Two Phase 3 Trials of Baricitinib for Alopecia Areata

In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks.

source: NEJM

Summary

[Posted 5/May/2022]

AUDIENCE: Family Medicine

KEY FINDINGS: In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata.

BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata.

DETAILS: Conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36. 654 patients were enrolled in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo.

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Source: King, B., Ohyama, M., Kwon, O., et al. (2022). Two Phase 3 Trials of Baricitinib for Alopecia Areata. N Engl J Med. 2022; 386: 1687-1699. Published: May 5, 2022. DOI: 10.1056/NEJMoa2110343.



Ruxolitinib In Patients With Polycythemia Vera With Hydroxyurea Resistance Or Intolerance

Interferon alfa-2b is approved in treatment-naive patients and for patients with hydroxyurea resistance or intolerance, 3 and ruxolitinib, a Janus kinase 1/2 inhibitor is exclusively approved for second-line treatment.

source: The Lancet

Summary

[Posted 19/May/2022]

AUDIENCE: Hematology, Family Medicine

KEY FINDINGS: Interferon alfa-2b is approved in treatment-naive patients and for patients with hydroxyurea resistance or intolerance, and ruxolitinib, a Janus kinase 1/2 inhibitor is exclusively approved for second-line treatment.

BACKGROUND: The clinical triumvirate of polycythemia vera include disease-related symptoms, vascular events, and transformation to myelofibrosis or blast phase.

DETAILS: Regulatory approval for polycythemia vera directed therapy is dependent on the achievement of a complete hematological response or phlebotomy associated goals (short-term clinical trial endpoints) that might not affect the most clinically relevant outcome measures of thrombosis, progression, and overall survival due to longer time to event, and lower incidence, which make polycythemia vera a challenging disease to evaluate in prospective trials. Although hydroxyurea is the mainstay of treatment in patients with polycythemia vera, approximately 15% of patients develop resistance or intolerance, which is deemed an adverse prognostic factor with higher risk for death (hazard ratio [HR] 5.6, 95% CI 2.7-11.9; p<0.001) and transformation to myelofibrosis or blast phase (HR 6.8, 3.0-15.4; p<0.001).

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Source: Venugopal, S. and Mascarenhas, J. (2022). Ruxolitinib In Patients With Polycythemia Vera With Hydroxyurea Resistance Or Intolerance. The Lancet. Published: May 18, 2022. DOI: 10.1016/S2352-3026(22)00139-9.



Offloading Devices For Neuropathic Foot Ulcers In Adult Persons With T1D Or T2D

There is limited evidence from RCTs to suggest that F-TCC has a shorter ulcer healing time compared with RCW among adults with diabetic NPFUs.

source: BMJ DRC

Summary

A Rapid Review With Meta-Analysis And Trial Sequential Analysis Of Randomized Controlled Trials

[Posted 13/May/2022]

AUDIENCE: Endocrinology

KEY FINDINGS: There is limited evidence from RCTs to suggest that F-TCC has a shorter ulcer healing time compared with RCW among adults with diabetic NPFUs. Properly designed and conducted RCTs are still required for a stronger evidence base.

BACKGROUND: Healing time for neuropathic planter foot ulcers (NPFUs) in persons with diabetes may be reduced through use of non-removable fiberglass total contact casting (F-TCC) compared with removable cast walkers (RCWs), although the evidence base is still growing.

DETAILS: A rapid review was conducted and systematically searched for, and critically assessed, randomized controlled trials (RCTs) that compared the efficacy of F-TCC versus RCW, focusing on the time to ulcer healing in adult persons (18+ years) with NPFUs and type 1 or type 2 diabetes. We meta-analysed the mean differences and associated 95% CIs using an inverse variance, random-effects model. Also conducted a trial sequential analysis (TSA) to assess if the available evidence is up to the required information size for a robust conclusion. Assessed and quantified statistical heterogeneity between the included studies using the I2 statistic. Out of 102 retrieved citations, five RCTs met the eligibility criteria. Participants' inclusion in relation to stage of ulcer was highly variable as was peripheral neuropathy complicating comparisons. F-TCC appeared to present a shorter ulcer healing time (-5.42 days, 95% CI -9.66 days to -1.17 days; I2 9.9%; 5 RCTs; 169 participants) compared with RCW. This finding was supported by the TSA.

