Of the 44 exposed pregnancies, 32 resulted in live births. Two babies were born with major congenital anomalies: one ventricular septal defect and one hypospadias. This amounts to 2 of 32 live births, or 6.3%.

Five pregnancies ended in spontaneous abortion, including one case of fetal anencephaly, and seven pregnancies were terminated electively. These small numbers document observed outcomes but cannot determine whether JAK inhibitor exposure caused the anomalies or pregnancy losses. Neonatal assessments among the live births identified two preterm births at 36 weeks’ gestation, three infants small for gestational age and two newborns large for gestational age.

The authors concluded that current evidence is insufficient to establish or exclude an association between JAK inhibitor exposure and adverse fetal outcomes. They stated that potentially harmful effects cannot yet be ruled out, that routine use during pregnancy is not recommended, and that treatment should be approached with caution and a critical risk-benefit assessment until more data are available.

Subject of Research: Pregnancy outcomes following first-trimester exposure to JAK inhibitors

Article Title: Pregnancy outcome after first-trimester exposure to JAK inhibitors – an evaluation of the German Embryotox cohort

Article References: Habbel, A.-S., Beck, E., Mueller, A., & Dathe, K. (2026). Pregnancy outcome after first-trimester exposure to JAK inhibitors – an evaluation of the German Embryotox cohort. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01263-4

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01263-4

Keywords: JAK inhibitors, pregnancy safety, first-trimester exposure, congenital anomalies, fetal risk, baricitinib, upadacitinib, tofacitinib, filgotinib, German Embryotox, Pregnancy, outcome

The research team, led by corresponding author Dr. Saurabh Mehandru, Professor of Medicine in Gastroenterology, set out to map the intestinal immune landscape in patients who developed enterocolitis after BCMA-directed CAR-T therapy. Using single-cell analysis of intestinal tissue, the investigators found something striking: CAR-T cells can persist in the intestinal mucosa long after the infusion, in a subset of patients. Rather than disappearing once their anti-cancer mission is complete, these engineered cells appear to take up residence in gut tissue, where they may sustain inflammatory signals indefinitely.

The study also revealed that the condition is not simply a matter of losing protective immune cells. Patients with enterocolitis showed a substantial depletion of B cells and plasma cells in the intestinal lining, the very cells that normally produce protective antibodies and help maintain mucosal integrity. But critically, some patients who never developed enterocolitis showed similar losses, indicating that B cell depletion alone cannot explain the severe inflammation. Something else must be driving the disease in susceptible individuals.

That something else, the data suggest, is a broad remodeling of the intestinal immune environment. Multiple cell types are affected simultaneously: immune cells, structural and vascular support cells, and the epithelial cells that line the intestine itself. This widespread disruption implies that CAR-T-associated enterocolitis is not a narrow, cell-specific side effect but a systemic disturbance of the gut’s immune architecture, involving crosstalk between many cellular compartments at once.

Among the pathways the researchers identified, one stood out with particular therapeutic relevance. JAK proteins, intracellular signaling molecules that help cells communicate and regulate inflammation, showed increased activity across multiple cell types in the intestine of affected patients. This finding suggested that the inflammatory cascade driving enterocolitis might be amenable to pharmacological interruption with drugs that already exist and are approved for other inflammatory conditions.

To test that idea, the team turned to upadacitinib, a selective JAK1 inhibitor. Two patients with CAR-T-associated enterocolitis who received the drug experienced meaningful improvements in symptoms, intestinal inflammation, and other measures of disease activity. In one of these patients, treatment was also associated with a substantial reduction in the number of CAR-T cells detectable in intestinal tissue, hinting that blocking JAK signaling may not only calm inflammation but may also affect the persistence of the engineered cells themselves.

Dr. Samir Parekh, Professor of Medicine and Director of the Center of Excellence for Multiple Myeloma at Mount Sinai, who co-supervised the study, emphasized the growing clinical urgency of the problem. As CAR-T therapies are deployed in more patients and earlier in the course of myeloma, understanding and managing complications becomes increasingly important. The findings, he noted, offer both an explanation for why some patients develop severe intestinal inflammation and a potential roadmap for treating or preventing it.

Dr. Nikhit Kethidi, the study’s first author, described the work as providing a detailed cellular view of the condition and demonstrating that it involves multiple components of the intestinal immune environment. Understanding these changes, he suggested, may help identify new therapeutic approaches and guide future studies aimed at preventing or managing the complication before it takes hold.

The scale of the collaboration reflects the rarity and complexity of the condition. Investigators from Mount Sinai worked alongside researchers at Weill Cornell Medicine, Johns Hopkins University, Memorial Sloan Kettering Cancer Center, Stanford University School of Medicine, Harvard Medical School, Boston Children’s Hospital, Northwestern University Feinberg School of Medicine, Charité-Universitätsmedizin Berlin, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Leipzig, and other national and international institutions, pooling tissue samples and clinical expertise from centers that treat large volumes of myeloma patients with CAR-T therapy.

For the myeloma community, the study marks a turning point in how CAR-T-associated enterocolitis is understood. What was previously a poorly characterized and frightening complication now has a defined cellular signature: persistent mucosal CAR-T cells, loss of antibody-producing lineages, widespread immune remodeling, and heightened JAK-mediated inflammatory signaling. With a plausible drug target already validated in a small number of patients, the path from mechanistic insight to clinical intervention appears shorter than it does for many rare treatment toxicities, offering hope that future patients can receive the transformative benefits of CAR-T therapy without paying the price of chronic intestinal disease.

Subject of Research: Mechanisms of severe intestinal inflammation after BCMA CAR-T therapy for multiple myeloma

Article Title: Mount Sinai study identifies why some patients develop severe intestinal inflammation after CAR-T therapy

Article References: Mount Sinai study identifies why some patients develop severe intestinal inflammation after CAR-T therapy. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: CAR-T cell therapy, multiple myeloma, enterocolitis, BCMA, intestinal inflammation, JAK inhibitors, upadacitinib, Nature Medicine, immune remodeling, gastrointestinal toxicity, Mount Sinai, mucosal immunity

Myelofibrosis belongs to a group of chronic blood cancers known as myeloproliferative neoplasms, in which the bone marrow overproduces different types of blood cells. In myelofibrosis specifically, the spongy interior of the bone that manufactures blood cells develops fibrotic scar tissue, progressively impairing its ability to produce enough healthy blood cells. The disease is rare, with estimates suggesting that up to six people per 100,000 are living with it. Despite its low prevalence, myelofibrosis carries serious consequences: individuals face an elevated risk of transformation to acute myeloid leukemia, as well as disease-related complications including enlargement of the spleen, the organ that helps fight infection and filter blood, and the development of blood clots.

For much of the modern treatment era, clinicians have relied on a relatively limited therapeutic arsenal. JAK inhibitors, a class of drugs that modulate signaling pathways driving the disease, can reduce spleen enlargement and ease other symptoms, and they remain the mainstay of pharmacologic management. The only potentially curative option, however, is allogeneic stem cell transplant, a procedure in which a patient’s faulty blood-forming cells are replaced with healthy stem cells from a donor. Because myelofibrosis is rare and its course can be unpredictable, approaches to treatment have historically varied substantially among clinicians, a problem the new guidelines were designed to address by synthesizing available evidence into practical, actionable recommendations.

Among the most consequential recommendations is extended molecular testing at diagnosis. Genetic profiling helps identify high-risk mutations that can inform prognosis and guide treatment selection, allowing clinicians to stratify patients more precisely than clinical criteria alone. The guidelines also call for early transplant consultation for higher-risk individuals who are receiving and responding to JAK inhibitors, a recommendation that reflects the delicate timing calculus of transplantation: referring too late can mean losing the window in which a patient is well enough to undergo the procedure, while referring patients who will never need it exposes them to unnecessary risk.

