Occult Crohn’s disease in childhood and adolescence remains a diagnostic challenge in clinical practice. The atypical presentation of the disease, including rare extraintestinal manifestations that may overshadow the extent of intestinal inflammation and damage, often complicates clinical assessment. Consequently, the persistent underestimation of alarm features may delay the diagnosis for several years. Aiming to provide clinical, diagnostic and therapeutic insights into the interplay of rare co-occurring disease entities, we present the instructive diagnostic journey of an adolescent with recurrent osteomyelitis finally diagnosed with smouldering inflammatory bowel disease. The challenging interpretation of ambiguous initial findings suggestive of septic osteomyelitis, as well as the routine clinical emphasis on ruling out this condition, had delayed its proper clinical management. Ultimately, the multidisciplinary work-up established the diagnosis of chronic non-bacterial osteomyelitis, a rare extraintestinal manifestation of Crohn’s disease—particularly in childhood-onset cases—and guided the initiation of appropriate treatment, resulting in sustained remission after 2 years of follow-up.

Late-life cognitive complaints seldom align with a single disease entity [...]

Kawasaki disease is a systemic pediatric vasculitis with a wide range of clinical presentations. Although often viewed as a single disease entity, emerging evidence indicates considerable phenotypic diversity. However, population-specific studies are still limited, especially in high-incidence areas like Japan. This study aimed to identify different clinical subgroups among patients with Kawasaki disease in Japan using cluster analysis. We retrospectively reviewed 321 patients diagnosed with Kawasaki disease from 2020 to 2025 at a single center in Japan. Eighteen clinical and laboratory variables were used for principal component analysis and hierarchical clustering. The clusters were compared based on clinical features, treatment responses, and coronary outcomes. Temporal and seasonal trends were also examined. Three phenotypic clusters were identified: Cluster 1 included younger children with classical Kawasaki disease's features and low treatment resistance; Cluster 2 exhibited hepatobiliary involvement, high intravenous immunoglobulin resistance prediction scores, and frequent need for additional therapy; and Cluster 3 comprised older children with elevated inflammation markers, cervical lymphadenopathy, and delayed diagnosis. Postpandemic, Cluster 3 increased, and seasonal peaks were observed in winter (Cluster 3) and spring (Cluster 2). Cluster analysis identified distinct Kawasaki disease subtypes in a high-incidence Japanese population, each with unique clinical and temporal features. These findings support using phenotypic clustering to improve risk stratification and guide personalized treatment approaches. Key Points • Three distinct Kawasaki disease phenotypes were identified in Japanese children, each with unique clinical features, biochemical profiles, and treatment responses. • Temporal and seasonal patterns suggest an interplay between environmental triggers and host genetic susceptibility in the expression of KD among Japanese children.

ImmunoglobulinG4 (IgG4)-related diseases are aheterogenous group of chronic inflammatory systemic disorders characterized by fibrosing inflammation with infiltration of IgG4-positive plasma cells. They can affect nearly any organ system. Typical manifestations include autoimmune pancreatitis, sclerosing cholangitis, lymphadenopathy, retroperitoneal fibrosis, and inflammatory orbitopathy as well as involvement of the salivary and lacrimal glands. Each manifestation may present in isolation or in combination with others. Diagnosis requires careful exclusion of malignant or other inflammatory conditions, as IgG4-related diseases can mimic awide range of disease entities. Amultimodal approach combining laboratory findings, histopathological evaluation and radiological imaging is essential for establishing the diagnosis. Astructured diagnostic algorithm and close interdisciplinary collaboration are crucial to avoid misdiagnosis and enable appropriate treatment.

