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Association of GLP-1 Receptor Agonists With Asthma and COPD Exacerbations in Patients With Type 2 Diabetes

Overview

Patients with concurrent type 2 diabetes and airway diseases such as asthma or chronic obstructive pulmonary disease (COPD) may experience fewer respiratory exacerbations when treated with glucagon-like peptide-1 (GLP-1) receptor agonists, particularly semaglutide. According to data presented at the European Respiratory Society International Congress, patients using semaglutide for type 2 diabetes management demonstrated a 38% reduction in asthma exacerbations and a 21% reduction in COPD exacerbations compared with those using sulfonylureas.

Providing context for the study’s rationale, lead researcher Chloe I. Bloom, MBChB, PhD, MSc, clinical associate professor in respiratory epidemiology at the National Heart and Lung Institute, Imperial College London, explained:

“Conditions such as type 2 diabetes and excess weight are very common in people with asthma and COPD and are linked to worse respiratory outcomes.”

Noting that prior evidence pointed toward anti-inflammatory and direct pulmonary benefits of GLP-1 therapies, Dr. Bloom added:

“We wanted to see whether people taking these drugs for diabetes also appeared to have fewer lung flare-ups.”

Study Methodology and Cohorts

The researchers conducted a comparative analysis utilizing the Clinical Practice Research Datalink in the United Kingdom. They compared respiratory outcomes among patients with asthma or COPD who initiated various GLP-1 receptor agonists against a control group of patients who utilized any type of sulfonylurea.

Table 1. Study Population by Initiated Medication Cohort

Outcomes and Reductions in Exacerbations

The study found that, as a drug class, GLP-1 receptor agonists were associated with a 14% overall reduction in respiratory exacerbations compared with sulfonylureas. However, efficacy varied significantly depending on the specific GLP-1 agent utilized. Drug dosage did not demonstrate any association with the rate of exacerbations.

“Previous studies have suggested that GLP-1 drugs may reduce respiratory flare-ups, but we wanted to know whether the newer drugs might be more effective than the older ones,” Dr. Bloom stated. “They were, with semaglutide showing the strongest association.”

Table 2. Reduction in Respiratory Exacerbations vs. Sulfonylureas

Notably, the robust reductions observed with semaglutide were independent of several potential confounding factors. Exacerbation rates were not affected by patient age, smoking status, eosinophil counts, baseline body mass index (BMI), baseline HbA1c, or insulin resistance. Furthermore, the clinical benefits were independent of the degree of weight loss or glycemic control achieved during treatment.

Highlighting this independence from metabolic changes, Dr. Bloom noted:

“The benefit was seen regardless of whether people lost more or less weight or had better or worse glucose control. That suggests the respiratory effects may not simply be a consequence of weight loss or improved diabetes control.”

Clinical Implications and Future Research

While patients presenting with asthma or COPD alongside type 2 diabetes may derive dual benefits from semaglutide, the investigators cautioned against off-label prescribing specifically for airway disease outside of current guidelines.

“Any respiratory benefit may partly reflect weight loss and improved glucose control,” Dr. Bloom remarked. “However, these factors do not appear to explain the whole association, and there may also be more direct beneficial effects in the lungs.”

Emphasizing that these observational findings represent a starting point for further investigation, Dr. Bloom concluded:

“It is too early to change clinical practice on the basis of these findings alone. What they do provide is a strong rationale for clinical trials to test whether GLP-1 drugs can genuinely prevent asthma and COPD flare-ups. We now need to understand why these drugs might help the lungs. Some of the benefit is likely to come from weight loss and improved metabolic health, but those factors do not seem to explain everything. There may also be direct effects within the lungs, and understanding those mechanisms is an important next step.”

Overview of Updated ACR Guidelines

The American College of Rheumatology (ACR) has revised its clinical guidance for the management of osteoarthritis (OA), updating its previous 2019 recommendations. The updated guidelines prioritize wellness interventions, establishing self-efficacy and self-management as the foundational elements of OA care.

Sharon L. Kolasinski, MD, principal investigator at the Perelman School of Medicine, University of Pennsylvania, explained the rationale behind the updates:

“These updated recommendations recognize that there is no single treatment pathway that fits every person living with osteoarthritis. Our strongest recommendations continue to center on helping people build confidence in managing their condition, remaining physically active and pursuing weight loss when appropriate. At the same time, the new evidence gives clinicians and patients additional options to discuss, in carefully selected situations”.

Therapeutic Recommendations

The guidelines outline both strong and conditional recommendations for pharmacologic and nonpharmacologic therapies.

