Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC).

BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).

A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease.

X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection and N-linked glycosylation defect (XMEN) disease is an inborn error of immunity caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. The original studies of XMEN patients focused on impaired magnesium regulation, leading to decreased EBV-cytotoxicity and the loss of surface expression of the activating receptor "natural killer group 2D" (NKG2D) on CD8+ T cells and NK cells. In vitro studies showed that supraphysiological supplementation of magnesium rescued these defects. Observational studies in 2 patients suggested oral magnesium supplementation could decrease EBV viremia. Hence, we performed a randomized, double-blind, placebo-controlled, crossover study in 2 parts. In part 1, patients received either oral magnesium L-threonate (MLT) or placebo for 12 weeks followed by 12 weeks of the other treatment. Part 2 began with 3 days of high-dose intravenous (IV) magnesium sulfate (MgSO4) followed by open-label MLT for 24 weeks. One EBV-infected and 3 EBV-naïve patients completed part 1. One EBV-naïve patient was removed from part 2 of the study due to asymptomatic elevation of liver enzymes during IV MgSO4. No change in EBV or NKG2D status was observed. In vitro magnesium supplementation experiments in cells from 14 XMEN patients failed to significantly rescue NKG2D expression and the clinical trial was stopped. Although small, this study indicates magnesium supplementation is unlikely to be an effective therapeutic option in XMEN disease.

Multifocal calcific periarthritis with distinctive clinical and radiological features in patients with CD73 deficiency.

OBJECTIVES: Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the ecto-5'-nucleotidase gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and SF crystals has not been systematically investigated. METHODS: Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin Red staining for synovial fluid along with X-ray diffraction and X-ray micro tomosynthesis scanner for periarticular calcification. RESULTS: Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with, eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate and calcium hydroxyapatite (CHA) crystals in SF specimens and determined that CHA crystals are the principal component of periarticular calcifications. CONCLUSION: This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and SF crystals. ACDC should be considered among the genetic causes of early-onset OA, as musculoskeletal disease signs may often precede vascular symptoms.

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.

BACKGROUND: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Catecholamine-Induced Cardiomyopathy in Pheochromocytoma: How to Manage a Rare Complication in a Rare Disease?

Pheochromocytomas and paragangliomas (PHEOs) are rare neuroendocrine tumors. Clinical manifestations include different cardiovascular signs and symptoms, which are related to excessive secretion of catecholamines. Catecholamine-induced cardiomyopathy in PHEO (CICMPP) is a rare but dreaded complication of PHEO. Once patient is diagnosed with this condition, the prognosis is worse and a surgical risk is much higher than expected. This article focuses on how catecholamines affect the heart and the pathophysiologic mechanism of CICMPP. The cardiovascular responses to catecholamine depend mostly on which catecholamine is released as well as the amount of catecholamine that is released. The acute release of norepinephrine and epinephrine from PHEO increases heart rate, systemic vascular resistance, myocardial contractility, and reduces venous compliance. The excessive adrenergic stimulation by catecholamine results in severe vasoconstriction and coronary vasospasm, myocardial ischemia, and subsequently damage, and necrosis. Chronically elevated catecholamine levels lead to significant desensitization of cardiac ß-adrenoceptors. The increased levels of the enzyme ß-adrenoceptors kinase (ßARK) in the heart seems to mediate these biochemical and physiological changes that are consistently correlated with attenuated responsiveness to catecholamine stimulation. Through these mechanisms different types of cardiomyopathy (CMP) can be formed. This review discusses extensively the 3 types of cardiomyopathies that can be present in a PHEO patient. It also provides the clinical presentation and diagnostic and therapeutic algorithm in managing patients with CICMPP.

Superiority of 68Ga-DOTATATE over 18F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population.

