRODUCTION: Dexamethasone (DEX)-sparing strategy with 5-hydroxytryptamine-3 receptor antagonist (5HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, is associated with poor control of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin (CBDCA)-based chemotherapy. This study aimed to evaluate whether using palonosetron (PALO) as a 5HT3RA provides superior control with CINV than first-generation (1st) 5HT3RA in triplet antiemetic prophylaxis with a DEX-sparing strategy. METHODS: Pooled patient-level data from a nationwide, multicenter, and prospective observational study were analyzed to compare the incidence of CINV between patients administered PALO and 1st 5HT3RA in combination with 1-day DEX and APR. RESULTS: No significant differences were observed in the incidence of CINV, pattern of CINV, or severity of nausea by type of 5HT3RA in triplet antiemetic prophylaxis with DEX-sparing strategy. In both groups, the incidence of nausea gradually increased from day 3, peaked on day 4 or 5, and then declined slowly. The visual analog scale scores in the delayed phase remained high throughout the 7-day observation period. CONCLUSION: Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV.

Steroid Sparing Maintenance Immunosuppression in Highly Sensitised Patients Receiving Alemtuzumab Induction.

This analysis reports on the outcomes of two different steroid sparing immunosuppression protocols used in the management of 120 highly sensitised patients (HSPs) with cRF>85% receiving Alemtuzumab induction, 53 maintained on tacrolimus (FK) monotherapy and 67 tacrolimus plus mycophenolate mofetil (FK + MMF). There was no difference in the median cRF or mode of sensitisation between the two groups, although the FK + MMF cohort received more poorly matched grafts. There was no difference in one-year patient or allograft survival, however rejection free survival was inferior with FK monotherapy compared with FK + MMF at 65.4% and 91.4% respectively, p < 0.01. DSA-free survival was comparable. Whilst there was no difference in rates of BK between the cohorts, CMV-free survival was inferior in the FK + MMF group at 86.0% compared with 98.1% in the FK group, p = 0.026. One-year post-transplant diabetes free survival was 89.6% and 100.0% in the FK and FK + MMF group respectively, p = 0.027, the difference attributed to the use of prednisolone to treat rejection in the FK cohort, p = 0.006. We report good outcomes in HSPs utilising a steroid sparing protocol with Alemtuzumab induction and FK + MMF maintenance and provide granular data on immunological and infectious complications to inform steroid avoidance in these patient groups.

Immunotherapy for keratinocyte cancers. Part II: Identification and management of cutaneous side effects of immunotherapy treatments.

Keratinocytic cancers (KCs), specifically cutaneous squamous cell and basal cell carcinomas, can respond to topical, intralesional, or systemic immunotherapies, but cutaneous adverse events (CAEs) may occur. Understanding these risks, early recognition of these CAEs, and effective treatment may enable patients to continue their anticancer immunotherapies without dose impact. Immune checkpoint inhibitor-related CAEs after KCs can have multiple clinical presentations, with specific observed types including psoriasis and bullous pemphigoid. Cutaneous toxicities can require biopsies to confirm the diagnosis, especially in patients who are not responsive to topical or oral steroids, since the selection of biologic drugs depends on accurate diagnosis. Different types of CAEs from immune checkpoint inhibitors have been associated with different oncologic outcomes in various primary cancer types, and this remains to be determined for KC patients. CAE characterization and management after immune checkpoint inhibitors in KC patients is a rapidly growing field that needs specific and prospective studies.

Therapeutic trials in difficult to treat steroid sensitive nephrotic syndrome: challenges and future directions.

Steroid sensitive nephrotic syndrome is a common condition in pediatric nephrology, and most children have excellent outcomes. Yet, 50% of children will require steroid-sparing agents due to frequently relapsing disease and may suffer consequences from steroid dependence or use of steroid-sparing agents. Several steroid-sparing therapeutic agents are available with few high quality randomized controlled trials to compare efficacy leading to reliance on observational data for clinical guidance. Reported trials focus on short-term outcomes such as time to first relapse, relapse rates up to 1-2 years of follow-up, and few have studied long-term remission. Trial designs often do not consider inter-individual variability, and differing response to treatments may occur due to heterogeneity in pathogenic mechanisms, and genetic and environmental influences. Strategies are proposed to improve the quantity and quality of trials in steroid sensitive nephrotic syndrome with integration of biomarkers, novel trial designs, and standardized outcomes, especially for long-term remission. Collaborative efforts among international trial networks will help move us toward a shared goal of finding a cure for children with nephrotic syndrome.

