'Key Abortion Paper Retracted'

 A journal and publisher have retracted three papers about abortion, including one that has been used in court cases to support the suspension of FDA approval for mifepristone, aka an "abortion pill."

Sage, the publisher of Health Services Research and Managerial Epidemiology, announced the retractions yesterday and posted a retraction notice covering the three articles.

For one of those articles, initially flagged by a reader, "an independent reviewer with expertise in statistical analyses evaluated the concerns and opined that the article's presentation of the data in Figures 2 and 3 leads to an inaccurate conclusion and that the composition of the cohort studied has problems that could affect the article's conclusions," according to the notice.

The notice also said Sage "confirmed that all but one of the article's authors had an affiliation with one or more of Charlotte Lozier Institute, Elliot Institute, and American Association of Pro-Life Obstetricians and Gynecologists, all pro-life advocacy organizations, despite having declared they had no conflicts of interest when they submitted the article for publication or in the article itself." 

One of the peer reviewers, Sage learned, "was affiliated with Charlotte Lozier Institute at the time of the review," leading the publisher and journal editor to determine "the peer review for initial publication was unreliable." That referee also reviewed the other two now-retracted papers, according to Sage.

James Studnicki, the lead author of the three papers, told Retraction Watch the retractions were "a blatant attempt to discredit excellent research which is incongruent with a preferred abortion narrative." He told The Daily Wire, a conservative news outlet that was first to report on the retractions, the move was "completely unjustified." The Daily Wire notes that "The Supreme Court is set to hear arguments in March on the legality of restricting the abortion pill based on [Judge Matthew] Kacsmaryk's ruling, proceedings that will certainly be impacted by the retractions."

Sage had subjected one of the papers to an expression of concern in August 2023, saying they were investigating "potential issues regarding the representation of data in the article and author conflicts of interest" after being alerted by a reader. As News From The States reported then, the notice came after Chris Adkins, a professor at South University who teaches pharmaceutical sciences, raised concerns with Sage. As News From The States noted in August:

Kacsmaryk leaned hard on a 2021 study that was designed, funded and produced by the research arm of one of the most powerful anti-abortion political groups in the U.S. The judge cited this paper — which looked at Medicaid patients' visits to the emergency room within 30 days of having an abortion — to justify that a group of anti-abortion doctors and medical groups have legal standing to force the FDA to recall mifepristone.

In a point-by-point response to Sage's critiques of the paper sent to the publisher in November and now shared with Retraction Watch, Studnicki and colleagues pointed out they had noted their affiliations in the original manuscript and the then-proposed retractions "misrepresent ICMJE disclosure standards," referring to the International Committee of Medical Journal Editors' guidelines. They also call some of the post-publication peer reviewers' critiques "factually incorrect" and "unfounded." They conclude:

• No single specific finding in any of the three papers has been explicitly challenged, let alone invalidated.
• There is no evidence of a major error, miscalculation, fabrication, or falsification.
• There is no breach of any of the COPE guidelines that could permit Sage to retract any of our published papers.
• The retraction of any of these papers, let alone all three, is demonstrably unwarranted.

Adkins told Retraction Watch he is "pleased the journal approached my concerns with legitimate and serious consideration." He continued:

It is reassuring that my initial concerns with the 2021 Studnicki et al. article were verified and affirmed by other experts. Despite the length of time spanning my initial communications with the journal and today's retractions, I understand that thorough investigations and re-review processes take time. Given that these now-retracted articles have been excessively cited by parties involved in ongoing federal judicial cases, now positioned before the SCOTUS, Sage's retractions should help our courts remain informed by the highest standards and quality in scientific and medical evidence.

Update, 2/6/24, 2100 UTC: We note that — contrary to best industry practices described by the Committee on Publication Ethics — Sage has removed the original versions of the articles. They are available at these links:

• "A Longitudinal Cohort Study of Emergency Room Utilization Following Mifepristone Chemical and Surgical Abortions, 1999–2015"
• "Doctors Who Perform Abortions: Their Characteristics and Patterns of Holding and Using Hospital Privileges"
• "A Post Hoc Exploratory Analysis: Induced Abortion Complications Mistaken for Miscarriage in the Emergency Room are a Risk Factor for Hospitalization"

DISCLOSURE: Adam Marcus, a cofounder of Retraction Watch, is an editor at Medscape.

https://www.medscape.com/s/viewarticle/key-abortion-paper-retracted-2024a10002pi

Oral IL-23 Inhibitor Calms Moderate to Severe Psoriasis

 A novel oral drug for plaque psoriasis that targets the same inflammatory pathway as currently available parenteral therapies showed promise for treating moderate to severe disease in a phase 2 dose-finding trial.

