The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of ...inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti-interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways.
Abstract
Janus kinase (JAK)/signal transducers and activators of transcription (STATs) are a group of molecules associated with one of the major pathways through which many cytokines exert and ...integrate their function, and as such they are increasingly recognized as playing critical role in the pathogenesis subserving various immune-mediated diseases, including RA, PsA, SpAs, IBD, skin disorders (e.g. alopecia areata, atopic dermatitis), single-gene disorders like interferonopathies, and others. JAKs are the key initiating players of the JAK/STAT pathway. Upon binding of their respective effector molecules (cytokines, IFNs, growth factors and others) to type I and type II receptors, JAKs are activated, and through phosphorylation of themselves and of other molecules (including STATs), they mediate signal transduction to the nucleus. A class of drugs-called JAK inhibitors or JAKinibs-that block one or more JAKs has been developed in the last decade, and now numbers >20 members. Although, so far, JAK inhibitors have been marketed only for RA and PsA, these drugs have been tested in phase 2 and phase 3 clinical trials for other inflammatory conditions and beyond. In this review, we summarize the clinical data, including efficacy and safety, available for JAK inhibitors used in some immune-mediated conditions other than RA.
Crop production requires large amounts of green and blue water. We developed the new global crop water model GCWM to compute consumptive water use (evapotranspiration) and virtual water content ...(evapotranspiration per harvested biomass) of crops at a spatial resolution of 5′ by 5′, distinguishing 26 crop classes, and blue versus green water. GCWM is based on the global land use data set MIRCA2000 that provides monthly growing areas for 26 crop classes under rainfed and irrigated conditions for the period 1998–2002 and represents multi-cropping. By computing daily soil water balances, GCWM determines evapotranspiration of blue and green water for each crop and grid cell. Cell-specific crop production under both rainfed and irrigated conditions is computed by downscaling average crop yields reported for 402 national and sub-national statistical units, relating rainfed and irrigated crop yields reported in census statistics to simulated ratios of actual to potential crop evapotranspiration for rainfed crops. By restricting water use of irrigated crops to green water only, the potential production loss without any irrigation was computed. For the period 1998–2002, the global value of total crop water use was 6685
km
3
yr
−1, of which blue water use was 1180
km
3
yr
−1, green water use of irrigated crops was 919
km
3
yr
−1 and green water use of rainfed crops was 4586
km
3
yr
−1. Total crop water use was largest for rice (941
km
3
yr
−1), wheat (858
km
3
yr
−1) and maize (722
km
3
yr
−1). The largest amounts of blue water were used for rice (307
km
3
yr
−1) and wheat (208
km
3
yr
−1). Blue water use as percentage of total crop water use was highest for date palms (85%), cotton (39%), citrus fruits (33%), rice (33%) and sugar beets (32%), while for cassava, oil palm and cocoa, almost no blue water was used. Average crop yield of irrigated cereals was 442
Mg
km
−2 while average yield of rainfed cereals was only 266
Mg
km
−2. Average virtual water content of cereal crops was 1109
m
3
Mg
−1 of green water and 291
m
3
Mg
−1 of blue water, while average crop water productivity of cereal crops was 714
g
m
−3. If currently irrigated crops were not irrigated, global production of dates, rice, cotton, citrus and sugar cane would decrease by 60%, 39%, 38%, 32% and 31%, respectively. Forty-three per cent of cereal production was on irrigated land, and without irrigation, cereal production on irrigated land would decrease by 47%, corresponding to a 20% loss of total cereal production. The largest cereal production losses would occur in Northern Africa (66%) and Southern Asia (45%) while losses would be very low for Northern Europe (0.001%), Western Europe (1.2%), Eastern Europe (1.5%) and Middle Africa (1.6%). Uncertainties and limitations are discussed in the manuscript, and a comparison of GCWM results to statistics or results of other studies shows good agreement at the regional scale, but larger differences for specific countries.
Achieving global food security is one of the major challenges of the coming decades. In order to tackle future food security challenges we must understand the past. This study presents a historical ...analysis of global food availability, one of the key elements of food security. By calculating national level dietary energy supply and production for nine time steps during 1965-2005 we classify countries based on their food availability, food self-sufficiency and food trade. We also look at how diets have changed during this period with regard to supply of animal based calories. Our results show that food availability has increased substantially both in absolute and relative terms. The percentage of population living in countries with sufficient food supply (>2500 kcal/cap/d) has almost doubled from 33% in 1965 to 61% in 2005. The population living with critically low food supply (<2000 kcal/cap/d) has dropped from 52% to 3%. Largest improvements are seen in the MENA region, Latin America, China and Southeast Asia. Besides, the composition of diets has changed considerably within the study period: the world population living with high supply of animal source food (>15% of dietary energy supply) increased from 33% to over 50%. While food supply has increased globally, food self-sufficiency (domestic production>2500 kcal/cap/d) has not changed remarkably. In the beginning of the study period insufficient domestic production meant insufficient food supply, but in recent years the deficit has been increasingly compensated by rising food imports. This highlights the growing importance of food trade, either for food supply in importing countries or as a source of income for exporters. Our results provide a basis for understanding past global food system dynamics which, in turn, can benefit research on future food security.