PURPOSE: To evaluate and compare diagnostic performance of 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTATATE) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) and anatomic imaging using computed tomography and/or magnetic resonance (CT/MR) imaging in detection of SDHx-related pheochromocytomas and paragangliomas (PPGLs) in pediatric patients. METHODS: Nine pediatric patients (5:4, girls:boys; 14.6 ± 2.0 years) with an SDHx-related mutation (SDHB:SDHA:SDHD, n = 7:1:1) were included in this retrospective study. At the time of initial diagnosis, 7/9 patients had metastatic disease. They underwent CT/MR imaging along with PET/CT using 68Ga-DOTATATE (n = 9), 18F-FDG (n = 8), and positron emission tomography-magnetic resonance imaging (PET/MR) using 18F-FDG (n = 1). In this manuscript, 18F-FDG PET/CT refers to both 18F-FDG PET/CT and 18F-FDG PET/MR. The per-lesion, per-region, and per-patient detection rates were compared and calculated for each of the imaging modalities. A composite of all functional and anatomic imaging studies served as the imaging comparator. RESULTS: Eight out of nine patients were positive for PPGLs on the imaging studies that demonstrated 107 lesions in 22 anatomic regions on the imaging comparator. The per-lesion detection rates for 68Ga-DOTATATE PET/CT, 18F-FDG PET/CT, and CT/MR imaging were 93.5% (95%CI, 87.0% to 97.3%); 79.4% (95%CI, 70.5% to 86.6%); and 73.8% (95%CI, 64.5% to 81.9%), respectively. The per-lesion detection rate for 68Ga-DOTATATE PET/CT was significantly higher than that of 18F-FDG PET/CT (p = 0.001) or CT/MR imaging (p < 0.001). In all of the anatomic regions except abdomen, the per-lesion detection rates for 68Ga-DOTATATE PET/CT was found to be equal or superior to 18F-FDG PET/CT, and CT/MR imaging. The per-region detection rate was 100% (95%CI, 84.6% to 100%) for 68Ga-DOTATATE PET/CT and 90.9% (95%CI, 70.8% to 98.9%) for both 18F-FDG PET/CT and CT/MR imaging. The per-patient detection rates for 68Ga-DOTATATE PET/CT, 18FDG PET/CT, and CT/MR imaging were all 100% (95%CI, 63.1% to 100%). CONCLUSION: Our preliminary study demonstrates the superiority of 68Ga-DOTATATE PET/CT in localization of SDHx-related PPGLs in pediatric population compared to 18F-FDG PET/CT and CT/MR imaging with the exception of abdominal (excluding adrenal and liver) lesions, and suggests that it might be considered as a first-line imaging modality in pediatric patients with SDHx-related PPGLs.

Characteristics of cardiomyopathy in Alström syndrome: Prospective single-center data on 38 patients.

BACKGROUND: Alström syndrome (AS) is a rare monogenetic disorder with multi-organ involvement. Complex metabolic disturbances are common and cardiomyopathy is a well-recognized feature in infants as well as in older children and adults. Although the mechanism of cardiomyopathy is not known, previous reports suggest that individuals with infantile-onset cardiac disease recover completely. METHODS: In this single center prospective series of 38 children and adults (age range 1.7 to 37.9years; 20 females) with AS, we evaluated cardiac manifestations in detail, in the context of specific ALMS1 mutations and multisystem involvement. All patients underwent ALMS1 sequencing, biochemical testing, electrocardiogram, and echocardiographic imaging with speckle tracking to evaluate systolic strain; 21 patients underwent cardiac magnetic resonance imaging with T1 mapping. RESULTS: Approximately half of patients (17/38) had a previous diagnosis of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in 94% of patients and correlated with body mass index (r=0.602, p=0.002) and C-reactive protein level (r=0.56, p=0.004), but only in children. Electrocardiographic abnormalities were seen in two-thirds of patients, and left ventricular dilatation and/or dysfunction was present in 4 adults and 4 children. CONCLUSION: AS patients with a history of resolved infantile cardiomyopathy continue to have residual impairment in cardiac function. For patients with a normal ejection fraction and no prior cardiac history, strain can be abnormal, suggesting subclinical cardiac involvement. Close cardiac screening and aggressive modification of other manifestations of AS that are risk factors for cardiac disease, including obesity, inflammation, diabetes and dyslipidemia, are essential in caring for patients with AS.