Among 255 patients with plaque psoriasis randomly assigned to receive either placebo or an oral interleukin (IL)–23 receptor antagonist peptide dubbed JNJ-77242113 (Janssen), 79% of those who were assigned to the oral agent at the highest dose of 100 mg twice daily had a reduction in the Psoriasis Area and Severity Index (PASI) score at week 16 of at least 75% (PASI 75) compared with 9% of patients assigned to placebo, reported Robert Bissonnette, MD, from Innovaderm Research in Montreal, Quebec, Canada, and colleagues.

"The level of reduction of psoriasis that was observed with higher doses of JNJ-77242113 at week 16 was similar in magnitude to the responses seen with several of the injectable biologics that are currently approved for psoriasis," investigators in the FRONTIER 1 trial wrote in The New England Journal of Medicine (NEJM).

The investigators noted that among patients assigned to the 100-mg dose of the active drug, 60% had a PASI 90 response, which compares favorably with that seen in phase 3 trials of two other orally available therapies for psoriasis, deucravacitinib (Sotyktu) and apremilast (Otezla). They cautioned, however, against drawing any further inferences from these data, because these agents have not been tested head-to-head against JNJ-77242113 in comparison trials.

Targets IL-23 and IL-17

The investigational agent is an oral IL-23 receptor antagonist peptide that selectively blocks IL-23 proximal signaling as well as the production of downstream inflammatory cytokines such as IL-17, according to the authors.

"Modulation of the interleukin-23 pathway with the use of monoclonal antibodies has shown efficacy in the treatment of psoriasis and is considered to be associated with a more favorable safety profile than older oral therapies (eg, cyclosporine, acitretin, methotrexate, and dimethyl fumarate)," the investigators wrote.

Currently available biologic agents targeting IL-23 include guselkumab (Tremfya), risankizumab (Skyrizi) and tildrakizumab (Ilumya). These agents require intravenous or subcutaneous administration, whereas JNJ-77242113 is taken orally, giving it a theoretical advantage in terms of patient preference.

The novel drug must be taken twice daily on an empty stomach at least 2 hours before food or drink, and those who take it must wait an additional 30 minutes to eat or drink after taking the drug. (Medscape Medical News has learned that in planned phase 3 studies, patients will be instructed to take a double daily dose on awakening and then wait 30 minutes for eating or drinking.)

'Profoundly Effective'

The results of this study have convinced at least one former skeptic of the efficacy of the novel agent.

"They asked me to do the trial, and I turned it down, because I didn't believe it would work," said Mark G. Lebwohl, MD, dean for Clinical Therapeutics at the Icahn School of Medicine at Mount Sinai and professor and chairman emeritus of the Department of Dermatology at Mount Sinai Medicine in New York, NY.

In an interview with Medscape Medical News, Lebwohl said that he was initially dubious that a peptide, a short chain of amino acids directed against a receptor, could be effective because it would likely be digested in the intestinal tract.

"Indeed, more than 99% of it is digested, but the data show that the tiny amount that gets through is profoundly effective," he said.

"I would never have believed that this was going to work — and it did," Lebwohl added.

He has signed on as an investigator in the currently recruiting phase 3 ICONIC-LEAD trial, in which JNJ-77242113 will be tested against placebo in adolescents and adults with moderate to severe plaque psoriasis. 

In an editorial accompanying the study in NEJM, Joel M. Gelfand, MD, MSCE, vice chair of clinical research and medical director of the Dermatology Clinical Studies Unit at the University of Pennsylvania in Philadelphia, noted that if confirmed in larger studies, the PASI 90 rate at the highest dose "would be similar to the most effective injectable biologics," with no evidence of increased adverse events at higher doses.

"However, two occurrences of infection (COVID-19 and an infected cyst) and a suicide attempt were reported as serious adverse events; larger trials will be needed to determine whether such events are attributable to chance, psoriasis itself, or inhibition of interleukin-23 signaling," cautioned Gelfand, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania.

