Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study.

BACKGROUND: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. METHODS: We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). FINDINGS: Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. INTERPRETATION: More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. FUNDING: Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

Identifying a patient-centered outcome measure for a comparative effectiveness treatment trial in myasthenia gravis.

INTRODUCTION/AIMS: Data regarding the comparative effectiveness of myasthenia gravis (MG) treatments is not available. We used patient input to identify a patient-centered outcome measure (PCOM) for PROMISE-MG, a comparative effectiveness trial of MG treatments. METHODS: First, a questionnaire survey was administered to 58 people with MG at the patient meeting of the Myasthenia Gravis Foundation of America (MGFA), evaluating the impact of MG-related symptoms and MG treatments on patients' lives. Second, an online focus group of 13 patients with MG was conducted. Third, a potential outcome measure was selected. Fourth, the selected PCOM was evaluated by patients to assess how completely and accurately it captured their experiences with MG. RESULTS: The patient survey showed that limb weakness had the most impact on patients' lives. Weight gain, mood swings, insomnia, and diarrhea were the most bothersome treatment side effects. Avoiding hospitalization was very important. Focus group participants reported fatigue as one of the most bothersome symptoms and differentiated it from myasthenic weakness. They defined an ideal treatment as having minimal or no side effects and an 80% improvement in symptoms. DISCUSSION: Based on patient input, the 15-item Myasthenia Gravis Quality of Life-Revised (MG-QOL15R) scale, a validated patient-reported outcome measure (PRO), was selected as the primary PCOM for PROMISE-MG. Avoiding hospitalization and having minimal to no treatment adverse effects were selected as additional outcome measures. The patient-centeredness of a PRO depends on the context of a study: PROs should be evaluated for appropriateness as a PCOM for every study.

Is a Right Angle the Right Angle? Normal Coronal Radiographic Alignment in the Pediatric Finger Phalanges.

BACKGROUND: Quantifying pediatric phalanx fracture displacement requires understanding the normal radiographic alignment of pediatric phalanges, which has never been assessed in the coronal plane, although prior studies have assumed the articular surfaces and physes to be perpendicular to the diaphyses. This study tests the hypothesis that these relationships are not uniformly perpendicular and instead vary by digit and age. METHODS: Normal hand bone age radiographs were retrospectively reviewed from 40 males and 40 females 2 to 18 years old. For each finger proximal phalanx (P1) and middle phalanx (P2), 2 raters each measured twice the angle between the diaphysis and distal articular surface (D-DA), diaphysis and physis (D-P, when physis present), and diaphysis and proximal articular surface (D-PA). Intra-rater and inter-rater reliability were calculated with intraclass correlation coefficients. 95% confidence intervals were calculated for each angle for each digit, phalanx, age group, and sex to determine which angles ~90 degrees. Variability among ages and sex was assessed with analysis of variance. RESULTS: Intra-rater and inter-rater intraclass correlation coefficients were >0.90, except in P2 ∠D-DA in children under 8 years old with unossified P2 condyles. Overall, only 173 (47.8%) of 362 confidence intervals included 90 degrees. Three angles of the small finger (P1 ∠D-DA, P2 ∠D-P, P2 ∠D-PA) never ~90 degrees at any age or sex, with an average 10 degrees ulnar tilt of the small finger proximal interphalangeal joint. Of the 24 angles across digits and phalanges, 10 varied significantly with age, especially in the index and middle finger P1 where initially wedge-shaped epiphyses progressively became more symmetric with age. CONCLUSIONS: The coronal radiographic angles between the phalangeal diaphyses and articular surfaces or physes differ from 90 degrees more than half the time in pediatric fingers, and nearly half the angles vary by age. These findings demonstrate that the articular surfaces and physes of the pediatric finger phalanges are not uniformly perpendicular to the diaphyses, underscoring the need to consider the variability among digits, phalanges, ages and subjects. LEVEL OF EVIDENCE: Level IV.

DNA polymerase θ specializes in incorporating synthetic expanded-size (xDNA) nucleotides.