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Source: Okoli GN, Rabbani R, Lam OLT, et al. (2022). Offloading Devices For Neuropathic Foot Ulcers In Adult Persons With Type 1 Or Type 2 Diabetes: A Rapid Review With Meta-Analysis And Trial Sequential Analysis Of Randomized Controlled Trials. BMJ DRC. 2022; 10(3): e002822. Published: May 12, 2022. DOI: 10.1136/bmjdrc-2022-002822.



Macular Thickness and Microvasculature Loss in Glaucoma Suspect Eyes

Whereas the rate of GCC thinning was faster on average in suspect eyes than in healthy eyes, some suspect eyes showed significant loss of vessel density and faster vessel density loss than GCC thinning.

source: Ophthalmology Glaucoma

Summary

[Posted 11/May/2022]

AUDIENCE: Ophthalmology

KEY FINDINGS: Whereas the rate of GCC thinning was faster on average in suspect eyes than in healthy eyes, some suspect eyes showed significant loss of vessel density and faster vessel density loss than GCC thinning. OCT and OCTA are complementary and useful for evaluating eyes with OHT or GON.

BACKGROUND: Objective of this study is to characterize the change of ganglion cell complex (GCC) thickness and macular vessel density in glaucoma suspect eyes with ocular hypertension (OHT) or glaucomatous optic neuropathy (GON).

DETAILS: OCT angiography (OCTA)-based vessel density and OCT-based structural thickness of the 3 x 3-mm1 GCC scan slab were evaluated at each visit. The rates of vessel density and thickness change were compared across diagnostic groups using a linear mixed-effects model. Significant mean rates of both GCC thinning and vessel density loss were detectable in OHT and GON groups. Of the individual suspect eyes, 49.1% showed significant loss (P < 0.05) with either vessel density or GCC thickness. Of the GON eyes, 31.0% showed both significant GCC loss and vessel density loss, 51.7% showed only significant GCC loss, whereas 17.2% showed only significant vessel density loss. Vessel density loss was faster than GCC thinning in half of the suspect eyes based on percent loss analysis. The age and scan quality-adjusted GCC thinning rates of the OHT group (-0.59 µm/year; P = 0.025) and GON group (-0.79 µm/year; P = 0.058) were faster than those of the healthy group (-0.11 µm/year), whereas the rate of vessel density loss was not significantly different among the diagnostic groups (all P > 0.2). Higher mean intraocular pressure during follow-up was associated with faster GCC thinning in the OHT group (P = 0.065) and GON groups (P = 0.015), but was not associated with the rate of vessel density decrease.

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Source: Hou, H., Moghimi, S., Kamalipour, A., et al. (2022). Macular Thickness and Microvasculature Loss in Glaucoma Suspect Eyes. Ophthalmology Glaucoma. 2022; 5(2): 170-178. Published: April, 2022. DOI: 10.1016/j.ogla.2021.07.009.



Fetal Growth and Spontaneous Preterm Birth In High-Altitude Pregnancy

Globally, the likelihood of adverse perinatal outcomes, including LBW, SGA, and sPTB, increases in high-altitude pregnancies.

source: Intl J Gynecol Obstet.

Summary

A Systematic Review, Meta-Analysis, and Meta-Regression

[Posted 10/May/2022]

AUDIENCE: Ob/Gyn, Family Medicine

KEY FINDINGS: Globally, the likelihood of adverse perinatal outcomes, including LBW, SGA, and sPTB, increases in high-altitude pregnancies. There is an inverse relationship between birth weight and altitude. These findings have important implications for the increasing global population living at altitudes above 2500 m.

BACKGROUND: Aim of the study is to understand the relationship between birth weight and altitude to improve health outcomes in high-altitude populations, to systematically assess the impact of altitude on the likelihood of low birth weight (LBW), small for gestational age (SGA), and spontaneous preterm birth (sPTB), and to estimate the magnitude of reduced birth weight associated with altitude.