Lebwohl told Medscape Medical News that currently available IL-23 signaling inhibitors have an excellent safety profile and that the investigational oral agent also appears to be very safe.

"It's seeing a target whose effects are known, and the effects are all good and not bad," he said.

FRONTIER-1 Details

The investigators enrolled eligible adults aged 18 years or older who had moderate to severe plaque psoriasis as defined by an Investigator's Global Assessment score ≥ 3, a total body-surface area of psoriasis involvement of at least 10%, and a PASI score ≥ 12 who had received their diagnosis of plaque psoriasis at least 6 months before starting the trial. The participants had to be candidates for phototherapy or systemic psoriasis therapy.

Patients were randomly assigned to the active agent at doses of 25 mg once or twice daily, 50 mg once daily, or 100 mg once or twice daily for 16 weeks. 

There was a clear dose response, with 37% of patients assigned to 25-mg once-daily dose meeting the primary endpoint of a PASI 75 response at week 16 compared with 51% of those assigned to the 25-mg twice-daily dose, 58% assigned to 50-mg once-daily dose, 65% assigned to 100-mg once-daily dose, and 79% assigned to 100-mg twice-daily dose (P for dose response < .001).

As noted previously, 9% of patients in the placebo group had a PASI 75 response at week 16.

After a mean duration of 15.9 weeks, adverse events after the first dose of JNJ-

77242113 (all dose groups were pooled for the safety analysis) were reported in 47% of patients on the 25-mg once-daily dose, 49% on 25-mg twice-daily dose, 60% on 50-mg once-daily dose, 44% on 100-mg once-daily dose, and 62% on 100-mg twice-daily dose. Adverse events after the first dose occurred in 51% of patients assigned to placebo.

The incidence of adverse events did not increase significantly with successively higher dose levels.

As noted by Gelfand in his editorial, there were three serious adverse events, all occurring in patients on the active drug: a case of COVID-19 in one patient and a suicide attempt in one patient, both in the 100-mg once-daily dose group, and an infected cyst in the 50-mg once-daily group. All three events were determined by the principal investigator and the sponsor to be unrelated to JNJ-77242113. 

There were no reports of deaths, major adverse cardiovascular events, or incident cancers during the trial.

The study was supported by Janssen Research and Development. Bissonnette disclosed institutional research funding and advisory board participation and honoraria with Janssen. Gelfand disclosed consulting for Janssen Biotech. Lebwohl disclosed institutional research funding from Janssen but no personal fees. 

https://www.medscape.com/viewarticle/oral-il-23-inhibitor-calms-moderate-severe-psoriasis-2024a10002q6

Preventing Autoimmune Diseases: New Findings on Vitamin D, Omega-3

 Two years after the end of a randomized trial that showed a benefit of daily vitamin D and omega-3 fatty acid (n-3 FA) supplementation for reducing risk for autoimmune diseases, the salubrious effects of daily vitamin D appear to have waned after the supplement was discontinued, while the protection from n-3 lived on for at least 2 additional years.

As previously reported, the randomized VITAL, which was designed primarily to study the effects of vitamin D and n-3 supplementation on incident cancer and cardiovascular disease, also showed that 5 years of vitamin D supplementation was associated with a 22% reduction in risk for confirmed autoimmune diseases, and 5 years of n-3 FA supplementation was associated with an 18% reduction in confirmed and probable incident autoimmune diseases.

Now, investigators Karen H. Costenbader, MD, MPH, of Brigham & Women's Hospital in Boston, Massachusetts, and colleagues reported that among 21,592 participants in VITAL who agreed to be followed for an additional 2 years after discontinuation, the protection against autoimmune diseases from daily vitamin D (cholecalciferol; 2000 IU/d) was no longer statistically significant, but the benefits of daily marine n-3 FAs (1 g/d as a fish-oil capsule containing 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) remained significant.

"VITAL observational extension results suggest that vitamin D supplementation should be given on a continuous basis for long-term prevention of [autoimmune diseases]. The beneficial effects of n-3 fatty acids, however, may be prolonged for at least 2 years after discontinuation," they wrote in an article published on January 25 in Arthritis & Rheumatology.

Costenbader told Medscape Medical News that the results of the observational extension study suggest that the benefits of vitamin D "wear off more quickly, and it should be continued for a longer period of time or indefinitely, rather than only for 5 years."

