Annual Review of Medicine - Volume 68, 2017

Catastrophic antiphospholipid syndrome (CAPS) is a potentially lethal disease that presents with rapidly progressive multiple organ thromboses. Anticoagulation, corticosteroids, intravenous immunoglobulin, and plasma exchange are the most commonly used treatments for CAPS patients. However, the high mortality despite these medications necessitates new treatment strategies. Following a brief review of current diagnostic and management strategies, we discuss the candidate therapies, i.e., hydroxychloroquine, rituximab, eculizumab, sirolimus, and defibrotide, that can be considered in CAPS patients refractory to traditional treatment.

Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN activation is induced by pattern-recognition receptors of the innate immune system that sense pathogen-derived nucleic acids. Cellular responses to type I IFN signaling are orchestrated by a complex network of regulatory pathways that involve both the innate and adaptive immune system. The genetic and molecular dissection of rare Mendelian disorders associated with constitutive overproduction of type I IFN has provided unique insight into cell-intrinsic disease mechanisms that initiate and sustain autoinflammation and autoimmunity and that are caused by disturbances in the intracellular nucleic acid metabolism or in cytosolic nucleic acid–sensing pathways. Collectively, these findings have greatly advanced our understanding of mechanisms that protect the organism against inappropriate immune activation triggered by self nucleic acids while maintaining a prompt and efficient immune response to foreign nucleic acids derived from invading pathogens.

The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.

Primary Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal, resulting in oral and ocular dryness, although virtually any organ system can be affected. SS-related systemic manifestations are classified as either related to the presence of periepithelial infiltrates in exocrine and parenchymal organs or resulting from immunocomplex deposition due to B cell hyperactivity with increased risk for B cell lymphoma development. Activation of both innate and adaptive immune pathways contributes to disease pathogenesis, with prominent interferon (IFN) signatures identified in both peripheral blood and affected salivary gland tissues. Recently, LINE-1 genomic repeat elements have been proposed as potential triggers of type I IFN pathway activation in SS through activation of Toll-like receptor–dependent and –independent pathways. In view of the increasingly appreciated variability of SS, elucidation of distinct operating pathways in relation to diverse clinical phenotypes and selection of the optimal therapeutic intervention remain major challenges. Inhibition of cathepsin S molecules, blockade of costimulation through administration of abatacept and inhibitors of B7-related molecules and CD40, blockade of B cell function and B cell survival factors, and disruption of the formation of ectopic germinal centers are considered the main therapeutic targets. Well-controlled multicenter clinical trials are ongoing and data are awaited.

The current standard of care for the treatment of hepatitis C virus (HCV) consists of interferon-free direct-acting antiviral (DAA) regimens, including combinations of DAAs and fixed-dose combination pills. DAAs for HCV are likely to be heralded as one of medicine's greatest advancements. Viral eradication rates are pushing 100% for many HCV-infected populations, including patients with HIV/HCV coinfection, decompensated cirrhosis, liver and kidney transplants, and end-stage liver disease. We highlight the greatest successes of combination DAA therapies, discuss the ongoing challenges, and identify the remaining patient subgroups with unmet medical needs.

As of the end of March 2016, the West Africa epidemic of Ebola virus disease (Ebola) had resulted in a total of 28,646 cases, 11,323 of them fatal, reported to the World Health Organization. Guinea, Liberia, and Sierra Leone were most heavily affected, but Ebola cases were exported to several other African and European countries as well as the United States, with limited further transmission, including to healthcare workers. We review the descriptive epidemiology of the outbreak, novel aspects and insights concerning the unprecedented response, scientific observations, and public health implications. The large number of Ebola survivors has highlighted the frequency of persistent symptoms and the possibility of virus persistence in sanctuary sites, sometimes leading to delayed transmission. Although transmission appears to have ceased in 2016, the West Africa Ebola epidemic has profoundly influenced discussions and practice concerning global health security.

Long-term control of viral outbreaks requires the use of vaccines to impart acquired resistance and ensuing protection. In the wake of an epidemic, established immunity against a particular disease can limit spread and significantly decrease mortality. Creation of a safe and efficacious vaccine against Ebola virus (EBOV) has proven elusive so far, but various inventive strategies are now being employed to counteract the threat of outbreaks caused by EBOV and related filoviruses. Here, we present a current overview of progress in the field of Ebola virus vaccine development.

In 2012, a zoonotic coronavirus was identified as the causative agent of Middle East respiratory syndrome and was named MERS coronavirus (MERS-CoV). As of August 11, 2016, the virus has infected 1,791 patients, with a mortality rate of 35.6%. Although MERS-CoV generally causes subclinical or mild disease, infection can result in serious outcomes, including acute respiratory distress syndrome and multi-organ failure in patients with comorbidities. The virus is endemic in camels in the Arabian Peninsula and Africa and thus poses a consistent threat of frequent reintroduction into human populations. Disease prevalence will increase substantially if the virus mutates to increase human-to-human transmissibility. No therapeutics or vaccines are approved for MERS; thus, development of novel therapies is needed. Further, since many MERS cases are acquired in healthcare settings, public health measures and scrupulous attention to infection control are required to prevent additional MERS outbreaks.

The emergence of the CRISPR/Cas system of antiviral adaptive immunity in bacteria as a facile system for gene editing in mammalian cells may well lead to gene editing becoming a novel treatment for a range of human diseases, especially those caused by deleterious germline mutations. Another potential target for gene editing are DNA viruses that cause chronic pathogenic diseases that cannot be cured by using currently available drugs. We review the current state of this field and discuss the potential advantages and problems with using a gene editing approach as a treatment for diseases caused by DNA viruses.

Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Aβ amyloid pathway and the tau pathway—leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD—continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy.

Demyelination of central nervous system axons, associated with traumatic injury and demyelinating diseases such as multiple sclerosis, causes impaired neural transmission and ultimately axon degeneration. Consequently, extensive research has focused on signaling systems that promote myelinating activity of oligodendrocytes or promote production of new oligodendrocytes from oligodendrocyte progenitor cells. Many receptor systems, notably including growth factor receptors and G protein–coupled receptors, control myelination. A number of recent clinical trials target these receptor signaling pathways.

Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease.

Noninvasive prenatal DNA testing is the vanguard of genomic medicine. In only four years, this screening test has revolutionized prenatal care globally and opened up new prospects for personalized medicine for the fetus. There are widespread implications for increasing the scope of human genetic variation that can be detected before birth, and for discovering more about maternofetal and placental biology. These include an urgent need to develop pretest education for all pregnant women and consistent post-test management recommendations for those with discordant test results. The reduction in invasive testing has had downstream effects on specialist training and caused many countries to re-examine their national approaches to prenatal screening. Finally, the accumulating datasets of genomic information on pregnant women and their fetuses raise ethical issues regarding consent for future data mining and intellectual property.