Research Spotlight

Benjamin, E. R., M. C. Della Valle, X. Wu, E. Katz, F. Pruthi, S. Bond, B. Bronfin, H. Williams, J. Yu, D. G. Bichet, D. P. Germain, R. Giugliani, D. Hughes, R. Schiffmann, W. R. Wilcox, R. J. Desnick, J. Kirk, J. Barth, C. Barlow, K. J. Valenzano, J. Castelli and D. J. Lockhart (2016). “The validation of pharmacogenetics for the identification of fabry patients to be treated with migalastat.” Genet Med: 2016 Sep [Epub ahead of print].

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PURPOSE: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of alpha-galactosidase A to restore lysosomal activity. METHODS: A pharmacogenetic assay was used to identify the alpha-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in alpha-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies. RESULTS: Comparison of the GLP HEK assay results in in vivo white blood cell alpha-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (>/=0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay. CONCLUSION: The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.

Brodsky, J. W., J. M. Kane, S. Coleman, J. Bariteau and S. Tenenbaum (2016). “Abnormalities of gait caused by ankle arthritis are improved by ankle arthrodesis.” Bone Joint J 98-b(10): 1369-1375.

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AIMS: The surgical management of ankle arthritis with tibiotalar arthrodesis is known to alter gait, as compared with normal ankles. The purpose of this study was to assess post-operative gait function with gait before arthrodesis. PATIENTS AND METHODS: We prospectively studied 20 patients who underwent three-dimensional gait analysis before and after tibiotalar arthrodesis. Cadence, step length, walking velocity and total support time were assessed. Kinetic parameters, including the moment and power of the ankle in the sagittal plane and hip power were also recorded. RESULTS: Significant improvement was recorded across numerous parameters compared with pre-operative measurements. Temporal-spatial data demonstrated a significant increase in step length (p = 0.003) and velocity (p = < 0.001). Total support time decreased for the unaffected limb (p = 0.01). Kinematic results demonstrated that in the affected limb, total sagittal range of movement did not change significantly (p = 0.1259). However, the arc of movement had a near congruent shift with mean maximal dorsiflexion increasing from 5 degrees (-17 degrees to 16 degrees ) to 12 degrees (5 degrees to 18 degrees ) (p < 0.001) and mean maximal plantarflexion decreasing from 6.8 degrees (6 degrees to 21 degrees ) to 0.9 degrees (-9 degrees to 8 degrees ) (p = 0.003). Mean hip joint range of movement increased by 6 degrees (-7 degrees to 24 degrees ; p = 0.003). Kinetic results demonstrated no statistically significant change in ankle power (p = 0.1292). However, there was an increase in ankle moment (p = 0.04) and hip power (p = 0.01) in the surgically treated extremity. Sagittal plane range of movement was not reduced after tibiotalar fusion. CONCLUSION: Although following tibiotalar arthrodesis the gait demonstrated never matched the gait shown in unaffected ankles, compared with the pre-operative analysis there was improvement in numerous temporal-spatial, kinematic, and kinetic measures.

Campa, M. and A. Menter (2016). “A review of emerging il-17 inhibitors in the treatment of psoriasis focusing on preclinical through phase ii studies.” Expert Opin Investig Drugs: 2016 Sep [Epub ahead of print].

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INTRODUCTION: Interleukin-17 has recently been identified as a key player in the pathogenesis of psoriasis. As such, several drugs targeting IL-17 are in various stages of clinical development. AREAS COVERED: In this review, the authors describe several emerging therapies and drug candidates targeting IL-17. The authors detail many biologic injectable drug candidates as well as numerous potential oral and topical small molecule drug candidates. EXPERT OPINION: Approval of IL-17 inhibitors has significantly improved the treatment options for psoriasis patients. Secukinumab and ixekizumab are approved in both Europe and the USA, and brodalumab is likely facing approval by the end of 2016. Numerous additional biologic and small molecule drug candidates are in the pipeline, and once deemed safe and effective will likely offer significant benefit to our psoriasis population.

Castillo, J. J., R. Garcia-Sanz, E. Hatjiharissi, R. A. Kyle, X. Leleu, M. McMaster, G. Merlini, M. C. Minnema, E. Morra, R. G. Owen, S. Poulain, M. J. Stone, C. Tam, M. Varettoni, M. A. Dimopoulos, S. P. Treon and E. Kastritis (2016). “Recommendations for the diagnosis and initial evaluation of patients with waldenstrom macroglobulinaemia: A task force from the 8th international workshop on waldenstrom macroglobulinaemia.” Br J Haematol 175(1): 77-86.

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The diagnosis of Waldenstrom macroglobulinaemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.

Cedars, A. M., S. Burns, E. L. Novak and A. P. Amin (2016). “Predictors of rehospitalization among adults with congenital heart disease are lesion specific.” Circ Cardiovasc Qual Outcomes 9(5): 566-575.

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BACKGROUND: Readmission is responsible for a large proportion of inpatient care costs in adult congenital heart disease. There are, however, few data available to identify at-risk patients or to suggest strategies for intervention to prevent rehospitalization. METHODS AND RESULTS: We conducted an analysis of admissions in patients over the age of 18 years with a 3-digit International Classification of Diseases-Ninth Revision code of 745 to 747 from the State Inpatient Databases of Arkansas (2008-2010), California (2003-2012), Florida (2005-2012), Hawaii (2006-2010), Nebraska (2003-2011), and New York (2005-2012). We investigated index admission diagnoses most commonly associated with 1-year readmission and the most common reasons for readmission. We then selected variables we thought would be associated with increased rates of 1-year readmission and constructed multivariable regression models grouping patients by congenital lesion, to examine the relative contribution of the specified variables to readmission risk for each lesion. A total of 64 420 patients were included in the final analysis. Thirty-nine percent of patients experienced a readmission within 12 months of an index admission. Compared with those who did not experience a readmission, those who did were more likely to have had a primary diagnosis of congestive heart failure at the time of index admission, and the most common diagnoses at the time of readmission were congestive heart failure and arrhythmia. There is lesion-specific heterogeneity in risk factors for readmission. CONCLUSIONS: Patients with adult congenital heart disease have high rates of readmission, predominantly for congestive heart failure and arrhythmia. Predictors of readmission are lesion specific, and future strategies aimed at decreasing readmission rate will likely need to be individualized.