In addition to the disparity in the duration of the protective effect, the investigators also saw differences in the effects across different autoimmune diseases.

"The protective effect of vitamin D seemed strongest for psoriasis, while for omega-3 fatty acids, the protective effects were strongest for rheumatoid arthritis and inflammatory bowel disease," she said.

Mixed Effects

In an interview with Medscape Medical News, Janet Funk, MD, MS, vice chair of research in the Department of Medicine and professor in the School of Nutritional Science and Wellness at the University of Arizona, Tucson, Arizona, who was not involved in the study, saidthat the results suggest that while each supplement may offer protection against autoimmune diseases, the effects are inconsistent and may not apply to all patients.

"I think the VITAL extension results suggest that either supplement (or both together) may have benefits in reducing risk of autoimmune diseases, including possible persistent effects posttreatment, but that these effects are nuanced (ie, only in normal weight post-vitamin D treatment) and possibly not uniform across all autoimmune diseases (including possible adverse effects for some — eg, inverse association between prior omega-3 and psoriasis and tendency for increased autoimmune thyroid disease for vitamin D), although the study was not powered sufficiently to draw disease-specific conclusions," she said.

In an editorial accompanying the study, rheumatologist Joel M. Kremer, MD, of Albany Medical College and the Corrona Research Foundation in Delray Beach, Florida, wrote that "[T]he studies by Costenbader, et al. have shed new light on the possibility that dietary supplements of n-3 FA [fatty acid] may prevent the onset of [autoimmune disease]. The sustained benefits they describe for as long as 2 years after the supplements are discontinued are consistent with the chronicity of FA species in cellular plasma membranes where they serve as substrates for a diverse array of salient metabolic and inflammatory pathways."

VITAL Then

To test whether vitamin D or marine-derived long-chain n-3 FA supplementation could protect against autoimmune disease over time, Costenbader and colleagues piggybacked an ancillary study onto the VITAL trial, which had primary outcomes of cancer and cardiovascular disease incidence.

A total of 25,871 participants were enrolled, including 12,786 men aged 50 and older and 13,085 women aged 55 and older. The study had a 2 × 2 factorial design, with patients randomly assigned to vitamin D 2000 IU/d or placebo and then further randomized to either 1 g/d n-3 FAs or placebo in both the vitamin D and placebo primary randomization arms.

In multivariate analysis adjusted for age, sex, race, and other supplement arm, vitamin D alone was associated with a hazard ratio (HR) of 0.68 (P = .02) for incident autoimmune disease, n-3 alone was associated with a nonsignificant HR of 0.74, and the combination was associated with an HR of 0.69 (P = .03). However, when probable incident autoimmune disease cases were included, the effect of n-3 became significant, with an HR of 0.82.

VITAL Now

In the current analysis, Costenbader and colleagues reported observational data on 21,592 VITAL participants, a sample representing 83.5% of those who were initially randomized, and 87.9% of those who were alive and could be contacted at the end of the study.

As in the initial trial, the investigators used annual questionnaires to assess incident autoimmune diseases during the randomized follow-up. Participants were asked about new-onset, doctor-diagnosed rheumatoid arthritis, polymyalgia rheumatica, psoriasis, autoimmune thyroid disease, and inflammatory bowel disease. Participants could also write in any other new autoimmune disease diagnoses.

There were 236 new cases of confirmed autoimmune disease that occurred since the initial publication of the trial results, as well as 65 probable cases identified during the median 5.3 years of the randomized portion, and 42 probable cases diagnosed during the 2-year observational phase.

The investigators found that after the 2-year observation period, 255 participants initially randomized to receive vitamin D had a newly developed confirmed autoimmune disease, compared with 259 of those initially randomized to a vitamin D placebo. This translated into a nonsignificant HR of 0.98.

Adding probable autoimmune cases to the confirmed cases made little difference, resulting in a nonsignificant adjusted HR of 0.95.

In contrast, there were 234 confirmed autoimmune disease cases among patients initially assigned to n-3, compared with 280 among patients randomized to the n-3 placebo, translating into a statistically significant HR of 0.83 for new-onset autoimmune disease with n-3.