Patients with concurrent malignancies pose significant diagnostic and therapeutic challenges. We report a rare and fatal case of synchronous ovarian mixed germ cell tumor and mast cell leukemia (MCL) in a 13-year-old female, characterized by a shared clonal origin. The patient initially presented with a large pelvic mass, elevated alpha-fetoprotein(AFP) and human chorionic gonadotropin (β-HCG), anemia, and thrombocytopenia. Exploratory laparotomy confirmed a diagnosis of mixed germ cell tumor, predominantly dysgerminoma with a minor choriocarcinoma component. Despite an initial decrease in serum tumor markers to platinum-based chemotherapy, persistent cytopenias and bone marrow infiltration raised concern for hematologic malignancy. Genomic analyses of both ovarian tumor and bone marrow samples identified identical somatic mutations, including KIT D816V, NRAS G12C and TP53 Y220C, strongly suggesting a common progenitor. Subsequent immunophenotyping, histology, and transcriptome sequencing confirmed the diagnosis of concurrent mast cell leukemia. Targeted therapy with avapritinib and ruxolitinib was initiated but yielded limited response. Further salvage therapy failed due to disease progression and treatment intolerance, and the patient succumbed to multiple organ failure. This case underscores the clinical and genetic overlap between germ cell tumors and hematological malignancies in pediatric patients, highlighting the role of KIT mutations as a potential unifying driver. Given the consistent co-occurrence of KIT mutations in previously reported similar cases, we propose the recognition of a distinct disease entity: ovarian germ cell tumor/mastocytosis with KIT mutations. This report emphasizes the importance of early genetic profiling and multidisciplinary collaboration in diagnosing and managing rare, genetically unified malignancies in pediatric oncology.

Immune-mediated diarrhea and colitis (IMDC) is a very common and severe toxicity to immune checkpoint inhibition that has generated a lot of scientific interest. The current guidelines do not capture the most recent literature on this disease entity, and few reviews if any have been published that describe the advances made in our understanding of IMDC. As more and more patients are being treated with immune checkpoint inhibitors (ICIs), it becomes essential to optimize treatment algorithms for ICI-related toxicities, especially IMDC. In our review, we discuss the findings of recent studies on IMDC epidemiology including incidence and risk factors, evaluation and treatment modalities, and surveillance and long-term outcomes. We note that while much has been learned regarding disease epidemiology and the utility of stool biomarkers over clinical symptoms, there remains a paucity of data where IMDC treatment options and long-term IMDC outcomes and surveillance is concerned. Our results highlight the most recent advances in our knowledge of IMDC and allow us to propose a management algorithm that improves on prior guidelines for IMDC by incorporating new study findings.

Cardio-oncology has rapidly evolved in the past decade. It is a continuous field that was founded on the manifestation of cardiac dysfunction in patients treated with anticancer therapy. Short- and long-term cardiovascular complications became known as cancer therapy-related cardiovascular toxicity (CTR-CVT). These may arise from a plethora of anticancer therapies, including broad classes such as chemotherapy, immunotherapy, and hormonal therapy. Recently, the first European Society of Cardiology guideline on cardio-oncology was published, providing expert consensus on definitions, diagnosis, treatment, and prevention for health-care professionals. This side of cardio-oncology focuses on the classical CTR-CVT, here termed forward cardio-oncology. On the other side is the paradigm of heart failure stimulating tumor growth, coined as reverse cardio-oncology. As cardio-oncology expanded, the knowledge of co-occurrence of these disease entities in the same individuals grew. This raised the question of whether this phenomenon was due to shared risk factors (i.e. diabetes mellitus, obesity, etc.) between cardiovascular disease (CVD) and cancer or because of shared underlying mechanisms, and thus whether the presence of one of the two disease entities could drive the onset or progression of the other. Indeed, mechanistic studies revealed that heart failure can stimulate tumor growth in a multifaceted manner, including through a protumor cardiac secretome, by immune system modulation, or even through the gut microbiome. This review provides an extensive and robust overview of the current knowledge on the entirety of cardio-oncology and highlights future perspectives for research.

Otolaryngologic evaluation and management of nasal chondromesenchymal hamartoma.

Potential contribution of oxysterols and cholestanol in the vascular inflammatory process occurring in patients with Behcet's disease.

ObjectivesTo assess diagnostic concordance and reclassification following an India-led, multinational virtual multidisciplinary discussion (V-MDD) platform for interstitial lung disease (ILD).DesignProspective, multicentre service-evaluation study.SettingTwenty-four Indian referral centres connected through a secure virtual platform, with international faculty participation from the UK, Greece and Sri Lanka.ParticipantsA total of 127 anonymised ILD cases discussed across 29 V-MDD sessions (February 2024–February 2025). Each panel included ≥4 pulmonologists, two pulmonary pathologists, one of three rotating thoracic radiologists and one of two rheumatologists, along with international experts.ResultsThe cohort (mean age 52.6±16.1 years; 53.5% female (68/127)) most frequently presented with dyspnoea (82.6%) and cough (73.2%). Pre-V-MDD diagnoses included hypersensitivity pneumonitis (HP) and sarcoidosis as distinct disease entities, and usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) as radiological patterns, along with connective tissue disease (CTD)-ILD and other ILDs. Concordance between pre- and post-V-MDD CT diagnoses was substantial (κ=0.658; 95% CI 0.562 to 0.754; p <0.001). Histopathology concordance was similarly high (κ=0.861 for HP; κ=0.650 for other ILDs). Overall, 23% of cases were reclassified following discussion. Diagnostic stability was greatest for organising pneumonia, CTD-ILD and UIP pattern, whereas HP and sarcoidosis showed the highest reclassification rates.ConclusionsThe India-led, multinational V-MDD model demonstrated substantial diagnostic concordance and refined nearly one-quarter of ILD diagnoses. This virtual, scalable framework expands access to subspecialty expertise and offers a practical blueprint for standardising ILD care in resource-limited and cross-border settings.

