Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.

Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.

Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys.

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFß and fibrosis pathways in muscle.

Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy.

Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax ), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50  = 186 ng·h/mL), followed by time to climb 4 stairs (E50  = 478 ng·h/mL), time to run/walk 10 m (E50  = 1220 ng·h/mL), and 6-minute walk test (E50  = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/ß2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.

Lung Delivery of Indacaterol and Mometasone Furoate Following Inhalation of QMF149 in Healthy Volunteers.

This single-dose, 4-period crossover study evaluated the pharmacokinetics (PK) of the ß2 -agonist indacaterol maleate and the corticosteroid mometasone furoate (MF) after inhalation of a fixed-dose combination (QMF149, indacaterol maleate/MF, 500/400 µg) via the Twisthaler (TH) device with and without activated charcoal and postdose mouth rinsing in healthy volunteers. The PK of indacaterol maleate 300 µg inhaled via the Breezhaler (BRZ) device was also characterized. Relative bioavailability of indacaterol and MF for inhalation with versus without charcoal, based on AUClast, was 0.25 (90% confidence interval [CI], 0.18-0.35) and 0.70 (90%CI, 0.52-0.93), respectively. Thus, 25% and 70% of systemic exposure of indacaterol and MF, respectively was due to pulmonary absorption and 75% and 30%, respectively, was due to gastrointestinal absorption. Mouth rinsing reduced the systemic exposure of indacaterol by approximately 35% but had no relevant effect on the exposure of MF. Dose-normalized AUClast for indacaterol inhaled via the BRZ device was 2.3-fold higher than QMF149 via the TH device. All treatments had a good safety profile and were well tolerated. Data from this study and comparison with inhalation of indacaterol via the BRZ device suggest that the latter was more efficient than the TH device regarding lung delivery of indacaterol.

A novel dissociative steroid VBP15 reduces MUC5AC gene expression in airway epithelial cells but lacks the GRE mediated transcriptional properties of dexamethasone.

Overproduction of secretory mucins contributes to morbidity/mortality in inflammatory lung diseases. Inflammatory mediators directly increase expression of mucin genes, but few drugs have been shown to directly repress mucin gene expression. IL-1ß upregulates the MUC5AC mucin gene in part via the transcription factors NFκB while the glucocorticoid Dexamethasone (Dex) transcriptionally represses MUC5AC expression by Dex-activated GR binding to two GRE cis-sites in the MUC5AC promoter in lung epithelial cells. VBP compounds (ReveraGen BioPharma) maintain anti-inflammatory activity through inhibition of NFκB but exhibit reduced GRE-mediated transcriptional properties associated with adverse side-effects and thus have potential to minimize harmful side effects of long-term steroid therapy in inflammatory lung diseases. We investigated VBP15 efficacy as an anti-mucin agent in two types of airway epithelial cells and analyzed the transcription factor activity and promoter binding associated with VBP15-induced MUC5AC repression. VBP15 reduced MUC5AC mRNA abundance in a dose- and time-dependent manner similar to Dex in the presence or absence of IL-1ß in A549 and differentiated human bronchial epithelial cells. Repression was abrogated in the presence of RU486, demonstrating a requirement for GR in the VBP15-induced repression of MUC5AC. Inhibition of NFκB activity resulted in reduced baseline expression of MUC5AC indicating that constitutive activity maintains MUC5AC production. Chromatin immunoprecipitation analysis demonstrated lack of GR and of p65 (NFκB) binding to composite GRE domains in the MUC5AC promoter following VBP15 exposure of cells, in contrast to Dex. These data demonstrate that VBP15 is a novel anti-mucin agent that mediates the reduction of MUC5AC gene expression differently than the classical glucocorticoid, Dex.

Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects.

PURPOSE: QMF149 is a fixed-dose combination of the long-acting ß2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler(®) device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. METHODS: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 µg, mometasone furoate 320 µg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 µg/mometasone furoate 320 µg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. RESULTS: Indacaterol AUC0-24h,ss and Cmax,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC0-24h,ss and Cmax,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC0-24h,ss and Cmax,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for Cmax,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. CONCLUSIONS: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC0-24h,ss and Cmax,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.

Effect of Nasal Corticosteroid on Secretory Immunoglobulin A Measured in Rat Nasal Lavage: Experimental Study.