Table 1. Strong and Conditional Recommendations for OA Management

Table 2. Strong Recommendations Against Specific Interventions

Good Practice Statements

The authors established three core good practice statements to guide clinical care:

• Patient Education: Clinicians should educate patients to actively enhance their self-efficacy.
• Rehabilitation Referrals: Physical or occupational therapy should be utilized when exercise limits a patient’s function or exacerbates their pain.
• Mobility Support: Canes or alternative mobility aids should be provided for patients whose hip or knee OA restricts walking.

Multidisciplinary and Individualized Care

An ACR press release emphasized that treatment paradigms must be individualized and multimodal:

“Treatment decisions should account for OA severity, pain and functional limitations, other health conditions, prior surgery, medication risks, transportation and financial barriers, insurance coverage, and the patient’s ability to participate in care. Many people may benefit from a multidisciplinary approach involving primary care clinicians, rheumatologists, physical therapists, occupational therapists, orthopedic surgeons, and other members of the care team”.

Here is a detailed paraphrase of the article, incorporating all original quotations and organizing the statistical data into comprehensive tables.

The Resurgence of Measles: A Back-to-School Crisis in 2026

As students across the United States head back to the classroom for the fall term, they are stepping into the most severe nationwide measles outbreak observed in decades. The combination of highly localized outbreaks and a continuous decline in childhood vaccination rates has sparked serious concerns among public health experts.

As of September 11, 2026, the infectious disease landscape is grim. The U.S. has recorded 3,294 confirmed cases of measles across 45 states and Washington, D.C. This figure not only exceeds the total cases from 2025 by over 1,000, but it also represents the highest single-year case count since 1991. Consequently, the United States is at risk of losing its status as a country that has eliminated measles—a milestone originally achieved in 2000.

Dr. Aaron E. Glatt, the chief of infectious diseases at Mount Sinai South Nassau in New York, described the combination of plummeting immunization rates and widespread viral circulation as “a very big concern” for the school year. Highlighting the extreme transmissibility of the virus, Dr. Glatt explained that if one infected individual sat in a lecture hall with an unvaccinated audience, roughly 90% of the room would contract the virus within an hour.

“It’s highly, highly, highly contagious,” Glatt stated. “Unfortunately, when people are exposed and they are not immune, they are going to get measles. The only question is how severe an illness it will be.”

State-by-State Outbreak Data and Responses

While cases are widespread nationally, several states are facing concentrated public health emergencies.

Table 1: Notable Statewide Measles Outbreaks (As of Sept. 2026)

In response to the severe outbreak in Pennsylvania, the state’s Department of Health took aggressive preventative measures ahead of the 2026-2027 school year. During August alone, health workers administered over 3,500 doses of the MMR (measles, mumps, and rubella) vaccine, a sharp increase from the sub-1,000 doses administered in prior months.

Furthermore, Pennsylvania launched a public transparency dashboard detailing the vaccination rates of kindergarteners, 7th graders, and 12th graders across all private and public schools. Over the summer, the state also held specialized training briefings for more than 1,000 school nurses to educate them on detecting and managing measles cases on campus.

The Root Cause: A Steep Decline in Immunization

The primary driver of this public health crisis is the steady drop in MMR vaccination rates since the onset of the COVID-19 pandemic in 2020. Public health experts maintain that a 95% vaccination rate is the minimum threshold required to achieve herd immunity and prevent community outbreaks.

Table 2: U.S. MMR Vaccination Coverage Trends (2024–2026)

Wisconsin represents a prominent example of how localized drops in coverage can fuel an outbreak. The state reported that only 85.1% of its kindergarteners were fully immunized against measles going into the 2025-2026 school year.

Table 3: MMR Coverage for 6-Year-Olds in Wisconsin Outbreak Zones (2025 Data)

Stephanie Schauer, PhD, who manages the Wisconsin Immunization Program, addressed the issue during a September press conference:

“Vaccination rates vary across Wisconsin, and some schools and communities have significantly lower vaccination rates than others. When a highly contagious disease like measles reaches a community with lower vaccination coverage, it has more opportunities to spread.”

Schauer added that the current situation is “a real reminder of why maintaining high vaccination coverage matters.”

Social Determinants and Barriers to Care

Medical professionals point out that the drop in vaccination rates isn’t solely due to anti-vaccine sentiment, but is heavily influenced by systemic barriers and social determinants of health.

During a press briefing with the Infectious Diseases Society of America, Dr. Julia Rosebush, a pediatric infectious disease specialist at the University of Chicago, highlighted how historical marginalization and modern political rhetoric intersect to depress vaccination rates.

“That is something we see in the city of Chicago, where in communities that are historically marginalized, there is already a history of mistrust and distrust,” Rosebush stated. “And when we are hearing the political rhetoric that is perhaps suggesting that vaccination is unsafe or linked to conditions like autism, these patients and these families — these communities — may be disproportionately affected in a negative way.”