DETAILS: Observational, cohort, or case-control studies were included if they reported a high altitude (>2500 m) and appropriate control population. Of 2524 studies identified, 59 were included (n = 1,604,770 pregnancies). Data were abstracted according to PRISMA guidelines, and were pooled using random-effects models. There are greater odds of LBW (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.33-1.62, P < 0.001), SGA (OR 1.88, 95% CI 1.08-3.28, P = 0.026), and sPTB (OR 1.23, 95% CI 1.04-1.47, P = 0.016) in high- versus low-altitude pregnancies. Birth weight decreases by 54.7 g (±13.0 g, P < 0.0001) per 1000 m increase in altitude. Average gestational age at delivery was not significantly different.

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Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Grant, I. D., Giussani, D. A., Aiken, C. E. (2022). Fetal Growth and Spontaneous Preterm Birth In High-Altitude Pregnancy: A Systematic Review, Meta-Analysis, and Meta-Regression. Intl J Gynecol Obstet.. 2022; 157(2): 221-229. Published: May, 2022. DOI: 10.1002/ijgo.13779.



Development and Validation of Bloomy Prediction Scores

The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections.

source: The Lancet

Summary

Development and Validation of Bloomy Prediction Scores For 14-Day and 6-Month Mortality In Hospitalised Adults With Bloodstream Infections

A Multicentre, Prospective, Cohort Study.

[Posted 20/Apr/2022]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections.

BACKGROUND: The burden of bloodstream infections remains high worldwide and cannot be confined to short-term in-hospital mortality. Study aimed to develop scores to predict short-term and long-term mortality in patients with bloodstream infections.

DETAILS: The Bloodstream Infection due to Multidrug-resistant Organisms: Multicenter Study on Risk Factors and Clinical Outcomes (BLOOMY) study is a prospective, multicentre cohort study at six German tertiary care university hospitals to develop and validate two scores assessing 14-day and 6-month mortality in patients with bloodstream infections. We excluded patients younger than 18 years or who were admitted to an ophthalmology or psychiatry ward. Microbiological, clinical, laboratory, treatment, and survival data were prospectively collected on day 0 and day 3 and then from day 7 onwards, weekly. Participants were followed up for 6 months. All patients in the derivation cohort who were alive on day 3 were included in the analysis. Predictive scores were developed using logistic regression and Cox proportional hazards models with a machine-learning approach. Validation was completed using the C statistic and predictive accuracy was assessed using sensitivity, specificity, and predictive values. Between Feb 1, 2017, and Jan 31, 2019, 2568 (61.5%) of 4179 eligible patients were recruited into the derivation cohort. The in-hospital mortality rate was 23.75% (95% CI 22.15-25.44; 610 of 2568 patients) and the 6-month mortality rate was 41.55% (39.54-43.59; 949 of 2284). The model predictors for 14-day mortality (C statistic 0.873, 95% CI 0.849-0.896) and 6-month mortality (0.807, 0.784-0.831) included age, body-mass index, platelet and leukocyte counts, C-reactive protein concentrations, malignancy (ie, comorbidity), in-hospital acquisition, and pathogen. Additional predictors were, for 14-day mortality, mental status, hypotension, and the need for mechanical ventilation on day 3 and, for 6-month mortality, focus of infection, in-hospital complications, and glomerular filtration rate at the end of treatment. The scores were validated in a cohort of 1023 patients with bloodstream infections, recruited between Oct 9, 2019, and Dec 31, 2020. The BLOOMY 14-day score showed a sensitivity of 61.32% (95% CI 51.81-70.04), a specificity of 86.36% (83.80-88.58), a positive predictive value (PPV) of 37.57% (30.70-44.99), and a negative predictive value (NPV) of 94.35% (92.42-95.80). The BLOOMY 6-month score showed a sensitivity of 69.93% (61.97-76.84), a specificity of 66.44% (61.86-70.73), a PPV of 40.82% (34.85-47.07), and a NPV of 86.97% (82.91-90.18).

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Copyright © Elsevier Ltd. All rights reserved.

Source: Tacconelli, E., Gopel, S., Gladstone, B. P., et al. (2022). Development and Validation of Bloomy Prediction Scores For 14-Day and 6-Month Mortality In Hospitalised Adults With Bloodstream Infections: A Multicentre, Prospective, Cohort Study. The Lancet. 2022; 22(5): 731-741.Published: May 1, 2022. DOI: 10.1016/S1473-3099(21)00587-9.



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