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Authors

Cryptococcus neoformansmost commonly infects personswith an underlying T-cellimmunodeficiency. It hasbeen nicknamed the "sugarcoatedkiller" because it cancause a devastating disseminatedillness in immunosuppressedpatients. C neoformansrarely causes primaryinfection in an immunocompetentpatient. We present acase of pulmonary cryptococcosisthat occurred in an otherwisehealthy man.

Cryptococcal cavitary pneumonia in an immunocompetent patient

A 76-year-old woman seeks your attention for an asymptomatic “red spot” on her neck. She has a history of multiple non-melanoma skin cancers.

Squamous cell carcinoma in situ (Bowen  disease)

Lichenoid keratosis (an inflammatory variant of seborrheic keratosis)

A 76-year-old woman seeks your attention for an asymptomatic “red spot” on her neck. What does this look like to you?

Clinical Topics

What's This "Red Spot"?

A 5-year-old boy with a history of atopic dermatitis since 6 weeks of age, presents with a rash around his mouth that has been present for approximately 1 year. The patient’s mother reports that desonide topical cream was applied to the affected area for about 5 days, which initially resulted in improvement, however the rash returned after this medication was discontinued. The rash also recently improved after the patient took amoxicillin for an infection. She also notes that the patient has been licking his lips more frequently.

On examination there is an erythematous papulopustular eruption restricted to the perioral region, with sparing of the vermillion border. Mild hyperpigmentation is noted on the patient’s neck. There is no active involvement of other areas of the body.

The eruption has been present for 1 year and is restricted to the perioral region. What is included in your differential? 

Rash Around the Mouth of a 5-year-old Child

Less than a week after the FDA granted traditional approval to Eisai’s antiamyloid agent lecanemab (Leqembi), the Alzheimer’s Clinical Trial Consortium announced a new study, AHEAD (NCT04468659), that will assess the agent in individuals with preclinical Alzheimer disease (AD) who have no cognitive symptoms present.

Funded by the National Institutes of Health, the trial aims to enroll 1165 participants from North America and to evaluate whether lecanemab can help stave off the memory problems caused by AD. The study will comprise than 100  locations worldwide and use change from baseline in Preclinical Alzheimer Cognitive Composite 5 (PACC5) score and change in amyloid PET standard uptake value ratio (SUVr) over a 216-week period as the primary end points.

"The advances in treating people who already have cognitive problems due to Alzheimer disease are incredibly exciting, but to have the greatest impact on the public health crisis of Alzheimer's disease, we may need treatments to start even earlier,” Reisa Sperling, MD, professor of neurology at Harvard Medical School, and co-principal investigator of AHEAD, said in a statement. "The AHEAD Study is the first study to test whether removing amyloid plaques from the brain before symptoms are evident could be effective at preventing memory problems from the beginning."

The study will enroll healthy individuals age 55 to 80 years old with a plasma biomarker result that is predictive of intermediate or elevated brain amyloid. Those aged 55 to 64 years, a demographic less likely to have amyloid positivity, must have 1 of the following additional risk factors before screening: first degree relative diagnosed with dementia before age 75; known to possess at least 1 apolipoprotein e4 variant allele; or, known before screening to have elevated brain amyloid according to previous PET or cerebrospinal fluid testing.

Eligible patients must have a Global Clinical Dementia Rating score of 0 at screening, with a Mini-Mental State Examination score greater than or equal to 27. The study will exclude women who are breastfeeding or pregnant at screening, females of childbearing potential, those with a history of transient ischemic attacks, stroke, or seizures within 12 months of screening. Other exclusion criteria include current or history within the past 2 years of psychiatric diagnosis or symptoms that, in the opinion of the investigator, could interfere with study procedures.

AHEAD is split into 2 trials, the A45 trial, which will assess whether lecanemab is superior to placebo on change in PACC5, and the A3 trial, comparing the 2 arms in reduction of amyloid accumulation based on PET scans. Secondary outcomes of A45 include change in amyloid PET SUVr, tau PET SUVr, and Cognitive Function Index; the sole registered secondary outcome of A3 will be change in tau PET SUVr.

In the A45 trial, participants will receive lecanemab 5 mg/kg, administered intravenously, every 2 weeks from week 0 to 6, followed by 10 mg/kg every 2 weeks from week 8 to 94, and 10 mg/kg every 4 weeks from week 96 to 216. Those in the A3 trial will receive lecanemab 5 mg/kg every 4 weeks from week 0 to 4, then 10 mg/kg every 4 weeks from week 8 to 216.

