Osteonecrosis in Gaucher disease in the era of multiple therapies: Biomarker set for risk stratification from a tertiary referral center.

Background: A salutary effect of treatments for Gaucher disease (GD) has been a reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT) , and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity, or anti-drug antibodies. Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center. Methods: Longitudinal follow-ups of 155 GD patients between 2001 and 2021 were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment. Results: The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI, 1.5-67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI, 1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001). Conclusions: There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found that increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization. Funding: LSD Training Fellowship from Sanofi to MB.

Incremental biomarker and clinical outcomes after switch from enzyme therapy to eliglustat substrate reduction therapy in Gaucher disease.

In Gaucher disease (GD), genetic deficiency of acid ß-glucosidase leads to accumulation of its substrate glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Lipid-laden cells, most prominently seen as macrophages engorged with GlcCer and GlcSph-laden lysosomes, trigger chronic metabolic inflammation and multisystemic phenotypes. Among the pleiotropic effects of inflammatory cascades, the induction of glucosylceramide synthase accentuates the primary metabolic defect. First-line therapies for adults with GD type 1 include Enzyme Replacement Therapy (ERT) and eliglustat Substrate Reduction Therapy (SRT). The ENCORE phase 3 clinical trial of eliglustat demonstrated non-inferiority compared to ERT. It is not known whether switching stable patients from long-term ERT to SRT results in the incremental reversal of the disease phenotype and its surrogate indicators. Herein, we report real-world experience from a single tertiary referral center of 38 adult GD type 1 patients, stable on long-term ERT (mean 13.3 years), who switched to eliglustat SRT (mean 3.1 years). After switch to SRT, there was significant reduction in spleen volume (P = 0.003) while liver volume, which was normal at baseline, remained unchanged. Platelet counts increased significantly (P = 0.026). Concomitantly, there was reduction of three validated biomarkers of Gaucher disease activity: plasma GlcSph decreased from 63.7 ng/ml (95% CI, 37.6-89.8) to 26.1 ng/ml (95% CI, 15.7-36.6) (P < 0.0001); chitotriosidase fell from 1136.6 nmol/ml/h (95% CI, 144.7-2128.6) to 466.9 nmol/ml/h (95% CI, 209.9-723.9) (P = 0.002); and glycoprotein non-metastatic melanoma B (gpNMB) decreased from 59.3 ng/ml (95% CI, 39.7-78.9) to 43.6 ng/ml (95% CI, 30.7-56.6) (P = 0.0006). There were no episodes of avascular necrosis or fractures in patients on SRT. Patients reported favorable experiences of switching from alternate week infusions to oral therapy. Collectively, these results demonstrate that the switch to eliglustat SRT from ERT leads to incremental response, even in stable patients after long-term ERT.

Sonographic Features of Salivary Glands in Sjögren's Syndrome and its Mimics.

PURPOSE OF REVIEW: For 30 years, ultrasound has been investigated as a means to evaluate salivary gland abnormalities in patients with autoimmune disease. We aim to review the test characteristics of ultrasound for diagnosing Sjögren's syndrome, the scoring systems used for this purpose, and the ultrasound similarities and differences between Sjögren's syndrome and some of its potential salivary gland mimics. RECENT FINDINGS: Hypo/anechoic glandular lesions are the major ultrasound characteristic found in Sjögren's syndrome. Most studies have reported such ultrasound abnormalities to have a sensitivity and specificity in the range of 65-85% and 85-95%, respectively, as well as a positive likelihood ratio between 4 and 12. However, similar findings can also be seen in sarcoidosis, amyloidosis, IgG4-related disease, HIV, and lymphoma. A "nodal" pattern of involvement or the ultrasound artifact of "through transmission" can help distinguish some of these mimics from Sjogren's syndrome. Ultrasound can substantially influence the diagnosis of Sjögren's syndrome.

Reversal of life-threatening hepatopulmonary syndrome in Gaucher disease by imiglucerase enzyme replacement therapy.

Advanced liver disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the disease can be ameliorated. We describe a splenectomized patient with Gaucher disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver disease. Our report suggests that Gaucher disease pathology involving advanced fibrosis and life-threatening complications can be reversed by imiglucerase enzyme therapy. SYNOPSIS: Effect of imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.

Significant Variation in the Detection Rates of Proximal Serrated Polyps Among Academic Gastroenterologists, Community Gastroenterologists, and Colorectal Surgeons in a Single Tertiary Care Center.

