Ocular adverse events following CAR-T cell therapy: A pharmacovigilance study and systematic review.

The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in hematologic malignancies. However, data on their adverse events, particularly of the eye, is under-reported. To assess the ocular adverse events associated with the six FDA-approved CAR-T cell therapies, a disproportionality analysis utilizing the FAERS database was conducted from the first quarter of 2017 to the third quarter of 2023, as well as a systematic review of case reports of ocular events following CAR-T cell therapy up to December 20, 2023. A total of 53 ocular adverse events were identified from the FDAs FAERS database. The adverse events most frequently observed were mydriasis and xerophthalmia with tisagenlecleucel (Kymriah). The systematic review resulted in 8 case reports encompassing 19 patients which included a total of 27 events. This study demonstrates the importance of anticipation of potential ocular adverse events by ophthalmologists and oncologists as they can greatly contribute to morbidity in patients with cancer.

Effect of alcohol consumption on breast cancer: probabilistic bias analysis for adjustment of exposure misclassification bias and confounders.

PURPOSE: This study was conducted to evaluate the effect of alcohol consumption on breast cancer, adjusting for alcohol consumption misclassification bias and confounders. METHODS: This was a case-control study of 932 women with breast cancer and 1000 healthy control. Using probabilistic bias analysis method, the association between alcohol consumption and breast cancer was adjusted for the misclassification bias of alcohol consumption as well as a minimally sufficient set of adjustment of confounders derived from a causal directed acyclic graph. Population attributable fraction was estimated using the Miettinen's Formula. RESULTS: Based on the conventional logistic regression model, the odds ratio estimate between alcohol consumption and breast cancer was 1.05 (95% CI: 0.57, 1.91). However, the adjusted estimates of odds ratio based on the probabilistic bias analysis ranged from 1.82 to 2.29 for non-differential and from 1.93 to 5.67 for differential misclassification. Population attributable fraction ranged from 1.51 to 2.57% using non-differential bias analysis and 1.54-3.56% based on differential bias analysis. CONCLUSION: A marked measurement error was in self-reported alcohol consumption so after correcting misclassification bias, no evidence against independence between alcohol consumption and breast cancer changed to a substantial positive association.

The effect of smoking on latent hazard classes of metabolic syndrome using latent class causal analysis method in the Iranian population.

BACKGROUND: The prevalence of metabolic syndrome is increasing worldwide. Clinical guidelines consider metabolic syndrome as an all or none medical condition. One proposed method for classifying metabolic syndrome is latent class analysis (LCA). One approach to causal inference in LCA is using propensity score (PS) methods. The aim of this study was to investigate the causal effect of smoking on latent hazard classes of metabolic syndrome using the method of latent class causal analysis. METHODS: In this study, we used data from the Tehran Lipid and Glucose Cohort Study (TLGS). 4857 participants aged over 20 years with complete information on exposure (smoking) and confounders in the third phase (2005-2008) were included. Metabolic syndrome was evaluated as outcome and latent variable in LCA in the data of the fifth phase (2014-2015). The step-by-step procedure for conducting causal inference in LCA included: (1) PS estimation and evaluation of overlap, (2) calculation of inverse probability-of-treatment weighting (IPTW), (3) PS matching, (4) evaluating balance of confounding variables between exposure groups, and (5) conducting LCA using the weighted or matched data set. RESULTS: Based on the results of IPTW which compared the low, medium and high risk classes of metabolic syndrome (compared to a class without metabolic syndrome), no association was found between smoking and the metabolic syndrome latent classes. PS matching which compared low and moderate risk classes compared to class without metabolic syndrome, showed that smoking increases the probability of being in the low-risk class of metabolic syndrome (OR: 2.19; 95% CI: 1.32, 3.63). In the unadjusted analysis, smoking increased the chances of being in the low-risk (OR: 1.45; 95% CI: 1.01, 2.08) and moderate-risk (OR: 1.68; 95% CI: 1.18, 2.40) classes of metabolic syndrome compared to the class without metabolic syndrome. CONCLUSIONS: Based on the results, the causal effect of smoking on latent hazard classes of metabolic syndrome can be different based on the type of PS method. In adjusted analysis, no relationship was observed between smoking and moderate-risk and high-risk classes of metabolic syndrome.