DNA polymerase θ (Polθ) is a unique A-family polymerase that is essential for alternative end-joining (alt-EJ) of double-strand breaks (DSBs) and performs translesion synthesis. Because Polθ is highly expressed in cancer cells, confers resistance to ionizing radiation and chemotherapy agents, and promotes the survival of homologous recombination (HR) deficient cells, it represents a promising new cancer drug target. As a result, identifying substrates that are selective for this enzyme is a priority. Here, we demonstrate that Polθ efficiently and selectively incorporates into DNA large benzo-expanded nucleotide analogs (dxAMP, dxGMP, dxTMP, dxAMP) which exhibit canonical base-pairing and enhanced base stacking. In contrast, functionally related Y-family translesion polymerases exhibit a severely reduced ability to incorporate dxNMPs, and all other human polymerases tested from the X, B and A families fail to incorporate them under the same conditions as Polθ. We further find that Polθ is inhibited after multiple dxGMP incorporation events, and that Polθ efficiency for dxGMP incorporation approaches that of native dGMP. These data demonstrate a unique function for Polθ in incorporating synthetic large-sized nucleotides and suggest the future possibility of the use of dxG nucleoside or related prodrug analogs as selective inhibitors of Polθ activity.

Simulating Serial-Target Antibacterial Drug Synergies Using Flux Balance Analysis.

Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts cannot predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of the most widely used antibiotic treatments. Here we extend FBA modeling to simulate responses to chemical inhibitors at varying concentrations, by diverting enzymatic flux to a waste reaction. This flux diversion yields very similar qualitative predictions to prior methods for single target activity. However, we find very different predictions for combinations, where flux diversion, which mimics the kinetics of competitive metabolic inhibitors, can explain serial target synergies between metabolic enzyme inhibitors that we confirmed in Escherichia coli cultures. FBA flux diversion opens the possibility for more accurate genome-scale predictions of drug synergies, which can be used to suggest treatments for infections and other diseases.

Health Insurance Paid Costs and Drivers of Costs for Patients With Crohn's Disease in the United States.

OBJECTIVES: The cost of medical care for Crohn's disease (CD) and comorbidities in the era of biologics is unclear. We examined insurance claims data from US health plans to understand this relationship. METHODS: Longitudinal CD patient data and reimbursement information from 11 health plans engaged with Accordant Health Services between 2011 and 2013 were analyzed. The analysis considered data for all CD patients and for the patient subgroup ≤20 years and >20 years of age. Descriptive statistics measured the mean health-plan paid costs per patient, the relative cost contribution of anti-tumor necrosis factor (TNF) agents, and health care costs for 31 specific comorbid conditions among CD patients. RESULTS: Overall, there were 5,090 CD patients (57% women) of which 587 CD patients were ≤20 years of age. The mean health-plan paid cost per member per year was $18,637 (s.d. $32,023) for all CD patients, $22,796 (s.d. $ 41,905) for CD patients ≤20 years, and $18,095 (s.d. $30,065) for patients >20 years of age. Twenty-eight percent of CD patients accounted for 80% of total costs. No differences were found in costs based on gender. Increased health-plan paid costs were significantly correlated with the number of comorbid conditions across all ages. Pharmacy utilization costs account for nearly one-half (45.5%) of the total CD-attributable costs, exceeding inpatient care costs. Anti-TNF agents alone comprised nearly one-third (29.5%) of total costs. Aside from anti-TNF costs, other major categories of expense were as follows: inpatient 23.1%, outpatient hospital setting 15.7%, and MD office 8.2%. CONCLUSIONS: Total health-care costs in CD exceed previous estimates, with the majority of costs being allocated to a relatively small subgroup of patients. Pharmacy utilization costs, owing to anti-TNF use, result in increasing total health-care costs and currently exceed costs for inpatient care. Pragmatic strategies to encourage gastroenterologists in the best clinical practice of optimizing anti-TNF use-in particular for younger age patients and those with multiple comorbidities-are necessary to reduce avoidable pharmacy utilization and inpatient care costs.

Covalent Modification of Synthetic Hydrogels with Bioactive Proteins via Sortase-Mediated Ligation.