She further noted, “I think, in addition to that, some of these communities face barriers to care, such as lack of transportation.”

Dr. Preeti Malani, an infectious diseases professor at the University of Michigan, echoed these sentiments, urging communities to address these inequities constructively rather than assigning blame.

“There are a lot of barriers to getting vaccinated for certain individuals, and those barriers are not equal,” Malani explained. “Hopefully those data are not just used to point fingers, but to bring resources in and bring in trusted voices, both from the community and from healthcare, and make it easy for families to choose vaccination.”

Actionable Advice for Healthcare Providers

As the disease continues to circulate, Dr. Glatt urges physicians to remain vigilant, identify symptoms early, and isolate suspected cases immediately—even in regions where vaccination rates appear robust. He noted that while the vaccine is incredibly effective, breakthrough cases are possible.

“The vaccine is very, very, very good, but it’s not perfect. It is about 97% effective, so there are going to be some people who are vaccinated who could still come down with measles — they are few and far between.”

Ultimately, Dr. Glatt stressed that empathetic, educational communication from healthcare providers is the best tool for combating vaccine hesitancy in undervaccinated areas.

“There are people that are concerned, but for the majority of people, I think the concerns can be allayed,” Glatt advised. “I think education, answering questions, being polite, not dismissing people and saying ‘Oh, you’re not vaccinated, you’re not a good person,” but explaining why it is dangerous and what risks they are putting their children at, hopefully you can change their opinion from being on the fence to getting vaccinated.”

Evaluation of Gabapentinoid Use and Fracture Risk in Older Adults: Findings From a Multinational Cohort Study

Importance

The prescribing of gabapentinoids (gabapentin and pregabalin) in older adults is common, yet concerns regarding their association with adverse events, including falls and subsequent fractures, remain prevalent. Recent findings from a population-based, multinational retrospective study published in The Lancet Healthy Longevity suggest that while an acute risk exists, long-term gabapentinoid treatment may not be independently associated with a sustained increase in fracture risk for older adult populations.

Objective and Design

Led by Kenneth K. C. Man, PhD, CStat, FHEA, FRSM, FRSPH, a pharmacoepidemiologist and medical statistician at University College London, alongside Andrew S. C. Yuen, PhD, and colleagues, the researchers sought to quantify fracture risk across different periods of gabapentinoid treatment.

The retrospective study evaluated adults aged 60 years or older who had been prescribed either pregabalin or gabapentin and subsequently required hospitalization for a fracture. The investigation pooled patient data from two large-scale national databases: the United Kingdom’s Clinical Practice Research Datalink (CPRD) and the South Korean National Health Insurance Service-National Health Screening Cohort.

Methodology and Key Findings

To accurately track fluctuating risk levels, the investigators stratified the patients’ observation periods into four distinct chronological windows related to their gabapentinoid prescriptions. The analysis utilized a random-effects model to pool the results.

The findings revealed that the incidence rate of fractures was actually highest in the 90 days immediately preceding the initiation of gabapentinoid therapy, rather than during the treatment itself. The researchers noted no sustained elevation in fracture risk during the subsequent, long-term treatment windows.

Note: Risk scores indicate the relative risk of fracture occurrence compared to the baseline referent window.

Despite the absence of sustained long-term risk, the initial phases of treatment still carry hazards, particularly when central nervous system depressants are coadministered. During Focal Window 1 (the first 60 days of therapy), patients receiving concomitant prescriptions experienced substantially heightened fracture incidence rates:

• Concurrent Opioid Use: Incidence rate ratio of 3.15
• Concurrent Benzodiazepine Use: Incidence rate ratio of 1.91

Conclusions and Clinical Relevance

The authors concluded that the pooled data “do not support a sustained causal relationship between gabapentinoid use and risk for fracture in older adults.” However, Dr. Man cautioned against misinterpreting these results as an absolute endorsement of safety, particularly during the initiation phase or during polypharmacy.

“We are not claiming that gabapentinoids are free from the risks,” Man stated. “Even when [patients] started the treatment on gabapentinoids, it had a 30% higher [fracture] risk compared with nontreatment periods. The more crucial one is when coprescribed with opioids and benzodiazepines…. It looks like the risks go even further.”

To mitigate early therapeutic risks, the investigative team stressed the necessity of robust fall-prevention strategies integrated into the point of prescribing. Dr. Man outlined specific clinical guidance for physicians managing this patient demographic:

“One crucial thing is for clinicians and physicians to assess the fall risks before they start the treatment. The second bit is to start at a lower dose and titrate the medication slowly, because we observed the risk is lower than pre-exposure, but it still attained a relatively higher level…. If the combination [of gabapentinoids and opioids or benzodiazepines] is unavoidable, treat the patient as a high risk for traumatic fracture, and review early.”