Lecanemab, an antiamyloid therapy, was granted traditional approval based on results from the phase 3 Clarity AD trial (NCT03887455), which further confirmed and verified its clinical benefit. With the approval, it became the second early AD treatment to get FDA greenlight in the past 20 years following the contentious approval of aducanumab (Aduhelm; Eisai/Biogen) in 2021, which remains under conditional approval.3

Lecanemab comes with a boxed warning and is contraindicated for patients with serious hypersensitivity to lecanemab-irmb or to any of its inactive ingredients. The prescribing information states that testing for apolipoprotein e4 status should be performed before starting treatment with lecanemab to inform the risk of developing amyloid-related imaging abnormalities (ARIA).

REFERENCES
1. The AHEAD study is testing lecanemab at the stage of preclinical Alzheimer’s disease. News release. Alzheimer’s Clinical Trials Consortium. July 11, 2023. Accessed July 12, 2023. 

https://www.prnewswire.com/news-releases/the-ahead-study-is-testing-lecanemab-at-the-stage-of-preclinical-alzheimers-disease-301874434.html


2. AHEAD 3-45 study: a study to evaluate efficacy and safety of treatment with lecanemab in participants with preclinical Alzheimer’s disease and elevated amyloid and also in participants with early preclinical Alzheimer’s disease and intermediate amyloid. Clinicaltrials.gov. Updated June 28, 2023. Accessed July 12, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04468659
3. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. FDA. News release. July 6, 2023. Accessed July 12, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval

The AHEAD study program will use plasma biomarker screening, novel PET agents, and other unique approaches to assessing lecanemab effect at the earliest stage of disease. 


Lecanemab Will Be Evaluated in Preclinical Alzheimer Disease with Novel Study Design 

The latest data from the Clarity AD open label long-term extension (OLE) trial of lecanemab in adults with early-stage Alzheimer disease showed that among study participants who had low baseline levels of amyloid accumulation and  received continuous lecanemab treatment for 3 years, nearly half (46%) either improved or showed no decline in symptoms and one-third (33%) showed improvement from baseline on the CDR-SB, a scale of global function and cognition, according to a news release from Eisai issued this morning

Similar findings were reported for performance on the ADAS-Cog14 measurement scale, according to an Eisai news release, with 46% of participants showing symptom improvement or no further decline and 43% showing improvement. The results were consistent for scores on the ADCS MCI-ADL, with half (51%) of the participants scored as improved or without decline (51%) and essentially half (48%) scored as showing improvement. Given the early stage of disease reflected by this group of Clarity AD participants, ie, with no or low tau (no tau/low tau) accumulation and low amyloid accumulation, the findings suggest that lecanemab treatment initiated earlier in adults diagnosed with AD "may have a positive impact on disease progression...and may provide continued benefits to patients with early AD over the long term," Eisai stated.

These findings, along with other study outcomes, were presented at the 17th Clinical Trials for Alzheimer’s Disease Conference, October 29 to November 1, in Madrid, Spain.  

Eisai reported early results of the OLE following the original phase 3 Clarity AD trial of lecanemab at the July 2024Alzheimer's Association International Conference (AAIC).

 Findings presented during the meeting showed a mean change from baseline CDR-SB in participants treated with lecanemab of -0.45 at 18 months. The change doubled at 36 months, to -0.95, compared to "a prespecified natural history cohort of AD," the company said.

 The reduction in relative risk for progression to the next stage of disease severity was 30%. The findings from a Clarity AD substudy using tau positron-emission tomography (PET) were also presented at AAIC. The results showed that after 3 years of continuous treatment with lecanemab, more than half (59%) of the participants with no tau/low tau levels at baseline had improvement in symptoms or no decline and 51% experienced improvement from baseline on the CDR-SB scale.

Investigators reported no new safety findings among Clarity AD participants treated with lecanemab over the 3-year OLE. Most amyloid-related imaging abnormalities (ARIA) were seen during the first 6 months of treatment with subsequent rates low and similar to ARIA rates observed among participants treated with placebo during the study's placebo-controlled phase.

 With regards to the incidence of ARIA by ApoEε4 status during the continuous treatment, the incidence was higher in ApoE4 homozygotes than in heterozygotes or non-carriers, but rates of new ARIA decreased after the completion of the 18-month core study as treatment continued, regardless of ApoEε4 status, according to the company statement.

Eisai’s supplemental biologics license application

New data from phase 3 Clarity AD OLE trial show sustained treatment benefit among participants with low baseline tau and brain amyloid with no new safety signals.  

New Phase 3 Data Suggest Benefits of Early Lecanemab Initiation on Alzheimer Disease Progression, Support Long-Term Safety 

Dorothea Direso, DO

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