Impact of the use of anti-glaucoma medications on the risk of herpetic keratitis recurrence.

PURPOSE: Numerous case reports have associated anti-glaucoma medications with recurrence of herpes simplex virus (HSV) and herpes zoster virus (HZV) keratitis. The aim of our study was to determine whether different anti-glaucoma agents are associated with recurrence of herpetic keratitis. METHODS: This was a retrospective cohort study using health databases from a Canadian province from January 2001 to December 2012. A new cohort of users on topical prostaglandins (PGs), beta blockers (BBs), alpha-2 agonists (AAs) and carbonic anhydrase inhibitors (CAIs) was created. The date of the third anti-glaucoma drug dispensation within 90 days was deemed the index date of the case. Herpetic keratitis events, as defined by an ICD-9/10 code for HSV or HZV keratitis, or the dispensation of an anti-viral medication by either an ophthalmologist or an optometrist, were examined prior to and following the index date. Risk ratios (RRs) were computed to compare the risk of HSV/HZV keratitis among the PG, BB, AA, and CAI groups individually and collectively while adjusting for age and sex. RESULTS: Among 19,986 users of glaucoma medications identified, there were 684 cases of HSV/HZV keratitis. There was no increased risk of HSV/HZV keratitis recurrence for any of the four glaucoma medications classes individually or collectively when adjusted for age and sex. There was also no increased risk for redeveloping either HSV keratitis only or HZV keratitis only amongst all anti-glaucoma users. CONCLUSION: There is no association between the use of topical ocular hypotensive therapies and HSV/HZV keratitis recurrence. Further studies are needed to confirm these findings.

Interaction Contrasts and Collider Bias.

Previous papers have mentioned that conditioning on a binary collider would introduce an association between its causes in at least 1 stratum. In this paper, we prove this statement and, along with intuitions, formally examine the direction and magnitude of the associations between 2 risk factors of a binary collider using interaction contrasts. Among level one of the collider, 2 variables are independent, positively associated, and negatively associated if multiplicative risk interaction contrast is equal to, more than, and less than 0, respectively; the same results hold for the other level of the collider if the multiplicative survival interaction contrast, equal to multiplicative risk interaction contrast minus the additive risk interaction contrast, is compared with 0. The strength of the association depends on the magnitude of the interaction contrast: The stronger the interaction is, the larger the magnitude of the association will be. However, the common conditional odds ratio under the homogeneity assumption will be bounded. A figure is presented that succinctly illustrates our results and helps researchers to better visualize the associations introduced upon conditioning on a collider.

Risk of maculopathy with pentosan polysulfate sodium use.

AIMS: Recent epidemiologic studies have examined the risk of maculopathy with pentosan polysulfate sodium (PPS), a drug indicated for the treatment of interstitial cystitis. However, results have been contradictory. Thus, we quantified the risk of maculopathy with PPS with a focus on risk with duration of use. METHODS: We used a new user, retrospective cohort study with an active comparator. We created a cohort of mutually exclusive 6221 PPS users and 89 744 amitriptyline users, a tricyclic antidepressant also used for the treatment of pain secondary to interstitial cystitis. Subjects were selected from the PharMetrics Plus database (IQVIA, Durham, NC) from 2006 to 2020. Cohort members were followed to the first event of the study outcome (maculopathy) or end of enrolment. A Cox regression model was constructed to adjust for potential confounders. RESULTS: The mean follow-up was 3.0 years for PPS users and amitriptyline users. The adjusted hazard ratio (HR) for maculopathy in PPS users was 2.64 (95% confidence interval [CI]: 1.90-3.68). The HR for the sensitivity analysis that combined maculopathy and age-related macular degeneration (AMD) was 1.38 (95% CI: 1.16-1.65). A cumulative duration-response pattern was observed, with use greater than 3 years having a 9.5-fold risk of maculopathy (HR = 9.56, 95% CI: 3.60-25.37) compared to a 2.3-fold risk of maculopathy with use for 1 year or less (HR = 2.27, 95% CI: 1.50-3.43). The number needed to harm for the first 4 years of use was 250. CONCLUSIONS: The results of this study suggest an increased risk of maculopathy with PPS use, particularly with longer duration of use.