Efficacy and Safety of AZD5462, a Novel Oral Relaxin Receptor Agonist, in Heart Failure: Findings From the Phase 2b LUMINARA Trial

Importance

The management of heart failure (HF) continues to evolve, with novel therapeutic targets emerging to improve hemodynamics and cardiac remodeling. According to findings prese oknted at the European Society of Cardiology (ESC) Congress in Munich and published concurrently in Circulation, a first-in-class oral relaxin receptor agonist has demonstrated favorable hemodynamic profiles across the spectrum of left ventricular ejection fraction (LVEF).

James L. Januzzi, MD, Hutter Family Professor of Medicine at Massachusetts General Hospital and Harvard Medical School, outlined the physiological premise of the therapy during his presentation:

“Relaxin biology affords a potentially novel approach to improving vascular function and cardiac remodeling in heart failure. Stimulation of the relaxin family peptide receptor 1, or RXFP1, reduces systemic vascular resistance and afterload, improves organ perfusion and fosters reverse cardiac remodeling.”

While relaxin has been historically investigated for both acute and chronic HF, prior RXFP1-stimulating therapies were strictly parenteral and yielded inconsistent results. Dr. Januzzi emphasized the therapeutic breakthrough:

“A key innovation here is the development of an oral therapy suitable for testing long-term chronic and perhaps more pulsatile activation of the RXFP1 receptor. Accordingly, AZD5462 is the first and only oral once-daily RXFP1 agonist in clinical development. So we therefore hypothesize that use of this agent may benefit individuals with chronic heart failure.”

Objective and Trial Design

The LUMINARA trial (Phase 2b) aimed to evaluate the safety, tolerability, and hemodynamic efficacy of AZD5462 (AstraZeneca) across two distinct heart failure populations over a 24-week period. The majority of enrolled participants were receiving robust, guideline-directed medical therapy, which included SGLT2 inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and ACE inhibitors/ARBs/ARNIs.

Participants were randomly assigned to receive either placebo or one of three once-daily AZD5462 dosing regimens (20 mg, 80 mg, or 360 mg).

Results and Hemodynamic Outcomes

The trial revealed nuanced, dose-dependent hemodynamic benefits. Notably, the lowest investigated dose of AZD5462 demonstrated the most promising clinical profile, particularly in patients with reduced ejection fraction.

In Cohort A, improvements in the end-systolic volume index trended toward statistical significance in the lower-dose arms but lost efficacy at the highest dose. Conversely, in Cohort B, the primary endpoint of improved systemic vascular resistance index was successfully met across all active treatment arms.

Secondary endpoints, including changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and LVEF changes at 24 weeks, did not achieve statistical significance in either cohort.

Note: Cohort A endpoint = change in end-systolic volume index; Cohort B endpoint = change in systemic vascular resistance index.

Safety and Tolerability Profile

The safety analysis yielded no major adverse signals. Overall adverse event rates were comparable between the placebo and AZD5462 cohorts. Regarding specific safety parameters, Dr. Januzzi reported:

“There was evidence for mild hemodilution that was dose-related, typically seen in the higher doses of AZD5462, but there was no excess of adverse events related to volume overload. Although, as expected, there was mild lowering of blood pressure, consistent with the phase 1 experience with the drug, there was no meaningful hypotension signal detected.”

A notable physiological observation was a dose-dependent elevation in renin levels among patients receiving AZD5462. Dr. Januzzi suggested this compensatory renin increase at higher doses may elucidate why the lowest dose (20 mg) yielded the most favorable efficacy outcomes in Cohort A.

Conclusions and Clinical Implications

The LUMINARA trial provides foundational evidence for the continued investigation of oral RXFP1 agonism in heart failure. Summarizing the clinical takeaways, Dr. Januzzi concluded:

“Treatment of chronic heart failure with the first oral RXFP1 agonist was well tolerated across a wide LVEF spectrum. AZD5462 treatment resulted in improvement of cardiac remodeling and hemodynamics compared with placebo, despite a high rate of background foundational medical therapy use. Among those individuals with reduced ejection fraction in the trial, there was a greater improvement in end-systolic volume index observed with lower AZD5462 doses. These findings, therefore, justify proceeding forward with further exploration of the drug. It seems clear that the 20 mg dose would be the go-forward dose.”

Serving as the discussant for the presentation, John R. Teerlink, MD, director of heart failure and the echocardiography laboratory at the San Francisco Veterans Affairs Medical Center, commended the structural integrity of the trial. He characterized LUMINARA as:

“…a well-designed and well-conducted phase 2b study with carefully selected and wide dose-ranging assessments. [The researchers] targeted groups of patients across the left ventricular ejection spectrum with excellent background therapy and [the trial] was reasonably well powered for the selected endpoints, given it was a phase 2b study.”