OBJECTIVE: In this study, we aimed to experimentally investigate the effects of nasal corticosteroids on the levels of secretory immunoglobulin A (sIgA) in nasal mucosa in rats. STUDY DESIGN: Prospective, randomized control trial. SETTING: Research laboratory. SUBJECT AND METHODS: Twenty-four male Sprague Dawley rats were included in our study. The rats were randomized into 3 groups. In group 1, nasal mometasone furoate was applied to the rats for 30 days. Saline was applied to group 2 for 30 days. Group 3 was the control group and received no treatment throughout the study period. Nasal lavage was conducted on both nasal openings of all rats in the 3 groups at the beginning of the study and on days 15 and 30, and the lavage solution (distilled water) was collected by aspiration. RESULTS: In group 1, the sIgA value was significantly higher at day 15 than at baseline. No significant difference was found between the sIgA values on day 15 and day 30. In groups 2 and 3, there were no significant differences in sIgA values at baseline, day 15, and day 30. The sIgA value of group 1 on day 15 was significantly higher than the values of groups 2 and 3. The sIgA value of group 1 on day 30 was significantly higher than the values of groups 2 and 3. CONCLUSION: Topical corticosteroids (mometasone furoate) applied to the nasal mucosa significantly increase nasal sIgA levels.

Pharmacokinetics of QMF149 in Japanese versus Caucasian subjects: an open-label, randomized phase I study.

OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting ß2-agonist, indacaterol (Onbrez® Breezhaler® for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex® Twisthaler® for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 µg and 150/320 µg via the Breezhaler® device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 µg or 150/320 µg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 - 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations.

Regional deposition of mometasone furoate nasal spray suspension in humans.

Nasal deposition studies can demonstrate whether nasal sprays treating allergic rhinitis and polyposis reach the ciliated posterior nasal cavity, where turbinate inflammation and other pathology occurs. However, quantifying nasal deposition is challenging, because in vitro tests do not correlate to human nasal deposition; gamma scintigraphy studies are thus used. For valid data, the radiolabel must distribute, as the drug, into different-sized droplets, remain associated with the drug in the formulation after administration, and not alter its deposition. Some nasal deposition studies have demonstrated this using homogenous solutions. However, most commercial nasal sprays are heterogeneous suspensions. Using mometasone furoate nasal suspension (MFS), we developed a technique to validate radiolabel deposition as a surrogate for nasal cavity drug deposition and characterized regional deposition and nasal clearance in humans. Mometasone furoate (MF) formulation was spiked with diethylene triamine pentacaetic acid. Both unlabeled and radiolabeled formulations (n = 3) were sprayed into a regionally divided nasal cast. Drug deposition was quantified by high pressure liquid chromatography within each region; radiolabel deposition was determined by gamma camera. Healthy subjects (n = 12) were dosed and imaged for six hours. Scintigraphic images were coregistered with magnetic resonance imaging scans to quantify anterior and posterior nasal cavity deposition and mucociliary clearance. The ratio of radiolabel to unlabeled drug was 1.05 in the nasal cast and regionally appeared to match, indicating that in vivo radiolabel deposition could represent drug deposition. In humans, MFS delivered 86% (9.2) of metered dose to the nasal cavity, approximately 60% (9.1) of metered dose to the posterior nasal cavity. After 15 minutes, mucociliary clearance removed 59% of the initial radiolabel in the nasal cavity, consistent with clearance rates from the ciliated posterior surface. MFS deposited significant drug into the posterior nasal cavity. Both nasal cast validation and mucociliary clearance confirm the radiolabel deposition distribution method accurately represented corticosteroid nasal deposition.

Does atopy influence the effectiveness of treatment of adenoid hypertrophy with mometasone furoate?

BACKGROUND: The effect of topical mometasone for adenoid hypertrophy treatment is well established. Nevertheless, the influence of atopy on this treatment remains ill defined. OBJECTIVE: This study aims to compare the effects of topical mometasone furoate treatment on the adenoid tissue between atopic and nonatopic children. METHODS: Fifty-one children with obstructive respiratory complaints underwent a semistructured clinical questionnaire on nasal symptoms, prick test, and nasoendoscopy. Nasoendoscopic images were digitalized, and both adenoid and nasopharyngeal areas were measured in pixels; the relative adenoid/nasopharyngeal area was calculated. Patients were initially treated for 40 days with nasal saline solution. In a subsequent 40-day period, topical mometasone furoate (total dose, 100 µg/day) was used. RESULTS: Topical mometasone significantly improved nasal obstruction, snoring, and apnea and also significantly reduced the adenoid tissue area related to the nasopharynx (p < 0.0001). Treatment with this glucocorticoid was not influenced by atopy, neither for symptoms nor for adenoid area. CONCLUSION: Topical mometasone furoate significantly reduced the adenoid tissue area and led to a supplementary improvement of nasal symptoms. This improvement was similar for atopic and nonatopic patients.