Synthetic extracellular matrices are widely used in regenerative medicine and as tools in building in vitro physiological culture models. Synthetic hydrogels display advantageous physical properties, but are challenging to modify with large peptides or proteins. Here, a facile, mild enzymatic postgrafting approach is presented. Sortase-mediated ligation was used to conjugate human epidermal growth factor fused to a GGG ligation motif (GGG-EGF) to poly(ethylene glycol) (PEG) hydrogels containing the sortase LPRTG substrate. The reversibility of the sortase reaction was then exploited to cleave tethered EGF from the hydrogels for analysis. Analyses of the reaction supernatant and the postligation hydrogels showed that the amount of tethered EGF increases with increasing LPRTG in the hydrogel or GGG-EGF in the supernatant. Sortase-tethered EGF was biologically active, as demonstrated by stimulation of DNA synthesis in primary human hepatocytes and endometrial epithelial cells. The simplicity, specificity, and reversibility of sortase-mediated ligation and cleavage reactions make it an attractive approach for modification of hydrogels.

Patient demographics and health plan paid costs in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: We determined health plan paid costs and healthcare resource usage of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: CIDP patients from 9 U.S. commercial health plans with claims in 2011 were identified from the Accordant Health Services claims database. We examined demographics, prevalence of comorbidities, prescribed drugs, place of service, and mean annual health plan paid costs per patient. RESULTS: From 6.5 million covered lives, 73 (56% men; mean age 47) met study entry criteria. The most prescribed therapies were intravenous immunoglobulin (IVIg) (26% of patients), gabapentin (26%), and prednisone (16%). The annual health plan paid cost was $56,953. Pharmacy cost was the major cost driver (57% of the total), and IVIg totaled 90% of the pharmacy costs. CONCLUSIONS: Healthcare costs for CIDP patients are substantial, with a large burden in pharmacy usage. Studies are needed to determine optimal long-term treatment strategies for CIDP, particularly related to IVIg.

Tailoring chimeric ligands for studying and biasing ErbB receptor family interactions.

Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR-HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance-dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor-mediated cell signaling pathways.

The Mycobacterium tuberculosis regulatory network and hypoxia.

We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory network based on 50 transcription factors. This network model revealed a direct interconnection between the hypoxic response, lipid catabolism, lipid anabolism and the production of cell wall lipids. As a validation of this model, in response to oxygen availability we observe substantial alterations in lipid content and changes in gene expression and metabolites in corresponding metabolic pathways. The regulatory network reveals transcription factors underlying these changes, allows us to computationally predict expression changes, and indicates that Rv0081 is a regulatory hub.

Fluorescent amino acids: modular building blocks for the assembly of new tools for chemical biology.

Fluorescence spectroscopy is a powerful tool for probing complex biological processes. The ubiquity of peptide-protein and protein-protein interactions in these processes has made them important targets for fluorescence labeling, and to allow sensitive readout of information concerning location, interactions with other biomolecules, and macromolecular dynamics. This review describes recent advances in design, properties and applications in the area of fluorescent amino acids (FlAAs). The ability to site-selectively incorporate fluorescent amino acid building blocks into a protein or peptide of interest provides the advantage of closely retaining native function and appearance. The development of an array of fluorescent amino acids with a variety of properties, such as environment sensitivity, chelation-enhanced fluorescence, and profluorescence, has allowed researchers to gain insights into biological processes, including protein conformational changes, binding events, enzyme activities, and protein trafficking and localization.

Health plan paid cost of epilepsy in 2009 in the U.S.

Our objectives were to estimate the health plan paid cost of epilepsy and to show major cost driver(s) of these costs. The health insurance claims and membership data from six U.S. health plans were analyzed. To prepare two comparison groups, individuals with epilepsy (n=5810) were match-paired with individuals without epilepsy (n=5810) using propensity scores derived from logistic regression using gender, age group, health plan product, and length of enrollment in the health plans. Total health plan paid cost per member per year (PMPY) was $11,232 for the epilepsy group and $3026 for the controls (p<0.001). The estimated cost PMPY for treatment of epilepsy was $8206. Relative distribution (%) of health plan paid costs ($) by cost driver category based on place of service (POS) indicated that the treatment of epilepsy places a larger cost burden in inpatient POS than in outpatient hospital or MD office POS compared to controls.