To Adjust or Not to Adjust: The Role of Different Covariates in Cardiovascular Observational Studies.

Covariate adjustment is integral to the validity of observational studies assessing causal effects. It is common practice to adjust for as many variables as possible in observational studies in the hopes of reducing confounding by other variables. However, indiscriminate adjustment for variables using standard regression models may actually lead to biased estimates. In this paper, we differentiate between confounders, mediators, colliders, and effect modifiers. We will discuss that while confounders should be adjusted for in the analysis, one should be wary of adjusting for colliders. Mediators should not be adjusted for when examining the total effect of an exposure on an outcome. Automated statistical programs should not be used to decide which variables to include in causal models. Using a case scenario in cardiology, we will demonstrate how to identify confounders, colliders, mediators and effect modifiers and the implications of adjustment or non-adjustment for each of them.

The association between hormonal contraceptive use and glaucoma in women of reproductive age.

AIMS: We aimed to investigate the association between hormonal contraceptive (HC) use and the incidence of glaucoma in females of reproductive age with a focus on duration and type of HCs used. METHODS: A retrospective cohort study with a case-control analysis (nested case-control) was undertaken using data from IQVIA's electronic medical record (IQVIA, USA) from 2008 to 2018. Within a cohort of 4 871 504 women, cases of glaucoma or ocular hypertension were identified. Subjects were followed to the first diagnosis of glaucoma. Each glaucoma case was matched to four controls by age, body mass index and follow up time. The main outcome measure was the first diagnosis of glaucoma defined by the first ICD-9/10 code for glaucoma or ocular hypertension. RESULTS: Among 4 871 504 women identified, there were 2366 cases of glaucoma and 9464 controls. Regular users of hormonal contraceptives had an elevated risk of glaucoma compared to non-users with an adjusted incident rate ratio (aIRR) of 1.57 (95% CI: 1.29-1.92). Current users were of greatest risk (aIRR of 2.38, 95% CI: 1.81-3.13), whereas the aIRR among past users was 1.08 (95% CI: 0.82-1.43). The aIRR for glaucoma increased from 0.82 (95% CI: 0.70-0.95) among those with one or two prescriptions in the 2 years prior to the first diagnosis of glaucoma to 1.54 (95% CI: 1.32-1.81) among those with greater than four prescriptions. CONCLUSIONS: This nested case-control study demonstrated an elevated risk, albeit low, of glaucoma in females of reproductive age who use regular hormonal contraception. Future studies are needed to confirm these findings.

Association between the use of hormonal contraceptives and risk of cholecystectomy in women of reproductive age.

PURPOSE: Previous studies have indicated an increased risk of gallbladder disease with hormonal contraceptives although with discordant results. The potential increased risk of gallbladder disease with hormonal contraceptives is concerning given that women are at increased risk of this disease. Thus, the aim of this study was to examine risk of surgery-confirmed gallbladder disease (cholecystectomy) with oral contraceptives, intrauterine devices, and injectable hormonal contraceptives. METHODS: We conducted a retrospective cohort study. Females aged 15-45 who initiated hormonal contraceptive use were identified in the United States IQVIA Ambulatory electronic medical record database between 2008 and 2018. Cox proportional hazards models were used to estimate adjusted hazards ratios and 95% confidence intervals for cholecystectomy with eight formulations of contraceptives compared with levonorgestrel and ethinyl estradiol combined oral contraceptive. Sensitivity analysis was conducted by lagging exposure by 90 days and by excluding patients with history of gallbladder disease. Secondary analyses were conducted by cumulative duration of use. RESULTS: We identified 1,425,821 females who initiated the use of hormonal contraceptives and generated 4417 cholecystectomy events. Overall, the use of medroxyprogesterone acetate (HR: 1.22, 95% CI: 1.07-1.40) and at least 1 year of levonorgestrel intrauterine device use (HR: 1.74: 95% CI: 1.19-2.54) were associated with increased risk of cholecystectomy when compared with levonorgestrel and ethinyl estradiol combined oral contraceptive. However, we did not observe an increased risk with other hormonal contraceptives. Consistent results were observed across sensitivity analyses. CONCLUSION: In this large population-based study, there was an increased risk of cholecystectomy with medroxyprogesterone acetate and intrauterine device but not other hormonal contraceptives. Additional large observational studies are required to corroborate these findings.

