Supplemental Digital Content is available in the text. Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM.18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation  was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM  in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM . Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM . Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose .In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease.http://www.clinicaltrials.gov. Unique identifier: NCT00703261.URL:  This question is of substantial importance because an association between atherosclerotic disease morphology and statin efficacy would provide a second reason to consider structural disease characteristics when deciding on primary prevention therapy.It is well accepted that the presence of nonobstructive atherosclerotic plaques, particularly those with high-risk morphological (HRM) features, is associated with an increased risk of future cardiovascular disease events.MehtaSee Editorial by See Clinical Perspective5; the anti-inflammatory actions of statins is one of its most important beneficial effects on atherosclerosis.6 Arterial imaging using 18-fluorodeoxy glucose positron emission tomography and computed tomography (FDG-PET/CT) is used to reproducibly measure atherosclerotic inflammation.10 Atherosclerotic FDG uptake can be quantified noninvasively and significantly correlates with systemic inflammatory biomarkers,11 macrophage infiltration, and inflammatory cell gene expression within the arterial wall.13 Furthermore, it provides an independent marker of risk for future atherothrombotic events15 and is modifiable by statin therapy.16 The majority of FDG-PET imaging studies have focused on extracoronary vessels.17 However, successful evaluation of coronary FDG uptake has been reported previously18 and has recently focused on the left main coronary artery (LMCA) segment, which does not have an epicardial course and thus lends itself to measurement of FDG uptake.19Atherosclerosis is a systemic inflammatory conditionWe hypothesized that atherosclerotic inflammation is greatest within LMCA manifesting HRM features. Accordingly, in this prospective treatment study, we tested the hypothesis that the anti-inflammatory actions of atorvastatin are greatest in LMCA with (versus without) HRM.9This study is part of a larger randomized double-blind trial that was conducted at 10 US centers to investigate the impact of atorvastatin therapy on arterial wall inflammation. The study complies with the Declaration of Helsinki. The protocol was reviewed and approved by each center’s institutional review board, and all participants provided written informed consent before any study procedures. Analysis of FDG uptake in the LMCA, carotid arteries, and aorta was performed before unblinding of the data. In the current study, we used computed tomographic angiography (CTA) images and performed a blinded analysis of plaque composition in carotids and coronary arteries and additionally assessed the relationship between FDG uptake and high-risk plaque morphology. Permission was received from the Partners Healthcare Institutional Review Board to perform these additional analyses on the anonymized images. The primary end point of the study, evaluating the effect of statin therapy on large-vessel inflammatory activity (assessed by FDG PET/CT), was previously reported.2 or waist circumference >102 cm in men and >88 cm in women. Subjects were excluded if they had a history of (1) type 1 diabetes mellitus, (2) significant cardiovascular event or intervention within 12 weeks of screening, (3) significant heart failure , (4) hepatobiliary disease, (5) chronic systemic inflammatory condition (such as rheumatoid arthritis or psoriasis), or (6) chronic infection. In addition, eligible subjects were required to have low-density lipoprotein cholesterol level ≥60 mg/dL and triglyceride level <350 mg/dL and were required to be statin naive or taking no more than low-dose statins .One hundred and sixty-three subjects were initially screened, and 83 subjects  underwent baseline FDG-PET/CT imaging. Criteria for inclusion were individuals aged 30 to 80 years with documentation or history of any one of the following: (1) coronary artery disease, (2) carotid artery disease, (3) cerebrovascular disease, (4) peripheral arterial disease , (5) type 2 diabetes mellitus, and (6) body mass index 30 to 40 kg/mAfter the initial clinical screening, subjects underwent baseline imaging with FDG-PET/CT. Because the study was originally designed to evaluate the effect of statin treatment on arterial wall inflammation, subjects without evidence of arterial inflammation  at baseline were excluded before randomization, resulting in the exclusion of ≈10% of the initially screened population. Follow-up FDG-PET/CT images were obtained after 12 weeks of atorvastatin therapy.9 Briefly,18F-FDG was administered intravenously (≈10 mCi for a 70 kg patient) after an overnight fast, and imaging was performed 90 minutes after FDG injection using a hybrid PET/CT scanner (Seimens Biograph 64 or similar). To suppress myocardial FDG uptake, subjects were instructed to consume a low-carbohydrate, high-fat diet starting with the dinner meal , the evening before the day of FDG-PET/CT imaging, to suppress myocardial FDG uptake. An attenuation correction CT scan using 140 kVp was performed followed by PET imaging of the neck and chest, with 15-minute acquisitions per bed position. The reconstruction of attenuation-corrected images was performed using ordered subset expectation maximization algorithm. All patients had a blood sugar concentration <200 mg/dL at the time of imaging.FDG-PET/CT imaging was performed using previously reported approaches.19 Investigators were blinded to the clinical history and temporal sequence of the images. Subsequently, the data sets (week 0 and 12 images) were batch analyzed after coregistration of PET and CT images . Maximum standardized uptake value of FDG was measured in LMCA by placing 4 regions of interest at the LMCA ostium, 5 and 10 mm distal to the