Costenbader and colleagues acknowledged that the study was limited by the use of doses intended to prevent cancer or cardiovascular disease and that higher doses intended for high-risk or nutritionally deficient populations might reveal larger effects of supplementation. In addition, they noted the difficulty of identifying the timing and onset of incident disease, and that the small number of cases that occurred during the 2-year observational period precluded detailed analyses of individual autoimmune diseases.

The study was funded by grants from the National Institutes of Health. Costenbader, Funk, and Kremer reported no relevant financial relationships.

https://www.medscape.com/viewarticle/preventing-autoimmune-diseases-new-findings-vitamin-d-omega-2024a10002nc

'Selecting Alzheimer's Patients for Anti-Amyloid Therapy'

 Recently approved disease-modifying treatments for Alzheimer's disease have created a sudden demand, but these and other drugs in the pipeline are not for all patients with clinical Alzheimer's symptoms, experts said.

"Alzheimer's disease has been recognized on clinical grounds for many decades, but the availability of targeted treatments has increased the importance of clinical biomarkers to establish the diagnosis with certainty," said Lyell Jones Jr., MD, of the Mayo Clinic in Rochester, Minnesota, who co-authored the American Academy of Neurology (AAN) Quality Committee's guidance about the drugsopens in a new tab or window.

The new anti-amyloid monoclonal antibodies "are specifically targeted for patients with Alzheimer's disease, not other causes of dementia such as dementia with Lewy bodies, frontotemporal dementia, or vascular cognitive impairment," Jones emphasized.

The AAN Quality Committee developed its report about Alzheimer's anti-amyloid drugs given "the urgent need to inform clinicians about these novel therapies," he added.

To date, two monoclonal antibodies targeting amyloid in early Alzheimer's disease have been approved by the FDA: lecanemabopens in a new tab or window (Leqembi), which received full approval in 2023; and aducanumabopens in a new tab or window (Aduhelm), which received accelerated approval in 2021 and is now being discontinuedopens in a new tab or window by the drugmaker. The FDA is expected to decide on full approval for a third agent in the class, donanemabopens in a new tab or window, early in 2024.

"Patients and families should be aware that these treatments involve careful patient selection, require a commitment to monitoring over time, and may be incompatible with other common therapies in this patient population such as anticoagulation," Jones pointed out.

The anti-amyloid treatments approved so far share the requirement that treatment candidates are patients with mild cognitive impairment or mild dementia due to Alzheimer's disease -- the same population used in clinical trials -- not people with presymptomatic Alzheimer's or moderate/severe dementia. Both mild cognitive impairment and mild dementia can be characterized by objective evidenceopens in a new tab or window of cognitive impairment.

Evidence of amyloid is also required. In the phase III trials, amyloid PET scans or cerebrospinal fluid (CSF) tests fulfilled this requirement, though acceptable blood tests may be available in the future. "Imaging or other biomarkers assessing tau protein deposition may help identify patients most likely to benefit from the therapies," Jones noted.

Pretreatment evaluations can help identify candidates with acceptable risk for adverse events. "The primary risks of anti-amyloid monoclonal antibody therapies that clinicians should be familiar with are ARIA [amyloid-related imaging abnormalities]," Jones said.

"These come in two categories, ARIA associated with cerebral edema [ARIA-E], and ARIA associated with hemorrhage [ARIA-H]," he continued. "These are usually asymptomatic but occasionally lead to clinically meaningful complications, and therefore require careful patient screening, selection, and monitoring clinically and with imaging."

Lecanemab prescribing information carries a boxed warningopens in a new tab or window about ARIA. In the phase III CLARITY-AD trialopens in a new tab or window, 12.6% of participants treated with lecanemab had ARIA-E. Most ARIA-E events were asymptomatic, occurred in the first 3 months of the treatment period, and resolved within 4 months after they were detected. The incidence of isolated ARIA-H was 8.9%, which occurred throughout the trial.

"MRI is useful for risk stratification by screening for microhemorrhages, which increase the risk of complications of the anti-amyloid monoclonal therapies, and also for excluding other potential causes of cognitive impairment," Jones noted. In addition to a screening MRI, candidates will need additional MRIs for treatment monitoring and for any urgent studies if adverse events occur.

Other important factors to consider include patients' APOE genotype and medical history. "Patients with APOE4, particularly those who have two copies of the gene, are at high risk for ARIA," noted Jeffrey Cummings, MD, ScD, of the University of Las Vegas, who led the independent Alzheimer's Disease and Related Disorders Therapeutics Work Group that produced appropriate use recommendationsopens in a new tab or window for lecanemab.

