Research Spotlight

Mochel, F., C. Delorme, V. Czernecki, J. Froger, F. Cormier, E. Ellie, N. Fegueux, S. Lehericy, S. Lumbroso, R. Schiffmann, P. Aubourg, E. Roze, P. Labauge and S. Nguyen (2019). “Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.” J Neurol Neurosurg Psychiatry 90(12): 1375-1376.

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We present the positive long-term outcome of haematopoietic stem cell transplantation (HSCT) in a patient with CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). This patient presented with a rapidly progressive disease evolution before HSCT, as usually observed in ALSP. Her dreadful neurological decline stopped from 6 months post-transplant and DWI lesions kept regressing 30 months post-transplant. A consecutive patient with similar age, sex and disease course who did not undergo HSCT suffered a dramatic worsening of her disease. A patient with ALSP, misdiagnosed as metachromatic leukodystrophy and transplanted for that reason, seems to have remained stable but no further detail is available. Instead, we provide the first detailed prospective report of HSCT in colony-stimulating factor 1 receptor (CSF1R)-related ALSP. Further observations are encouraged to confirm the ability of HSCT to halt disease progression in ALSP. These observations emphasise how critical it is to diagnose ALSP, particularly in patients with rapidly progressive pyramidal signs and/or cognitive alterations associated with white matter lesions. Important diagnostic clues for ALSP are hyperintense white matter dots on DWI and/or punctate calcifications in the absence of gadolinium enhancement, T2* microbleeds or spine lesions. The favourable clinical outcome of patient 1 post-transplant, the rapid disease progression in ALSP and the possibility of acute exacerbations (e.g., following head trauma) suggest that HSCT should be considered in the early phase of the disease. Patient 1 continued to deteriorate and MRI lesions progressively extended in the first months post-transplant as the colonisation of the donor cells into the brain takes several months to occur while the disease continues to progress. A major challenge for HSCT in ALSP is the identification of biomarkers reflecting disease progression. Neurofilament light chain is elevated in the plasma and CSF of patients with ALSP. Its potential as a biomarker of disease activity is yet to be shown. Novel imaging methods that can monitor demyelination may also help to properly time HSCT in patients with ALSP. (Excerpt from p. 1375; no abstract available.)

McMurray, J. J. V., A. M. Jackson, C. S. P. Lam, M. M. Redfield, I. S. Anand, J. Ge, M. P. Lefkowitz, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, A. R. Rizkala, S. V. Sabarwal, A. M. Shah, S. J. Shah, V. C. Shi, D. J. van Veldhuisen, F. Zannad, M. R. Zile, M. Cikes, E. Goncalvesova, T. Katova, A. Kosztin, M. Lelonek, N. K. Sweitzer, O. Vardeny, B. Claggett, P. S. Jhund and S. D. Solomon (2019). “Effects of Sacubitril-Valsartan, versus Valsartan, in Women Compared to Men with Heart Failure and Preserved Ejection Fraction: Insights from PARAGON-HF.” Circulation Nov 17. [Epub ahead of print].

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Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction (HFpEF), the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women, compared with men. Methods: In a pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial which compared sacubitril-valsartan and valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in KCCQ-CSS was less in women than in men. The difference in adverse events, between sacubitril-valsartan and valsartan, was similar in women and men. Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding (Clinicaltrials.gov unique identifier: NCT01920711).

Mathai, S. K., S. Humphries, J. A. Kropski, T. S. Blackwell, J. Powers, A. D. Walts, C. Markin, J. Woodward, J. H. Chung, K. K. Brown, M. P. Steele, J. E. Loyd, M. I. Schwarz, T. Fingerlin, I. V. Yang, D. A. Lynch and D. A. Schwartz (2019). “MUC5B variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis.” Thorax 74(12): 1131-1139.

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BACKGROUND: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT. METHODS: First-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed. FINDINGS: In 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex. INTERPRETATION: PrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

Lo, K. B., F. Gul, P. Ram, A. Y. Kluger, K. M. Tecson, P. A. McCullough and J. Rangaswami (2019). “The Effects of SGLT2 Inhibitors on Cardiovascular and Renal Outcomes in Diabetic Patients: A Systematic Review and Meta-Analysis.” Cardiorenal Med Nov 19. [Epub ahead of print].