INTRODUCTION: Recent studies have demonstrated that the protective effect of colonoscopy against colorectal cancer is lower in the proximal colon. Proximal serrated polyps, including sessile serrated adenomas and proximal hyperplastic polyps, can be frequently missed and pose a risk of interval cancers. AIM: To investigate the overall adenoma detection rate (ADR) and the proximal serrated polyp detection rate (PSPDR) among academic gastroenterologists, community gastroenterologists, and colorectal surgeons from a single institution, all of whom have received formal training in colonoscopy during their fellowship. METHODS: All complete screening colonoscopies for patients aged 50 or older with a good to excellent bowel preparation performed by different endoscopists at Medstar Washington Hospital Center (Washington, DC) from July 2015 to December 2017 were reviewed. Pathology reports of the resected polyps were manually reviewed. RESULTS: A total of 2850 screening colonoscopies meeting the inclusion criteria were performed by 18 endoscopists (6 academic, 7 community, and 5 colorectal surgeons). There was no significant difference in the mean ADR among the three groups of endoscopists: academic gastroenterologists, community gastroenterologists, and colorectal surgeons (40.3% vs 36.0% vs 39.6%, respectively). However, academic gastroenterologists had a significantly higher PSPDR compared to community gastroenterologists or colorectal surgeons (12.3% vs 5.4% vs 4.5%, respectively, ANOVA p = 0.006). CONCLUSION: Our novel data show that academic gastroenterologists had a significantly higher PSPDR compared to community gastroenterologists or colorectal surgeons despite a comparable overall ADR among the three groups. PSPDR may be considered as an important quality indicator for colonoscopy, apart from ADR.

Pericardial Effusion due to Infliximab Therapy for Ulcerative Colitis.

Ulcerative colitis is characterized by ulcers and inflammation of the inner lining of the gastrointestinal tract. Antitumor necrosis factor alpha (anti-TNF alpha) agents such as infliximab are drugs that have been used for the treatment of ulcerative colitis for decades. Infliximab is known to be associated with various adverse effects including anti-TNF alpha induced lupus (ATIL). We present a rare case of a 51-year-old female with pericardial effusion secondary to infliximab therapy for treatment of her ulcerative colitis. Discontinuation of infliximab led to resolution of the pericardial effusion.

Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease.

In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms.

Glucosylsphingosine is a key biomarker of Gaucher disease.

Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3-1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4-216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2-129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r = 0.59 P < 0.001), CCL18 (r = 0.62 P <0.001), hepatomegaly (r = 0.28 P < 0.001), splenomegaly (r = 0.27 P = 0.003), splenectomy (P = 0.01) and treatment mode (P < 0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (P < 0.001), splenectomy (P = 0.02), Chitotriosidase (P < 0.001) and CCL18 levels (P = 0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136-90.3 ng/ml P < 0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT. Am. J. Hematol. 91:1082-1089, 2016. © 2016 Wiley Periodicals, Inc.

NF-κB Essential Modulator Deficiency Leading to Disseminated Cutaneous Atypical Mycobacteria.

NF-κB essential modulator (NEMO) is a kinase integral to the macrophage TNF-α pathway, which leads to the intracellular destruction of Mycobacteria species. Defects in the NEMO pathway result in spectrum of diseases, including but not limited to ectodermal dysplasia, Mendelian susceptibility to mycobacterial diseases, and incontinentia pigmenti. In addition, paucity of NEMO can lead to the inability to mount a proper immune response against opportunistic pyogenic and mycobacterial infections, leading to dissemination to various organ systems. This manuscript will discuss the numerous clinical manifestations of NEMO deficiency, the differential diagnosis of atypical mycobacterial infections in immunocompetent adults, and feature a case report of rare isolated susceptibility to disseminated atypical mycobacteria due to a mutation in the first exon of the NEMO gene.

The mystery of recurrent idiopathic cerebrovascular and coronary arterial thrombosis.

A 46-year-old man presented to our hospital with ST elevation myocardial infarction (STEMI). Previous records revealed a history of recurrent non-STEMI, stroke and transient ischaemic attacks. He was thoroughly investigated with coronary angiography, a cerebral CT angiography, thrombophilia panel and autoimmune screening tests, all of which proved negative. His current episode of STEMI resulted while on dual antiplatelet therapy; the patient was investigated for P2Y12 receptor resistance, which was also negative. A diagnosis of idiopathic recurrent arterial thrombosis was established and the patient was discharged home on aspirin and warfarin. Routine follow-up has revealed no recurrence of symptoms.

Mitral valve prolapse and electrolyte abnormality: a dangerous combination for ventricular arrhythmias.

A 27-year-old woman with a history of bileaflet mitral valve prolapse and moderate mitral regurgitation presented to our emergency with untractable polymorphic wide complex tachycardia and unstable haemodynamics. After cardiopulmonary resuscitation, return of spontaneous circulation was achieved 30 min later. Her post-resuscitation ECG showed a prolonged QT interval which progressively normalised over the same day. Her laboratory investigations revealed hypocalcaemia while other electrolytes were within normal limits. A diagnosis of ventricular arrhythmia secondary to structural heart disease further precipitated by hypocalcaemia was made. Further hospital stay did not reveal a recurrence of prolonged QT interval or other arrhythmias except for an episode of non-sustained ventricular tachycardia. However, the patient suffered diffuse hypoxic brain encephalopathy secondary to prolonged cardiopulmonary resuscitation.