ostium, and LMCA bifurcation. The measurements from those LMCA locations were averaged to produce mean of maximum LMCA standardized uptake value. Care was taken to avoid the spillover activity from the myocardium, as performed in a previous study by our group.18 The fact that coronary artery activity measurements were limited to the LMCA, a nonepicardial segment of the coronary tree, facilitated the avoidance of myocardial activity. Target-to-background ratios were derived from the ratio of the arterial standardized uptake value to background venous blood standardized uptake value from the superior vena cava. In addition, FDG uptake was measured in the aorta and carotids using previously described methods.9PET/CT images were analyzed using previously detailed methods.9 The mean TBR of the index vessel was defined as the average of the maximum TBR activity for all of the axial segments that compose the index vessel.FDG uptake (TBR) was evaluated in 3 extracoronary arterial locations (right and left carotid and aorta). The extracoronary artery with the highest FDG uptake at baseline was identified as the index vessel, as previously described.Coronary CTA, to assess coronary artery plaque morphology, was performed in helical mode on multidetector CT scanners with ≥64 slices. Imaging parameters included rotation time of ≤420 ms, tube current of ≈750 to 850 mAs (effective), and voltage of 120 kVp. Image acquisition characteristics were slice thicknesses of 0.75 mm and pitch of 0.2 to 0.4. Iopamidol 300 mg/mL or a similar drug was used as an intravenous contrast agent and infused at 5 to 6 mL/s. Immediately after coronary CT angiography, the table was repositioned for acquisition of carotid images. Settings for carotid CT scanning were as follows: pitch 2.8, rotation time of ≤500 ms, tube current of ≈180 to 300 mA, and voltage of 120 kVp.21 An analysis examining morphological features of atherosclerotic plaques in the entire coronary arterial tree and carotid circulation was also performed .Evaluation of the CTA images was performed while blinded to PET data and clinical information. Plaque morphology was assessed in the LMCA. HRM plaques in the LMCA were identified by presence of noncalcified or partially calcified plaques as described in previous studies.C-reactive protein (CRP) and matrix metalloproteinase-3 (MMP-3) concentrations were obtained at baseline and 12 weeks. Serum biomarker analyses were performed in batches.t test was used for cross-sectional comparison of normally distributed continuous variables. Mann–Whitney U test was used for the similar analyses of continuous variables without normal distribution (such as CRP). A linear regression model was fitted to adjust for potential confounding factors on the effects of statin therapy in reduction of FDG uptake (TBR). The potential confounders for adjustment were selected based on the previous studies or clinical relevance. In the linear regression model to adjust for baseline left main TBR, we used tertiles of baseline TBR. Adjustment for Fisher exact test was performed for comparison of dichotomous variables. Pearson correlation coefficient (R) was used to assess correlations between continuous variables once normal distribution was verified, and Spearman ρ was reported as correlation coefficient for non-normally distributed variables. Two-tailed probability values are reported, and statistical significance is defined as P<0.05. All statistical analyses were performed using SPSS version 22 .Descriptive data are presented as mean±SD for continuous normally distributed variables, median (interquartile range) for continuous non-normally distributed data, and frequency with proportions for nominal variables, as appropriate. Independent samples Baseline characteristics of study subjects are detailed in the Table. Seventy-one subjects completed the 12-week treatment period. In 68 of those subjects, PET/CT image quality was sufficient to analyze FDG uptake in the LMCA and extracoronary vessels . Fifty-five subjects provided adequate-quality coronary CTA images to assess plaque morphology in the LMCA and carotid arteries .LMCA inflammation (TBR) was higher in LMCA with HRM  than those without HRM . The relationship remained statistically significant after adjusting for baseline TBR . Additionally, the relationship between LMCA plaque morphology and change in LMCA inflammation (TBR) after atorvastatin remained significant after adjusting for body mass index  and after adjusting for baseline low-density lipoprotein and statin dose .We evaluated the impact of statin therapy on LMCA and observed that after 12 weeks of statin therapy, FDG uptake was reduced in LMCA with HRM but not in LMCA without HRM . Because of the relative abundance of plaques across the entire coronary tree, we were able to use a more stringent definition of HRM, in this case, plaques with both positive remodeling and low attenuation (double positives). At baseline, CRP was significantly higher in subjects with HRM than those without HRM within the entire coronary arterial tree . We did not observe significant association between CRP concentrations and LMCA inflammation (TBR), although we observed a correlation between serum MMP-3 and LMCA inflammation .For the comparison between blood biomarkers and coronary plaques, we assessed plaque morphology across the entire coronary tree , carotid vessel , and index vessel  correlated with inflammation (TBR) in the aorta  in the aorta was associated with the presence of HRM coronary plaque features (by CTA) such that subjects with higher aortic TBR (≥median) exhibited a higher frequency of high-risk structural plaque features throughout the coronary tree , in which among individuals eligible for primary prevention, the majority of CHD and CVD events occurred in those with coronary artery calcium scores >100.22 From that, the authors suggested that preventative therapies should be preferentially prescribed to individuals with imaging evidence of more advanced atherosclerotic disease.The key finding of this study is the observation that the anti-inflammatory effect of statins is seen