The guidance takes a nuanced position on JAK inhibitor use depending on disease risk. For lower-risk individuals with disease-related symptoms, the guidelines support the use of these agents to improve quality of life. Conversely, for higher-risk individuals without disease-related symptoms, the recommendations advise avoiding JAK inhibitors, a stance that underscores a central tension in myelofibrosis care: symptom relief must be weighed against disease control and the pursuit of curative intent in patients whose biology portends aggressive disease. This risk-adapted framework is one of the clearest signals the panel has sent about how personalized the management of this cancer should become.

Anemia receives dedicated attention in the guidelines, covering strategies for managing low blood counts that arise either from myelofibrosis itself or from JAK inhibitor therapy. Anemia is among the most burdensome manifestations of the disease, contributing to fatigue, transfusion dependence, and diminished survival, yet evidence for its optimal management has remained fragmented. By consolidating guidance in this area, the panel aims to give clinicians a more consistent framework for a problem that routinely complicates long-term treatment.

Another notable recommendation concerns low-dose aspirin for patients carrying the JAK2 V617F mutation, the most common genetic alteration in myelofibrosis. Because these patients face an elevated risk of blood clots, the guidelines address whether aspirin therapy can meaningfully reduce thrombotic complications in this specific molecular subgroup. The inclusion of a mutation-specific recommendation illustrates how deeply genetic testing now permeates the management of myeloproliferative neoplasms, extending beyond diagnosis and prognosis into preventive care.

Guideline panel chair Brady Stein, MD, professor of medicine at Northwestern University’s Feinberg School of Medicine, emphasized the practical intent behind the effort. According to Stein, the recommendations address questions that routinely come up for clinicians and patients managing myelofibrosis, and the hope is that they will enable hematologists to more confidently deliver better care to their patients. He also acknowledged that important gaps in evidence remain, expressing hope that the questions the panel asked can help set a future research agenda to further improve care for patients with this disease.

Indeed, the guidance explicitly identifies several areas where more research is needed. These include enhancing the prediction of which patients will benefit from specific treatments, establishing better approaches to myelofibrosis-related anemia, and clarifying the optimal timing for transplant. Each of these gaps reflects a broader challenge in rare-disease medicine: with limited patient populations, randomized trials are difficult to mount, and evidence often accrues slowly. By articulating a research agenda alongside its clinical recommendations, the panel has effectively mapped the frontier for the next generation of myelofibrosis studies.

For patients, the practical message is that the guidance clinicians use for treating myelofibrosis has changed. The new ASH guidelines emphasize individualized care based on a patient’s symptoms, spleen enlargement, anemia, genetic testing results, transplant eligibility, and personal preferences. Patients may want to ask their care team whether extended molecular testing is appropriate for them, whether a JAK inhibitor may help with symptoms or spleen enlargement, how anemia should be managed, and whether they should be referred for a stem cell transplant consultation. For those with the JAK2 V617F mutation, the guidelines also address the use of low-dose aspirin to help prevent blood clots. Additional resources, including snapshots, visual summaries, and teaching slides, are available through the Society’s website, offering patients and clinicians alike a shared foundation for navigating a disease that has long demanded more certainty than the evidence could provide.

Subject of Research: Clinical practice guidelines for the management of myelofibrosis, a rare bone marrow cancer

Article Title: ASH issues new recommendations to improve myelofibrosis care

Article References: ASH issues new recommendations to improve myelofibrosis care. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: myelofibrosis, American Society of Hematology, Blood Advances, JAK inhibitors, stem cell transplant, molecular testing, JAK2 V617F, anemia, aspirin, myeloproliferative neoplasm, clinical guidelines, hematology

Acute severe ulcerative colitis is a potentially life-threatening emergency marked by frequent bloody stools, systemic toxicity, and the need for urgent hospitalization. It develops in up to one-quarter of ulcerative colitis patients during their disease course. Intravenous corticosteroids remain the recommended first line of attack, yet roughly 30 to 40 percent of patients fail to respond adequately after three to five days. At that point, clinicians must choose quickly between medical rescue therapy and colectomy, because delayed surgery or ineffective drug treatment can compound the danger.

For decades, the two established rescue options have been infliximab, a monoclonal antibody that neutralizes tumor necrosis factor, and calcineurin inhibitors such as ciclosporin. Landmark randomized trials, including the CySIF trial and the pragmatic CONSTRUCT study, found no meaningful difference between the two drugs in treatment failure, colectomy, or serious adverse events. But the therapeutic landscape has grown more complicated. Accelerated and high-dose infliximab regimens have been proposed to counteract the rapid drug clearance seen in severely inflamed patients, while oral Janus kinase inhibitors such as tofacitinib and upadacitinib have emerged as candidates, particularly for patients already exposed to biologic therapy.

To untangle this crowded field, an international team of researchers led by investigators at Brookdale University Hospital and Medical Center in New York, with collaborators spanning institutions in the United States, Egypt, and beyond, searched five major electronic databases from inception through June 30, 2026. They screened 5,498 records and ultimately included 18 studies: three randomized controlled trials and 15 comparative observational studies. The team conducted separate frequentist random-effects network meta-analyses for four outcomes: colectomy at approximately 12 to 14 weeks, colectomy during hospitalization or within 30 days, colectomy at approximately 12 months, and serious adverse events. The review was registered with PROSPERO under identifier CRD420261412884.

The headline result concerned the classic head-to-head comparison. At the short-term follow-up window of roughly 12 to 14 weeks, ciclosporin was associated with significantly higher odds of colectomy than standard-dose infliximab, with an odds ratio of 2.19 and a 95 percent confidence interval of 1.17 to 4.12. The pattern held at earlier and later time points: ciclosporin showed roughly three-fold higher odds of early colectomy, defined as surgery during the index hospitalization or within 30 days, and more than three-fold higher odds of colectomy at 12 months. Notably, serious adverse events were statistically indistinguishable between the two drugs, with an odds ratio of 0.94.

By contrast, neither accelerated infliximab induction, in which the second and third infusions are given earlier than the conventional week-2 and week-6 schedule, nor high-dose infliximab at 10 milligrams per kilogram showed a significant advantage over the standard 5-milligram-per-kilogram regimen. The confidence intervals for these intensified strategies were strikingly wide, reflecting small treatment groups and sparse event counts. Tacrolimus, another calcineurin inhibitor, also did not differ significantly from standard-dose infliximab at either early or 12-month follow-up, though its network estimate rested on a single retrospective study of just 61 patients.

The Janus kinase inhibitor evidence told an intriguing but incomplete story. In a retrospective matched case-control study, tofacitinib was associated with a lower adjusted 90-day colectomy risk than matched standard-care controls among biologic-experienced hospitalized patients, with an adjusted hazard ratio of 0.28. A separate international comparison of tofacitinib and upadacitinib found nearly identical colectomy-free survival, 79 percent versus 80 percent at day 98, with no difference between the survival curves. However, these studies could not be validly connected to the main infliximab-ciclosporin network because they lacked a common comparator, so no global ranking across drug classes was possible.

Beneath the surface of the pooled estimates lies a critical tension. The apparent efficacy advantage of infliximab over ciclosporin was driven predominantly by observational studies, which pooled to an odds ratio of 2.88 favoring infliximab, whereas the direct randomized comparison in the Laharie trial was essentially neutral, with an odds ratio of 0.78. The authors identify several plausible explanations for this divergence. Many observational cohorts compared patients treated in nonoverlapping calendar periods, meaning ciclosporin cohorts often predated infliximab cohorts and may have benefited less from improvements in supportive care, infection screening, thromboprophylaxis, and surgical decision-making. Moreover, ciclosporin was frequently used as a temporary bridge to thiopurines, while infliximab could be continued as long-term maintenance therapy, potentially skewing 12-month colectomy rates in favor of the latter strategy.

Risk of bias assessments reinforced the need for caution. All three randomized trials were judged to have some concerns, largely because open-label designs could have influenced decisions about additional rescue treatment or the timing of surgery. Among the 15 observational studies, 14 were rated as having serious risk of bias, primarily due to confounding by indication: patients with more severe inflammation, lower albumin, or prior biologic failure were more likely to receive intensified infliximab, tacrolimus, or JAK inhibitors. Using the GRADE framework, the certainty of evidence ranged from low to very low, and no comparison achieved moderate or high certainty.