Dr. Teerlink acknowledged that while “the inverse dose relationship for end systolic volume is rather atypical and needs further discussion,” the collective findings ultimately signal that “LUMINARA provides the potential basis for the future development of AZD5462 in heart failure.”

Clinical Overview of Alexander Disease and the FDA Approval of Zanvastro

Alexander disease represents an ultra-rare, progressive, and frequently fatal neurological disorder estimated to impact approximately 300 individuals across the United States. The pathology of the condition extensively compromises motor, cognitive, autonomic, and gastrointestinal functions. Until recently, clinical management was strictly confined to supportive care and symptom mitigation.

A historic milestone was reached with the regulatory approval of Zanvastro (zilganersen), an antisense oligonucleotide (ASO) developed by Ionis Pharmaceuticals. Recognized as the first approved disease-modifying treatment for Alexander disease, Zanvastro alters the underlying biological trajectory of the disorder. Dr. Amy Waldman, a pediatric neurologist at the Children’s Hospital of Philadelphia, highlighted the transformative nature of this development:

“There’s tremendous excitement about the fact that we now have a disease-modifying therapy for Alexander disease, that Zanvastro gets to the underlying biology.”

The approval follows more than a decade of focused research built upon a natural history study initiated in 2016, with foundational investigations into the biology and clinical trajectories of Alexander disease tracing back to the 1980s.

Mechanism of Action and Administration Protocols

Zanvastro functions as an antisense oligonucleotide designed to directly target and reduce the pathological accumulation of glial fibrillary acidic protein (GFAP). In Alexander disease, excess GFAP forms toxic intracellular aggregates within astrocytes, known as Rosenthal fibers, which severely disrupt neurological function. Dr. Waldman explained this mechanism:

“As an antisense oligonucleotide (ASO), Zanvastro works by reducing glial fibrillary acidic protein (GFAP), a toxic accumulation of astrocytes in the brain that leads to the creation of the Rosenthal fibers that disrupt neurological function.”

The therapeutic regimen is approved as a 50 mg dose administered quarterly via intrathecal injection.

Global Clinical Trial Design and Efficacy Outcomes

The safety and efficacy of Zanvastro were evaluated in a global, randomized, double-blind, placebo-controlled study encompassing 53 participants aged 2 to 53 years. Patients were randomized in a 2:1 ratio into 25 mg Zanvastro, 50 mg Zanvastro, and control cohorts.

Gait Speed and Motor Function Outcomes

In participants aged 5 years and older, the therapy demonstrated significant stabilization of gait speed, evaluated via the 10-Meter Walk Test after 60 weeks of treatment.

• At baseline, the 50 mg treatment group ($n = 17$) presented with a mean gait speed of 1.2 meters per second, compared to 1.1 meters per second in the control group ($n = 13$).
• Following 61 weeks, the Zanvastro cohort demonstrated a least squares mean (LSM) percent change of –2.1% (95% CI; –23, 18.8).
• Conversely, the control group experienced a marked LSM percent change of –35.4% (95% CI; –59.3, –11.5), yielding an LSM difference of 33.3% (95% CI, 1.4–65.3).

Reflecting on the rapid clinical decline observed in the untreated group, Dr. Waldman noted:

“It was very humbling that in those just 15 months … there was a decline in patients who were relatively stable to begin with. The fact that patients continued to worsen in the control arm compared to the stability that was seen in Zanvastro was quite an achievement.”

Biomarker and Pediatric Subgroup Findings

Significant divergence between treatment and control arms was also documented in plasma glial fibrillary acidic protein (GFAP) levels from baseline at week 61, demonstrating targeted modulation of the disease’s underlying biology (LSM difference 33.6%, $P = .003$). Among younger participants aged 2 to 4 years, evaluations using the Gross Motor Function Measure-88 revealed significant differences at week 61 (LSM difference 22.9%, $P = .034$). Furthermore, researchers successfully incorporated an open-label evaluation involving four patients under the age of 2 years. Dr. Waldman emphasized the broad applicability of the trial:

“It’s a very heterogeneous disease, and we were very fortunate that this trial was for all ages, all disease phenotypes, so we could offer it to everyone. Even with such heterogeneity, that it met its statistical endpoints and had clinical meaningful benefits is really tremendous.”

