Long-term and rapid evolution in powdery mildew fungi.

The powdery mildew fungi (Erysiphaceae) are globally distributed plant pathogens with a range of more than 10,000 plant hosts. In this review, we discuss the long- and short-term evolution of these obligate biotrophic fungi and outline their diversity with respect to morphology, lifestyle, and host range. We highlight their remarkable ability to rapidly overcome plant immunity, evolve fungicide resistance, and broaden their host range, for example, through adaptation and hybridization. Recent advances in genomics and proteomics, particularly in cereal powdery mildews (genus Blumeria), provided first insights into mechanisms of genomic adaptation in these fungi. Transposable elements play key roles in shaping their genomes, where even close relatives exhibit diversified patterns of recent and ongoing transposon activity. These transposons are ubiquitously distributed in the powdery mildew genomes, resulting in a highly adaptive genome architecture lacking obvious regions of conserved gene space. Transposons can also be neofunctionalized to encode novel virulence factors, particularly candidate secreted effector proteins, which may undermine the plant immune system. In cereals like barley and wheat, some of these effectors are recognized by plant immune receptors encoded by resistance genes with numerous allelic variants. These effectors determine incompatibility ("avirulence") and evolve rapidly through sequence diversification and copy number variation. Altogether, powdery mildew fungi possess plastic genomes that enable their fast evolutionary adaptation towards overcoming plant immunity, host barriers, and chemical stress such as fungicides, foreshadowing future outbreaks, host range shifts and expansions as well as potential pandemics by these pathogens.

Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis.

BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFα inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL-12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89-1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest.

Disease-Modifying Therapies for Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Cost-Utility Analysis.

BACKGROUND: Several disease-modifying therapies (DMTs) treat relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Few comprehensive cost-effectiveness analyses exist in this area, particularly from a payer perspective, despite rapidly increasing prices of DMTs. OBJECTIVE: We aimed to systematically compare cost effectiveness of all relevant DMTs for first-line treatment of RRMS, second-line treatment of RRMS, and first-line treatment of PPMS. METHODS: We used a Markov model with health states based on Expanded Disability Status Score categories. Upon discontinuing first-line treatment, RRMS patients continued to second-line therapy then to supportive care, and PPMS patients moved directly to supportive care. Data was sourced from clinical trials and commercially and publicly available sources. The target population was treatment-naïve adults with RRMS or PPMS. We used a lifetime horizon from a US payer perspective, and compared DMTs for RRMS (first-line: dimethyl fumarate, glatiramer acetate, interferon ß-1a, interferon ß-1b, peginterferon ß-1a, teriflunomide, natalizumab, fingolimod, and ocrelizumab; second-line: alemtuzumab, natalizumab, fingolimod, and ocrelizumab), ocrelizumab for PPMS, and supportive care. Outcome measures included total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: For RRMS first-line therapy, ocrelizumab dominated the other DMTs with an ICER of US$166,338/QALY compared with supportive care. For RRMS second-line therapy, alemtuzumab dominated the other three DMTs, providing more QALYs for lower costs. For PPMS, ocrelizumab had an ICER of US$648,799/QALY compared with supportive care. Wide variability in results was observed in the probabilistic sensitivity analysis. Results were sensitive to the relative risk of progression and cost of DMTs. CONCLUSIONS: Ocrelizumab would likely be cost effective as a first-line treatment for RRMS with a discounted price but was not cost effective for PPMS. Alemtuzumab dominated other options for second-line treatment of RRMS. Other DMTs were generally similar in terms of costs and health outcomes, providing health benefits compared to supportive care but with significant added costs. If drug prices were lowered, more DMTs could be cost effective.

Comparative effectiveness of targeted immunomodulators for the treatment of moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis.

BACKGROUND: The comparative effectiveness of available targeted immunomodulators for moderate-to-severe psoriasis has not been evaluated. OBJECTIVE: To evaluate the comparative effectiveness of targeted immunomodulators for adults with moderate-to-severe plaque psoriasis. METHODS: Systematic literature review of placebo-controlled and head-to-head randomized trials of 8 targeted immunomodulators that evaluated clinical benefits or harm. The primary outcome was a 75% improvement on the Psoriasis Area and Severity Index. We also conducted a network meta-analysis adjusted for placebo response to perform indirect comparisons between agents. RESULTS: In the network meta-analysis, the targeted immunomodulators ordered by increasing relative risk (demonstrating greater likelihood) of achieving a 75% improvement on the Psoriasis Area and Severity Index relative to placebo were as follows: apremilast (6.2), etanercept (9.6), adalimumab (13.0), ustekinumab (14.0), secukinumab (15.4), infliximab (16.2), brodalumab (17.3), and ixekizumab (17.9). Ixekizumab, brodalumab, and infliximab were all statistically superior to ustekinumab, adalimumab, etanercept, and apremilast; results were similar to those of head-to-head studies where data were available. LIMITATIONS: Much of the evidence is short-term (covering 10-16 weeks); limited direct comparisons. CONCLUSIONS: The interleukin 17A inhibitors are more effective in achieving clearance than ustekinumab, and they are generally more effective than etanercept, adalimumab, and apremilast.

Long-term clinical impact and cost-effectiveness of obeticholic acid for the treatment of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune liver disease that mainly affects middle-aged women. Obeticholic acid (OCA), which was recently approved by the Food and Drug Administration for PBC treatment, has demonstrated positive effects on biochemical markers of liver function. Our objective was to evaluate the long-term clinical impact and cost-effectiveness of OCA as a second-line treatment for PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA. We developed a mathematical model to simulate the lifetime course of PBC patients treated with OCA+UDCA versus UDCA alone. Efficacy data were derived from the phase 3 PBC OCA International Study of Efficacy trial, and the natural history of PBC was informed by published clinical studies. Model outcomes were validated using the PBC Global Study. We found that in comparison with UDCA, OCA+UDCA could decrease the 15-year cumulative incidences of decompensated cirrhosis from 12.2% to 4.5%, hepatocellular carcinoma from 9.1% to 4.0%, liver transplants from 4.5% to 1.2%, and liver-related deaths from 16.2% to 5.7% and increase 15-year transplant-free survival from 61.1% to 72.9%. The lifetime cost of PBC treatment would increase from $63,000 to $902,000 (1,330% increment). The discounted quality-adjusted life years with UDCA and OCA+UDCA were 10.74 and 11.78, respectively, and the corresponding costs were $142,300 and $633,900, resulting in an incremental cost-effectiveness ratio of $473,400/quality-adjusted life year gained. The results were most sensitive to the cost of OCA. CONCLUSION: OCA is a promising new therapy to substantially improve the long-term outcomes of PBC patients, but at its current annual price of $69,350, it is not cost-effective using a willingness-to-pay threshold of $100,000/quality-adjusted life year; pricing below $18,450/year is needed to make OCA cost-effective. (Hepatology 2017;65:920-928).