Severe cardiac iron toxicity in two adults with sickle cell disease.

BACKGROUND: Use of chronic blood transfusions as a treatment modality in patients with blood disorders places them at risk for iron overload. Since patients with ß-thalassemia major (TM) are transfusion-dependent, most studies on iron overload and chelation have been conducted in this population. While available data suggest that compared to TM, patients with sickle cell disease (SCD) have a lower risk of extrahepatic iron overload, significant iron overload can develop. Further, previous studies have demonstrated a direct relationship between iron overload and morbidity and mortality rates in SCD. However, reports describing the outcome for patients with SCD and cardiac iron overload are rare. STUDY DESIGN AND METHODS: We performed a retrospective analysis and identified two SCD patients with cardiac iron overload. We provide detailed descriptions of both cases and their outcomes. RESULTS: Serum ferritin levels ranged between 17,000 and 19,000 µg/L. Both had liver iron concentrations in excess of 35 mg of iron per gram of dried tissue as well as evidence of cardiac iron deposition on magnetic resonance imaging. One patient died of an arrhythmia and had evidence of severe multiorgan iron overload via autopsy. On the other hand, after appropriate therapy, a second patient had improvement in cardiac function. CONCLUSION: Improper treatment of iron overload in SCD can lead to a fatal outcome. Alternatively, iron overload may potentially be prevented or reversed with judicious use of blood transfusions and early use of chelation therapy, respectively.

TNF-Blockade for Primary Stroke Prevention in Adenosine Deaminase 2 Deficiency: A Case Series.

OBJECTIVES: Adenosine deaminase 2 deficiency (DADA2) is a genetic, neurologic, and systemic vasculitis syndrome, which can lead to recurrent strokes, typically lacunar. In the cohort of now 60 patients followed up at the NIH Clinical Center (NIH CC), no patient has had a stroke since starting tumor necrosis factor (TNF) blockade. We present a family with multiple affected children to highlight the importance of TNF blockade not just as secondary stroke prevention but also as primary stroke prevention in genetically affected but clinically asymptomatic patients. METHODS: A proband with recurrent cryptogenic strokes was referred for evaluation at the NIH CC. The parents and 3 clinically asymptomatic siblings were also evaluated. RESULTS: The proband was diagnosed with DADA2 based on biochemical testing; her antiplatelet therapies were discontinued, and she was started on TNF blockade for secondary stroke prevention. Her 3 asymptomatic siblings were subsequently tested and 2 were found to be biochemically affected. One of them elected to start TNF blockade for primary stroke prevention and the other sibling declined this approach and experienced a stroke. A second genetic sequence variant was subsequently identified in the ADA2 gene. DISCUSSION: This family illustrates the importance of testing for DADA2 in young patients with cryptogenic stroke, given the hemorrhagic risks with antiplatelet drugs in these patients and effectiveness of TNF blockade as secondary stroke prevention. In addition, this family highlights the importance of screening all siblings of affected patients because they may be presymptomatic, and we advocate starting TNF blockade for primary stroke prevention in those who are found to be genetically or biochemically affected.

The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort.

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort's experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

Morphology and chemical identity of periarticular and vascular calcification in a patient with the rare genetic disease of arterial calcification due to deficiency of CD73 (ACDC).