"Our appropriate use recommendations suggest testing all patients being considered for monoclonal antibody therapy for their APOE genotype, so that an informed risk discussion can occur between the clinician and the potential recipient of therapy," Cummings said.

Medical history includes reviewing all other medications, including anticoagulants, that patients are using. The lecanemab labelopens in a new tab or window cautions against using blood thinners while on the medication.

"There may be a slight increase in ARIA in patients on lecanemab and anticoagulants, and our appropriate use recommendations currently suggest not using lecanemab in patients who require anticoagulants. This may be revised as new data accumulate," Cummings said.

"As far as we can tell, aspirin poses no additional risk of ARIA, and this would not be a factor in selecting patients for treatment with monoclonal antibodies," he added.

While much patient selection guidance comes from data in phase III anti-amyloid trials, the AAN committee noted that a flexible interpretation may be appropriate for some treatment candidates. Some patients outside the age groups or Mini-Mental Status Examination (MMSE) scores used in the lecanemab phase III trial might be considered reasonable candidates for therapy, including younger patients with sporadic Alzheimer's disease, the committee said.

The key is judicious patient selection, observed AAN Quality Committee member Vijay Ramanan, MD, PhD, also of the Mayo Clinic in Minnesota. "This places a premium on clinicians having a strong working understanding of treatment indications, goals, side effects and lifestyle impacts, and alternatives, and utilizing that foundation to engage in shared decision-making with patients and caregivers to chart the best path forward," he said.

Disclosures

Jones reported serving in a voluntary capacity on boards of directors of the Mayo Clinic ACO and the American Academy of Neurology Institute. He is the editor-in-chief of Continuum.

Cummings has provided consultation to Acadia, Actinogen, Acumen, Alpha Cognition, Aprinoia, AriBio, Artery, Biogen, BioVie, Cassava, Cerecin, Diadem, EIP Pharma, Eisai, GemVax, Genentech, GAP Innovations, Janssen, Jocasta, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, PRODEO, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sunbird Bio, Suven, SynapseBio, TrueBinding, Vaxxinity, and Wren Pharmaceutical. He reported grant support from the NIH and others.

Ramanan reported he is a site clinician in the Eisai-supported AHEAD 3-45 trial, the co-principal investigator for a trial sponsored by the Alzheimer's Association, and a site clinician for trials supported by the Alzheimer's Treatment and Research Institute at USC and Transposon Therapeutics. He reported research funding from the NIH and the Mangurian Foundation.

https://www.medpagetoday.com/spotlight/alzheimers-disease/108619

Mexico Surgery Clinic Mold Meningitis Cases Caused Severe Injury to Brain Stem

 An outbreak of iatrogenic Fusarium solani meningitis led to nine deaths resulting from "devastating" injury to the brain stem's blood supply, a report showed.

The nine deaths occurred among 13 patients hospitalized for meningitis in southeastern Texas, who had undergone surgery with epidural anesthesia at two clinics in Matamoros, Mexico, reported Nora Strong, MD, of the McGovern Medical School at the University of Texas Health Science Center at Houston, and colleagues in the New England Journal of Medicineopens in a new tab or window.

Several patients responded to variable combinations of the investigational antifungal fosmanogepix, steroids, and/or surgical interventions.

"This was really important to document because the treatment is not just antifungals and not just steroids -- it was a combination of not only existing antifungals, but also novel antifungals, steroids, and advanced neurovascular procedures that ultimately was able to rescue some of these poor women," co-author Luis Ostrosky-Zeichner, MD, also of the McGovern Medical School, told MedPage Today.

The CDC first issued a health advisoryopens in a new tab or window about the F. solani outbreak on May 17, 2023.

Most of the affected individuals were young, female, and otherwise healthy, and had undergone surgery at the clinics from January to May 2023. Among U.S. residents who had traveled to Mexico for surgical procedures, Mexican and U.S. authorities identified 185 people from 23 states who were potentially exposed to the fungus. Of those patients, there were nine suspected cases, 14 probable cases, and 10 confirmed cases. To date, 12 patients with probable or confirmed F. solani meningitis associated with the outbreak have died.

