Infliximab for Treatment of Immune Adverse Events and Its Impact on Tumor Response.

Background: Immune-related adverse events (irAEs) challenge the use of immune checkpoint inhibitors (ICIs). We performed a retrospective study to evaluate response to infliximab for immune-related adverse event management, and infliximab's effect on progression-free survival (PFS) and overall survival (OS) with a focus on melanoma and genitourinary cancers. Methods: We retrospectively reviewed records of all cancer patients exposed to infliximab after immune checkpoint inhibitor (ICI) treatment from 2004 to 2021 at the MD Anderson Cancer Center. Survival was assessed utilizing the Kaplan-Meier method. Univariate and multivariate logistic regression was utilized to evaluate predictors of infliximab response, OS, and PFS. Results: We identified 185 cancer patients (93 melanoma and 37 genitourinary cancers) treated with ICI and who received infliximab to treat irAEs. Within 3 months of treatment initiation, 71% of the patients responded to infliximab, 27% had no response, and 2% had unknown response. Among different irAEs, colitis was associated with increased response to infliximab at 3 months, irrespective of the type of malignancy. We evaluated best tumor response before and after infliximab in the entire cohort and again in the melanoma and genitourinary (GU); the findings were similar in the melanoma cohort and the entire cohort, where best tumor response before and after infliximab was not significantly different. In the melanoma cohort, acute kidney injury (AKI) was associated with increased risk of death, p = 0.0109, and having response to infliximab was associated with decreased risk of death, p = 0.0383. Interestingly in GU cancer patients, myositis was associated with increased risk of death, p = 0.0041, and having a response to infliximab was marginally associated with decreased risk of death, p = 0.0992. As regards PFS, in a multivariate Cox regression model, having a history of cardiovascular disease remained significantly associated with shorter PFS in the melanoma cohort. For patients with GU cancers, response to infliximab was associated with longer PFS. Conclusions: Our study is among the largest retrospective analyses of infliximab use for irAE management. Patients with colitis were the best responders to infliximab. AKI before initiation of infliximab in the melanoma subcohort and myositis in GU subcohort are associated with higher risk of death. Our results indicate no association between infliximab and cancer progression with the exception of genitourinary cancers.

Health Care Service Price Comparison Suggests That Employers Lack Leverage To Negotiate Lower Prices.

Almost two-thirds of the 153 million nonelderly people in the United States who have health insurance through their employer are in self-insured plans. In contrast to fully insured plans, employers using self-insured plans assume responsibility for employees' medical costs and therefore have an incentive to reduce the prices of health care services. We compared prices for common services in self-insured plans with those in fully insured plans. Using the Health Care Cost Institute's data set of claims for one-third of the US population with employer-sponsored insurance, we found that unadjusted prices were higher in self-insured plans for most of the services we studied, with the largest differences found for endoscopies (approximately 8 percent higher in self-insured plans), colonoscopies (approximately 7 percent), laboratory tests (approximately 5 percent), and moderate-severity emergency department visits (4 percent). When patient characteristics, plan type, and geography were adjusted for, differences were generally smaller but were consistent with these findings. Higher prices in self-insured plans suggest that there may be opportunities for employers to lower prices and for policy makers to act where employers have limited leverage to negotiate with providers.

Prescribing of low- versus high-cost Part B drugs in Medicare Advantage and traditional Medicare.

OBJECTIVE: Examine whether Medicare Advantage (MA) coverage is associated with more efficient prescribing of Part B drugs than traditional Medicare (TM) coverage. DATA SOURCES: Twenty percent sample of 2016 outpatient and carrier TM claims and MA encounter records and Master Beneficiary Summary File data. STUDY DESIGN: We analyzed whether MA enrollees compared to TM enrollees more often received the low-cost Part B drug in four clinical scenarios where multiple similarly effective drugs exist: (1) anti-VEGF agents to treat macular degeneration, (2) bone resorption inhibitors for osteoporosis, (3) bone resorption inhibitors for malignant neoplasms, and (4) intravenous iron for iron deficiency anemia. We then estimated differences in spending if TM prescribing aligned with MA prescribing. Finally, using linear probability models, we examined whether differences in MA and TM prescribing patterns were attributable to differences in the hospitals and clinician practices who treat MA and TM enrollees or differences in how these hospitals and clinician practices treat their MA versus TM patients. DATA COLLECTION/EXTRACTION METHODS: Not applicable. PRINCIPAL FINDINGS: In all cases, a larger share of MA enrollees received the low-cost drug compared to TM enrollees, ranging from 8 percentage points higher for anemia to 16 percentage points higher for macular degeneration in the unadjusted analysis. Results were similar in regression analyses controlling for enrollee characteristics and market factors (5-13 percentage points). If TM prescribing matched MA prescribing, we estimated savings ranging from 6% to 20% of TM spending for each scenario. Differences in prescribing patterns were driven both by MA enrollees receiving treatment at more efficient hospitals and clinician practices and hospitals and clinician practices more often prescribing low-cost drugs to their MA patients. CONCLUSIONS: Our findings show MA enrollees were more likely than TM enrollees to receive low-cost Part B drugs in four clinical scenarios where multiple similarly or equally effective treatment options exist.