primarily within more advanced lesions. The association between plaque morphology and statin effect was evident in both the coronary and extracoronary circulation and remained robust after correcting for potential confounders such as baseline TBR, prestudy statin use, low-density lipoprotein concentration, and statin dose. Accordingly, the findings of this study provide additional support for the hypothesis that assessment of atherosclerosis, including arterial wall inflammatory activity, might help to identify individuals who would derive the greatest benefit from statin therapy .24 recently demonstrated that the presence of nonobstructive atherosclerotic plaques is associated with an increased risk of future atherosclerotic cardiovascular disease events and that incorporating information on nonobstructive coronary artery disease results in more accurate allocation of statin therapy. Our findings add an important additional consideration, by indicating that the underlying plaque morphology may additionally affect the local efficacy of statins. Together, these findings suggest that available imaging data might be useful for guiding treatment decisions on the use of statins or newer antiatherosclerotic approaches, especially in cases where there may be relative equipoise when deciding on primary prevention. Given the likely emergence of several new pharmacological tools (such as novel lipid-lowering drugs and anti-inflammatory drugs) with which to reduce the risk of incident atherothrombotic events, the medical community will likely experience a greater need to better allocate those new treatments, a paradigm that is in-line with the contemporary emphasis on precision medicine.25Similarly, Emami et al27 the current study is the first to extend that observation to the coronary circulation. This observation provides further validation of FDG-PET/CT imaging as a tool to characterize proximal coronary atherosclerosis, in that it demonstrates that coronary FDG uptake (by PET) associates with high-risk structural features that are identified using an orthogonal technique (CTA).In this study, we also tested the hypothesis that atherosclerotic inflammatory activity (represented as FDG uptake in LMCA) is highest in coronary plaques with HRM. Although the relationship between HRM and inflammation has been previously reported for the carotids,15Furthermore, we investigated the relationship between inflammation in coronary and extracoronary vessels. In this evaluation, we observed several important associations. First, we found that individuals with higher extracoronary arterial inflammation had greater coronary inflammation and were also more likely to have coronary plaques containing high-risk structural features. Furthermore, we observed that the anti-inflammatory actions of statins were similarly manifested in the extracoronary and coronary circulation. These observations provide additional confidence that the data derived by looking at the large arteries (which are much more amenable to imaging) provide important insights into the coronary atherosclerotic milieu (where the atherothrombotic events of greatest concern originate). The data also provide additional insights as to why imaging of the aorta with FDG-PET/CT functions as an independent marker of risk of future CV events.11 and here, we replicate that finding but further demonstrate that this relationship extends to the coronary artery as well. Similar to other groups, we show a significant association between CRP and high-risk coronary plaque features.28 Collectively, our findings emphasize the systemic nature of atherosclerosis and arterial inflammation by providing insights on the biological links between resident plaques in both large and small arteries and circulating proinflammatory markers.Finally, we studied the relationship between both plaque morphology and inflammation and established serum proinflammatory biomarkers, MMP-3 and CRP. MMP-3 has been shown to correlate with inflammation (FDG uptake) in the aorta,Of the patients enrolled in the larger randomized controlled prospective study, this study was limited to only those patients with evaluable CTA images and, thus, limits the generalizability of the results, In this subset of patients, a smaller proportion had CT evidence of high-risk plaques and perhaps may have limited our ability to detect a consistent relationship with CRP and MMP-3. It is also worth noting that analyses were not sufficiently powered to assess the impact of statin dose (high dose versus low dose) on LMCA.30 suggests that the underlying inflammation-mediated high-risk plaque features may have been favorably modified. Although the image analyses in our study were prespecified before initiation of any study procedures, future studies are warranted to confirm our findings.In addition, coronary CTA was performed at a single time point, thereby precluding longitudinal assessment of changes or stability of coronary plaques at 12 weeks (after treatment). However, the reduction in both the coronary and extracoronary artery FDG signals, which has been validated histopathologically as an inflammatory marker,In summary, we show, for the first time, that statin therapy results in reduction in coronary inflammation and that the anti-inflammatory impact of statins is substantially greater within morphologically more advanced coronary plaques. Collectively, these findings suggest one potential mechanism by which statins may disproportionately benefit individuals with more advanced atherosclerotic disease.Dr Singh received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (5T32 HL076136) and Marfan Foundation. Dr Rudd is partly supported by the National Institute for Health Research Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust.Drs Alon and Shankar are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Whitehouse Station, NJ. Dr Alon owns stock in Merck Sharp & Dohme Corp. Drs Tawakol and Fayad received consulting fees, and their institutions received grants from Merck Sharp & Dohme Corp. The other authors report no conflicts.