Risk of sexual dysfunction with progestin-based contraceptives in women of child-bearing age.

PURPOSE: To examine whether there is a positive association between sexual dysfunction (SD) and different types of progestin-based contraceptives. METHODS: Nested case-control study in women of child-bearing age (15-45 years) from the IQVIA® Ambulatory electronic medical record database from 2008 to 2018. Cases defined by diagnosis of sexual dysfunction identified by international classification for disease clinical modification code 9th and 10th. Each case was matched to four controls and rates of prescriptions of the following were compared: levonorgestrel intra-uterine device (IUD), progestin, and ethinyl estradiol (EE) combined oral contraceptive (COC) formulations including levonorgestrel, norgestimate, drospirenone, desogestrel, norethindrone, and norgestrel; etonogestrel vaginal ring; and medroxyprogesterone injection. RESULTS: Overall, 6689 cases of patients with SD were matched to 26,756 matched controls. Compared with matched controls, more subjects with SD used levonorgestrel IUD (OR 1.24, 95% CI 1.08-1.44), EE-levonorgestrel COC (OR 1.18, 95% CI 1.00-1.41), EE-drospirenone (OR 1.28, 95% CI 1.00-1.67), and medroxyprogesterone (OR 1.38, 95% CI 1.12-1.70). The use of norgestrel exhibited a protective effect (OR 0.83, 95% CI 0.73-0.95). When using the EE-levonorgestrel COC as a comparator, norgestrel users exhibited a protective effect (OR 0.70, 95% CI 0.57-0.87) while no other contraceptives showed a statistically significant difference in association with SD. CONCLUSION: Our study found an increase in the use of levonorgestrel (COC and IUD), drospirenone, and medroxyprogesterone in subjects with SD. The risk of contraceptives did not differ when compared with oral levonorgestrel. The small association size and lack of difference between drug formulations suggest a minimal impact of progestin-based contraceptives on sexual dysfunction.

Oral fluoroquinolones and risk of fibromyalgia.

The Food and Drug Administration (FDA) has recently included a black box warning on fibromyalgia-like symptoms with fluoroquinolones (FQs) but no large epidemiologic study is to date available. We undertook a case-control study using a random sample of 9 053 240 subjects obtained from the PharMetrics Plus health claims database in the United States. Cases received at least two fibromyalgia diagnoses coded by a rheumatologist matched to ten randomly selected controls. After identifying 5148 cases of fibromyalgia and 51 480 controls, the adjusted rate ratio (RR) of fibromyalgia for use of any fluoroquinolones, amoxicillin and azithromycin were 1.63 (95% CI: 1.41-1.87), 1.64 (95% CI: 1.46-1.85) and 1.68 (95% CI, 1.49-1.89), respectively. The adjusted RR for any use of FQ compared to any use of amoxicillin or azithromycin was 0.99 (95% CI: 0.83-1.18) and azithromycin is 0.97 (95%CI: 0.82-1.16), respectively. The risk of fibromyalgia with FQs is similar to that with amoxicillin and azithromycin.

Statin medications and the risk of gynecomastia.

OBJECTIVE: Case reports have suggested an increased risk of gynecomastia with HMG-CoA reductase inhibitors (ie, statins). A recent meta-analysis also found that statins decrease circulating testosterone levels in men. We investigated whether statin use was associated with an increased risk of gynecomastia. DESIGN: Case-control study. PATIENTS: A cohort of patients from a random sample of 9 053 240 US subjects from the PharMetrics Plus™ health claims database from 2006 to 2016 was created. MEASUREMENTS: New cases of gynecomastia requiring at least two ICD-9 codes were identified from the cohort and matched to 10 controls by follow-up time and age using density-based sampling. Rate ratios (RRs) for users of statins were computed using conditional logistic regression adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, obesity, hypogonadism, hyperprolactinemia and use of spironolactone, ketoconazole, H2 receptor antagonists (H2 blockers), risperidone, testosterone and androgen deprivation therapy. RESULTS: Our cohort included 6147 cases of gynecomastia and 61 470 corresponding matched controls. The adjusted RR for current, recent and past statin use with respect to gynecomastia was 1.19 (1.04-1.36), 1.38 (1.15-1.65) and 1.20 (1.03-1.40), respectively. CONCLUSIONS: Statin use is associated with an increased risk of developing gynecomastia. Clinicians should be cognizant of this effect and educate patients accordingly.