Iatrogenic meningitis due to fungal inoculation is not new, the authors noted. They cited a 2012 outbreakopens in a new tab or window in Massachusetts involving meningitis and paraspinal and joint infections due to compounded injectable medications contaminated with Exserohilum rostratum, and another outbreak of Fusarium meningitis associated with epidural anesthesia in Durango, Mexico in 2022. The latter resulted in 41 deaths out of 80 cases.

Are these types of outbreaks becoming more common? George Thompson, MD, of the University of California Davis in Sacramento doesn't think so. "We're doing more interventional procedures on patients than we ever have in the past. So it would make sense that a single contamination event can lead to disastrous consequences," he told MedPage Today.

Thompson suggested that healthcare providers maintain a high index of suspicion. "If you see an unusual infection where you don't think it should be, those are circumstances where you should reach out to your local health agency to see if others are seeing the same thing," he said.

That is how the current F. solani meningitis outbreak first came to attention, he noted. "Someone posted on the Emerging Infections Network and someone else said, 'oh, I just saw a case like this.'"

Of the patients in this report, mean age was 31, and 12 of the 13 patients were women. The median time from symptom onset to hospitalization among the 13 patients was 39 days. Presenting symptoms were indicative of meningitis, and eight of 10 patients with measured opening pressures had elevated pressure.

Initial testing of cerebrospinal fluid (CSF) in two patients revealed "yeast-like" fungal forms on initial gram staining, but notably all fungal, mycobacterial, and bacterial CSF cultures were negative. Panfungal polymerase chain reaction (PCR) testing of samples from 10 patients identified five positive patients. Of these, four had gene sequencing indicative of F. solani species, and in one patient, results indicated the phylum Ascomycota, which includes F. solani.

On imaging, there were striking abnormalities in the CSF-containing structures of the skull base and fungal invasion of the vertebrobasilar arterial system. Arterial stenosis and occlusion led to subarachnoid and intraparenchymal hemorrhage, with infarction of the brain stem and cerebellum, visible on contrast MRI.

Treatment included systemic antifungal therapy in all patients, except one who presented before the identification of the outbreak. The majority of patients (10) received glucocorticoids to treat vascular stenosis and vasculitis, and nine patients received intrathecal liposomal amphotericin B.

When tissue culture from one patient at autopsy identified F. solani species, and susceptibility testing found the mold was resistant to all approved antifungals in the U.S., compassionate use of the investigational antifungal fosmanogepix was initiated in four patients, of whom three survived.

Some patients also underwent various surgical procedures, such as CSF diversion, arterial stenting, angioplasty, or intra-arterial vasodilator infusion.

Patients frequently responded initially to antifungal therapy, but later deteriorated clinically and developed vascular complications. Angiography revealed irregularities in the posterior circulation vessels that progressed over time to severe segmental stenosis, aneurysm formation, occlusion, or rupture.

"Of the four patients who were surviving at the time of this report, three continued to take fosmanogepix monotherapy, and one was no longer receiving antifungal medication because of the adverse effects of the medications," Strong and colleagues wrote. Three of the four patients have no residual neurologic sequelae. One had a subarachnoid hemorrhage.

On autopsy, one patient had multiple vertebrobasilar thromboses and infarcts, with purulent material covering the base of the brain stem. Histopathology identified perivascular fungal hyphae around the basilar and pontine arteries, and in a perforating branch of the basilar artery. Findings in an autopsy of a second patient were similar.

Disclosures

Strong reported no relevant disclosures.

Ostrosky-Zeichner reported consulting to Cidara, Eurofins Viracor, F2G, Gilead Sciences, GSK, Pfizer, and Scynexis. His institution has received grants from Gilead Sciences, Pfizer, Pulmocide, and Scynexis.

Several other authors also reported ties to industry.

Thompson reported no relevant disclosures.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowStrong N, et al "Neurovascular complications of iatrogenic Fusarium solani meningitis" N Engl J Med 2024; DOI: 10.1056/NEJMoa2308192.

https://www.medpagetoday.com/infectiousdisease/generalinfectiousdisease/108628

Madrigal Resmetirom Poised to Become First NASH Treatment

 Groundbreaking results from a phase III trial have set the stage for resmetirom to become the first drug approved for patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

In the so-called MAESTRO-NASH study, NASH resolution with no worsening of fibrosis was achieved in 25.9% of patients who received the investigational drug at the 80-mg dose and 29.9% of those receiving the 100-mg dose, as compared with 9.7% of those in a placebo group (P<0.001 for both comparisons with placebo), reported Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio, and colleagues in the New England Journal of Medicineopens in a new tab or window (NEJM).