Background: Mastocytic enterocolitis has been proposed as a cause of chronic diarrhea and abdominal pain, characterized by increased mast cells in gastrointestinal mucosal biopsies. However, its clinical significance remains uncertain. Methods: We present a case report of a patient identified to have high levels of mast cells on gastrointestinal biopsies. We then reviewed cases at Mayo Clinic where patients had &gt;20 mast cells per high-power field (HPF) on gastrointestinal biopsies. Patients with alternative explanations for mast cell elevation, including systemic mastocytosis were excluded. We analyzed demographics, clinical presentations, pathology reports, serum and urine mast cell mediators, inflammatory markers, bone marrow biopsies, motility testing, and treatment responses. Results: We identified 42 patients (30 female and 12 male) with elevated mast cells on biopsy (mean age: 41 y, range: 17 to 81). Mast cells were quantified using KIT (CD117) staining, with no abnormal clumping or morphology, and CD25 immunostaining was negative in all cases. Eosinophilic infiltration was absent in all but one case. Small intestinal bacterial overgrowth (SIBO) was found in 78% of patients tested. Treatments varied widely, with antihistamines and cromolyn being the most common. Among 21 patients with sufficient follow-up, only 5 (24%) reported partial or complete symptom improvement, while 76% experienced persistent symptoms. Conclusion: Routine assessment of mast cells on gastrointestinal biopsies is not supported by our findings. Elevated mucosal mast cells, in the absence of systemic mast cell disorders, may not indicate a distinct disease entity. Evaluation should focus on ruling out other inflammatory, allergic, infectious, and motility disorders, as well as SIBO. Further research is needed to determine the clinical significance of increased mucosal mast cells and their role in gastrointestinal symptomatology.

Leptospirosis is a widespread zoonotic, infectious disease associated with abortion, stillbirth, as well as liver and kidney failure. Leptospiral Pulmonary Haemorrhage Syndrome (LPHS) has increasingly been reported in human and canine patients infected by Leptospira and is associated with a high fatality rate. In equine medicine, pulmonary haemorrhage has mainly been described in foals with leptospiral infections, but rarely in adult horses. To characterise the clinicopathological features of pulmonary haemorrhage as a distinct disease entity in adult horses with leptospirosis, termed Equine Leptospiral Pulmonary Haemorrhage Syndrome. Retrospective case series. The clinical presentation, with blood biochemical, tracheobronchoscopic, ultrasonographic, and radiographic findings, as well as treatment and outcomes, is described in six adult horses. Leptospiral infection was confirmed by urinary PCR analysis and paired serology. Cases had pulmonary haemorrhage accompanied by concurrent azotaemia. Thoracic radiographs revealed a structured interstitial pattern, with marked accentuation in the caudodorsal lung fields in all cases. Leptospiral infection was confirmed in 5/6 horses by urinary PCR analysis, and in all horses by early seroconversion. Four cases survived to hospital discharge. Small case series, incomplete clinical data, limited long-term follow-up. The term Equine Leptospiral Pulmonary Haemorrhage Syndrome is proposed to designate equine leptospirosis characterised by acute respiratory distress caused by pulmonary haemorrhage associated with blood biochemical disturbances including hyponatraemic and hypochloraemic azotaemia and increased serum amyloid A concentrations. The exact pathophysiology of pulmonary haemorrhage in equine leptospirosis remains incompletely elucidated. Urinary PCR analysis and paired serum microagglutination assays were useful to diagnose active leptospiral infection. The diagnostic benefit of tracheobronchial secretions remains an area for further investigation considering its potential source as a biohazard.