Summary of Clinical Trial Findings and Trial Demographics

Safety Profile and Tolerability

Adverse reactions associated with Zanvastro were predominantly mild to moderate in severity. The most frequently reported events included:

• Vomiting
• Back pain
• Cough
• Headache
• Post-lumbar puncture syndrome

One isolated case of aseptic meningitis occurred during the trial; however, the patient successfully continued therapy and was re-dosed without lasting complications. Dr. Waldman summarized the safety profile:

“The drug was very well tolerated. There weren’t really any of those significant things that didn’t resolve with just some supportive care.”

Broader Scientific Implications and Future Horizons

Beyond Alexander disease, clinical investigators view the successful validation of Zanvastro as a vital proof-of-concept for addressing other neurological conditions involving gain-of-function pathologies and rare leukodystrophies. Dr. Waldman highlighted the expanding pharmacological toolkit:

“I think people are so focused right now on gene therapy or CRISPR-Cas9 or other things, and it’s just a reminder that we really do have a number of tools that can work for these incurable neurologic conditions.”

To facilitate safe and structured distribution, Ionis Pharmaceuticals announced plans to roll out Zanvastro across 12 designated leukodystrophy centers of excellence throughout the United States, while simultaneously establishing broader outreach channels to identify new patients. The therapy will launch at a list price of $285,000 per dose, accompanied by dedicated reimbursement and financial assistance programs to support patient access and continuity of care.

Expert Perspective: Clinical Realities and Societal Challenges

Albee Messing, VMD, PhD, Chair of the Scientific Advisory Committee for the End AxD Foundation, provided an expert clinical perspective on the approval, contextualizing its emotional and practical significance for affected families:

“There’s no question that it’s really a dream come true for the Alexander disease community in many ways. They’ve been waiting. I’ve been contacted by several parents whose children died decades ago.”

Dr. Messing noted the limitations of the current therapeutic iteration while emphasizing its foundational importance:

“It’s not a cure. It’s imperfect, but hopefully it provides the foundation for future improvements. There are various ways you can imagine improving it. I’m hoping Ionis is working on that. But at least this sets the ground rules for it. It’s got the FDA endorsement behind it as a strategy, and that’s terrific.”

Addressing the clinical expectations of disease stabilization versus slowing progression, Dr. Messing observed:

“The real hope is that it either stabilizes patients in their current state or they actually improve. But really the most obvious benefit right now is hope more than anything else. I think there is a possibility, which we’ve always known was a possibility, that it slows the progression. In some people, it’s still a progressive disease, but it doesn’t progress as fast. Some people may be happy about that. They have more time with their family. Some people may find that an agonizing experience, and it really all depends on the individual and their current state.”

Emphasizing the value of early intervention down to infancy, Dr. Messing added:

“I think there’s been the general notion, and certainly from the animal work, that the earlier you treat, the more effective it will be. That’s one of the reasons why I’m really happy that they approved it down through infancy. The way the trial was initially set up, it started at 2 years old, but a_l_o_t of kids start having problems before then. So, the earlier you can give the treatment, the better off you’re going to be.”

Regarding future optimizations, dosing schedules, and drug delivery modalities, Dr. Messing remarked:

“This is my personal opinion because the End AxD Foundation’s Scientific Advisory Committee has not really gathered to talk about this. For Zanvastro specifically, I would think the obvious thing to consider is doses, and whether, if they play around with the doses, they can get better results. For instance, a higher dose might give you more suppression and be more effective. There may be some people who can be weaned off the ASO after a while, and we don’t know that. The earlier treatment will be more effective, and they just need more patients and more experience with that, more data and longitudinal studies to see. I think there’s a lot that can be done with Zanvastro as it is. I think from the medical science side, biology side, there are the obvious things that we all want to see, such as improved means of delivery so you don’t have to do intrathecal administration – something that you can give via an intravenous route or something like that, or subcutaneously. There are people working on that, but I think the results are a long way off.”

Finally, Dr. Messing raised critical considerations regarding healthcare equity, administration infrastructure, and broader economic models associated with ultra-orphan therapeutics:

“It goes beyond the biology. I think the other really serious problem is the cost and equity and availability and how that will roll out. I think a lot of places can do intrathecal administration. That’s not such a huge deal. I think right now Ionis is trying to limit it to the places that have been part of the clinical trial. Intrathecal administration by itself is not such a limiting factor. Whatever they say about insurance coverage or adjustments, that’s all a black box, as far as we’re concerned. You have more and more of these kinds of very highly specialized treatments, not so personalized, but for an ultra-rare disorder, astronomical costs are attached to that. How that gets settled at a societal level is a major problem.”

