Progestogen hypersensitivity (PH), historically termed autoimmune progesterone dermatitis, is an exceedingly rare condition documented almost exclusively in reproductive-age women. Although the pathophysiology remains incompletely understood, affected patients typically develop cutaneous and mucocutaneous findings, bronchospasm, and/or anaphylaxis following exposure to endogenous progesterone or exogenous progestins. Diagnosis rests on clinical history and characteristic physical findings, supported where available by progesterone skin testing, which is not standardized and has limited sensitivity and specificity. Cases in men are exceptionally rare, and the resulting scarcity of literature contributes to frequent misdiagnosis. We report a 56-year-old man with coronary artery disease, prior resection of an intestinal carcinoid tumor, and recurrent documented episodes of PH since 2006. He presented to the emergency department with a diffuse rash, facial angioedema, and nausea, and received intravenous fluids, epinephrine, antihistamines, and corticosteroids. Because his symptoms persisted and further epinephrine dosing was limited by chest pain in the setting of coronary artery disease, he was admitted to the intensive care unit for airway monitoring. Inpatient management consisted of dexamethasone, cromolyn sodium, testosterone cypionate, analgesia, and supportive care, with rapid improvement and discharge on hospital day three. This report describes a symptom-directed approach to the management of PH in a male patient in the critical care setting and considers the comorbidities and possible mechanisms that may underlie his presentation. Given the rarity of the condition and the limited literature in men, effective management currently depends on an individualized, symptom-directed strategy.

Alzheimer's disease (AD) is now widely accepted as a complex disorder involving multiple interconnected pathological processes. Increasing evidence suggest that neuroinflammation and immune system dysregulation actively contribute to neurodegeneration, extending beyond the traditional view that the disease is driven solely by amyloid-β (Aβ) and tau pathology. With the advent of studies showing anti-amyloid antibodies to have only modest effects with significant toxicity, there has been a growing interest in investigating non-amyloid non-tau (NANT) treatment approaches. This review provided a general review of small molecules for neuroinflammation-based NANT therapies in AD. We reviewed several agents that affect the brain/immune axis, namely, kinase inhibitors (nelflamaimod and masitinib), NLRP3 inflammasome inhibitors (MCC950, selnoflast, and dapansutrile), TREM2 activators (VG-3927), gingipain inhibitors, PPARγ activators, KCa3.1 inhibitors, and repurposed drugs such as ambroxol and cromolyn. Some common drawbacks were identified for the drugs that failed to provide their anticipated effects. It was found that they all suffered from late-stage treatment, patient heterogeneity, inadequate central nervous system penetration, and poorly designed preclinical studies. Additional translational challenges included sex-specific differences in neuroimmune responses, APOE ε4-associated immune dysfunction, and the need for biomarker-guided patient selection. Although immune-targeted therapies remain strongly supported by biological evidence in AD, meaningful clinical progress will likely require earlier intervention strategies guided by biomarkers and therapies capable of targeting multiple disease pathways simultaneously.

Mast Cell Activation Syndrome (MCAS) is an underrecognized multisystem disorder causing nonspecific and diverse symptoms, making it difficult for clinicians to diagnose and treat. This comprehensive review provides an overview of the signs and symptoms of MCAS while investigating the known pathophysiological signaling pathways and mediators that contribute to mast cell (MC) dysregulation. Unraveling the mechanisms of MC activation is essential for elucidating the underlying disease and exploring techniques to improve quality of life. Immunoglobulin E (IgE)- and non-IgE-mediated pathways are emphasized in addition to the various intracellular signaling like PI3K/Akt/mTOR, RAS/MAPK, and JAK/STAT that play pivotal roles in the amplification of MC activation and dysregulation. After activation of intracellular pathways, MC degranulation releases mediators, notably histamine, tryptase, heparin, leukotrienes, prostaglandins, and cytokines, thus facilitating further aberrant regulation. Finally, with a thorough understanding of these advanced molecular processes, there are numerous opportunities to be able to apply specialized inhibitors and novel therapies for treating MCAS. With antihistamines remaining the most well-established first-line treatment, the goal is to continue strengthening research in the field through education on the immunology of MCAS and to encourage discoveries that improve diagnostic biomarkers and therapeutic strategies.

Mast cell stabilizers such as disodium cromoglycate have been used for decades as prophylactic anti-allergic agents, yet their molecular targets remained unknown, and their intracellular mechanisms were long debated. Identification of GPR35 as a receptor engaged by multiple mast cell stabilizers provided a new framework to reinterpret classical pharmacology. Here, historical and recent evidence linking mast cell stabilizers to GPR35 is integrated and pharmacological characteristics of GPR35 are described in the context of species difference and intracellular signaling. GPR35 is expressed in epithelial, myeloid, and sensory neuronal compartments, raising the possibility that some "mast cell stabilizer" phenotypes reflect actions outside mast cells. This perspective becomes particularly relevant in inflammatory bowel disease, where genetic studies support a protective role for GPR35 in mucosal homeostasis, potentially through epithelial barrier integrity and macrophage function. Emerging data also implicate GPR35 in neurogenic inflammation/itch pathways and vascular remodeling, further broadening therapeutic considerations. Accumulating evidence suggests that GPR35 exhibits physiologically relevant constitutive activity, implying that the GPR35-mediated actions may depend not only on ligand engagement but also on expression levels and cellular states. Implications for drug repositioning of mast cell stabilizers and future GPR35-targeted therapeutics are also discussed.