Species respond to changes in their environments. A core goal in ecology is to understand the process of plant community assembly in response to a changing climate. Examining the performance of functional traits and trait-based assembly patterns across species among different growth forms is a useful way to explore the assembly process. In this study, we constructed a habitat severity gradient including several environment factors along a 2300 m wide elevational range at Taibai Mountain, central China. Then we assessed the shift on functional trait values and community assembly patterns along this gradient across species among different growth forms. We found that (1) although habitat-severity values closely covaried with elevation in this study, an examined communities along a habitat severity gradient might reveal community dynamics and species responses under future climate change. (2) the occurrence of trait values along the habitat severity gradient across different growth forms were similar, whereas the assembly pattern of herbaceous species was inconsistent with the community and woody species. (3) the trait-trait relationships of herbaceous species were dissimilar to those of the community and woody species. These results suggest that (1) community would re-assemble along habitat severity gradient through environmental filtering, regardless of any growth forms and that (2) different growth forms' species exhibiting similar trait values' shift but different trait-trait relationship by different trait combinations. The climate acts as a filter for the species pool on a regional scale  or resource availability  the community assembly pattern would show convergence in more stressful habitat, and (2) economic spectrum-related functional trait-trait relationships and functional trait distributions would demonstrate different patterns across different growth forms.The study was carried on the Taibai Mountain Nature Reserve, central China, located on 33°59′45″N−34°05′12″N, 107°41′18″E−107°48′22″E. This temperate zone is expected to permit a wider range of trait combinations than the tropical zone , topographic slope (by a specific compass), and canopy coverage.All species within each plot were identified, the abundance and coverage of the species in each plot were documented. The abundance of woody species (DBH > 8 cm) was counted as the number of stems. The abundance of herbaceous species was calculated by its relative coverage via assignment: We established eight 0.3 × 0.3 m quadrats within each plot for recording the abundance and coverage of each herbaceous species. Based on these data, we estimated the total abundance of herbaceous species within each plot . It is fine to assess the community assembly patterns for using these traits, as it would minimize the number of traits but maximize the number of dimensions  mentioned above, we measured leaf morphologic and chemometrical traits by using leaf samples we collected. Leaf area (LA) is a trait determined by gradients in available moisture and temperature  of all these traits for dimensionality reduction Shipley, . The PC1Thereafter, we constructed the habitat-severity values for above three levels. All the habitat factors were normalized to , the more stressful for plant growth, the value is more nearby 1. Therefore, we used these scores as the habitat-severity values, in other words, as habitat severity gradient.We performed linear regression between weighted mean traits values and habitat-severity values in community, woody species and herbaceous species levels. In addition, we assessed the functional trait distribution of each plot in community, woody species and herbaceous species level as well by using SES of traits. The SES which describes functional trait distribution is the degree of discrepancy of trait observed value to null expectation value  were dominated by MAT and RH, and MAT and RH were calculated using the elevations of plots. The correlation analysis between HV and elevation confirmed the notion that other environmental factors might correlate with elevation, even across three different levels . Without exception, the functional distributions of LA, SLA, Hmax, and SM across community and woody species levels showed convergent tendencies with higher habitat severity. For herbaceous species, although there were convergent tendencies on LA and SLA along habitat severity, the inflection points of divergence-convergence were inconsistent with community and woody species. The SES of herbaceous LNC showed a divergent tendency at higher habitat severity. The SES of other traits did not show significant correlation with the habitat severity gradient Figure .Variation of traits among the community, woody species, and herbaceous species along habitat severity gradients displayed similar patterns to each other Figure . For HmaThe Pearson correlation semi-matrices of woody species and herbaceous species were compared with the semi-matrix of community Tables , 3. TraiThe plant responses to environmental gradients seems to be a result of habitat severity, which links to the environmental filtering effect .Analyses of intra-community trait-trait relationships can reveal the functional trade-offs operating along gradients of environmental stress. Dwyer and Laughlin  proposedJX and MY: Conceived and designed the experiments; YFC and MW: Analyzed the data; HD: Wrote the paper; YG: Conducted field work; YC, TL, and LZ: Performed the experiments and collected the data; CZ: Helped completing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Psoriasis is a chronic immune-mediated inflammatory disease affecting women of childbearing potential. Biologic agents, notably Tumor Necrosis Factor inhibitors (TNFi), are the only current non-contraindicated systemic treatment option during pregnancy. TNFi comprised of complete immunoglobulin G (IgG) antibodies antibodies  actively cross the placenta from the second trimester and are detectable in the child up to one year postpartum. Data on safety of TNFi are conflicting; however a trend towards drug-specific harm has been reported, with increased risk of