Nature Reviews Disease Primers最新文献

Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Bullous pemphigoid is a chronic, subepidermal autoimmune blistering disease characterized by tense blisters on erythematous or normal skin that predominantly affects the older population. The disease arises from autoantibodies targeting hemidesmosomal proteins BP180 and BP230, which are crucial for dermal-epidermal adhesion. The incidence of bullous pemphigoid is increasing, attributed to an ageing population and improved diagnostic recognition. Genetic predisposition, environmental triggers and associations with other autoimmune disorders underline its multifactorial nature. Diagnosis involves clinical presentation, histopathology, direct immunofluorescence and serological tests. Treatment aims to reduce symptoms and prevent new blister formation, using corticosteroids, immunosuppressive agents and biologics such as rituximab and omalizumab. Despite therapeutic advancements, challenges persist in long-term management, especially in older patients with comorbidities. Ongoing research into molecular mechanisms and novel therapeutic targets and clinical trials are crucial for the development of safer and more effective treatments.

Osteoarthritis is a heterogeneous whole-joint disease that can cause pain and is a leading cause of disability and premature work loss. The predominant disease risk factors - obesity and joint injury - are well recognized and modifiable. A greater understanding of the complex mechanisms, including inflammatory, metabolic and post-traumatic processes, that can lead to disease and of the pathophysiology of pain is helping to delineate mechanistic targets. Currently, management is primarily focused on alleviating the main symptoms of pain and obstructed function through lifestyle interventions such as self-management programmes, education, physical activity, exercise and weight management. However, lack of adherence to known effective osteoarthritis therapeutic strategies also contributes to the high global disease burden. For those who have persistent symptoms that are compromising quality of life and have not responded adequately to core treatments, joint replacement is an option to consider. The burden imparted by the disease causes a substantial impact on individuals affected in terms of quality of life. For society, this disease is a substantial driver of increased health-care costs and underemployment. This Primer highlights advances and controversies in osteoarthritis, drawing key insights from the current evidence base.