The practical message for clinicians is nuanced rather than revolutionary. Standard-dose infliximab emerges as an effective and practical default rescue strategy, with the added advantage that it can be continued for maintenance after successful induction. Yet ciclosporin should not be dismissed as obsolete; randomized trials continue to support it as a legitimate option, particularly in thiopurine-naïve patients, those with contraindications to anti-TNF therapy, or centers experienced in therapeutic drug monitoring. The PREDICT-UC randomized trial, which found no benefit of an initial 10-milligram-per-kilogram dose or accelerated induction over standard dosing, argues against routine intensification for all patients, though individualized escalation may still help those with profound hypoalbuminemia or suspected rapid drug clearance.

The authors conclude that adequately powered randomized comparisons are urgently needed, incorporating contemporary biologic-exposed populations and newer small-molecule therapies, with standardized definitions of steroid failure and consistent reporting of colectomy across time points. Until such trials arrive, treatment selection should remain individualized, weighing previous therapy, disease severity, serum albumin, comorbidities, and institutional expertise. And one principle remains nonnegotiable: early surgical consultation should run in parallel with medical rescue planning, because no drug ranking, however sophisticated the statistics, should justify delaying colectomy in a deteriorating patient.

Subject of Research: Comparative efficacy and safety of medical rescue therapies for steroid-refractory acute severe ulcerative colitis

Article Title: Comparative outcomes of advanced medical rescue therapies in steroid-refractory acute severe ulcerative colitis: a systematic review and network meta-analysis

Article References: Alabdallat, M. Y., Al Ta’ani, O., Bakain, T., Al-Dwairy, A., Ghannam, M., Atasi, A., Mashal, F., Moghib, K., Bakheet, N., Jagroo, J. G., Hehr, R., Salem, A., & Cheung, D. (2026). Comparative outcomes of advanced medical rescue therapies in steroid-refractory acute severe ulcerative colitis: a systematic review and network meta-analysis. Frontiers in Gastroenterology, 5, Article 1937925. https://doi.org/10.3389/fgstr.2026.1937925

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1937925

Keywords: ulcerative colitis, infliximab, ciclosporin, colectomy, network meta-analysis, rescue therapy, tacrolimus, JAK inhibitors, steroid refractory, acute severe ulcerative colitis, gastroenterology, systematic review

The research team, led by Mahnaz Jamee of the Garvan Institute of Medical Research in Sydney together with collaborators in Egypt, Iran, and Saudi Arabia, searched PubMed, Web of Science, and Scopus from their beginnings through April 2026. After screening more than 5,200 records and assessing 129 full-text articles, they identified 81 studies describing 172 patients with sequencing-confirmed genetic diagnoses who had received a biologic or a JAK inhibitor specifically for atopic manifestations. The review followed the PRISMA 2020 reporting standard, appraised study quality with Joanna Briggs Institute checklists, and rated the certainty of evidence using GRADE principles, which placed every outcome at very low certainty because nearly all the underlying reports were single-patient case reports or small series.

The genetic landscape of the treated patients was strikingly concentrated. STAT3 loss-of-function disease, the classic form of hyper-IgE syndrome, accounted for 52 patients, or 30.2 percent of the cohort. Netherton syndrome, a devastating epithelial-barrier disorder caused by SPINK5 mutations, contributed 32 patients, and DOCK8 deficiency, a combined immunodeficiency notorious for severe eczema and recurrent viral infections, accounted for 19. JAK1 gain-of-function disease and CARD11-associated atopy with dominant interference of NF-kappa-B signaling rounded out the leading diagnoses. Nearly half of the patients carried multiple atopic manifestations at once, most often atopic dermatitis overlapping with asthma or with food allergy, and almost two-thirds were children at the time treatment began.

Dupilumab dominated the published experience. The antibody, which blocks the shared alpha subunit of the receptors for the type 2 cytokines interleukin-4 and interleukin-13, had been given to 120 patients, roughly 70 percent of the entire cohort. It was used most often in STAT3 loss-of-function disease, DOCK8 deficiency, Netherton syndrome, and CADINS, with atopic dermatitis as the leading indication, followed by asthma and food allergy. Among the 118 patients with reported outcomes, a complete or major clinical response was described in 82.2 percent, with partial responses, relapses, and non-response making up the remainder. Beyond the skin, clinicians documented broader benefits in more than two-thirds of patients, including fewer cutaneous infections, weight and height gain, hair and nail regrowth, and improved sleep and quality of life.

The biology behind these responses is instructive. Type 2 inflammation, driven by helper T cells, mast cells, and innate lymphoid cells producing interleukins 4, 5, 13, and 31, sits at the center of allergic disease, recruiting eosinophils and driving B cells toward IgE production. By binding a single target, IL-4Rα, dupilumab silences signaling through both type I and type II interleukin-4 and interleukin-13 receptors, and the breadth of reported benefit reflects the pleiotropic downstream consequences of blocking that shared subunit rather than action on multiple molecular targets. Adverse effects were subtle, chiefly conjunctivitis and transient hypereosinophilia, consistent with large real-world studies in ordinary atopic dermatitis. Notably, dupilumab also served as a bridge to hematopoietic stem cell transplantation in seven patients, most of them with DOCK8 deficiency, holding severe disease at bay until a potentially curative transplant could be performed.

Omalizumab, the anti-IgE antibody that binds circulating free IgE and strips it from FcεRI receptors on mast cells and basophils, appeared in 16 patients, most frequently those with STAT3 loss-of-function disease. Outcomes were reported for 14 of them, and a complete or major response was described in 78.6 percent, with particular benefit in atopic dermatitis and asthma. Thirty-seven and a half percent of these patients were able to stop corticosteroids entirely, and several experienced a reduction in infection rate, an observation the authors suggest may make omalizumab especially valuable for immunodeficient patients who cannot tolerate steroids. The reviewers caution, however, that measured total IgE often rises after omalizumab initiation because drug-IgE complexes clear slowly, so the laboratory changes reported in the literature must be read descriptively rather than as proof of mechanism.

JAK inhibitors occupied a conceptually distinct niche. These small molecules interrupt the Janus kinase–STAT pathway, the main conduit by which cytokines transmit inflammatory signals from the cell membrane to the nucleus. Twenty-one patients received them, most commonly baricitinib and ruxolitinib, and the pattern of use was strikingly genotype-specific: ruxolitinib was given to patients with JAK1, STAT5B, and STAT6 gain-of-function disease, baricitinib exclusively to JAK1 gain-of-function patients, and abrocitinib only to those with Netherton syndrome. A complete or major response was described in 76.2 percent of published patients, and additional benefits included resolution of food intolerance and normalization of hepatic inflammation. Adverse events such as anemia, lightheadedness with nausea, and body odor appeared in a minority, but the authors emphasize that with so few patients and a median follow-up of only two years, the data cannot exclude serious infections, cytopenias, thrombosis, or malignancy, particularly in patients whose antiviral or antifungal immunity is already compromised.

Perhaps the most intellectually valuable contribution of the review is its framework for thinking about when these drugs make sense. The authors distinguish four therapeutic models: pathway-corrective treatment, in which the drug directly counters the causal signaling abnormality, as with ruxolitinib in JAK1 gain-of-function disease; phenotype-directed treatment, in which a downstream atopic manifestation is targeted without fixing the underlying defect, as with dupilumab in STAT3 loss-of-function or Netherton syndrome; bridge therapy before stem cell transplantation; and symptomatic adjunctive therapy after conventional treatment has failed. These models carry different expectations and should not be pooled into a single conclusion about effectiveness. Organized by mechanism, the published experience spans dominant type 2 signaling disorders, JAK-STAT hyperactivation, combined immunodeficiencies with severe atopy, hyper-IgE syndromes, epithelial-barrier defects, and regulatory T-cell disorders such as IPEX.