Comparing the efficacy and safety of salmeterol/fluticasone pMDI versus its mono-components, other LABA/ICS pMDIs and salmeterol/fluticasone Diskus in patients with asthma.

INTRODUCTION: Pressurized metered dose inhalers (pMDIs) are evolving to be a very effective drug delivery option in patients with airway diseases. They offer comparable lung deposition and reduced oropharyngeal deposition similar with the dry powder inhalers. As recommended by the Global Initiative for Asthma guidelines, the ideal maintenance treatment for asthma is a combination of long acting ß2-agonists (LABAs) and inhaled corticosteroids (ICSs). One of the available LABA/ICS combinations is the salmeterol/fluticasone propionate combination (SFC) and a plethora of evidence supports its clinical efficacy and safety. AREAS COVERED: This article focuses on the SFC hydrofluroalkane pMDI and compares the efficacy and tolerability with salmeterol and fluticasone given individually, and with other fixed-dose combinations namely formoterol/fluticasone, formoterol/beclometasone and formoterol/mometasone furoate, all delivered via pMDI. Also discussed is the efficacy and tolerability of the SFC delivered via a pMDI, as compared to the SFC via Diskus. EXPERT OPINION: pMDIs play an important role in inhalation therapy given the low price, low maintenance and convenience of use. LABA/ICS combinations are the preferred choice of medication for asthma treatment and will remain the mainstay for the decades to come. In our opinion, pMDI should be the choice of device to administer LABA/ICS maintenance therapy, as it is already being used by the patients for reliever therapy, which may eventually improve patient adherence and compliance.

The influence of mometasone furoate ear solution on intradermal test immediate reactions in dogs with atopic dermatitis.

BACKGROUND: Topical ear medications, often containing a glucocorticoid, are used to treat the clinical signs of atopic otitis in dogs. Studies have looked at the inhibitory effect of topical glucocorticoids on intradermal testing (IDT), but only one previously published study evaluated the influence of an otic glucocorticoid on the results of IDT in dogs. HYPOTHESIS/OBJECTIVES: To assess what influence the absorption of the diester glucocorticoid mometasone furoate (MF) had on intradermal test immediate reactions, to determine an appropriate withdrawal time prior to IDT. METHODS: Twenty atopic dogs were enrolled. On day 0, histamine, rabbit anticanine IgE antiserum and saline were injected intradermally. After 20 min, a global wheal score (GWS) was determined. The otic medication, MF, was applied once daily for 14 days. Intradermal injections were then repeated and, if the GWS was within 25% of pretreatment values, the study was completed for this dog. If the GWS had decreased by ≥25% from the baseline value, the otic medication was withdrawn, and the GWS was repeated every 7 days until its value was within 25% of the original GWS. RESULTS: Three of the 20 dogs completed the study on day 14, while 17 of 20 dogs ended it on day 21, 7 days after withdrawal of the drug, MF. CONCLUSIONS AND CLINICAL IMPORTANCE: Results from this study show that a withdrawal period of ≤7 days is possible before performing IDT in atopic dogs with active otitis externa treated with ≤14 days of MF.

Role of mometasone furoate aqueous nasal spray for management of adenoidal hypertrophy in children.

OBJECTIVES: To study the role of mometasone furoate aqueous nasal spray for the management of adenoidal hypertrophy in children with more than 50 per cent obstruction, and to assess its impact on change in quality of life. METHODS: A prospective, randomised, double-blind, interventional placebo-controlled study was conducted. A total of 100 children aged 2-12 years completed treatment and follow up. The symptoms and degree of obstruction were evaluated by nasopharyngoscopy conducted pre-treatment and 24 weeks post-treatment. Subjects received mometasone furoate nasal spray at a daily dose of 200 µg for 8 weeks, followed by a dose of 200 µg on alternate days for 16 weeks. RESULTS were compared with those of a matched control group who were given saline nasal spray. RESULTS: With mometasone treatment, there was an 89.8 per cent reduction in clinical symptom score, and the degree of obstruction dropped from 87 to 72 per cent (p < 0.0001). A statistically significant change in quality of life scores was seen in patients treated with the mometasone nasal spray (score change of 37.47) as compared with those given saline nasal spray (score change of 11.25) (p = 0.0001). CONCLUSION: Mometasone nasal spray appears to be effective in treating children with obstructive adenoids.