Clinical Background and Pathophysiological Context

Hidradenitis suppurativa (HS) is a chronic, painful, and debilitating autoinflammatory skin disease characterized by deep-seated nodules, abscesses, draining sinus tracts, and extensive scarring, typically localized to intertriginous anatomical regions such as the axillae, groin, buttocks, and inframammary folds. In recent years, substantial clinical research has underscored an intimate epidemiological and immunologic link between HS and inflammatory bowel disease (IBD), encompassing both Crohn’s disease and ulcerative colitis. Patients presenting with HS inherently exhibit an elevated baseline vulnerability to developing gastrointestinal inflammation compared to the general population.

Concurrently, the therapeutic landscape for moderate-to-severe HS has evolved beyond conventional antibiotics and anti–tumor necrosis factor (anti-TNF) agents like adalimumab. Biologics targeting the interleukin-17 (IL-17) signaling cascade have emerged as core therapeutic options. Among the three targeted biologic therapies approved for HS, two function through IL-17 inhibition:

• Secukinumab (Cosentyx, Novartis): A selective human monoclonal antibody that neutralizes interleukin-17A (IL-17A), validated through pivotal clinical trials including the SUNSHINE and SUNRISE programs.
• Bimekizumab (Bimzelx, UCB): A humanized monoclonal antibody designed to selectively and simultaneously inhibit both interleukin-17A and interleukin-17F (IL-17A/F), which proved superior efficacy in the BE HEARD clinical trial program.

Despite the robust efficacy demonstrated across these large-scale phase 3 initiatives, the clinical application of IL-17 inhibitors has been met with vigilance and prescriber hesitancy. This caution stems from earlier findings across dermatological, rheumatological, and gastroenterological trials—particularly in psoriasis, ankylosing spondylitis, and failed trials of IL-17 blockers in active Crohn’s disease—where IL-17 blockade was linked to paradoxical flares of bowel disease or reports of de novo intestinal inflammation. Because the IL-17 cytokine family serves a dual role by driving cutaneous inflammation while simultaneously reinforcing the gut mucosal barrier, the clinical community has debated whether IL-17 targeted therapies impose an independent, additive risk of IBD onto a population already predisposed to gastrointestinal pathology.

Systematic Review and Meta-Analysis Architecture

To rigorously evaluate this safety concern, Marley Cutrona, BS, a medical student in the Department of Dermatology at the Icahn School of Medicine at Mount Sinai, along with colleagues, conducted a comprehensive systematic review and meta-analysis published in JAMA Dermatology (Cutrona M, et al. JAMA Dermatol. 2026; doi:10.1001/jamadermatol.2026.3373).

The investigators aggregated global evidence to quantify the exact frequency and relative risk of de novo IBD onset and underlying IBD flares among HS patients undergoing IL-17 pathway blockade. The analysis evaluated 24 studies comprising a total cohort of 3,015 patients receiving an IL-17 inhibitor:

• 10 Randomized Controlled Trials (RCTs)
• 11 Observational Cohort Studies
• 3 Case Series

The primary objective was to determine whether IL-17 inhibition imposes a tangible, drug-induced additive risk of IBD above the pre-existing baseline incidence associated with hidradenitis suppurativa.

Quantitative Findings and Risk Stratification

The investigation demonstrated that gastrointestinal adverse events culminating in verified IBD were remarkably infrequent across all therapeutic trials and real-world cohorts.

In the high-evidence tier of randomized controlled trials:

• Across the 10 evaluated RCTs, 2,572 HS patients received an IL-17 inhibitor.
• Within this substantial population, only six patients developed new-onset IBD.
• Through the primary randomized control period (week 16), new-onset IBD materialized in 0.23% of participants receiving an active IL-17 inhibitor, compared to 0% among those randomized to placebo.
• The risk difference between the active treatment arms and the placebo cohorts was calculated at 0.002 (95% CI, 0.003 to 0.007).

In nonrandomized real-world cohorts and observational investigations:

• Across 11 cohort studies capturing 469 patients treated with IL-17 inhibitors, seven instances of new-onset IBD were identified.
• This corresponded to a crude incidence rate of 1.49% and an estimated pooled incidence rate of 3.9% (95% CI, 2.3% to 6.5%).
• The comparatively higher event rates documented within observational datasets relative to RCTs likely reflect longer clinical follow-up periods, the inclusion of medically complex patients routinely excluded from phase 3 protocols, and confounding by indication.

Across all 24 evaluated clinical studies (comprising 3,015 patients), the researchers identified a cumulative total of:

• 17 cases of new-onset IBD
• 4 instances of pre-existing IBD flares

A critical temporal pattern was identified regarding the time-to-onset of gastrointestinal pathology: the documented adverse events manifested predominantly within the first 6 months following the initiation of IL-17 targeted therapy. This finding indicates that the period of maximal clinical vulnerability for either unmasking latent subclinical bowel inflammation or triggering new gastrointestinal pathology falls squarely within the earliest stages of biologic administration.