congenital malformations and preterm birth. TNFi exposure may alter the immune system of the infant towards hypersensitivity and reduced response to intracellular infections. Confounding by indication should be considered, as chronic inflammatory disease itself may pose a risk of adverse pregnancy outcomes. The quality of the current evidence is very low and no studies specifically address TNFi safety in women with psoriasis. Nonetheless, risks associated with TNFi treatment must be balanced against the as-yet uncertain risk of adverse outcomes in infants born to women with severe psoriasis. We searched PubMed using Medical Subject Headings (MeSH) terms and identified relevant studies and guidelines. Herein, we present the current knowledge of the use and safety of TNFi during pregnancy in women with psoriasis. Psoriasis is a chronic immune-mediated inflammatory disease that affects 2–4% of the world’s population ; approxiSince the late 1990s, TNF-inhibitors (TNFi), in particular adalimumab, etanercept and infliximab, have become a cornerstone in the treatment of psoriasis. These three TNFi accounted for about 25% of the use of psoriasis treatment in a 2013 survey performed in the US . ConsequKnowledge of safety of TNFi during pregnancy is limited but expanding . It is eThe inflammatory process and lifestyle factors in women with psoriasis may pose an individual risk to the pregnant mother and child ,11 and pTherefore it is crucial for doctors to have an up to date knowledge both of the natural course of psoriasis and of treatment with TNFi during pregnancy to assess the risks and benefits in each individual case.Herein, we present an overview of the current knowledge of the use and safety of TNFi during pregnancy in women with psoriasis.Research question: Are TNFi safe to use during pregnancy in women with psoriasis?T helper (Th) cells Th1 and Th17 are predominantly responsible for the inflammatory immune response in psoriasis by inducing a cascade of inflammatory cytokines, notably tumor necrosis factor (TNF) ,13. TNF is the driving force behind initiation and maintenance of the inflammatory process and psoriatic skin is infiltrated with a myriad of immune cells showing elevated expression of TNF including epidermal keratinocytes, intra-epidermal Langerhans cells, papillary dermal macrophages, and upper dermal blood vessels ,14,15. FIn 1999, the first TNFi, infliximab, was authorized by the European Medicines Agency for treatment of psoriasis and psoriasis arthritis among other inflammatory diseases. Since then etanercept (2000), adalimumab (2003), golimumab, and certolizumab pegol (2009) were authorized. TNFi works by antagonizing and thereby neutralizing the activity of transmembrane and soluble TNF, thus preventing its binding to the two different TNF-receptors Tumor Necrosis Factor receptor (TNFR)1 and TNFR2. TNFi often works in a dose-dependent manner, blocking the pro-inflammatory activities of TNF ,17. The Psoriasis fluctuates in pregnancy and 55% of women with psoriasis reported an improvement in skin symptoms, 23% reported worsening, and 21% reported no change . A substPsoriasis may pose a risk of adverse pregnancy outcomes. Until recently, there has been no clear evidence found of increased adverse pregnancy and birth outcome in women with psoriasis . UnfortuActive disease and the underlying immunopathology could contribute to overall adverse pregnancy outcomes in women with psoriasis. Yang et al.  found thThe pathogenesis underlying psoriasis’ effect on pregnancy is poorly studied. Increased activity of Th17 and to some extent Th1 cells plays a critical role in the immune pathogenesis of psoriasis . ChangesMaternally-acquired antibodies are critical to provide immunity to the newborn and protect it against infections during the first months of life before its own immune system matures .Complete immunoglobulin G (IgG) antibodies—both maternal and therapeutic—cross placenta via active transport facilitated by the neonatal fragment crystallizable (Fc) receptor on the placenta. This occurs after the twenty-second week of gestation and throughout the pregnancy, where fetal levels surpass maternal levels of IgG ,22. IgG1This is relevant to adalimumab, golimumab, and infliximab which are complete IgG1 anti-TNF antibodies, and to a smaller extent etanercept that only contains the IgG1 Fcportion. A summary of indications and transplacental transport of the different TNFi is listed in All three of these TNFi are complete IgG1 antibodies, thus transplacental transport is expected. An international multicenter prospective cohort study of 80 pregnant women with inflammatory bowel disease (IBD) who either received adalimumab or infliximab, found an inverse correlation between the time from last drug exposure during pregnancy and concentration in cord blood. Mean time for drug clearance in the infants was 4 months for adalimumab and 7.3 months for infliximab. The latter was detectable up to 12 months of age .Etanercept is comprised of the Fc domain of human IgG1 fused with the extracellular ligand binding domain of human tumor necrosis factor receptor-2. Transplacental transport via the neonatal Fc receptor would theoretically be plausible. However, a case report found an etanercept concentration ratio between maternal blood and umbilical cord blood of 14:1 at delivery, in a woman with ankylosing spondylitis receiving etanercept 25 mg subcutaneously once weekly during the second and third trimester . This suIn contrast to the complete IgG1 anti-TNF antibodies, infliximab, golimumab, and adalimumab, certolizumab pegol differs structurally as it is a humanized PEG (polyethylene glycol)-ylated antibody Fab’ fragment lacking the IgG1 Fc portion . WithoutThe current TNFi indicated for psoriasis and psoriasis arthritis are adalimumab, infliximab, golimumab, etanercept, and certolizumab pegol, respectively. The British Association of Dermatologists states in their guideline that decision making on treatment during pregnancy should be made on a case by case basis, with no defined gestational cutoff for drug discontinuation. The guideline underlines