RESOLVE: a randomized, controlled, blinded study of bioabsorbable steroid-eluting sinus implants for in-office treatment of recurrent sinonasal polyposis.

BACKGROUND: Patients with recurrent sinonasal polyposis after endoscopic sinus surgery (ESS) have limited treatment options. This study evaluated the safety and efficacy of a bioabsorbable steroid-eluting implant with 1350 µg of mometasone furoate for its ability to dilate obstructed ethmoid sinuses, reduce polyposis, and reestablish sinus patency. METHODS: This was a randomized, controlled, blinded study including 100 patients chronic rhinosinusitis with nasal polyposis (CRSwNP) refractory to medical therapy and considered candidates for revision ESS. Follow-up included endoscopic grading by investigators and patient-reported outcomes. RESULTS: Treated patients (n = 53; age as mean ± standard deviation [SD] 47.8 ± 12.6 years; 55% male) underwent in-office bilateral placement. Control patients (n = 47; age 51.6 ± 13.1 years; 66% male) underwent a sham procedure. At 3 months, treated patients experienced a significant reduction in bilateral polyp grade (p = 0.0269) and ethmoid sinus obstruction (p = 0.0001) compared to controls. Treated patients also experienced a 2-fold improvement in the mean nasal obstruction/congestion score (-1.33 ± 1.47 vs -0.67 ± 1.45; p = 0.1365). This improvement reached statistical significance (p = 0.025) in patients with greater polyp burden (grade ≥2 bilaterally; n = 74). At 3 months, 53% of treated patients compared to only 23% of controls were no longer indicated for repeat ESS. There was no serious adverse event or clinically significant increases in intraocular pressure or cataract formation. CONCLUSION: The symptomatic improvement and statistically significant reduction in polyp grade and ethmoid sinus obstruction supported the efficacy of the steroid-eluting implant for in-office treatment of CRS patient with recurrent polyposis after ESS. The study results demonstrated that the steroid-eluting implant represents a safe and effective alternative to current management for this patient population.

Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study.

BACKGROUND: Long-term use of systemic glucocorticoid therapy has been associated with hypothalamic-pituitary-adrenal axis suppression and other systemic adverse events. This pharmacokinetic study evaluated the systemic safety and performance of a bioabsorbable sinus implant that gradually releases 1350 µg of mometasone furoate directly to the sinus mucosa. METHODS: A prospective, single-center study treating 5 adult patients with recurrent polyposis after bilateral total ethmoidectomy. Each patient received 2 steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day follow-up, which also included endoscopic grading and patient-reported outcomes. RESULTS: Five patients (mean age 46.2 ± 9.2 standard deviation [SD] years; 60% male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30 pg/mL). Cortisol concentrations at follow-up ranged from 3.9 to 5.7 mg/dL compared to 4.7 mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and 22-item Sino-Nasal Outcome Test (SNOT-22) (p = 0.010) compared to baseline. CONCLUSION: The reported 100% placement success, negligible systemic exposure to mometasone furoate released over time, lack of adrenal suppression, and the absence of serious adverse events suggest that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. Randomized, controlled, blinded clinical studies are underway to provide further evidence of safety and efficacy.

Healing of granulomatous skin changes in ataxia-telangiectasia after treatment with intravenous immunoglobulin and topical mometasone 0.1% ointment.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by faulty DNA damage repair. The disease affects multiple systems and is noted to be particularly difficult to diagnose in children because of the wide spectrum of clinical presentations. We present an unusual case of a child in whom the primary cutaneous manifestation of AT was noninfectious cutaneous caseating granulomas. A 3-year-old girl presented to the emergency department with ataxia, poor growth, and multiple ulcerated plaques on both upper extremities that had been present for 2 years. She had two prolonged hospitalizations and underwent extensive examination to identify an etiology for the skin lesions. She was diagnosed with AT after immunology examinaton and genetic testing. Outpatient intravenous immunoglobulin (IVIG) therapy was initiated and she was prescribed twice-daily mometasone 0.01% ointment under occlusion. After 6 weeks on this regimen her lesions had completely healed. Twenty-two cases of AT have been reported in which patients presented with cutaneous granulomas. This report demonstrates the first reported case in which the granulomatous skin lesions of AT healed after aggressive application of topical steroids with concurrent IVIG therapy, without oral steroids. A brief review of cutaneous granulomas in the setting of immunodeficiency is also presented.