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BACKGROUND: Previous meta-analyses demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) primarily on patients with established atherosclerotic cardiovascular disease (ASCVD), but with questionable efficacy on patients at risk of ASCVD. Additionally, evidence of beneficial cardiorenal outcomes in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 with the CV outcomes trials remains unclear. Canagliflozin, one of the SGLT2i, has recently been studied in a large randomized controlled trial in diabetic patients with chronic kidney disease. Thus, there is a need to understand the combined outcomes on the population targeted for treatment with SGLT2i as a whole, regardless of ASCVD status. This meta-analysis will therefore assess the efficacy of SGLT2i in cardiovascular and renal outcomes in general, and in patients with eGFR under 60 mL/min/1.73 m2 in particular. METHODS: We searched PubMed and Cochrane databases for randomized, placebo-controlled studies involving SGLT2i. We examined composite cardiovascular outcomes of death from cardiovascular causes, nonfatal myocardial infarctions, nonfatal stroke, and heart failure hospitalizations. Renal composite outcomes and progression of albuminuria were also analyzed. Pooled relative risks (RR) and their 95% confidence intervals (CI) were calculated using a fixed-effects model. RESULTS: The search yielded a total of 252 articles. Four studies were ultimately included in the meta-analysis after exclusion of other irrelevant studies. The pooled RR (95% CI) for the composite cardiovascular outcome was 0.93 (0.87-0.99) with a number needed to treat (NNT) of 167 in the general study population and 0.89 (0.77-1.02) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for all-cause mortality was 0.9 (0.84-0.97) with NNT = 143. The pooled RR for death from cardiovascular causes alone was 0.89 (0.81-0.99) in the general population and 0.82 (0.62-1.07) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for heart failure hospitalizations was 0.71 (0.63-0.79) with NNT = 91. With respect to renal outcomes, the pooled RR for the composite renal outcome was 0.63 (0.56-0.71) with NNT = 67; this was true even in patients with eGFR <60 mL/min/1.73 m2 0.67 (0.59-0.76). Lastly, the pooled RR for progression of albuminuria was 0.80 (0.76-0.84). CONCLUSION: SGLT2i are associated with significantly lower major adverse cardiovascular events, heart failure hospitalizations, and all-cause mortality. The evidence is strongest in reducing heart failure hospitalizations. However, the evidence is weaker when it comes to the population subset with eGFR <60 mL/min/1.73 m2. SGLT2i are also associated with significantly lower adverse renal events, with these effects apparent even in the population with eGFR <60 mL/min/1.73 m2.

Lebwohl, M. G., A. Blauvelt, A. Menter, K. A. Papp, S. Guenthner, R. Pillai, R. J. Israel and A. Jacobson (2019). “Efficacy, Safety, and Patient-Reported Outcomes in Patients with Moderate-to-Severe Plaque Psoriasis Treated with Brodalumab for 5 Years in a Long-Term, Open-Label, Phase II Study.” Am J Clin Dermatol 20(6): 863-871.

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BACKGROUND: Chronic inflammatory diseases such as psoriasis require treatment options that maintain efficacy and tolerability during extended treatment. OBJECTIVE: The aim of the study was to assess the long-term efficacy and safety of brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: Patients who completed a 12-week, phase II, dose-ranging clinical trial received brodalumab 210 mg every 2 weeks in an open-label extension study. Efficacy was assessed by static physician’s global assessment (sPGA) and psoriasis area and severity index (PASI). Quality of life, assessed by dermatology life quality index (DLQI), and safety were also evaluated. RESULTS: Overall, 181 patients received brodalumab for a median of 264 weeks. Brodalumab treatment resulted in rapid improvements in sPGA, PASI, and DLQI that were maintained through week 264. Achieving PASI 90 to < 100 or PASI 100 at weeks 12, 240, and 264 was associated with greater likelihood for DLQI 0 or 1 compared with achieving PASI 75 to < 90. Over 5 years, one adverse event of suicidal ideation was reported, no suicides occurred, and no new safety signals emerged. CONCLUSIONS: Brodalumab demonstrated skin clearance and improved quality of life, with an acceptable safety profile, throughout 5 years of treatment. ClincalTrials.gov: NCT01101100.