that live vaccination ) should be avoided in infants of mothers taking biologic therapy beyond gestational week 16 . Women with IBD are at increased risk of adverse maternal and neonatal outcomes if their disease is active during pregnancy. The European Crohn’s and Colitis Organization recommends in their consensus statement that these women are best treated appropriately and without delay. And if the disease activity allows it, treatment with TNFi should be discontinued around gestational week 24–26 .Consensus across these guidelines is that pregnant women with an inflammatory disease should receive multidisciplinary care involving a team with experience in handling women with active disease during pregnancy and in the postpartum period.Most TNFi safety studies have been conducted in indirect populations, such as women with IBD and rheumatoid arthritis, consequently no studies specifically address TNFi potential risk of harm in pregnant women with psoriasis or the outcomes in their infants .Previous safety studies often focus on composite adverse outcomes both regarding the pregnancy itself and the infant, but to a far less extent investigating the potential risks for the mother . AdversePreeclampsia is considered to be an exacerbation of the normal inflammatory response present in the last trimester of the pregnancy ,38. In aAdverse pregnancy outcomes have been examined in TNFi-exposed pregnancies and are often defined as spontaneous abortion, elective termination, ectopic pregnancies, intrauterine death, and still birth. A meta-analysis in TNFi-exposed women with IBD found that the rate of elective terminations was 17% compared to 0.02% in the background population. Spontaneous abortions were 12% in the TNFi-exposed pregnancies compared to 20% expected and there were no ectopic pregnancies or still births registered compared to a normal population incidence both of 1% . In contConfounding by indication—the fact that the disease itself and not necessarily the drug indicated for the disease, can cause a given adverse outcome—may be a part of the explanation to why higher rates of abortions are reported in women with chronic inflammatory diseases. Active disease at time of conception has been associated with increased rates of spontaneous abortions in women with IBD . And conThe words fetal and neonatal adverse outcomes are often used interchangeably and cover congenital malformations, preterm birth, low birth weight, small for gestational age, intrauterine growth retardation, respiratory distress syndrome, neonatal infections, admission to neonatal intensive care unit, and death. The most recent systematic review found a trend towards drug-specific harm with increased risk of major congenital malformations and preterm birth in infants of women with other chronic inflammatory diseases than psoriasis exposed to TNFi . SupportIn contrast, a 2016 meta-analysis found no increased risk of congenital malformations in TNFi-exposed women with IBD compared with disease-matched controls . FurtherLow birth weight is defined as a birth weight less than 2500 g. However, this definition does not take gestational age, sex, race, and clinical features into account . Thus, lThe presence and activity of TNF in both mother and fetus during pregnancy seems to play a leading role in the determination of birth weight. Increased maternal TNF-levels and placental TNF-production have been associated with low birth weight and IUGR ,39,44.A prospective observational multicenter cohort study, investigated pregnancy outcomes in women with chronic inflammatory diseases treated with TNFi compared to non-exposed non-disease matched random sampled pregnant women. They found a significantly increased risk of preterm birth and low birth weight in the exposed pregnancies. Unfortunately the control group was not disease-matched—hence the increased risks of adverse neonatal outcomes could either be due to the disease itself (confounding by indication) or a result of TNFi exposure . Contradicting these findings, a following meta-analysis found that TNFi treatment did not increase the risk of preterm birth nor low birth weight in children of women with IBD compared with disease-matched controls .Due to accelerated active transplacental transport in the second and third trimester, treatment with TNFi during pregnancy is hypothesized to lead to neonatal immunosuppression with increased risk of neonatal infections. A tragic case of neonatal death due to disseminated BCG infection occurred after BCG vaccination in an infant born to a mother treated with infliximab throughout pregnancy . FollowiHow fetal TNFi exposure potentially may alter the development of their immune system is poorly studied. A clinical immunology study from 2017 examined seven infants exposed to either adalimumab or infliximab throughout pregnancy. They presented more immature B- and Th cells that normalized within the first year of life. A decreased frequency of Tregs in the infants at birth was inversely correlated with maternal peripartum TNFi levels.Furthermore, a reduced response to mycobacteria was found and four infants developed atopic dermatitis within the first year of life. Esteve-Solé et al. hypothesized that the observed decrease in Tregs could facilitate hypersensitivity leading to atopy, and defects in interleukin 12/interferon-gamma pathways could make TNFi-exposed infants more susceptible to intracellular infections caused by e.g., mycobacteria such as the tuberculosis bacteria BCG .Contrasting these findings, an animal study in the macaque monkey exposed to golimumab throughout pregnancy showed no effect on T and B cells and a normal immune response to antigen challenge in the infants .Long-term safety of in utero exposure to TNFi is another concern with limited evidence despite nearly 20 years on the market . RelevanWith a mean follow-up of 4 years Chaparro et al.  found noTo our knowledge, only one case series (data reported to the American Food and Drug Administration) reports two cases of malignancies: leukemia (age 4) and neuroblastoma (less than 1 year old) in children exposed