BACKGROUND: We have previously observed depressive-like behaviors in mice following the development of chronic allergic lung inflammation that potentially involved brain mast cell activation. However, the specific brain regions that might be responsible for the observed behavioral changes were not identified. The anterior cingulate cortex (ACC) has been implicated in depression, and hypoactivity of this region is seen in the electroencephalogram of patients with depression. In the current study, we tested our hypothesis that chronic allergic lung inflammation causes mast cell activation that affects neuronal activity in the ACC, leading to depressive-like behavioral changes in mice. We further explored whether preventing mast cell activation during allergen administration modulates neuronal activity and attenuates behavioral changes. METHODS: Wild-type C57BL/6 J and Thy1-GCaMP6 mice were sensitized with intranasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. Intraperitoneal injection of cromolyn sodium was performed during HDM sensitization. Neurocognitive tests were carried out before and after the sensitization. In vivo cortical calcium imaging was performed through cranial windows in head-restrained awake mice, and spontaneous calcium activity was measured. Brain and lung tissues were harvested for assessment of inflammatory changes. RESULTS: Coronal sections of frontal cortex showed that mast cell-derived protease chymase expression was substantially increased in the ACC after 6 weeks of HDM treatment compared with PBS controls. The frequency of somatic calcium activity in ACC pyramidal neurons was reduced in HDM compared with PBS. Intraperitoneal administration of cromolyn sodium, a mast cell stabilizing agent, during HDM sensitization inhibited this frequency reduction observed in HDM sensitized mice. Behavioral changes observed in HDM sensitized mice by open field, light–dark and sucrose preference tests, were attenuated in mice that received cromolyn sodium during HDM sensitization. CONCLUSIONS: Cerebral mast cell degranulation and decreased somatic calcium activity of pyramidal neurons were observed in the ACC of mice with allergic lung inflammation. Co-administration of mast cell stabilizer cromolyn prevented this allergen-induced hypoactivity and behavioral changes. The activation of mast cells in ACC and decreased pyramidal neuronal activity may play a role in the depressive behaviors observed in mice after chronic HDM sensitization.

There is a pressing need for effective alternatives to opioid analgesics, the development of which requires the identification of novel anti-nociceptive drug targets. Here, we have further investigated the anti-nociceptive properties of a GPR35 agonist, cromolyn, in an in vitro model of inflammatory sensitisation. We used ratiometric Ca[2+] imaging of cultured sensory neurons to examine the effect of cromolyn on prostaglandin E2 (PGE2)-mediated sensitisation of the pro-nociceptive ion channel, transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The sensitisation of TRPV1 by PGE2 was inhibited by cromolyn in a GPR35-dependent manner. These observations provide further evidence in support of an anti-nociceptive role for GPR35, highlighting the potential use of GPR35 agonists as analgesics.

Our clinical experience in the last four years using oral cromolyn in patients with mast cell activation syndrome (MCAS) suggests that a continuous oral regimen of high-dose cromolyn may enhance compliance with the medication. The five patients described in this retrospective case series were given instructions to take oral cromolyn using a continuous dosing regimen, placing the entire day's dose in an opaque bottle that is then filled with water, and sipping the solution throughout the day. If a conventional maximum dose of eight vials daily (800 mg) was tolerated but ineffective after a week, the patients were instructed to increase to 1600-2400 mg daily until reaching an optimal effect. We report that a cromolyn dose of 1600-2400 mg daily, administered using the continuous oral dosing regimen during the day, was effective in controlling signs and symptoms of mast cell activation. All five patients benefitted from a dose of cromolyn that is higher than usual and customary recommendations, but within the safety guidelines of the original Food and Drug Administration (FDA) application. The continuous oral regimen has some theoretical advantages over four discrete doses per day, though further study is needed.

Subglottic stenosis (SGS) may arise from both mechanical and inflammatory airway injury. Patients with mast cell activation syndrome (MCAS) are uniquely vulnerable, due to both direct effects of systemic inflammation and indirect effects of repeated intubation for anaphylaxis that can converge to cause life-threatening airway compromise. We describe a sentinel case of a 34-year-old female with MCAS and multiple prior intubations who presented with progressive dyspnea. Flexible laryngoscopy revealed grade III SGS. She underwent urgent endoscopic intervention, including balloon dilation, carbon dioxide (CO2) laser radial incisions, and steroid injection. Airway patency was restored, and postoperative care focused on optimizing systemic mast cell control with cromolyn, fexofenadine, montelukast, and omalizumab. Literature review supports a mechanistic role for mast cell mediators in airway fibrosis and impaired wound healing, compounding the effects of mechanical trauma in MCAS. This sentinel case highlights clinically significant risk of SGS in patients with MCAS. By integrating case findings with mechanistic insights, this report underscores the urgent need for interdisciplinary awareness, proactive airway evaluation, and research into surveillance and prevention strategies in MCAS and related disorders.Level of Evidence: Level V/Case Report and Narrative Review.