Annual review of medicine最新文献

Complement constitutes a major part of the innate immune system. The study of complement in human health has historically focused on infection risks associated with complement protein deficiencies; however, recent interest in the field has focused on overactivation of complement as a cause of immune injury and the development of anticomplement therapies to treat human diseases. The kidneys are particularly sensitive to complement injury, and anticomplement therapies for several kidney diseases have been investigated. Overactivation of complement can result from loss-of-function mutations in complement regulators; gain-of-function mutations in key complement proteins such as C3 and factor B; or autoantibody production, infection, or tissue stresses, such as ischemia and reperfusion, that perturb the balance of complement activation and regulation. Here, we provide a high-level review of the status of anticomplement therapies, with an emphasis on the transition from rare diseases to more common kidney diseases.

Dilated cardiomyopathy (DCM) is defined as dilation and/or reduced function of one or both ventricles and remains a common disease worldwide. An estimated 40% of cases of familial DCM have an identifiable genetic cause. Accordingly, there is a fast-growing interest in the field of molecular genetics as it pertains to DCM. Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. In addition to standard treatment of heart failure and prevention of arrhythmias and sudden cardiac death, patients with genetic cardiomyopathy stand to benefit from gene mechanism-specific therapies.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD heterogeneity has hampered progress in developing pharmacotherapies that affect disease progression. This issue can be addressed by precision medicine approaches, which focus on understanding an individual's disease risk, and tailoring management based on pathobiology, environmental exposures, and psychosocial issues. There is an urgent need to identify COPD patients at high risk for poor outcomes and to understand at a mechanistic level why certain individuals are at high risk. Genetics, omics, and network analytic techniques have started to dissect COPD heterogeneity and identify patients with specific pathobiology. Drug repurposing approaches based on biomarkers of specific inflammatory processes (i.e., type 2 inflammation) are promising. As larger data sets, additional omics, and new analytical approaches become available, there will be enormous opportunities to identify high-risk individuals and treat COPD patients based on their specific pathophysiological derangements. These approaches show great promise for risk stratification, early intervention, drug repurposing, and developing novel therapeutic approaches for COPD.

The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.

The porphyrias are a group of rare diseases, each resulting from a defect in a different enzymatic step of the heme biosynthetic pathway. They can be broadly divided into two categories, hepatic and erythropoietic porphyrias, depending on the primary site of accumulation of heme intermediates. These disorders are multisystemic with variable symptoms that can be encountered by physicians in any specialty. Here, we review the porphyrias and describe their clinical presentation, diagnosis, and management. We discuss novel therapies that are approved or in development. Early diagnosis is key for the appropriate management and prevention of long-term complications in these rare disorders.

Mpox, previously known as monkeypox, is caused by an Orthopoxvirus related to the variola virus that causes smallpox. Prior to 2022, mpox was considered a zoonotic disease endemic to central and west Africa. Since May 2022, more than 86,000 cases of mpox from 110 countries have been identified across the world, predominantly in men who have sex with men, most often acquired through close physical contact or during sexual activity. The classical clinical presentation of mpox is a prodrome including fever, lethargy, and lymphadenopathy followed by a characteristic vesiculopustular rash. The recent 2022 outbreak included novel presentations of mpox with a predominance of anogenital lesions, mucosal lesions, and other features such as anorectal pain, proctitis, oropharyngeal lesions, tonsillitis, and multiphasic skin lesions. We describe the demographics and clinical spectrum of classical and novel mpox, outlining the potential complications and management.

Hospitalists are generalists who specialize in the care of hospitalized patients. In the 25 years since the term hospitalist was coined, the field of hospital medicine has grown exponentially and established a substantial footprint in the medical community. There are now more hospitalists than practicing physicians in any other internal medicine subspecialty. Several key forces catalyzed the growth in the field of hospital medicine, including the quality, safety, and value movements; residency duty hour restrictions; the emergence of electronic health records; and the COVID-19 pandemic. Looking ahead, we see new opportunities in the realms of technology and telemedicine, and challenges persist in regard to balancing financial considerations with increasing workload and burnout. Hospitalists must remain nimble and seize emerging opportunities to continue supporting the field's prominence and growth.

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are large-vessel vasculitides affecting the aorta and its branches. Arterial damage from these diseases may result in ischemic complications, aneurysms, and dissections. Despite their similarities, the management of GCA and TAK differs. Glucocorticoids are used frequently but relapses are common, and glucocorticoid toxicity contributes to significant morbidity. Conventional immunosuppressive therapies can be beneficial in TAK, though their role in the management of GCA remains unclear. Tumor necrosis factor inhibitors improve remission rates and appear to limit vascular damage in TAK; these agents are not beneficial in GCA. Tocilizumab is the first biologic glucocorticoid-sparing agent approved for use in GCA and also appears to be effective in TAK. A better understanding of the pathogenesis of both conditions and the availability of targeted therapies hold much promise for future management.

Increasing numbers of transgender and gender-diverse (TGD) youth, from early puberty through late adolescence, are seeking medical services to bring their physical sex characteristics into alignment with their gender identity-their inner sense of self as male or female or elsewhere on the gender spectrum. Numerous studies, primarily of short- and medium-term duration (up to 6 years), demonstrate the clearly beneficial-even lifesaving-mental health impact of gender-affirming medical care in TGD youth. However, there are significant gaps in knowledge and challenges to such care. Long-term safety and efficacy studies are needed to optimize medical care for TGD youth.

Cytokine storm syndrome (CSS), which is frequently fatal, has garnered increased attention with the ongoing coronavirus pandemic. A variety of hyperinflammatory conditions associated with multiorgan system failure can be lumped under the CSS umbrella, including familial hemophagocytic lymphohistiocytosis (HLH) and secondary HLH associated with infections, hematologic malignancies, and autoimmune and autoinflammatory disorders, in which case CSS is termed macrophage activation syndrome (MAS). Various classification and diagnostic CSS criteria exist and include clinical, laboratory, pathologic, and genetic features. Familial HLH results from cytolytic homozygous genetic defects in the perforin pathway employed by cytotoxic CD8 T lymphocytes and natural killer (NK) cells. Similarly, NK cell dysfunction is often present in secondary HLH and MAS, and heterozygous mutations in familial HLH genes are frequently present. Targeting overly active lymphocytes and macrophages with etoposide and glucocorticoids is the standard for treating HLH; however, more targeted and safer anticytokine (e.g., anti-interleukin-1, -6) approaches are gaining traction as effective alternatives.