The coexistence of immune-mediated inflammatory diseases with depression has long been recognised. Data that illustrate the intimate associations between peripheral and brain immune responses raise ...the possibility of shared pathophysiological mechanisms. These associations include the negative effects of proinflammatory cytokines on monoaminergic neurotransmission, neurotrophic factors, and measures of synaptic plasticity. The evidence supporting this association is accumulating and includes findings from clinical trials of immunomodulatory therapy, indicating that these interventions can provide benefits to mental health independent of improvements in physical disease scores. In this Review, we assess this evidence in relation to rheumatoid arthritis and depression, with a focus on innate immune and molecular responses to inflammation, and discuss the challenges of assessing causation in this population, acknowledging the difficulty of assessing the confounding and contributory effects of pain and fatigue. We also discuss how future clinical and preclinical research might improve diagnosis of depression in people with rheumatoid arthritis and shed light on mechanisms that could be substrates for therapeutic interventions.
Changing crop phenology is considered an important bio-indicator of climate change, with the recent warming trend causing an advancement in crop phenology. Little is known about the contributions of ...changes in sowing dates and cultivars to long-term trends in crop phenology, particularly for winter crops such as winter wheat. Here, we analyze a long-term (1952-2013) dataset of phenological observations across western Germany and observations from a two-year field experiment to directly compare the phenologies of winter wheat cultivars released between 1950 and 2006. We found a 14-18% decline in the temperature sum required from emergence to flowering for the modern cultivars of winter wheat compared with the cultivars grown in the 1950s and 1960s. The trends in the flowering day obtained from a phenology model parameterized with the field observations showed that changes in the mean temperature and cultivar properties contributed similarly to the trends in the flowering day, whereas the effects of changes in the sowing day were negligible. We conclude that the single-cultivar concept commonly used in climate change impact assessments results in an overestimation of winter wheat sensitivity to increasing temperature, which suggests that studies on climate change effects should consider changes in cultivars.
To support global-scale assessments that are sensitive to agricultural land use, we developed the global data set of monthly irrigated and rainfed crop areas around the year 2000 (MIRCA2000). With a ...spatial resolution of 5 arc min (about 9.2 km at the equator), MIRCA2000 provides both irrigated and rainfed crop areas of 26 crop classes for each month of the year. The data set covers all major food crops as well as cotton. Other crops are grouped into categories (perennial, annual, and fodder grasses). It represents multicropping systems and maximizes consistency with census-based national and subnational statistics. According to MIRCA2000, 25% of the global harvested areas are irrigated, with a cropping intensity (including fallow land) of 1.12, as compared to 0.84 for the sum of rainfed and irrigated harvested crops. For the dominant crops (rice (1.7 million km2 harvested area), wheat (2.1 million km2), and maize (1.5 million km2)), roughly 60%, 30%, and 20% of the harvested areas are irrigated, respectively, and half of the citrus, sugar cane, and cotton areas. While wheat and maize are the crops with the largest rainfed harvested areas (1.5 million km2 and 1.2 million km2, respectively), rice is clearly the crop with the largest irrigated harvested area (1.0 million km2), followed by wheat (0.7 million km2) and maize (0.3 million km2). Using MIRCA2000, 33% of global crop production and 44% of total cereal production were determined to come from irrigated agriculture.
Cardiometabolic comorbidities present a considerable burden for patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Both RA and PsA are associated with an increased risk of ...cardiovascular disease (CVD). PsA more often exhibits an increased risk of metabolically linked comorbidities such as obesity, insulin resistance, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Although both RA and PsA are characterized by a state of chronic inflammation, the mechanisms that contribute to CVD risk in these conditions might not be identical. In RA, systemic inflammation is thought to directly contribute to CVD risk, whereas in PsA, adiposity is thought to contribute to a notable metabolic phenotype that, in turn, contributes to CVD risk. Hence, appropriate management strategies that consider the increased risk of cardiometabolic comorbidities in patients with inflammatory arthropathy are important. In RA, such strategies should focus on the prediction of CVD risk and its management through targeting chronic inflammation and traditional CVD risk factors. In PsA, management strategies should additionally focus on targeting metabolic components, including weight management, which might not only help improve disease activity in the joints, entheses and skin, but also reduce the risk of metabolic comorbidities and improve the quality of life of patients.
The discovery of the biological functions of the interleukin-23 -17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated ...diseases. Therapeutic agents targeting these cytokines and or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12 -23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.
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