Outcomes of adalimumab therapy in refractory punctate inner choroidopathy and multifocal choroiditis.

PURPOSE: This study aims to evaluate the outcomes of adalimumab (ADA) therapy in patients with refractory punctate inner choroidopathy (PIC) and multifocal choroiditis (MFC). METHODS: Demographic and clinical data, including LogMAR best-corrected visual acuity (BCVA), were retrospectively collected. Doses of prednisone, immunomodulatory therapies (IMT), and anti-vascular endothelial growth factor (VEGF) injections before and after baseline (ADA initiation) were recorded, as well as the time to clinical remission, time to first flare, and drug-associated adverse events. RESULTS: Seven patients (4 females, ten eyes) were included. The mean follow-up after baseline was 17.8 ± 11.1 months (range 6-33). The mean LogMAR BCVA was 0.35 ± 0.77 at 6 months before baseline and remained stable throughout 12 months after baseline (0.31 ± 0.46 at 12 months; p = 0.47). The mean dose of prednisone decreased from 17.3 ± 19.6 mg/day 6 months before baseline (range 0-60) to 2.6 ± 2.4 mg/day at the last follow-up (range 0-6, p = 0.03). The mean number of flares decreased significantly from 1.43 ± 0.79 over a 6-month period before baseline to 0.2 ± 0.45 (p = 0.02) at 6-12 months after baseline. The mean number of anti-VEGF injections was 4.17 ± 3.92 over the 12-month period before baseline, and it was 2.17 ± 3.06 (p = 0.31) during the first 12 months after baseline. No adalimumab-related adverse events were noted. CONCLUSION: Adalimumab therapy for refractory PIC/MFC enabled a significant steroid-sparing effect, decreased disease flares, and preserved vision over a mean follow-up of 17.8 months.

Network meta-analysis-based comparison of first-line steroid-sparing adjuvants in the treatment of pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND: Steroid-sparing adjuvants may enhance oral glucocorticoid benefits in pemphigus treatment. Selecting the optimal therapeutic option among various first-line steroid-sparing adjuvants is often a clinical challenge due to the lack of head-to-head clinical trials. OBJECTIVE: To determine the best first-line steroid-sparing adjuvants for pemphigus treatment. METHODS: Randomized controlled trials comparing different steroid-sparing adjuvants in patients with pemphigus were identified through a systematic literature search and subjected to a network meta-analysis. The primary outcomes were the proportion of remission and the mean cumulative glucocorticoid dose. RESULTS: Ten trials involving 592 patients were analyzed. Among the 7 steroid-sparing adjuvants evaluated, rituximab was the most effective for achieving remission and was more effective than steroid alone (odds ratio, 14.35; 95% confidence interval [CI], 4.71-43.68). Rituximab, azathioprine, and cyclophosphamide pulse therapy enabled the reduction of the cumulative glucocorticoid doses compared to the use of steroid alone: mean differences, -11,830.5 mg (95% CI, -14,089.48 to -9571.52), -3032.48 mg (-4700.74 to -1364.22), and -2469.54 mg (-4128.42 to -810.66), respectively. LIMITATIONS: The results were driven primarily by a small number of studies, and the effect estimates are imprecise because of indirect comparisons. CONCLUSION: Network meta-analysis showed that rituximab appears to be an efficacious, well tolerated steroid-sparing adjuvant for pemphigus.

Impact of steroids and steroid-sparing agents on quality of life in children with nephrotic syndrome.