to TNFi in utero . No studies investigate adverse pregnancy outcomes in TNFi-exposed women with psoriasis  and veryThe current psoriasis guidelines refers to no gestational cutoff for TNFi discontinuation and emphasize that the decision should be made on a case by case basis .Chronic inflammatory diseases  are associates with adverse pregnancy outcomes ,19,36,37TNFi comprising of complete IgG1 antibodies  actively cross placenta from the second trimester and are detectable in the child up to one year postpartum ,22,23.Data on elective terminations and spontaneous abortions are conflicting, however TNFi treatment can yield a successful pregnancy in severe cases of IBD .TNFi-exposed infants of women with chronic inflammatory diseases trend towards drug-specific harm with increased risk of major congenital malformations and preterm birth ,30.TNFi exposure may alter the immune system of the infant towards hypersensitivity and reduced response to intracellular infections .Confounding by indication should be considered when studying adverse pregnancy outcomes in TNFi-treatment.The risks associated with TNFi-treatment must be balanced against the as-yet uncertain risks of adverse pregnancy outcomes in infants born to women with severe psoriasis ,51.Despite the growing numbers of observational studies regarding safety of TNFi in pregnancy, there still exists a critical gap in our knowledge specifically addressing safety in women with psoriasis and long-term outcomes in the exposed children. The available studies indicate the following: Major congenital malformations can occur due to exposure to teratogenic agents during the organogenesis from gestational week three to eight, whereas functional defects and minor malformations can occur during the fetal period week 9–38 . Adalimularge heterogeneity between studies—limiting generalizability of their findingsindirectness —thus findings may not be applicable to women with psoriasisimprecision with wide confidence intervals on adverse outcomesoften underpowered and some lacking disease-matched controls and multivariate adjustment.Safety assessment of treatment with TNFi during pregnancy is primarily based on observational studies, which inherently have low level of evidence. The current studies are weakened byUsing Grading of Recommendations Assessment, Development and Evaluation (GRADE) Pottinger et al.  classifiMore than a fifth of women with psoriasis experience a worsening of their skin symptoms during pregnancy leaving a potential need for treatment . Low- toFirst-line systemic therapies methotrexate and acitretin are contraindicated for women planning pregnancy due to their highly teratogenic effects. Cyclosporine has been associated with increased risk of maternal hypertension, low birth weight, and prematurity ,9.Interleukin (IL)-17 antagonists: secukinumab (IgG1 mAb), ixekizumab (IgG4 mAb), and brodalumab (IgG2 mAb)IL-12/23 antagonist: ustekinumab (IgG1 mAb)IL-23 antagonist: guselkumab (IgG1 mAb).Newer biologics indicated for psoriasis are: They are all IgG monoclonal antibodies, thus expected to be transported actively across placenta during the second trimester like the IgG TNFi adalimumab, golimumab, and infliximab. However, their mechanism of action are different from TNFi. Evaluation of newer biologics during pregnancy can be performed through retrospective post marketing non-interventional studies comparing them with TNFi.A case series described use of TNFi and the IL-12/23 antagonist, ustekinumab, with no adverse pregnancy outcomes or negative effects on the infants . Yet, nodisease-matched and healthy controlsadjustment for all drug use and confounders such as disease activity and patient demographicslong-term follow-up of >10 years to uncover potential immunological defects, lymphoid cancers, or mental and intellectual impairments among the exposed children.Although psoriasis can flare during pregnancy it rarely becomes an acute life-threatening condition. Thus, dermatologists experience that women with psoriasis often wish to discontinue systemic treatment prior to conception to avoid unnecessary drug exposure of the fetus. This notion is supported by a systematic review on drug survival of biologic treatment in psoriasis, which showed that pregnancy was a cited reason for drug discontinuation . This faOnly then, can we make an informed decision on treatment with TNFi during pregnancy based on sound evidence.We searched PubMed using the following MeSH terms (“psoriasis” OR “psoriasis arthritis” OR “psoriasis arthropathy”) AND  AND . We then identified meta-analysis, systemic reviews, narrative reviews, observational studies, and guidelines and selected relevant English-language publications based on their abstracts. Additionally, we found relevant guidelines and studies from the reference lists of the initially included publications.


Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease. Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy originating in the mesothelial cells of the pleural cavity. It is primarily caused by occupational or environmental inhalation exposure to asbestos, an abundant natural mineral with heat-resistance properties and low cost, which has been mined worldwide for over a century . FollowiThe immune system has been thought to play an important role in cancer surveillance and tumor rejection in humans , as evidThe clinical impact of the immune microenvironment has also been implicated in MPM. In preclinical studies, regulatory T cells (Tregs) and immunosuppressive soluble factors promote MPM tumor growth by blunting any antitumor immune responses . In an iThese findings stress the importance of understanding the dynamic associations between the pro-tumorigenic and anti-tumorigenic components of the MPM immune microenvironment. The interaction of these factors influences tumor growth, tumor progression, patient prognosis, and treatment response. This has led to the development of novel immunotherapeutic strategies aimed at activating the host’s immune system or overcoming components of the immunosuppressive tumor microenvironment. A number of