Resmetirom also improved liver fibrosis in patients with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3.

Fibrosis improvement by at least one stage with no worsening of non-alcoholic fatty liver disease (NAFLD) activity score was achieved in 24.2% of the patients in the 80-mg group and 25.9% of the 100-mg group versus 14.2% of placebo recipients (P<0.001 for both comparisons with placebo).

"This is the first treatment to achieve meaningful effects on both primary liver endpoints and [to be] reasonably likely to produce clinical benefit with these NASH patients," Harrison said last year at the European Association for the Study of the Liver (EASL) Congress, where the results were first presentedopens in a new tab or window.

Resmetirom is an oral, liver-directed, thyroid hormone receptor-β selective agonist designed to target key underlying causes of NASH (also referred to as metabolic dysfunction-associated steatohepatitis, or MASH) in the liver.

MAESTRO-NASH is planned to continue for 54 months in order to evaluate liver-related outcomes, including progression to cirrhosis, and is one of several studies evaluating the safety and efficacy of the drug for NASH. Developer Madrigal Pharmaceuticals is seeking accelerated approval of resmetirom for the treatment of NASH with liver fibrosis, and the FDA is expected to decideopens in a new tab or window by mid-March.

"When this drug is approved, it will honestly be a game changer," said Aleksander Krag, MD, PhD, of the University of Southern Denmark in Odense, during an EASL Congress press briefing. "Both the change in NASH and the ability to stabilize or improve fibrosis are really, really important and meaningful."

In an editorial accompanying the NEJM paperopens in a new tab or window, Kenneth Cusi, MD, of the University of Florida in Gainesville, called the results "encouraging to the field."

If FDA grants a conditional approval, "it may boost guideline recommendations to screen in primary care persons at high risk for NASH, especially to identify those with stage F2 or higher fibrosis (known as 'at risk' NASH)," he wrote.

Cusi also speculated that if resmetirom is approved to treat moderate to advanced fibrosis it will likely be expensive and lead to issues regarding access.

"How would resmetirom be used among less expensive medications that are effective for NASH and recommended in current guidelines?" he asked, and noted that since the estimated prevalence of stage F2 or F3 fibrosis is 12% to 15% among patients with type 2 diabetes -- a population with the highest risk of cirrhosis -- there could be as many as 4 to 5 million potential candidates for treatment in the U.S. alone.

"The large number of persons needing treatment will open a debate about treatment access and about how to best monitor treatment response and when to discontinue resmetirom in patients who do not have a response in order to avoid futile long-term therapy," Cusi said.

From March 2019 to July 2021, the phase III MAESTRO-NASHopens in a new tab or window trial randomly assigned patients 1:1:1 to resmetirom (at 80-mg or 100-mg doses) or to placebo. The 966 patients who had a fibrosis stage of F1B, F2, or F3 at baseline represented the primary population for evaluating safety and efficacy.

Regarding its safety, 92% of patients who received resmetirom and 93% of those who received placebo reported an adverse event, most of which were mild to moderate in severity. The most common of these were gastrointestinal, with nausea, vomiting, and diarrhea occurring more frequently with resmetirom than with placebo.

The incidence of serious adverse events was similar across the three groups -- 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.

Harrison and colleagues noted that the safety of long-term use of resmetirom still needs to be assessed in subsequent analyses.

Disclosures

The study was funded by Madrigal Pharmaceuticals.

Harrison reported multiple relationships with industry, including consulting for Madrigal.

Cusi reported relationships with 89 Bio, Aligos Therapeutics, AstraZeneca, Boehringer Ingelheim, Echosens North America, Eli Lilly, Inventiva, LabCorp, Madrigal, Novo Nordisk, Sagimet Biosciences, Siemens, and Terns Pharma.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowHarrison SA, et al "A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis" N Engl J Med 2024; DOI: 10.1056/NEJMoa2309000

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowCusi K "Selective agonists of thyroid hormone receptor beta for the treatment of NASH" N Engl J Med 2024; DOI:10.1056/NEJMe2314365

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