Comparative Data Synthesis

Pooled incidence: 3.9% (95% CI, 2.3% to 6.5%) | Not applicable (observational/non-placebo designs) |
| Total Evidence Base (RCTs + Cohorts + Case Series) | 3,015 patients across 24 studies | 17 new cases

4 disease flares | Events concentrated within the initial 6 months of therapy | Overall risk remains low and non-additive to underlying disease baseline |

Summary of Approved IL-17 Biologics in Hidradenitis Suppurativa

Author Conclusions and Clinical Guidance

Synthesizing their quantitative findings, Marley Cutrona and colleagues concluded that while hidradenitis suppurativa carries an undisputed intrinsic association with inflammatory bowel disease, the administration of IL-17 inhibitors does not superimpose an additive pharmacological risk:

“In this systematic review and meta-analysis, IBD events during IL-17 inhibitor therapy for HS were uncommon, with higher incidence rates in nonrandomized studies compared with RCTs, although events remained rare overall,” Marley Cutrona, BS, a medical student in the department of dermatology at Icahn School of Medicine at Mount Sinai, and colleagues wrote. “Although HS is associated with IBD, an additive risk with IL-17 inhibitor treatment was not observed.”

The investigative team reiterated that their conclusions support the overall therapeutic safety profile of this class of medications in managing HS, while highlighting the importance of clinical diligence:

“The findings of our study support a low risk of IBD in patients with HS treated with IL-17 inhibitors,” the researchers wrote. “However, current guidelines recommend avoiding IL-17 inhibitors in patients with concomitant active IBD. For patients with HS without known IBD, a thorough gastrointestinal history should be obtained before treatment with IL-17 inhibitors and patients should be monitored for gastrointestinal symptoms.”

Expert Perspective and Practical Implications

In an accompanying clinical perspective, Christopher J. Sayed, MD, of the University of North Carolina at Chapel Hill, emphasized that these data provide crucial clarity for practicing dermatologists who manage severe, recalcitrant HS:

“This is very reassuring news. The increased risk for IBD in patients with HS has generated some hesitancy in prescribing IL-17 inhibitors. This reinforces that, if the risk exists, it is exceptionally low and should not interfere with appropriate treatment in the absence of concerning gastrointestinal symptoms.”

Dr. Sayed’s commentary highlights that the theoretical hazard of drug-induced bowel inflammation should not become a therapeutic barrier preventing patients from accessing clinically efficacious biologics. Provided that patients are free of unmanaged or suspicious gastrointestinal symptoms—such as persistent hematochezia, unexplained chronic diarrhea, involuntary weight loss, or severe abdominal cramping—IL-17 blockade represents a sound therapeutic modality.

Disclosures and Industry Affiliations

The perspective author, Dr. Christopher J. Sayed, documented financial associations (encompassing research support, advisory roles, or consulting arrangements) with multiple biotechnology and pharmaceutical entities, including:

• AbbVie
• Alumis
• AstraZeneca
• Cantargia
• Elasmogen
• Incyte
• InflaRx
• MoonLake Immunotherapeutics
• Novartis
• Sandoz
• Sanofi
• Sonoma Biotherapeutics
• Takeda Pharmaceuticals
• UCB

Methodological Limitations and Investigative Nuances

While the conclusions offer strong reassurance for clinical practice, the authors identified several methodological caveats that warrant careful interpretation:

1. Statistical Power Constraints: Because true de novo IBD presentations and unmasked flares occurred at exceptionally low absolute numbers, the statistical power to uncover subtle differences between various IL-17 targeting molecules (e.g., selective IL-17A inhibition versus dual IL-17A/F blockade) remained constrained.
2. Endpoint Designations: Across the majority of the randomized controlled trials evaluated, inflammatory bowel disease was monitored solely as a treatment-emergent adverse event rather than an adjudicated primary or secondary study endpoint. Consequently, surveillance protocols, gastrointestinal screening questionnaires, and diagnostic confirmation methods lacked standardization across protocols.
3. Follow-Up Inconsistencies: The observation windows varied considerably among the pooled investigations. While randomized phases offered uniform, highly monitored 16-week intervals, real-world observational cohorts and open-label extensions exhibited widely disparate durations of follow-up, which may account for the discrepancy in reported crude incidence rates between RCTs (0.23%) and observational cohorts (3.9%).

Overall, this extensive systematic synthesis clarifies the clinical safety parameters of IL-17 pathway inhibition in hidradenitis suppurativa, indicating that the inherent risk profile of these therapeutics does not exacerbate the pre-existing risk of inflammatory bowel disease in this patient population. Baseline gastrointestinal risk assessments and early-phase clinical symptom surveillance remain prudent best practices.