BackgroundCerebrovascular disease (CeVD) is a clinically significant disease entity, known to be associated with increased risk of cognitive decline [1]. However, the lack of validated blood biomarkers for CeVD, limits advances in detection and intervention. We thus aim to identify the plasma protein signatures of CeVD, its phenotypes, and progression.MethodA prospective Singaporean memory clinic cohort was followed‐up for 4 years. Baseline and 2‐yearly brain magnetic resonance imaging (MRI) scans were performed. Significant CeVD was defined as the presence of cortical infarcts, and/or ≥ 2 lacunes, and/or ARWMC (age related white matter changes) score of ≥ 8.The burden of CeVD lesions by phenotypes (lacunes, cortical infarcts, white matter hyperintensity volume (WMHv) and cerebral microbleeds (CMBs)) was then evaluated at baseline. The longitudinal progression of WMHv was evaluated using volumetric measurements of WMHv on 2‐yearly MRI brain scans.The Olink Explore platform was used to profile 1536 plasma proteins at baseline. Their associations with cross‐sectional and longitudinal CSVD imaging markers were evaluated using multivariable regression models, accounting for multiple testing correction (target FDR 5%).ResultOf 508 included subjects (mean age 72.8±7.8 years, 56.1% female, 72% hypertensive), 53% had significant CeVD.We identified 345 proteins associated with significant CeVD, implicated in biological pathways related to inflammation, immune dysregulation, and cell adhesion (top 3 over‐represented biological pathways presented in Figure 1).We identified distinct and shared proteins associated with lacunes, CMBs, cortical infarcts, and WMHv. The most significantly dysregulated protein for CMBs was CHRDL1 (RR 5.30, 95% C.I. 2.93‐9.61, q‐value<0.05). The most significant protein associated with cortical infarcts was NTproBNP (RR 1.38, 95% C.I. 1.23‐1.54, q‐value<0.05). NFL (RR 1.44, 95% C.I. 1.44, 95% C.I. 1.29‐1.60, q‐value<0.05) was most significantly associated with lacune burden, and WMHv (β 1.15, 95% C.I. 0.76‐1.54, q‐value<0.05).In a separate analysis of 493 subjects with longitudinal WMHv data, the most significant proteins of longitudinal WMHv progression included TNRSF11B, SERPINA11 and NFL (Figure 2).ConclusionWe report plasma proteomic signatures for CeVD. Further studies are required to evaluate the mechanistic underpinnings of these plasma biomarkers as therapeutic targets for CeVD pathology.

Current epidemiological thinking is that classic Hodgkin lymphoma (cHL) comprises multiple aetiologically distinct disease entities that may in part be defined by either histological subtype or the presence of Epstein-Barr virus (EBV) in the malignant cells, or by both. This study aimed to advance our understanding of epidemiological differences between cHL subtypes, in particular EBV-positive and EBV-negative cHL. We retrospectively collected and EBV-typed 1992 cHL primary tumour tissues from among all 2811 patients diagnosed with incident HL in Denmark in the period 1990 through 2010 'Hodgkin lymphoma in Denmark' [HOLYDAN] project. Based on characteristics of retrieved samples combined with additional information from national registers, we projected nationwide age-, sex-, histology- and EBV-specific cHL incidence rates. The analyses demonstrated age- and sex-dependent variation in histology- and EBV-tumour status-specific cHL incidence rates, details of which yielded new aetiological clues. cHL incidence increased markedly around the age of puberty, irrespective of histological subtype and EBV status. The incidence of all subtypes of cHL increased with age after age 50 years, with the exception of EBV-negative nodular sclerosis cHL in females, which therefore showed a single peak in incidence and was higher than in males among young adults. These results were obtained in a small homogeneous population and might, therefore, only apply to rich, industrialised, Western populations. Nevertheless, we propose that puberty creates an immunological host environment conducive to cHL development irrespective of EBV status and histology, and that age-related decline in immune function facilitates the development of both EBV-positive and EBV-negative cHL.

Abstract Membranoproliferative glomerulonephritis (MPGN), though rare, poses challenges in diagnosis and treatment. MPGN is a histologic lesion and not a specific disease entity. The pathological diagnosis of MPGN prompts the clinician for immediate and specific diagnostic intervention. Formerly, it was classified into type I, type II, and type III depending on the electron microscopic findings, which is obsolete now due to the overlapping features between type I and type III. Recently, the classification of membranous proliferative glomerulonephritis has been updated and is constructed upon the distinct pathogenetic process and direct immunofluorescence findings. Our illustrative case series fulfills the criteria of each three recent pathogenetic distinctive subtypes with a brief overview of the underlying pathogenesis, clinical presentation, and diagnosis of MPGN based on the light microscopy and direct immunofluorescence findings.