BACKGROUND: Steroids and/or steroid-sparing medications are commonly used for nephrotic syndrome treatment; however, the impact of these medications on health-related quality of life over time is not well described. METHODS: Longitudinal cohort is up to 5 years where children were assessed with baseline and annual Pediatric Quality of Life Inventory questionnaire. A mixed-effects linear regression determined differences in scores among children receiving steroids and/or steroid-sparing agents for at least 30 days compared with those not on medication at 1, 3, 6, and 12 months prior to assessment. RESULTS: Among 295 children, 64% were male, with a median age of 3.7 (interquartile range [IQR], 2.7, 5.9) years at diagnosis, and comprised 25% Europeans, 40% South Asians, and 8% East/Southeast Asians. Adjusted HRQOL scores were reduced among children taking steroids and steroid-sparing agents among 705 HRQOL measures (median 2 [IQR, 1, 3] per child). Compared to children without medication, steroid and steroid-sparing agent use up to 12 months prior to assessment were associated with an overall HRQOL drop of 3.17 (95% confidence interval [CI], - 5.25, - 1.08) and 3.18 (95% CI, - 5.24, - 1.12), respectively, after adjustment. Functioning domain scores were reduced by 4.41 points (95% CI, - 6.57, - 2.25) in children on steroids, whereas fatigue domain scores were reduced by 5.47 points (95% CI, - 9.28, - 1.67) in children on steroid-sparing agents after adjustment. CONCLUSIONS: HRQOL is consistently decreased in children receiving steroids and steroid-sparing agents, with differential effects on functioning and fatigue. Counseling families on possible effects of prolonged treatment periods is important in the management of childhood nephrotic syndrome.

Efficacy of one-day versus multiple-day dexamethasone for chemotherapy-induced nausea and vomiting in lung cancer patients receiving carboplatin-based chemotherapy: a propensity score-matched analysis.

PURPOSE: Dexamethasone (DEX)-sparing strategies (one-day DEX) with palonosetron as doublet antiemetic prophylaxis have previously been studied. However, DEX-sparing regimens with 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, have not been evaluated. This study aimed to evaluate the efficacy of a combination of 5-HT3RA, APR, and DEX on day 1 of carboplatin (CBDCA)-based chemotherapy in patients with lung cancer. METHODS: Data were pooled from a nationwide, multicenter, prospective observational study using propensity score-matched analysis to compare the incidence of chemotherapy-induced nausea and vomiting (CINV) between one- and multiple-day DEX regimens in combination with 5-HT3RA plus APR. RESULTS: Incidence of delayed nausea was significantly higher in the one-day than in the multiple-day DEX group. Incidence of nausea was also significantly higher in the one-day than in the multiple-day DEX group on days 3-5. Kaplan-Meier curves for nausea showed a significant difference between the two groups; however, there was no significant difference in the occurrence of vomiting or the Kaplan-Meier curves of time to vomiting. CONCLUSION: To the best of our knowledge, this study is the first to evaluate the efficacy of a DEX-sparing regimen by comparing one- and multiple-day DEX combined with 5-HT3RA and APR concerning CINV incidence in lung cancer patients receiving CBDCA-based chemotherapy. Antiemetic regimens of one-day DEX result in poor control of delayed nausea; therefore, we recommend the application of the DEX-sparing strategy only after careful patient selection while considering the development of nausea.

Diagnosis and management of giant cell arteritis: Major review.

Giant cell arteritis is a medical emergency because of the high risk of irreversible blindness and cerebrovascular accidents. While elevated inflammatory markers, temporal artery biopsy and modern imaging modalities are useful diagnostic aids, thorough history taking and clinical acumen still remain key elements in establishing a timely diagnosis. Glucocorticoids are the cornerstone of treatment but are associated with high relapse rates and side effects. Targeted biologic agents may open up new treatment approaches in the future.

SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma.

BACKGROUND: Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study. METHODS: SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes. CONCLUSIONS: SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose. TRIAL REGISTRATION: NCT03406078 ( ClinicalTrials.gov ). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078.

Evaluation of belimumab treatment in patients with systemic lupus erythematosus in a clinical practice setting: Results from a 24-month OBSErve study in Argentina.