The authors are careful about the limits of their evidence. Favorable outcomes are far more likely to be published than treatment failures, so the response proportions are descriptive summaries of published experience, not estimates of how well these drugs work in the underlying population. Many patients received concurrent corticosteroids, immunoglobulin replacement, antimicrobial prophylaxis, or other targeted agents, making it impossible to attribute improvement to a single drug. Adverse events were systematically under-ascertained in reports whose primary purpose was to showcase success, and a median follow-up of twelve months is far too short to detect late complications such as malignancy or opportunistic infection. No biologic or JAK inhibitor holds regulatory approval for atopic manifestations in these disorders, meaning every use described is off-label with respect to the underlying genetic condition.

Even with those caveats, the synthesis marks a turning point for a field long dependent on anecdote. It suggests that dupilumab offers the largest and most encouraging published experience across multiple genetic backgrounds, that omalizumab may be a steroid-sparing option for immunodeficient patients with asthma and eczema, and that JAK inhibitors are uniquely suited to disorders driven by gain-of-function mutations in their own target pathway. The authors call for long-term longitudinal studies with standardized allergy testing, objective outcome measures, and systematic safety surveillance. Until such data exist, they conclude, treatment should remain individualized and genotype-informed, accompanied by careful infection monitoring, a prescription that captures both the promise and the prudence demanded by precision medicine in some of the rarest and most difficult allergic diseases known.

Subject of Research: Use of biologics and JAK inhibitors to treat atopic manifestations in inborn errors of immunity

Article Title: Biologics and JAK inhibitors for atopic manifestations in inborn errors of immunity: a systematic review

Article References: Jamee, M., Al-Gaweesh, R. M., Hajialigol, A., Mohammed, S. G., Tirandazi, P., Alangari, A. A., & El-Owaidy, R. (2026). Biologics and JAK inhibitors for atopic manifestations in inborn errors of immunity: a systematic review. Frontiers in Allergy, 7, Article 1867183. https://doi.org/10.3389/falgy.2026.1867183

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1867183

Keywords: inborn errors of immunity, dupilumab, omalizumab, JAK inhibitors, atopic dermatitis, hyper-IgE syndrome, Netherton syndrome, DOCK8 deficiency, STAT3, systematic review, type 2 inflammation, precision medicine

At the heart of the review is a deceptively simple biochemical story. Melanocytes, the cells responsible for producing the pigment melanin, are intrinsically fragile when it comes to oxidative damage. The very chemistry of melanin synthesis generates reactive oxygen species, or ROS, as a byproduct, meaning that every act of pigmentation places the melanocyte under a degree of self-inflicted chemical stress. In healthy skin, antioxidant enzymes such as catalase and superoxide dismutase keep this stress in check. In vitiligo, the review argues, that protective machinery falters. Hydrogen peroxide and other reactive species accumulate to toxic levels, damaging cellular components and triggering a cascade of inflammatory signals that ultimately doom the melanocyte.

The consequences of this oxidative overload extend far beyond simple chemical damage. The review details how excess ROS promotes the production of inflammatory cytokines, the signaling molecules that recruit and activate immune cells. This creates a dangerous feedback loop: stressed melanocytes release danger signals, immune cells respond with inflammatory attacks, and the resulting inflammation generates even more oxidative stress. The authors also highlight two increasingly studied forms of regulated cell death, ferroptosis and pyroptosis, as critical executioners in this process. Ferroptosis, driven by the iron-dependent peroxidation of lipids in cell membranes, is particularly relevant because oxidative stress directly fuels the lipid damage that defines this death pathway.

Pigment loss in vitiligo is not only a matter of cell death, however. The review also examines how the regulatory pathways governing melanogenesis itself become derailed. Key signaling systems, including those mediated by MITF, WNT, Kit, and alpha-melanocyte-stimulating hormone, normally orchestrate the production of melanin by controlling enzymes such as tyrosinase, TYRP1, and TYRP2. When these pathways are deregulated, the activity of these melanogenic enzymes drops, compounding the problem even before melanocytes begin to die. The result is a double hit: the cells that remain are less capable of producing pigment, while the cells under the greatest stress are progressively eliminated by oxidative and inflammatory assault.

Genetics adds another layer of complexity to this picture. Genome-wide association studies have repeatedly linked vitiligo to polymorphisms in immune-regulating genes, and the review emphasizes the roles of the human leukocyte antigen system and CTLA-4, a checkpoint molecule that normally restrains T-cell activity. Variants that weaken these immune brakes help explain why vitiligo behaves as an autoimmune disease, with CD8-positive T cells targeting melanocytes at the edges of depigmenting lesions. At the same time, genetic variation in antioxidant defenses, including genes encoding catalase and superoxide dismutase, helps explain why some individuals’ melanocytes are more vulnerable to oxidative damage than others. The disease, in this framing, emerges at the intersection of a susceptible immune system and an inadequate antioxidant shield.

Against this backdrop, the transcription factor Nrf2 emerges as the review’s central therapeutic protagonist. Under normal conditions, Nrf2 is held in check by its cytosolic partner Keap1, which tags the transcription factor for destruction. When oxidative stress rises, the Keap1-Nrf2 system is disengaged, allowing Nrf2 to travel to the nucleus and switch on a battery of detoxifying and antioxidant genes. This pathway protects melanocytes from the reactive oxygen species that would otherwise kill them, and studies cited in the review show that Nrf2 activation can shield pigment cells from hydrogen peroxide-induced damage. The Keap1-Nrf2 axis has become one of the most intensively studied drug targets in redox medicine, with natural and synthetic modulators under active investigation across inflammatory diseases.

Compounds that activate Nrf2 have already shown promise in laboratory models of vitiligo. Berberine, a plant-derived alkaloid, has been reported to protect human melanocytes from hydrogen peroxide-induced oxidative stress by activating both Nrf2 and MITF signaling. Baicalein, a flavonoid from the traditional medicinal herb Scutellaria baicalensis, similarly protects vitiligo melanocytes through Nrf2 activation. Resveratrol, the celebrated polyphenol of red grapes, has also been shown to mediate anti-inflammatory effects through Nrf2 in other disease contexts. These findings suggest a pharmacological strategy in which bolstering the cell’s intrinsic antioxidant response could complement existing immunosuppressive treatments, addressing both sides of the vitiligo equation simultaneously.

Yet the review delivers a cautionary twist: Nrf2 is not an unambiguous hero. The authors note that excessive activation of Nrf2 under certain physiological conditions may actually have negative effects on melanogenesis, the very process that therapies are trying to restore. This biphasic behavior underscores a recurring theme in redox biology, where the optimal level of antioxidant signaling is a narrow window rather than a simple case of more being better. It also helps explain why broad antioxidant supplementation has produced inconsistent results in clinical practice, and why the next generation of treatments will likely need to fine-tune Nrf2 activity rather than simply maximize it. The review’s authors point to recent work on Nrf2 modulators as a roadmap for achieving that precision.

The therapeutic landscape of vitiligo is already evolving rapidly, and the review situates Nrf2-targeted strategies within this broader context. Current options range from topical corticosteroids and calcineurin inhibitors to narrowband ultraviolet B phototherapy, excimer laser treatment, and PUVA photochemotherapy. More recently, Janus kinase inhibitors such as ruxolitinib cream have demonstrated efficacy in phase 3 trials, offering the first approved pharmacological option for repigmentation in many markets. The IFN-gamma-CXCL9/CXCL10-CXCR3 chemokine axis, which recruits destructive T cells to the skin, has become a major drug target, and researchers are exploring microneedle-assisted delivery systems to push drugs more effectively into depigmented skin. Antioxidant approaches, the review suggests, could be layered onto these immunomodulatory regimens to protect surviving melanocytes while the immune attack is being suppressed.

Environmental and chemical triggers round out the review’s comprehensive account. Chemical leukoderma, the depigmentation caused by exposure to certain phenolic compounds such as 4-tertiary butyl phenol found in some industrial and consumer products, illustrates how exogenous stressors can precipitate vitiligo-like loss in susceptible individuals. These chemicals sensitize melanocytes to immune-mediated killing and disrupt protein folding in the endoplasmic reticulum, adding yet another route by which oxidative stress converges with immune dysregulation. Similarly, ultraviolet radiation and particulate air pollution generate ROS in the skin, further burdening melanocytes in vulnerable patients. The unified message of the review is that vitiligo is a disease of converging stresses, and that the Nrf2 pathway, sitting at the junction of oxidative defense, inflammation control, and melanocyte survival, represents one of the most promising points of intervention. As clinical trials of Nrf2 modulators advance, the prospect of treatments that do more than suppress the immune system, and instead rebuild the skin’s own chemical resilience, moves steadily closer to reality.