Acquired von Willebrand syndrome (AVWS) is a rare condition characterized by an acquired functional and/or absolute deficiency of the von Willebrand factor (VWF) protein. The absence of widely accepted diagnostic criteria has hampered accurate estimates of incidence and prevalence, which are largely currently unknown. As bleeding symptoms are not included in the most widely used definitions, AVWS should be managed as a risk factor for bleeding, rather than a specific disease entity. The diagnostic workup is cumbersome, involving measurement of both VWF antigen, VWF glycoprotein Ib binding activity, VWF collagen binding activity, and, preferentially, also VWF multimer analyses. Moreover, since the presence of bleeding symptoms is not required for diagnosis, the condition is probably underdiagnosed. In contrast to acquired hemophilia, AVWS is seldom caused by the presence of specific antibodies, but rather secondary to another disorder, most commonly lymphoproliferative, myeloproliferative, cardiovascular, and autoimmune disorders. Pathogenesis of AVWS varies according to the underlying disorder and includes nonspecific adsorption of VWF to antibodies, adsorption onto surfaces of neoplastic cells, mechanical injury, or VWF proteolysis. Treatment includes treating the underlying cause as well as stopping acute bleeds. Here, we present a comprehensive review of what is currently known regarding demographics, diagnostics, and clinical presentation of the syndrome. Since no prospective treatment studies have been performed, treatment choices must be based on data from registries and case reports that are also summarized. Moreover, we present treatment experiences of previously unpublished Nordic cases.

Background: Adult-Onset Still's Disease is a rare inflammatory disorder with an estimated incidence of 1 in 1,000,000 that presents with a rash, fever, and arthritis. Furthermore, there have only been three reported cases in the Philippines. Its presentation is similar to other more commonly encountered inflammatory disorders; however, it is the negative immunologic and serologic workup that typically distinguishes this rare specific inflammatory disorder along with the fulfillment of diagnostic criteria set by Yamaguchi and Cush. Case: This is a case of an 18-year-old female who presented with recurrent fever, rash, and polyarthritis. The patient underwent extensive workup, but immunologic studies were negative. A consideration of Adult-Onset Stills Disease was made and along with the fulfillment of the classification criteria set by Yamaguchi and Cush, the diagnosis was clinched and the patient was started on glucocorticoid therapy where improvement of the patient's condition was noted with the resolution of the fever, rash and minimal complaints of joint pain. Conclusion: Adult-Onset Still’s Disease is an uncommon inflammatory disorder that confers high morbidity and disability. It commonly presents with shared clinical features among other inflammatory disorders; thus, recognition of the existence of this disease entity could pose a diagnostic dilemma. A high clinical suspicion along with negative studies and fulfillment of the diagnostic criteria avoids unnecessary workup and inappropriate management. Keywords: Still’s Disease, Arthritis, Autoimmune, Yamaguchi Criteria, Cush Criteria, Fautrel Criteria

Background and ObjectivesSerum myelin oligodendrocyte glycoprotein (MOG) antibodies are a hallmark of the newly defined neuroinflammatory disease entity MOG antibody–associated disease (MOGAD). Yet, the lack of patient-derived recombinant human MOG (hMOG)–reactive autoantibodies limits investigations into the molecular mechanisms by which these autoantibodies mediate CNS pathology, thereby hindering rational therapeutic approaches. To understand the origins and disease-relevant mechanisms of autoantibodies in MOGAD, we generated and characterized monoclonal anti-hMOG antibodies (MOG-mAbs) from circulating B cells of patients with MOGAD.MethodsWe isolated MOG-specific B-cell receptor (BCR) sequences from unique circulating B-cell clones of 6 patients with MOGAD using an antigen selection approach. BCR sequences were expressed as immunoglobulin (Ig)G1 antibodies, and their molecular features, epitope specificity, and binding to MOG isoforms were investigated. The MOG-mAbs’ ability to mediate antibody-dependent cellular phagocytosis (ADCP), natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) toward MOG-expressing cells was assessed by live cell-based assays.ResultsOf the 15 MOG-mAbs generated, 4 revealed evidence of affinity maturation, whereas the remaining 11 were germline encoded. Binding capacities to hMOG varied considerably, with the most frequent putative epitope mapping to a region that includes residue P42. The efficacy of these antibodies in mediating ADCP, ADCC, and CDC of MOG-expressing cells was heterogeneous and associated with their binding characteristics to MOG and its isoforms.DiscussionTaken together, the molecular characteristics and binding patterns of these patient-derived MOG-mAbs reveal a diverse repertoire of MOG-binding autoantibodies with pathogenic capacity in vitro. Consequently, these well-characterized patient autoantibodies offer a foundation for developing in vivo models of MOGAD, serve as tools to standardize diagnostic assays, and guide development of therapeutic strategies targeting either B cells or autoantibodies and their effector functions.