A 54-year old female patient with the genetic disease of arterial calcification due to deficiency of CD73 was studied under the Undiagnosed Disease Program of the National Institutes of Health. She presented with symptoms of claudication in her 40s and later developed arthritic symptoms, ectopic calcification in her left hand and severe arterial calcifications of the lower extremities. Since little was known about the composition of the calcifications in arterial calcification due to deficiency of CD73, we investigated their chemical identity and microscopic morphology in this patient with imaging and x-ray diffraction analysis. We found that, microscopically, the bulk calcifications consisted of fragments of either solid or porous internal structure. Both periarticular and arterial calcifications were primarily hydroxyapatite crystals of the same crystalline anisotropy, but different crystalline grain sizes. This was consistent with the presence of hydroxyapatite crystals along with birefringent calcium pyrophosphate dihydrate crystals in the synovial fluid of the patients by polarized light microscopy. The result suggests that tissue calcification in both locations follow a similar biochemical mechanism caused by an increase in extracellular tissue-nonspecific alkaline phosphatase activity.

Postoperative Management in Patients with Pheochromocytoma and Paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare catecholamine-secreting neuroendocrine tumors of the adrenal medulla and sympathetic/parasympathetic ganglion cells, respectively. Excessive release of catecholamines leads to episodic symptoms and signs of PPGL, which include hypertension, headache, palpitations, and diaphoresis. Intraoperatively, large amounts of catecholamines are released into the bloodstream through handling and manipulation of the tumor(s). In contrast, there could also be an abrupt decline in catecholamine levels after tumor resection. Because of such binary manifestations of PPGL, patients may develop perplexing and substantially devastating cardiovascular complications during the perioperative period. These complications include hypertension, hypotension, arrhythmias, myocardial infarction, heart failure, and cerebrovascular accident. Other complications seen in the postoperative period include fever, hypoglycemia, cortisol deficiency, urinary retention, etc. In the interest of safe patient care, such emergencies require precise diagnosis and treatment. Surgeons, anesthesiologists, and intensivists must be aware of the clinical manifestations and complications associated with a sudden increase or decrease in catecholamine levels and should work closely together to be able to provide appropriate management to minimize morbidity and mortality associated with PPGLs.

Successful 5-fluorouracil (5-FU) infusion re-challenge in a metastatic colorectal cancer patient with coronary artery disease who experienced symptoms consistent with coronary vasospasm during first 5-FU infusion.

5-fluorouracil (5-FU) is an important component of chemotherapy for metastatic colon cancer and can be administered as an intravenous infusion or bolus. Coronary vasospasm is a known complication of infusional and bolus 5-FU administration. In patients who experience coronary vasospasm, 5-FU is often discontinued. Several cases of successful re-challenge with bolus 5-FU, utilizing calcium channel blockers (CCBs) and nitrates to prophylaxis against coronary vasospasm recurrence, have been reported in the literature. However, since there is increased variability of time to symptom onset with infusional 5-FU, re-challenge with infusional 5-FU has not been widely studied. Given potential differences in the toxicity profile and exposure time, infusional may be more appropriate than bolus for some patients. Here we report successful re-challenge with infusional 5-FU, following coronary vasospasm during the first cycle of 5-FU plus leucovorin plus oxaliplatin chemotherapy, in a patient with metastatic colon cancer and coronary artery disease (CAD). The 5-FU re-challenge plan included dose reduction, CCB and nitrate prophylaxis, and telemetry monitoring.

Myocarditis in a patient treated with Nivolumab and PROSTVAC: a case report.