OBJECTIVE: To describe clinical effectiveness of belimumab for systemic lupus erythematosus (SLE) in real-world practice in Argentina. METHODS: This retrospective, observational study analysed medical record data of patients with SLE treated with belimumab in 15 centres in Argentina. Primary endpoint: overall clinical response (assessed on a scale similar to the 6-point Physician Global Assessment) at months 6, 12, 18 and 24, all versus index (belimumab initiation). Secondary endpoints: improvement in disease activity (SELENA-SLEDAI), SLE manifestations, and corticosteroid dose change. RESULTS: Records for 81 patients (91% female) were analysed. Clinical improvements were reported for 95%, 95%, 98% and 100% patients at 6, 12, 18, and 24 months post index, respectively. Mean SELENA-SLEDAI score decreased from 11.21 at index to 4.76, 3.77, 3.86 and 2.17 at 6, 12, 18, and 24 months post index, respectively. Number of flares decreased from 1.05 at index to 0.21, 0.09, 0.22 and 0.30 at 6, 12, 18, and 24 months post index, respectively. Mean corticosteroid dose was 14.59 mg/day at index, and 6.45, 5.18, 5.17 and 4.78 mg/day at 6, 12, 18, and 24 months post index, respectively. CONCLUSIONS: Real-world patients with SLE treated with belimumab in Argentina demonstrated clinical improvements and reductions in corticosteroid dose.

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents.

In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

Relapsing polychondritis in children: A review.

Relapsing polychondritis (RP) is a rare auto-immune disease that causes progressive destruction of cartilaginous structures. Most cases of pediatric-onset RP were published as a single case report or hand-full case series although the prevalence of RP is unknown. This review aimed to describe the characteristics of pediatric-onset RP in order to provide a comparison between childhood and adulthood features of the disease and to review the experiences of biological agents used in children with RP. In children, the diagnosis of RP is either delayed or overlooked due to low incidence and variability in clinical features. Treatment of RP is challenging due to the recurrent episodic nature of the disease. Different immunosuppressive medications, including steroid and steroid-sparing disease-modifying antirheumatic drugs (DMARDs), such as methotrexate or azathioprine, are used to treat RP. There is no rigorous clinical research to support the use of new therapeutic modalities, including biological agents. It is challenging to protocolize the treatment of pediatric-onset RP due to the rarity of the disease. Corticosteroids are the primary form of therapy. However, DMARDs and biological agents may have a role in treating patients with sustained or refractory disease.

Efficacy and safety of pulsed intravenous methylprednisolone in early active thyroid eye disease.

Introduction: The mainstay of therapy for active inflammatory phase of thyroid eye disease (TED) is immunosuppression. Patients in our centre with early active TED are treated with pulsed intravenous methylprednisolone (IVMP). Two different protocols are offered in our centre: High dose (1g/day for 3 days, monthly for 6 months), or EUGOGO protocol (500 mg weekly for six weeks, followed by 250 mg weekly for the next 6 weeks). Methods: A prospective cohort study of patients undergoing the two IVMP protocols was performed from January 2009 to May 2015. Main outcome measures were improvement of Clinical Activity Score (CAS) and International Thyroid Eye Disease (ITEDS) - VISA Inflammatory Index. Results: We had a total of 63 patients. Mean age was 43.1 ± 13.1years, females comprised 49.2% (n = 31), and 31 (49.2%) had a positive smoking history. Following IVMP, 65.0% (n = 41) had good response, 31.7% (n = 20) partial, and 3.3% (n = 2) poor. There were significant differences (p < 0.001) in CAS and ITEDS scores between pre-IVMP and post-IVMP visits, for both protocols. A higher proportion of patients receiving the modified EUGOGO protocol (58.3%) had persistent activity and required additional immunosuppression compared to those who underwent the high dose protocol (33.3%). Mild side effects were experienced by 5 (7.9%) and 3 (4.8%) patients at 3 and 6 months, respectively. There were no severe side effects, cardiovascular events or liver failure. Conclusion: With adequate screening and follow-up, six repeated cycles of high dose pulsed IVMP is an effective treatment for TED and can significantly reduce the morbidity associated with this debilitating condition. None of the 51 patients from the high dose protocol met with any serious side effects.