Association of Antidepressant Use With Drug-Related Extrapyramidal Symptoms: A Pharmacoepidemiological Study.

BACKGROUND: Antidepressants are one of the most prescribed classes of medications. A number of case reports have linked these drugs to extrapyramidal symptoms (EPSs), but no large epidemiologic study to date has examined this association. We sought to quantify the association of EPSs with different antidepressants by undertaking a large pharmacoepidemiologic study. METHODS: A nested case-control study was conducted using a large health claims database in the United States from June 2006 to December 2015. Subjects with a diagnosis of primary Parkinson disease and those who received prescriptions of levodopa, ropinirole, pramipexole, domperidone, metoclopramide, entacapone, benztropine, selegiline, rasagiline, diphenhydramine, trihexyphenidyl, typical and atypical antipsychotics, and tricyclic antidepressants were excluded. Cases were followed to the first billing code for an extrapyramidal event or last date of enrollment in the cohort. For each case, 10 control subjects were matched by follow-up time, calendar time, and age through density-based sampling. Rate ratios were computed using conditional logistic regression adjusting for other covariates. RESULTS: We identified 3,838 subjects with EPSs compared with 38,380 age-matched control subjects. Rate ratios with respect to EPSs were as follows: duloxetine, 5.68 (95% confidence interval [CI], 4.29-7.53); mirtazapine, 3.78 (95% CI, 1.71-8.32); citalopram, 3.47 (95% CI, 2.68-4.50); escitalopram, 3.23 (95% CI, 2.44-4.26); paroxetine, 3.07 (95% CI, 2.15-4.40); sertraline, 2.57 (95% CI, 2.02-3.28); venlafaxine, 2.37 (95% CI, 1.71-3.29); bupropion, 2.31 (95% CI, 1.67-3.21); and fluoxetine, 2.03 (95% CI, 1.48-2.78). CONCLUSIONS: This observational study demonstrates a harmful association between the incidence of Parkinson disease or associated EPSs and use of the antidepressants duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine.

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.

This database study examines the association between glucagon-like peptide 1 agonists (eg, semaglutide, liraglutide) used for weight loss and reports of gastrointestinal adverse events.

Fluoroquinolone Use and Risk of Carpal Tunnel Syndrome: A Pharmacoepidemiologic Study.

Fluoroquinolone-induced peripheral neuropathies and tendinopathies are well documented, but there are no epidemiologic studies on the risk of carpal tunnel syndrome (CTS). We conducted a case-control study of >6 million patients. Fluoroquinolone use is associated with increased risk of CTS (rate ratio, 1.34 [95% confidence interval, 1.31-1.37]).

Risk of Gambling Disorder and Impulse Control Disorder With Aripiprazole, Pramipexole, and Ropinirole: A Pharmacoepidemiologic Study.

BACKGROUND: Recently, the US Food and Drug Administration issued a warning regarding the potential risk of gambling disorder, but large epidemiologic studies are lacking. METHODS: We used a large health claims database from the United States and conducted a nested case-control study. Cases were defined as subjects newly diagnosed with gambling disorder or impulse control disorder. For each case, 10 controls were selected and matched to cases by age and follow-up time and calendar time. Adjusted rate ratios were computed with conditional logistic regression. RESULTS: There are 355 cases of gambling disorder and 3550 controls along with 4341 cases of impulse control disorder and 43,410 corresponding controls. After adjusting for confounders, users of aripiprazole demonstrated an increased risk of pathologic gambling (rate ratio [RR], 5.23; 95% confidence interval [CI], 1.78-15.38) and impulse control disorder (RR, 7.71; 95% CI, 5.81-10.34). The risk was also elevated for pramipexole or ropinirole for both gambling disorder and impulse control disorder (RR, 7.61; 95% CI, 2.75-21.07; RR, 3.28; 95% CI, 2.31-4.66, respectively). CONCLUSIONS: Our study confirms an association between aripiprazole, pramipexole, or ropinirole and impulse control disorder and gambling disorder.