Estimated cost of treating myasthenia gravis in an insured U.S. population.

INTRODUCTION: In this study we estimated the costs paid by U.S. health plans for treating myasthenia gravis (MG) in 2009 and determined the major cost drivers. METHODS: One hundred thirteen MG patients were matched by propensity scores with 339 non-MG patients from a comprehensive health-care insurance database. The mean annual costs paid by the health plan for treating MG, costs by place of service, and costs for intravenous immunoglobulin (IVIg) and plasma exchange were determined. RESULTS: Mean annual costs paid by the health plan per MG patient were $20,190 (SEM $4,763) and costs attributable to treating MG were $15,675. Home health services accounted for 23% of MG patient costs and represented almost exclusively IVIg infusion costs. Six MG patients had a total of 136 outpatient IVIg infusions at an average annual cost of $109,463 ± $57,303. CONCLUSIONS: The estimated annual health plan paid costs for treating MG were $15,675. Home health services represented 23% of MG patient costs, largely driven by IVIg administration.

Cost analysis of myasthenia gravis from a large U.S. insurance database.

INTRODUCTION: Little is known about the costs of managing rare diseases, and comprehensive healthcare costs have not been reported for myasthenia gravis (MG). We evaluated the direct costs and healthcare resource utilization in insured MG patients. METHODS: Costs were obtained from 1288 patients diagnosed with MG who were identified from the Accordant Health Services nationwide medical and pharmacy claims database. RESULTS: Average annual medical/pharmacy claims costs per patient were: $6710/$1196 (age 0-19 years); $17,949/$19,573 (20-39 years); $15,112/$12,498 (40-64 years); and $12,597/$8,089 (65(+) years). Total annual MG-related pharmacy costs were $9.4 million; IVIg accounted for 85% of all MG-related pharmacy costs. Non-steroidal immunosuppressives, cholinesterase inhibitors, and corticosteroids accounted for 9.3%, 5.7%, and 0.2% of pharmacy costs, respectively. CONCLUSIONS: Costs related to the treatment of MG are higher than those of many other chronic neurological diseases. A large percentage of costs result from IVIg use, particularly among a subset of patients who receive frequent IVIg infusions.

Encoding phenotype in bacteria with an alternative genetic set.

An unnatural base-pair architecture with base pairs 2.4 Å larger than the natural DNA-based genetic system (xDNA) is evaluated for its ability to function like DNA, encoding amino acids in the context of living cells. xDNA bases are structurally analogous to natural bases but homologated by the width of a benzene ring, increasing their sizes and resulting in a duplex that is wider than native B-DNA. Plasmids encoding green fluorescent protein were constructed to contain single and multiple xDNA bases (as many as eight) in both strands and were transformed into Escherichia coli. Although they yielded fewer colonies than the natural control plasmid, in all cases in which a modified plasmid (containing one, two, three, or four consecutive size-expanded base pairs) was used, the correct codon bases were substituted, yielding green colonies. All four xDNA bases (xA, xC, xG, and xT) were found to encode the correct partners in the replicated plasmid DNA, both alone and in longer segments of xDNA. Controls with mutant cell lines having repair functions deleted were found to express the gene correctly, ruling out repair of xDNA and confirming polymerase reading of the unnatural bases. Preliminary experiments with polymerase deletion mutants suggested combined roles of replicative and lesion-bypass polymerases in inserting correct bases opposite xDNA bases and in bypassing the xDNA segments. These experiments demonstrate a biologically functioning synthetic genetic set with larger-than-natural architecture.

Fluorescent xDNA nucleotides as efficient substrates for a template-independent polymerase.