Subject of Research: The role of oxidative stress and Nrf2-mediated antioxidant signaling in the pathogenesis and treatment of vitiligo

Article Title: Oxidative stress and Nrf2-mediated antioxidant therapeutic strategies in vitiligo

Article References: Chauhan, K., Singh, B. K., Singh, S., Singh, H., Chopra, S., & Chopra, H. (2026). Oxidative stress and Nrf2-mediated antioxidant therapeutic strategies in vitiligo. Archives of Dermatological Research, 318(1), Article 522. https://doi.org/10.1007/s00403-026-04946-4

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04946-4

Keywords: vitiligo, oxidative stress, Nrf2, melanocytes, ferroptosis, pyroptosis, Keap1, antioxidants, autoimmunity, melanogenesis, JAK inhibitors, dermatology

The review, led by Fiona S. Gruzmark and colleagues at the University of Illinois College of Medicine in Chicago, was registered with PROSPERO and conducted according to PRISMA guidelines. The team searched PubMed, Embase, and Scopus from database inception through November 2025, ultimately including 37 studies covering 269 patients. Because the evidence base consists almost entirely of case reports and case series, with no controlled trials identified, the authors emphasize that their synthesis maps the landscape of current practice rather than ranking therapies with statistical confidence. Still, the patterns that emerge are striking enough to question the status quo.

The clinical stakes are higher than many readers might expect. When lichen planus involves the nail matrix, the structure where the nail plate is generated, it can produce longitudinal ridging, thinning and fragmentation of the nail plate, a red lunula, and dorsal pterygium, a scarring process in which the proximal nail fold fuses to the nail bed. Nail bed involvement produces onycholysis, subungual hyperkeratosis, and splinter hemorrhages. In severe cases the damage is permanent, resulting in irreversible nail loss and significant impairment in quality of life. Histopathologically, the disease shows sawtooth acanthosis of the nail epithelium and a lymphocytic infiltrate at the dermoepidermal junction, hallmarks of a lichenoid tissue reaction.

The underlying immunology is increasingly well characterized. The pathogenesis involves abnormal Toll-like receptor signaling, accumulation of plasmacytoid dendritic cells, and destruction of keratinocytes by autoreactive CD8-positive T lymphocytes. Recent work has also implicated Death-Associated Protein Kinase 1, which mediates keratinocyte apoptosis and counteracts necroptosis and inflammatory gene regulation. Diagnosis rests on clinical examination, with nail biopsy used for confirmation; a longitudinal biopsy targeting the most involved area shows a 96.30 percent concordance between clinical and histopathologic localization, and taking two specimens may increase diagnostic yield. The procedure carries a reported risk of permanent nail dystrophy or scarring in roughly 28 to 29 percent of patients, underscoring why better noninvasive outcome measures are needed.

Against that backdrop, the review’s treatment data are revealing. Intralesional corticosteroids were the most frequently used therapy, accounting for 34.2 percent of treated patients, followed by systemic corticosteroids at 18.6 percent, steroid-sparing immunomodulatory agents at 16.7 percent, combination therapies at 8.9 percent, Janus kinase inhibitors at 5.2 percent, oral retinoids at 3.4 percent, topical corticosteroids at 2.2 percent, and laser therapy at 0.4 percent. Ten percent of participants received no treatment at all. The current expert consensus, last updated in 2020, recommends intralesional triamcinolone acetonide as first-line therapy, with systemic corticosteroids reserved for more aggressive disease.

Yet when the authors tabulated outcomes, the hierarchy of efficacy looked very different from the hierarchy of use. Only 1.1 percent of patients treated with intralesional steroids achieved complete recovery, and 27.2 percent showed partial improvement. Systemic steroids fared somewhat better, with 62.0 percent achieving complete improvement and 34.0 percent partial improvement. By contrast, patients receiving Janus kinase inhibitors showed 35.7 percent complete and 64.3 percent partial improvement, and those on oral retinoids showed 21.1 percent complete and 68.4 percent partial improvement. Among the steroid-sparing immunomodulatory agents, 6.7 percent achieved complete and 57.8 percent partial improvement, with the complete recoveries occurring in patients treated with mycophenolate mofetil and chloroquine. Low-dose naltrexone, a novel addition to the armamentarium, produced partial improvement in 57.1 percent of treated patients.

The mechanistic rationale for the JAK inhibitors is particularly compelling. In lichen planus, interferon-gamma primes keratinocytes and increases their susceptibility to cytotoxic CD8-positive T cell attack through upregulation of MHC class I molecules, a process dependent on JAK2 and STAT1 signaling. By blocking the JAK-STAT pathway, agents such as baricitinib, ruxolitinib, tofacitinib, abrocitinib, and upadacitinib interrupt this interferon-driven inflammatory cascade, reducing T cell-mediated cytotoxicity against nail matrix keratinocytes. Work in oral lichen planus further suggests these drugs prevent cytotoxic T cell migration and enhance mucosal barrier integrity through increased expression of tight junction proteins. Notably, no adverse events were reported among JAK inhibitor-treated patients in the review, although the authors caution that follow-up durations were limited and that the class carries an FDA boxed warning for serious infections, malignancy, major cardiovascular events, and thrombosis, risks particularly relevant to the middle-aged and older adults who most often develop the disease.

Oral retinoids such as alitretinoin and acitretin, which modulate epithelial differentiation through nuclear retinoid receptors, achieved the highest partial response rate of any drug class but come with a heavier toxicity burden. Reported adverse events included headache, elevated liver enzymes, acute diverticulitis, cheilitis, facial flushing, xerosis, and mucocutaneous dryness. Retinoids are contraindicated in children and adolescents because of the risk of premature epiphyseal closure, require mandatory contraception in women of childbearing potential due to teratogenicity, and demand caution in elderly patients. Corticosteroid-related adverse events were also documented, including pain, subungual hematoma, hypopigmentation, and atrophy with intralesional injections; one case of Nicolau syndrome, localized tissue ischemia at the injection site; and weight gain, transient cushingoid features, mood changes, and gastrointestinal symptoms with systemic use. Cyclosporine produced hypertension in two patients.

Among the newer alternatives, low-dose naltrexone stands out for its unusual pharmacology. At doses of around 3 milligrams daily, the opioid receptor antagonist paradoxically increases endogenous opioid synthesis and exerts anti-inflammatory effects through antagonism of Toll-like receptor 4, a pathway with elevated signaling in lichen planus. In a retrospective case series cited in the review, four of seven biopsy-proven nail lichen planus patients achieved a clinical response with no adverse events, and the drug has shown benefit across a range of inflammatory dermatoses including psoriasis, hidradenitis suppurativa, and dermatomyositis. However, disease reactivation was observed after elective discontinuation, and the authors stop short of endorsing it given the small sample sizes reported so far.

The review’s limitations are candidly acknowledged and considerable. The search strategy used only American English drug names, potentially missing studies indexed under British equivalents, and only English-language publications were included, introducing language bias. Publication and outcome reporting bias may have inflated apparent efficacy. Most critically, 81.1 percent of included studies were case reports or case series, no controlled studies were identified, and the absence of a validated scoring system made cross-study comparison nearly impossible, with many studies reporting vague categories like clinical or moderate improvement. One study applied the Nail Lichen Planus Severity Index, a promising but not yet formally validated tool that incorporates irreversible damage and extent of nail unit involvement. The authors conclude that a re-evaluation of current management is warranted, and that larger, well-designed controlled studies with validated outcome measures are the essential next step for a disease that can quietly destroy nails permanently.