Background and ObjectivesAnti–contactin-associated protein-like 2 (CASPR2) disease—previously considered a subtype of anti–voltage-gated potassium channel (VGKC-complex) encephalitis—is a relatively new disease entity, and information on long-term outcomes and relapses is limited. We investigated long-term clinical outcomes and factors associated with higher relapse rates. In addition, we compared different treatment strategies.MethodsIn this nationwide observational cohort study, patients with anti-CASPR2 disease were included. Clinical data were collected at diagnosis and during follow-up, both retrospectively and prospectively.ResultsForty-four patients with anti-CASPR2 disease were included (42 male patients [96%]; median age at onset 66 years [interquartile range (IQR) 61–71; range 40–86]). The median follow-up time was 55 months (IQR 38–78; range 8–200). Sixty percent of the patients experienced at least one relapse. Most patients experienced similar but fewer symptoms during relapse(s). However, new symptoms could occur during a relapse episode, mainly involving the peripheral nervous system. The median time to relapse was 10.5 months (IQR 6–14; range 3–58). Twelve of the 44 patients were diagnosed with cancer, with 3 cancers identified only at relapse. We found significantly higher anti–VGKC-complex concentrations at diagnosis (p = 0.043) and a higher occurrence of seizures (p = 0.041) in relapsing patients. In 94%, a clear correlation was observed between anti–VGKC-complex concentrations and the clinical status (59% decrease from diagnosis to post-treatment stage, 122.5% increase during the first relapse). In our total cohort, tapering with oral steroids seemed effective in reducing relapses during administration (annual relapse rate [ARR] 0.12) but did not prevent relapses beyond the taper. Second-line therapy also appeared effective (ARR 0.09) while steroid-sparing agents provided limited benefits (ARR 0.22). In patients prone to relapse, repeated courses of rituximab seem necessary to prevent further relapses (hazard ratio 26.33, p < 0.0005 in post–second-line treatment group; ARR 0.09 vs 0.81).DiscussionThe relapse rate in anti-CASPR2 disease is much higher than previously reported. In patients prone to relapse, (repeated) courses of rituximab appear to be most effective in preventing future relapses beyond acute therapy and tapering with oral steroids. Anti–VGKC-complex concentrations in serum can aid in monitoring of relapses and disease course in most of the patients. It is recommended to repeat tumor screening when patients relapse.Classification of EvidenceThis study provides Class IV evidence that, in anti-CASPR2 disease, prolonged immunotherapy is associated with reduced relapse rates.

Acharya Madhavakara was the first to recognize Amavata as a distinct disease entity in the classical Ayurvedic text Madhava Nidana. The manifestation of Amavata is attributed to the intake of specific causative factors (Nidanas), such as Mandagni (weak digestive fire), Viruddha Ahara-Chesṭa (incompatible diet and lifestyle), Niscalata (physical inactivity), and engaging in strenuous physical activity (Vyayama) immediately after consuming Snigdha Bhojana (unctuous or heavy meals). These factors contribute to the impairment of Agni, leading to the formation of Ama - a toxic, undigested metabolic waste. the accumulation of Ama (undigested toxic material) and the vitiation of Vata Doṣa. Among the primary etiological factors, Mandagni (low digestive fire) and Viruddha Ahara (incompatible diet) play a central role in the formation of Viruddha Ahara. When the digestive fire is impaired, food is not properly metabolized, leading to Ama production. Additionally, the frequent consumption of incompatible food combinations disturbs Agni and Doshic balance, further contributing to disease pathogenesis. This explores the pathological link between Mandagni, Viruddha Ahara, and the onset of Amavata, as described in classical Ayurvedic texts.