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BACKGROUND: Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among individuals of African ancestries. OBJECTIVE: We tested whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. DESIGN: Retrospective cohort study. SETTING: Two tertiary care centers. PATIENTS: Thiopurines users with White or Black race. MEASUREMENTS: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted last dose, white blood cell (WBC) and delta WBC counts. RESULTS: The discontinuation rate of azathioprine attributed to hematopoietic toxicity was 3.92/100 person-years among patients with the CC genotype (n=101) and 1.34/100 person-years among patients without the CC genotype (n=1,365) [hazard ratio (HR)=2.92, 95%CI: 1.57–5.41, competing hazards model]. The risk remained significant when adjusted by race (HR=2.61, 1.01–6.71). The risk associated with race alone (HR=2.13, 1.21–3.75) was abrogated by adjustment for genotype (HR=1.13, 0.48–2.69). Lower dosing and other secondary outcomes, except delta WBC count, were significant among patients who did not discontinue for hematopoietic toxicity. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia (ALL). The CC genotype was independently associated with lower 6-MP intensity dosages relative to the target daily dose—75 mg/m(2) (CC: median 0.83 interquartile range [0.70–0.94] vs TT or TC: 0.94 [0.73–1.13], P=0.013). LIMITATIONS: Unmeasured confounding. Data limited to tertiary centers. CONCLUSION: Patients with the CC genotype faced higher risk for discontinuation for attributed hematopoietic toxicity and lower doses. Genotype, even adjusted for race, is associated with those risks. PRIMARY FUNDING SOURCE: National Institutes of Health

ImportanceTwo risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whetherAPOL1high-risk genotypes are associated with either progression from infection to sepsis or sepsis-related phenotypes, independent of their association with severe renal disease.ObjectiveTo examine the association betweenAPOL1high-risk genotypes and the risk of progression from infection to sepsis and sepsis-related phenotypes.Design, setting, and participantsA retrospective cohort study of 2,242 Black patients hospitalized with an infection.ExposuresCarriage ofAPOL1high-risk genotypes.Main outcomes and measuresThe primary outcome was sepsis; secondary outcomes were death and organ failure related to sepsis.ResultsOf 2,242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-riskAPOL1genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00–1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR=1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR=0.99 [95% CI, 0.70-1.39; p=0.95].APOL1high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR=1.64 [95% CI, 1.21–2.22; p=0.001], but not with other sepsis-related organ dysfunction or death. The association between high-riskAPOL1genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR=1.36 [95% CI, 1.00–1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR=1.16 [95% CI, 0.74–1.81; p=0.52]).Conclusion and relevanceAPOL1high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing renal disease.

Polymorphisms thiopurine-S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) can increase the risk of azathioprine myelotoxicity, but little is known about other genetic factors that increase risk for azathioprine-associated side effects. PrediXcan is a gene-based association method that estimates the expression of individuals’ genes and examines their correlation to specified phenotypes. As proof of concept for using PrediXcan as a tool to define the association between genetic factors and azathioprine side effects, we aimed to determine whether the genetically predicted expression of TPMT or NUDT15 was associated with leukopenia or other known side effects. In a retrospective cohort of 1364 new users of azathioprine with EHR-reported White race, we used PrediXcan to impute expression in liver tissue, tested its association with pre-specified phecodes representing known side effects (e.g., skin cancer), and completed chart review to confirm cases. Among confirmed cases, patients in the lowest tertile (i.e., lowest predicted) of TPMT expression had significantly higher odds of developing leukopenia (OR=3.30, 95%CI: 1.07-10.20, p=0.04) versus those in the highest tertile; no other side effects were significant. The results suggest that this methodology could be deployed on a larger scale to uncover associations between genetic factors and drug side effects for more personalized care.

Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.

Background Blood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden. Methods We studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients’ characteristics. Results Patients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8–11.8%) than the control group 9.2% (7.4–11.2%), P Conclusion Patients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.

Tizanidine, a widely used muscle relaxant that can lower blood pressure, is metabolized by the cytochrome P450 1A2 (CYP1A2). We studied 1,626 patients prescribed tizanidine and 5,012 prescribed cyclobenzaprine concurrently with a strong CYP1A2 inhibitor. The primary outcome was severe hypotension, defined as systolic blood pressure (SBP) ≤ 70 mmHg during periods of drug co-exposure. Severe hypotension occurred more often in the tizanidine group (2.03%; n = 33) than the cyclobenzaprine group (1.28%; n = 64); odds ratio (OR) = 1.60; P = 0.029. This difference remained statistically significant after adjustment for a log-transformed propensity score that included age, sex, race, Charlson's comorbidity index, and concurrent use of antihypertensive medications (OR = 1.57; P = 0.049). A sensitivity analysis that defined hypotension as SBP < 90 mmHg also yielded higher rates of hypotension among patients prescribed tizanidine. In conclusion, CYP1A2 inhibition increases the risk of hypotensive episodes associated with the use of tizanidine in routine clinical practice.

Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95%CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models one, two, three and four, respectively. During the replication phase, models two and four (AUC=0.64, 95%CI: 0.59-0.70 and AUC=0.63, 95%CI: 0.58-0.69, respectively) were significant in an independent group. Compared to TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.

OBJECTIVE To compare the risk of resistant hypertension (RHTN) in patients with systemic lupus erythematosus (SLE) and in controls without SLE, and to define factors associated with RHTN in patients with SLE. METHODS We studied 1,044 patients with SLE and 5,241 control subjects using de-identified electronic health records from a tertiary care center. SLE was defined as ≥4 International Classification of Diseases, Ninth Revision codes for SLE and antinuclear antibody titer ≥1:160. RHTN was defined as uncontrolled blood pressure on 3 antihypertensive medications or requiring 4 or more antihypertensives to attain control. First, we compared the risk of RHTN between groups. Second, we examined the association between RHTN and all-cause mortality in patients with SLE. RESULTS RHTN was nearly twice as prevalent in patients with SLE compared to control subjects (10.2% and 5.3%, respectively), with an incidence rate of 10.2 versus 6.1 cases per 1,000 person-years of observation (hazard ratio [HR] 1.72 [95% confidence interval 1.28-2.30]; P < 0.001, adjusted for age, sex, race, baseline end-stage renal disease [ESRD], creatinine, and calendar year). In patients with SLE, we found associations between RHTN and black race, lower renal function, hypercholesterolemia, and increased inflammatory markers. RHTN was associated with a significantly higher mortality risk (HR 2.91, P = 0.0005) after adjustment for age, sex, race, calendar year, creatinine, baseline ESRD, and number of visits. CONCLUSION Patients with SLE have a higher risk of RHTN compared to frequency-matched controls, independent of multiple covariates. RHTN is an important comorbidity for clinicians to recognize in SLE, because it is associated with a higher risk of mortality.

Background Resistant hypertension (RHTN) is characterised by blood pressure that remains ≥140/90 mmHg despite concurrent use of 3 antihypertensive drugs. In the general population, RHTN is associated with a 47% increased risk of cardiovascular events. 1 Patients with systemic lupus erythematosus (SLE) have increased cardiovascular risk; however, no research has addressed the incidence, prevalence, or risk factors associated with RHTN in patients with SLE. Objectives To compare the risk of RHTN in patients with SLE and frequency-matched controls without SLE; to define factors associated with RHTN in patients with SLE. Methods We used a validated algorithm (94% PPV) to identify patients with SLE from the electronic health records (EHR) at an academic medical centre. 2 We established a control cohort matched by age, race, and sex with a 5:1 control-case ratio. Follow-up began at first ICD9 code for SLE (cases) or first ICD9 code (controls) and continued until RHTN diagnosis or last note. RHTN diagnosis required either the simultaneous use of 3 antihypertensive drugs and a mean blood pressure ≥140/90 mm Hg in the following 6 months, or the use of ≥4 antihypertensive drugs simultaneously. We used logistic regression and Cox proportional hazards (CPH) models to compare risk of RHTN between groups, with CPH performed on incident cases only. Results We studied 1044 patients with SLE and 5241 controls (median age 42, [31–54] 90% female and 70% Caucasian). Of the total cohort, RHTN developed in 106 SLE patients (10%) and 278 controls (4%). The incidence rate of RHTN was 14.7 cases/1000 person-years in SLE patients compared to 7.4 in controls [HR 1.66, 95% CI, 1.25–2.21] (figure 1). In logistic regression models, RHTN was associated with older age, black race, male gender and end stage renal disease (ESRD). Patients with SLE had a higher risk of RHTN when adjusted for age, sex, race, calendar year, and ESRD [HR 1.53, 1.15–2.05]. In an analysis among SLE patients, RHTN was associated with mortality in an unadjusted model [HR 3.38, 2.20–5.18]. This association remained when age, sex and race were added to the model [HR 2.58, 1.65–4.03], but when ESRD, calendar year and creatinine were included, the association was no longer significant [HR 1.51, 0.91–2.51]. Log rank test: p=0.000391 Conclusions Patients with SLE have a higher risk of RHTN compared to frequency-matched controls. RHTN is an important comorbiditiy for clinicans to recognise in SLE, as it is associated with a 3.3-fold higher risk of mortality. References [1] Muntner P, et al. Hypertension2014;64(5):1012–1021. [2] Barnado A, et al. Arthritis Care Res2017;69(5):687–693. Acknowledgements VUMC’s Synthetic Derivative supported by institutional funding and by the CTSA grant ULTR000445 from NCATS/NIH. CTSA awaUL1TR000445 from NCATS, The Rheumatology Research Foundation, Lupus Research Alliance and K-23 award from the NIAMS. Disclosure of Interest None declared