Subject of Research: Therapeutic management of nail lichen planus

Article Title: Therapeutic management of nail lichen planus: a systematic review

Article References: Gruzmark, F. S., Ramir, J., Aggarwal, I., & Haber, R. (2026). Therapeutic management of nail lichen planus: a systematic review. Archives of Dermatological Research, 318(1), Article 422. https://doi.org/10.1007/s00403-026-04838-7

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04838-7

Keywords: nail lichen planus, systematic review, JAK inhibitors, corticosteroids, oral retinoids, low-dose naltrexone, immunomodulatory therapy, nail matrix, dermatology, triamcinolone, PRISMA, treatment outcomes

The epidemiology of the disease is strikingly concentrated in early childhood. Roughly 90 percent of pediatric cases present between the ages of 2 and 14, with a mean age of onset between 7.3 and 8.8 years. Clinicians classify morphea into several subtypes, including circumscribed plaque disease, linear morphea, generalized morphea, pansclerotic morphea, and mixed forms. Linear morphea is the most common subtype in children, and it is also among the most feared. When linear lesions cross the forehead and frontotemporal region, a presentation known as en coup de sabre, patients face a heightened risk of neurological involvement, facial asymmetry, and permanent deformity of the underlying skull and bone during critical growth windows. A related variant, Parry Romberg syndrome, can produce progressive hemifacial atrophy with or without visible skin hardening.

What makes morphea particularly dangerous in children is that it is not merely a skin disease. Approximately 20 percent of patients develop extracutaneous manifestations, including arthritis, uveitis, and neurological symptoms. Because the disease can scar actively growing bones and the developing skull, experts emphasize prompt and aggressive systemic treatment for deep or linear subtypes. Differentiating morphea from systemic sclerosis is also crucial: systemic sclerosis is characterized by sclerodactyly, Raynaud’s phenomenon, nail-fold capillary changes, telangiectasias, and internal organ involvement, features that generally distinguish it from the localized form. Interestingly, about half of morphea cases may undergo spontaneous resolution, complicating decisions about how intensively to treat.

The pathogenesis of morphea involves a complex interplay between genetic susceptibility, immune dysregulation, vascular injury, and aberrant fibrotic responses. Early lesions show a perivascular and interstitial inflammatory infiltrate of lymphocytes, macrophages, and plasma cells, accompanied by endothelial cell injury and microvascular dysfunction. Fibrosis itself is driven by persistent fibroblast activation and excessive deposition of type I and type III collagen. At the center of this process sits transforming growth factor-beta, or TGF-β, a master regulator that promotes fibroblast proliferation, drives differentiation into myofibroblasts, and boosts collagen synthesis while suppressing matrix degradation. Additional profibrotic mediators, including connective tissue growth factor, platelet-derived growth factor, and endothelin-1, amplify the fibrotic cascade.

Recent immunological insights have opened the door to precision therapies. A predominance of Th2-associated cytokines, particularly interleukin-4 and interleukin-13, promotes fibrosis through direct stimulation of fibroblast activity, and both cytokines signal through the Janus kinase-STAT pathway, especially STAT6. This provides a biological rationale for drugs targeting IL-4/IL-13 signaling, such as dupilumab, and for broader JAK-STAT inhibition. Even more dramatic was the discovery of novel gain-of-function STAT4 variants, inherited in an autosomal dominant manner or arising de novo, in children with disabling pansclerotic morphea, the most severe deep form of the disease. In a landmark study, four affected individuals from three families treated with oral ruxolitinib showed resolution of inflammatory biomarkers and clinical symptoms, with single-cell RNA sequencing revealing an immunodysregulatory signature that was effectively modulated by JAK inhibition.

For the majority of patients, treatment still follows a severity-based algorithm developed by the Childhood Arthritis and Rheumatology Research Alliance, or CARRA. Low-severity disease, defined as circumscribed superficial morphea without subcutaneous atrophy, extracutaneous involvement, or scalp hair loss, can be managed with high-potency topical corticosteroids, topical tacrolimus, calcipotriol, or imiquimod, often combined with phototherapy using broadband UVA, UVA1, or narrowband UVB. Tacrolimus ointment 0.1 percent demonstrated significant improvement in a randomized placebo-controlled trial after 12 weeks, while a case report of topical ruxolitinib cream 1.5 percent and another of the pan-JAK inhibitor delgocitinib in a 2-year-old suggest that topical JAK blockade may soon join the armamentarium. Imiquimod, an immune response modifier that induces interferon-gamma release and inhibits fibroblast collagen production, reduced lesion thickness in a prospective open-label study of nine children.

Moderate to severe disease demands systemic therapy, and methotrexate remains the undisputed first line. Dosing is calculated either by weight, at 0.3 to 0.6 mg/kg/week orally or up to 1 mg/kg/week subcutaneously, or by body surface area at 15 mg/m²/week, generally capped at 25 mg per week. Subcutaneous administration is often preferred for superior bioavailability and fewer gastrointestinal side effects. A systematic review found methotrexate effective in 93 percent of children, compared with 71 percent for phototherapy alone, and a randomized double-blind placebo-controlled trial showed that methotrexate combined with an initial prednisone course produced significantly better outcomes than placebo. Treatment is typically maintained for 12 to 24 months before tapering, and pulsed intravenous methylprednisolone may be added for severe or rapidly progressive cases, with side effects such as Cushingoid facies generally reversible after tapering.

For children who fail methotrexate, several alternatives have emerged. Mycophenolate mofetil achieved remission in 35 percent of patients within one year in a retrospective cohort, and in a separate study 90.9 percent of methotrexate-refractory children attained sustained remission over a mean follow-up of 9.4 years. Abatacept, which blocks T-cell costimulation, produced clinical improvement in 83 percent of eighteen refractory pediatric patients over 12 months, with some maintaining response to 24 months. Tocilizumab, an interleukin-6 receptor antagonist, significantly improved disease activity scores in five resistant patients after six months, though damage and quality-of-life measures did not change. Infliximab and the JAK inhibitors tofacitinib and baricitinib have each shown benefit in small case series, with tofacitinib reducing modified Localized Scleroderma Skin Activity Index and Damage Index scores without reported adverse effects.

The review’s authors caution that evidence for these emerging agents rests largely on case reports and small series, precluding definitive conclusions about comparative efficacy and long-term safety. Methotrexate and systemic corticosteroids remain the standard of care despite known risks including systemic toxicity and decreased bone density. Monitoring is especially critical in children, where corticosteroids can suppress growth velocity and bone mineral accretion. Objective assessment tools are improving: the Morphea Activity Measure correlates well with physician global assessments, and a novel multispectral imaging device using a handheld Antera 3D camera can predict new or enlarging lesions within three months with 90 percent sensitivity and 100 percent specificity, even in darkly pigmented skin. Ultrasound, magnetic resonance imaging, and 3D imaging add further objective windows into deep tissue involvement.

Finally, the review underscores that morphea is a whole-child disease. Although standardized quality-of-life instruments often show minimal impairment, qualitative studies of 690 pediatric patients across 13 studies reveal elevated stress, low self-worth, feelings of being different, and experiences of bullying tied to visible skin changes and treatment burden. The authors call for disease-specific psychosocial instruments, multidisciplinary care involving dermatology, rheumatology, physical therapy, psychology, and, for craniofacial disease, neurology, ophthalmology, and maxillofacial specialists, alongside standardized outcome metrics, robust disease registries, and personalized medicine approaches that tailor therapy to each child’s genetic and immunologic profile. As targeted therapies mature, the prospect of controlling fibrosis before it inflicts irreversible damage on growing bodies is moving steadily closer to reality.