recent clinical trials of immunotherapy, including intrapleural administration of an adenovirus expressing interferon alpha (Ad.IFNα), vaccination with a Wilm’s tumor-1 (WT-1) peptide analogue, the use of a dendritic cell vaccine, and anti-PD1 antibody treatment have suggested efficacy ,16,17,18Adoptive Cell Therapy (ACT) is defined as the isolation of a patient’s own leukocytes  that are expanded ex vivo, and then re-infused into to the patient. The concept behind ACT is that the re-infused tumor-reactive T cells will recognize and bind to tumor-associated antigens (TAAs) on the tumor cell surface, thus destroying the cancer cells. Early successes in melanoma patients were achieved by isolating autologous T cells from tumor biopsy specimens and rapidly expanding the most active TIL cultures screened for the greatest antitumor activity . RosenbeChimeric antigen receptors are fused receptors engineered to provide antigen specificity to T cells against TAAs on the cell surface of target cells. CARs can bind directly to an expanded range of cell surface targets including lipids, carbohydrates, or proteins .“First-generation” CARs consisted of an extracellular domain that bound the tumor antigen via a single-chain variable antibody fragment (scFv) that was fused to a CD3ζ intracellular activating domain . After aOnce constructed, CARs can be transduced into autologous T cells using viral  or non-viral (transposon) gene transfer systems  to achieA requirement for successful CAR T cell therapy, however, is a specific and highly expressed candidate TAA. In MPM, two such candidate target TAAs are currently being investigated in clinical trials: mesothelin, which is overexpressed on the tumor cells, and fibroblast activation protein (FAP) that is overexpressed on tumor stromal cells.Overexpressed differentiation antigens are attractive targets for CAR T cell therapy because they are expressed at low levels on normal tissues while being pathologically expressed at high levels on cancer cells. Mesothelin is one such cell-surface glycoprotein that is expressed at low levels on normal mesothelial cells of the pleura, pericardium, peritoneum, and tunica vaginalis, whereas it is overexpressed in the majority of MPM, lung, pancreatic, and ovarian carcinomas . MesotheMesothelin CARs have been and are currently being investigated in multiple Phase I clinical trials . Based on potent anti-tumor effects observed in preclinical studies using mRNA electroporation , an initInvestigators at the Memorial Sloan Kettering are also conducting an MPM clinical trial using mesothelin CAR T cells (NCT02414269). Their approach is based on preclinical studies in an orthotopic MPM mouse model showing potent and long-lasting antitumor efficacy of intrapleurally administered mesothelin CAR T-cell therapy . This PhIn addition to tumor-cell-specific antigens, it has been proposed that CARs that target essential components of the tumor-associated stroma, such as fibroblasts or endothelial cells, might also be valuable to enhance anti-tumor activity. There are multiple potential advantages to this approach: (1) stromal cells are more genetically stable and less likely to lose antigen expression, (2) attacking the stromal components may alter the tumor microenvironment to improve standard chemotherapeutic or ACT efficacy, and (3) it could be used on multiple different tumor types. Two proposed stromal candidates are fibroblast activation protein (FAP) and vascular endothelial growth factor receptor 2 (VEGFR2). FAP, a transmembrane serine protease, is highly expressed in the cancer-associated stromal cells (CASCs) of virtually all epithelial cancers with low expression on normal cells . FAP is Preclinical studies have demonstrated that CAR T cells targeted to murine FAP have anti-tumor efficacy in subcutaneous MPM models with minimal toxicity . An antiIn a recently published study, Klampatsa et al. investigated the efficiency of a CAR targeting the four members of the ErbB family  in MPM . They fiThe oncofetal cell surface glycoprotein, 5T4, is overexpressed in numerous malignancies, including testicular, breast and colon cancer, while its expression in normal tissues is restricted to specialized epithelial cells . RecentlThe cell surface proteoglycan chondroitin sulfate proteoglycan 4 (CSPG4) has been found to be overexpressed MPM where it has been reported that CSPG4 was overexpressed in six out of eight MPM cell lines, and in 25 out of 41 MPM biopsies . In 2014To date, the success of CAR T cells seen in hematologic malignancies has not yet been reproduced in solid tumors and successful MPM treatment with CAR T cells will doubtlessly be challenging. This will be due to multiple mechanisms that include poor trafficking of cells into the tumors, CAR T cell suppression due to soluble mediators , the upregulation of checkpoint inhibitors (such as PD1) on the CARs, and CAR suppression due to intrinsic inhibitory T cell programs . In addiAccordingly, many groups are already anticipating these problems and are developing approaches to overcome these hurdles. Strategies include systemic drugs that may affect immune function in general, such as the use of checkpoint blockade using antibodies , inhibitThe ability to genetically manipulate CARs allows the possibility of generating “better” CARs by inserting or removing specific genes, thus adding an additional level of opportunity and excitement. As examples, TGFβ inhibition has been blocked by expressing a decoy receptor , PD1-indWith an ever-evolving understanding of tumor biology and the recent exciting advances in tumor immunology, the use of the body’s own defense systems to fight disease is more current and relevant than ever. The exciting successes seen in hematologic malignancies have prompted development of CAR T cell therapy for solid tumors, such as MPM. Clinical trials of CARs for use in mesothelioma are underway. The results of these trials will be used to iteratively improve the next series of trials, eventually leading, it is hoped, to adoptive T cell transfer as an important part of the MPM therapeutic armamentarium.