BACKGROUND: Immune checkpoint inhibitors have revolutionized treatment and improved survival in many cancers. However, since immune-related adverse events (irAEs) are potentially fatal, early recognition and prompt treatment are warranted. One of the rarest but most dramatic irAE is myocarditis, which has significant morbidity and mortality if not recognized and treated early. OBJECTIVE: To report the first case of myocarditis in a patient with metastatic castration-resistant prostate cancer (mCRPC) treated with a combination of nivolumab, an anti-programmed cell death protein 1 antibody, and PROSTVAC, a vector-based therapeutic prostate cancer vaccine. CASE REPORT: A 79-year-old man with mCRPC metastatic to bone and lymph nodes and a history of atrial fibrillation presented with blurred vision and pain and stiffness in the upper back after 8 weeks on a clinical trial with nivolumab (1 mg/kg) and PROSTVAC, both given every 2 weeks. Eye exam was within normal limits, while musculoskeletal exam revealed tenderness in trapezius muscles and decreased motor strength in arms (III/V) and neck (IV/V). The rest of the physical exam was within normal limits, with the exception of an irregular heart rhythm. Laboratory tests were as follows: creatinine kinase (CK) 3200 U/L (normal: 39-308 U/L), CK-MB 65.7 mcg/L (normal: 0-7.6 mcg/L), troponin I 0.209 ng/mL (normal: 0-0.056 ng/mL). Electrocardiogram (ECG) revealed atrial fibrillation with QT prolongation (QTc 514 msec) and left anterior fascicular block, unchanged from baseline. 2D-echocardiogram showed a left ventricular ejection fraction of 65% with an enlarged left atrium, dilated right ventricle, and increased pulmonary artery pressure (45 mmHg). ProBNP was elevated at 1463 pg/mL and peaked at 3066 pg/mL one day after hydration. With a presumed diagnosis of autoimmune myositis and possible myocarditis, the patient was admitted and started on methylprednisolone 1 mg/kg/day. Cardiac MRI showed elevated native myocardial T1 values consistent with myocarditis (Fig. 1). The patient was discharged on a prednisone taper after normalization of cardiac enzymes on day 4. Treatment with PROSTVAC continued for three more months; nivolumab was discontinued. Six months later, patient is doing well, with no residual cardiac damage. DISCUSSION: Cardiovascular irAEs are relatively rare (< 1%) and have a variety of clinical presentations. Myocarditis is potentially life-threatening and can range from subclinical to fulminant. Therefore, clinical suspicion, early detection, and prompt treatment are imperative (1). The initial diagnostic workup should include cardiac enzymes, ECG, and 2D-echocardiogram. The most commonly observed ECG changes are generalized repolarization abnormalities, prolonged QT interval, and conduction abnormalities (2). An elevated troponin I in the absence of overt coronary artery disease is suggestive of myocarditis and should be evaluated further. Myocardial biopsy is the standard diagnostic procedure; however, a cardiac MRI can achieve a diagnosis when biopsy is not feasible (3). Advancements in parametric mapping techniques have allowed the use of native myocardial T1 in the detection of myocarditis, as it has superior diagnostic performance and higher sensitivity than older parameters (3). Our patient had been treated with an immune checkpoint inhibitor and a therapeutic cancer vaccine to induce effective antitumor activity through immunogenic intensification and presented with muscle stiffness and elevated CK. Although he had no new cardiovascular symptoms, cardiac enzymes were tested to rule out myocardial involvement. MRI with gadolinium confirmed the diagnosis of myocarditis. To date, none of the 1360 patients treated with PROSTVAC as a single agent have developed myocarditis, while myocarditis has been rarely reported in patients treated with nivolumab (< 1%) (1). Whether the combination of PROSTVAC and nivolumab presents an additional risk of myocarditis is unclear. To our knowledge, this is the first case of myocarditis in a patient with mCRPC receiving simultaneous treatment with an immune checkpoint inhibitor and a prostate cancer vaccine. Our experience highlights the importance of suspicion and early intervention in patients who present with cardiac abnormalities after receiving cancer immunotherapy. We propose following protocol: baseline troponin, ECG, and 2D-echocardiogram prior to treatment, then repeated troponin at 2, 4, and 12 weeks post-treatment, then monthly. If troponin becomes positive without alternative explanation, myocarditis should be ruled out with cardiac MRI or myocardial biopsy, and patient should be admitted for treatment with high-dose steroids as early intervention may minimize myocardial injury.

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.