Subject of Research: Advances in the diagnosis and treatment of pediatric morphea (localized scleroderma)

Article Title: Advances in the management of pediatric morphea: a narrative review

Article References: Kashyap, A., Jafari, A. J., Klimas, N., Koshelev, M., Mays, S. R., & Hebert, A. A. (2026). Advances in the management of pediatric morphea: a narrative review. Archives of Dermatological Research, 318(1), Article 448. https://doi.org/10.1007/s00403-026-04890-3

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04890-3

Keywords: pediatric morphea, localized scleroderma, autoimmune disease, methotrexate, JAK inhibitors, biologic therapy, fibrosis, STAT4, tocilizumab, abatacept, multidisciplinary care, skin disease

The first node is the intestinal epithelium, the single-cell-thick lining that decides what passes from the gut lumen into the body. Its integrity depends on tight junctions built from proteins such as claudins and occludins, on a protective mucus layer, and on antimicrobial peptides secreted into the lumen. In Crohn’s disease, disruption of these tight junctions produces the phenomenon known as leaky gut: paracellular leakage that allows microbial antigens to cross into the lamina propria, where they encounter the immune system. Pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 can worsen the damage, and a decline in Wnt/beta-catenin signaling, a pathway essential for epithelial proliferation and differentiation, may impair mucus synthesis and tissue repair. The result is a barrier that fails precisely when the tissue needs regeneration most.

The review emphasizes that epithelial cells are not passive bricks in a wall. They actively participate in immune surveillance, secreting cytokines and chemokines such as interleukin-8 that recruit neutrophils to inflammatory sites. When pathobionts such as adherent-invasive Escherichia coli remodel this crosstalk, the recruitment and activation of immune cells becomes distorted, protective pathogen-clearance responses falter, and inflammation deepens. Meanwhile, intracellular signaling systems including NF-kappaB, Notch and PI3K/Akt govern how epithelial cells proliferate, differentiate and respond to stress; NF-kappaB activation during inflammatory interactions can remodel cytokine production and downregulate tight-junction expression, compounding the very barrier defect that triggered it.

The second node is the immune system. In Crohn’s disease, the balance between pro-inflammatory cytokines such as TNF-alpha and interleukin-6 and anti-inflammatory mediators such as interleukin-10 and transforming growth factor-beta tips sharply toward inflammation. T helper 17 cells expand, interleukin-17 mediates tissue injury, and regulatory T cells, the custodians of immune tolerance, lose ground. Chemokines such as CCL2 and CXCL10, which normally direct monocytes and T cells to sites of infection, instead orchestrate a chronic influx of activated immune cells into the gut wall. The review stresses that restoring inflammatory balance without disabling the immune system’s ability to fight infection remains one of the central therapeutic challenges in the field.

The third node is the gut microbiota. In Crohn’s disease, microbial diversity falls, beneficial short-chain fatty acid-producing members of the phylum Firmicutes are depleted, and potential pathobionts, most notably adherent-invasive E. coli, expand. This matters because microbial metabolites are among the most important chemical messengers between the microbiota and the host. Short-chain fatty acids such as acetate, propionate and butyrate, produced by the fermentation of dietary fiber, serve as the primary energy source for colonic epithelial cells, upregulate tight-junction expression, and promote the differentiation of regulatory T cells while suppressing pro-inflammatory Th17 responses through histone deacetylase-dependent mechanisms. When butyrate-producing taxa vanish, the epithelium loses fuel, the immune system loses a brake, and tolerance gives way to activation.

The heart of the review is its description of three positive feedback loops that weld these nodes together. In the IL-23/Th17 axis, interleukin-23 drives Th17 polarization, leading to interleukin-17 secretion, epithelial barrier disruption, microbial translocation and sustained IL-23 release. In the TNF-alpha-driven pathway, TNF-alpha disrupts epithelial tight junctions, enabling pathobiont translocation, TLR4/NF-kappaB activation and amplified TNF-alpha production. In the SCFA depletion cycle, reduced short-chain fatty acid levels impair regulatory T cell differentiation, promoting Th17 dominance, inflammation and further depletion of the very microbes that produce these metabolites. Each loop can, in principle, start anywhere, and once running, any one of them can keep the others alive.

This circuit model carries a pointed therapeutic implication: single-pathway drugs can be highly effective in selected patients, yet persistent activity in other compartments of the circuit may explain why some responses are incomplete or not durable. The clinical evidence reviewed supports this reading. The IL-23 inhibitor risankizumab produced greater endoscopic response than placebo at week 52 in patients with moderate-to-severe Crohn’s disease, including those who had failed anti-TNF therapy, with a relative risk of 3.40 in the ADVANCE/CD-101 program. The oral JAK1 inhibitor upadacitinib demonstrated efficacy for both induction and maintenance in phase 3 trials. For perianal fistulizing disease, darvadstrocel, an adipose-derived stromal-cell therapy, achieved fistula resolution in 56 percent of patients at 24 weeks in the ADMIRE-CD II trial and has been authorized in the European Union and Japan.

Non-drug strategies fit the same framework. The Crohn’s Disease Exclusion Diet, which removes specific food components, has shown efficacy for inducing and sustaining remission in randomized trials of patients with mild-to-moderate disease over 12 to 24 weeks, plausibly by reshaping the microbial and metabolic arm of the circuit. Fiber-rich diets that promote Bifidobacterium and Lactobacillus, SCFA supplementation, and probiotics targeting butyrate-producing taxa all aim to restore the microbial node. The review also flags a broader metabolic dimension: shared pathways involving dysbiosis, barrier impairment and chronic low-grade inflammation suggest that conditions such as Type 2 diabetes and metabolic syndrome should be viewed as potential modifiers of the epithelial-immune-microbiota axis rather than incidental comorbidities.

The framework is explicitly hypothesis-generating rather than a clinical guideline, and the authors are candid about its limits. Animal models such as TNF-delta-ARE mice and AIEC-colonized rodents capture fragments of the disease but none reproduces the full polygenic susceptibility, transmural inflammation and relapsing course seen in patients. A long-standing controversy remains over whether dysbiosis is a primary cause or a secondary consequence of inflammation; the review’s integrative position is that dysbiosis may act as a primary driver in young-onset or treatment-naive disease while functioning mainly as a disease-perpetuating amplifier once inflammation has established a permissive microbial niche. Environmental factors, including high-fat diets and psychological stress, can push the network in either direction by reshaping microbial composition and mucosal immune competence.

Where the framework becomes actionable is in measurement and stratification. Each node of the circuit can be paired with observable indicators: intestinal permeability markers, endoscopic and transmural healing, fecal calprotectin, cytokine profiles, microbial diversity, pathobiont enrichment and metabolite levels. Longitudinal profiling of these measures could, in principle, sort patients into barrier-dominant, immune-dominant, microbiota-dominant or mixed phenotypes, each pointing toward a different therapeutic priority. Multi-omics platforms combining shotgun metagenomics, metabolomics and proteomics, together with machine-learning models such as those predicting endoscopic response to ustekinumab from genomic and transcriptomic data, and AI-assisted endoscopy systems like EndoBrain and CAD-EYE, are already moving in this direction, though the authors caution that most current biomarkers capture only one dimension of disease biology and that cross-sectional observations cannot reliably distinguish primary drivers from secondary consequences. The STRIDE-II treat-to-target recommendations, which emphasize endoscopic healing and, in selected settings, transmural assessment by intestinal ultrasound or MRI, provide the monitoring backbone. What remains to be proven, through longitudinal validation and controlled trials, is whether treatments chosen by mechanism rather than by convention genuinely deliver more durable mucosal healing, lower relapse risk and better lives for people with Crohn’s disease.

Subject of Research: The interplay of epithelial barrier dysfunction, immune dysregulation and gut microbiota dysbiosis in Crohn's disease pathogenesis and therapy

Article Title: Tripartite Interplay of Epithelial, Immune, and Microbiota Dysregulation in Crohn's Disease: Mechanisms and Translational Strategies

Article References: Lai, Q., Zhang, Q.-Y., Yang, W.-P., & Luo, C.-Y. (2026). Tripartite Interplay of Epithelial, Immune, and Microbiota Dysregulation in Crohn's Disease: Mechanisms and Translational Strategies. Immunity, Inflammation and Disease, 14(10), Article e70538. https://doi.org/10.1002/iid3.70538

Image Credits: AI Generated

DOI: 10.1002/iid3.70538

Keywords: Crohn's disease, intestinal epithelial barrier, gut microbiota, Th17 cells, IL-23, TNF-alpha, short-chain fatty acids, AIEC, JAK inhibitors, risankizumab, dysbiosis, precision medicine

The review’s authors systematically mapped six signaling pathways that may fall under interferon-gamma’s influence: JAK/STAT, PI3K/AKT, NF-κB, MAPK, WNT/β-catenin, and the IDO–kynurenine–AhR axis. Crucially, they graded the evidence behind each link, acknowledging that direct mechanistic data in Sjögren’s-associated interstitial lung disease remain scarce. The JAK/STAT pathway, through which interferon-gamma signals via JAK1 and JAK2 to phosphorylate STAT1, carries the strongest support. The intermediate pathways rest on extrapolation from related autoimmune and fibrotic lung diseases, while the WNT and IDO–kynurenine–AhR connections are explicitly labeled exploratory. This candor distinguishes the work from typical mechanistic reviews and provides a roadmap for what must be validated rather than a settled biological hierarchy.