Template independent polymerases, and terminal deoxynucleotidyl transferase (TdT) in particular, have been widely used in enzymatic labeling of DNA 3'-ends, yielding fluorescently-labeled polymers. The majority of fluorescent nucleotides used as TdT substrates contain tethered fluorophores attached to a natural nucleotide, and can be hindered by undesired fluorescence characteristics such as self-quenching. We previously documented the inherent fluorescence of a set of four benzo-expanded deoxynucleoside analogs (xDNA) that maintain Watson-Crick base pairing and base stacking ability; however, their substrate abilities for standard template-dependent polymerases were hampered by their large size. However, it seemed possible that a template-independent enzyme, due to lowered geometric constraints, might be less restrictive of nucleobase size. Here, we report the synthesis and study of xDNA nucleoside triphosphates, and studies of their substrate abilities with TdT. We find that this polymerase can incorporate each of the four xDNA monomers with kinetic efficiencies that are nearly the same as those of natural nucleotides, as measured by steady-state methods. As many as 30 consecutive monomers could be incorporated. Fluorescence changes over time could be observed in solution during the enzymatic incorporation of expanded adenine (dxATP) and cytosine (dxCTP) analogs, and after incorporation, when attached to a glass solid support. For (dxA)(n) polymers, monomer emission quenching and long-wavelength excimer emission was observed. For (dxC)(n), fluorescence enhancement was observed in the polymer. TdT-mediated synthesis may be a useful approach for creating xDNA labels or tags on DNA, making use of the fluorescence and strong hybridization properties of the xDNA.

Toward a designed genetic system with biochemical function: polymerase synthesis of single and multiple size-expanded DNA base pairs.

The development of alternative architectures for genetic information-encoding systems offers the possibility of new biotechnological tools as well as basic insights into the function of the natural system. In order to examine the potential of benzo-expanded DNA (xDNA) to encode and transfer biochemical information, we carried out a study of the processing of single xDNA pairs by DNA Polymerase I Klenow fragment (Kf, an A-family sterically rigid enzyme) and by the Sulfolobus solfataricus polymerase Dpo4 (a flexible Y-family polymerase). Steady-state kinetics were measured and compared for enzymatic synthesis of the four correct xDNA pairs and twelve mismatched pairs, by incorporation of dNTPs opposite single xDNA bases. Results showed that, like Kf, Dpo4 in most cases selected the correctly paired partner for each xDNA base, but with efficiency lowered by the enlarged pair size. We also evaluated kinetics for extension by these polymerases beyond xDNA pairs and mismatches, and for exonuclease editing by the Klenow exo+ polymerase. Interestingly, the two enzymes were markedly different: Dpo4 extended pairs with relatively high efficiencies (within 18-200-fold of natural DNA), whereas Kf essentially failed at extension. The favorable extension by Dpo4 was tested further by stepwise synthesis of up to four successive xDNA pairs on an xDNA template.

Therapeutic selectivity and the multi-node drug target.

Drug combinations are an increasingly favored strategy for increasing therapeutic windows for potential drugs, but enthusiasm for this approach is tempered by concerns that therapeutic synergy will too often be mirrored by synergistic toxicity. Here we review our recent experimental results and numerical simulations that establish the context-specificity of synergistic combinations. Thus systematic testing of chemical combinations in cell-based disease models can preferentially discover synergies with beneficial therapeutic selectivity. For an anti-inflammatory combination, we demonstrate how such selective synergy is achieved through differential expression of its targets in cells associated with therapeutic and toxic effects, and validate the combination's therapeutic relevance in animals. The narrower context specificity of synergistic combinations creates many new opportunities for such therapeutically relevant selectivity, and reinforces the realization that the most useful paradigm for a drug target is often a set of biomolecules that cooperate to produce a therapeutic response with reduced side effects.

Synergistic drug combinations tend to improve therapeutically relevant selectivity.

Drug combinations are a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects that limit the utility of many potential drugs. However, enthusiasm for this approach is tempered by concerns that the therapeutic synergy of a combination will be accompanied by synergistic side effects. Using large scale simulations of bacterial metabolism and 94,110 multi-dose experiments relevant to diverse diseases, we provide evidence that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities. We highlight six combinations whose selective synergy depends on multitarget drug activity. For one anti-inflammatory example, we show how such selectivity is achieved through differential expression of the drugs' targets in cell types associated with therapeutic, but not toxic, effects and validate its therapeutic relevance in a rat model of asthma. The context specificity of synergistic combinations creates many opportunities for therapeutically relevant selectivity and enables improved control of complex biological systems.