The clinical stakes are considerable. Epidemiologic studies place the prevalence of interstitial lung disease in Sjögren’s patients at 3 to 11 percent, and the histopathological spectrum ranges from nonspecific interstitial pneumonia, the most common pattern, to usual interstitial pneumonia, which a large cohort of 558 patients recently linked to impaired pulmonary function and increased mortality. High-resolution computed tomography typically reveals ground-glass opacities, reticulation, and traction bronchiectasis, while pulmonary function tests show restrictive defects with a disproportionate drop in diffusing capacity. Within the lung, injury to alveolar epithelial type II cells impairs surfactant production and repair, while aberrantly activated fibroblasts deposit extracellular matrix and stiffen tissue, creating the structural context in which interferon-gamma-driven signaling could operate.

Interferon-gamma itself is a type II interferon, structurally distinct from the type I interferons that have long dominated Sjögren’s research. It circulates as a homodimer and engages a tetrameric receptor complex displayed on both immune and non-immune cells. Produced chiefly by activated CD4-positive Th1 cells, CD8-positive T cells, and natural killer cells, the cytokine activates macrophages, licenses dendritic cells by up-regulating MHC molecules and co-stimulatory markers, and steers naïve T cells toward a Th1 fate. It also primes production of tumor necrosis factor-alpha, interleukin-12, and interleukin-1β, and can synergize with toll-like receptor signals to create a self-reinforcing inflammatory loop. In Sjögren’s disease specifically, elevated circulating interferon-gamma has been associated with higher disease activity, and an elevated Th1-to-Th2 ratio correlates significantly with the presence of interstitial lung disease.

The review highlights several mechanisms that could amplify interferon-gamma output in patients. The rs2069705 polymorphism enhances STAT4 binding to the interferon-gamma promoter and increases susceptibility to Sjögren’s disease. Regulatory T cells, which normally restrain Th1 responses, are reduced in both peripheral blood and salivary glands, with the deficit inversely correlating with disease activity as measured by the ESSDAI index. Meanwhile, interferon-responsive chemokines CXCL9, CXCL10, and CXCL11 are sharply up-regulated in serum and salivary gland tissue, potentially recruiting additional CXCR3-expressing T cells into an expanding inflammatory circuit. Recent work also identifies interferon-gamma as a key effector driving salivary gland epithelial cell death and hypofunction, suggesting the cytokine’s pathogenic reach extends beyond immune cells to the structural tissue itself.

At the network level, the proposed model organizes these pathways into layers. Upstream, the interferon-gamma–JAK/STAT axis drives immune-cell activation and chemokine production. In the middle, PI3K/AKT, NF-κB, and MAPK function as amplification and regulatory modules. PI3K/AKT governs immunometabolic reprogramming and B-cell survival, a relevant point given that aberrant B-cell activation and autoantibody production are hallmarks of Sjögren’s pathology, and lupus studies have demonstrated interactions between interferon-gamma signals and PI3K-dependent B-cell responses. NF-κB integrates inflammatory signals and may sustain a pro-inflammatory macrophage state, while MAPK cascades coordinate stress and growth-factor inputs, with experimental evidence linking interferon-gamma-associated p38 and ERK activation to epithelial-to-mesenchymal transition, a pro-fibrotic cellular program.

Downstream, the WNT/β-catenin pathway emerges as the fibrotic executor. Chronic inflammation can switch WNT from a developmental signal into a pathological remodeling program: inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1β, and transforming growth factor-beta influence β-catenin stability, while inflammatory stress represses WNT antagonists, lifting the brakes on the pathway. Across chronic lung diseases, WNT/β-catenin activation correlates with fibroblast proliferation, myofibroblast differentiation, collagen deposition, and tissue stiffness. Altered WNT signaling has been documented in Sjögren’s salivary glands, though its role in the diseased lung remains poorly characterized. The more speculative IDO–kynurenine–AhR axis adds a metabolic layer: sustained interferon-gamma exposure induces indoleamine 2,3-dioxygenase in macrophages and dendritic cells, shunting tryptophan toward kynurenine, which activates the aryl hydrocarbon receptor and reshapes immune tolerance and immune–stromal interactions.

The therapeutic implications are among the most consequential aspects of the framework. Because the JAK/STAT axis carries the strongest evidence, JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib represent the most immediate candidates for modulating interferon-gamma-driven inflammation, particularly in inflammation-dominant disease, although clinical benefit in Sjögren’s-associated interstitial lung disease has not been established. B-cell-directed therapies intersect with the same immune network; real-world data from a multicenter European cohort of 191 patients showed rituximab was used in 25.1 percent of cases, though observational data cannot establish efficacy. For patients who progress to a fibrotic phenotype, the antifibrotic nintedanib, which has demonstrated efficacy in progressive fibrosing interstitial lung diseases across diagnoses, offers a rationale for intervention even though it does not directly target interferon-gamma signaling. The extensive cross-talk among downstream pathways suggests, however, that single-pathway inhibition may prove insufficient for established fibrosis, pointing toward combinatorial, stage-specific strategies.

The authors are careful to frame their model as hypothesis-generating rather than validated. Much of the mechanistic scaffolding derives from associative data, experimental models, or extrapolation from idiopathic pulmonary fibrosis and other connective tissue disease-associated lung diseases. Disease heterogeneity, including variability in immune-cell composition, inflammatory burden, and genetic background, likely shapes which pathways dominate in individual patients. The proposed hierarchy of upstream, intermediate, and downstream modules is explicitly a theoretical synthesis. Prospective validation in longitudinal cohorts, ideally integrating spatial transcriptomics and single-cell profiling, will be required to confirm the temporal sequence and relative contribution of each pathway.

If that validation succeeds, the payoff could be substantial. Biomarkers such as serum CXCL9, CXCL10, KL-6, and even CA125, which a prospective multicenter cohort of 395 patients independently associated with adverse outcomes, could enable patient stratification and disease monitoring aligned with specific pathway activity. More broadly, the review exemplifies a conceptual shift in autoimmune lung disease research: away from linear cytokine cascades and toward multidimensional signaling networks in which immune activation, metabolic reprogramming, and fibrotic remodeling are coupled layers of a single pathogenic architecture. For a disease whose pulmonary complications quietly quadruple mortality risk, that systems-level perspective may finally offer a path toward precision medicine.

Subject of Research: Interferon-gamma-associated signaling networks in Sjögren's disease-associated interstitial lung disease

Article Title: IFN‐γ‐Associated Signaling Networks in Interstitial Lung Disease Associated With Sjögren's Disease

Article References: Chen, Q., Li, Y., Chen, Y., Su, Y., Wang, X., & Guan, C. (2026). IFN‐γ‐Associated Signaling Networks in Interstitial Lung Disease Associated With Sjögren's Disease. Immunity, Inflammation and Disease, 14(10), Article e70547. https://doi.org/10.1002/iid3.70547

Image Credits: AI Generated

DOI: 10.1002/iid3.70547

Keywords: Sjögren's disease, interstitial lung disease, interferon-gamma, JAK/STAT, pulmonary fibrosis, NF-κB, PI3K/AKT, MAPK, WNT/beta-catenin, CXCL10, JAK inhibitors, autoimmunity