Payment incentives and the use of higher-cost drugs: a retrospective cohort analysis of intravenous iron in the Medicare population.

OBJECTIVES: Medicare Part B payment methods incentivize the use of more expensive injectable and infused drugs. We examined prescribing patterns in the context of intravenous (IV) iron, for which multiple similarly safe and efficacious formulations exist, with wide variations in price. STUDY DESIGN: We conducted a retrospective cohort analysis of IV iron utilization and payment in the Medicare population between 2015 and 2017. METHODS: This analysis used a national, random 20% sample of Medicare fee-for-service beneficiaries with Part B claims for IV iron between January 2015 and December 2017-a period before, during, and after a national shortage of iron dextran. This sample included 66,710 Medicare fee-for-service beneficiaries with at least 1 Part B claim for IV iron. RESULTS: The greatest increase in utilization occurred in the most expensive iron formulation, ferric carboxymaltose; its market share rose from 27.4% of use in 2015 to 47.7% in 2017. The use of a less expensive formulation, iron dextran, decreased from 26.7% to 18.7% over the same period. An alternative payment model in Maryland hospitals was associated with markedly less utilization of ferric carboxymaltose, accounting for 4.7% of IV iron utilization in Maryland hospitals. CONCLUSIONS: There was an increase in the dispensing of a higher-priced IV iron formulation associated with a shortage of a less expensive drug that persisted once the shortage ended. These findings in IV iron have broader implications for Part B drug payment policy because the price of the drug determines the physician and health system payment.

Comparing patient OOP spending for specialty drugs in Medicare Part D and employer-sponsored insurance.

OBJECTIVES: Per capita spending on specialty drugs increased 55% between 2014 and 2018. Individuals aged 55 to 75 years using specialty drugs make the transition from employer-sponsored insurance (ESI) to Medicare Part D coverage. We compared out-of-pocket (OOP) spending across ESI, Medicare fee-for-service (FFS), and Medicare Advantage (MA) prescription drug plans to examine the impact of benefit design on OOP spending. STUDY DESIGN: Analyses consisted of Truven MarketScan and Medicare Part D prescription drug claims from 2013 to 2017 for individuals enrolled in ESI, FFS, and MA drug plans taking at least 1 drug among the top 4 specialty drug classes: rheumatoid arthritis (RA), multiple sclerosis (MS), cancer, and hepatitis C. METHODS: Multivariate regression analyses with fixed effects were used to assess whether there are differences in OOP spending by insurance type and the impact of benefit design differences. A secondary outcome was drug choice within a therapeutic class. RESULTS: There were small differences in drug choice between Medicare and ESI but significant differences in OOP spending. Monthly OOP spending for ESI relative to FFS was $108 less for RA drugs, $288 less for MS drugs, $504 less for cancer drugs, and $1437 less for hepatitis C drugs. Spending was slightly greater for beneficiaries in MA plans compared with FFS. Higher Medicare spending was driven by gaps in coverage in the Part D benefit phases because beneficiaries pay a percentage of list price. CONCLUSIONS: OOP spending was substantially higher for Medicare enrollees compared with ESI enrollees as a result of the Part D benefit structure.

Financial Eligibility Criteria and Medication Coverage for Independent Charity Patient Assistance Programs.

Importance: Although independent charity patient assistance programs improve patient access to costly prescription drugs, recent federal investigations have raised questions about their potential to increase pharmaceutical spending and to violate the federal Anti-Kickback Statute. Little is known about the design of the programs, patient eligibility, or drug coverage. Objective: To examine the eligibility criteria of the independent charity patient assistance programs and the drugs covered by them. Design, Setting, and Participants: Descriptive cross-sectional study of the 6 largest independent charities offering patient assistance programs for patients including, but not limited to, Medicare beneficiaries in 2018. These charities offered 274 different disease-specific patient assistance programs. Drugs were identified for subgroup analysis that had any use reported on the Medicare Part D spending dashboard and any off-patent brand-name drugs that incurred more than $10 000 in Medicare spending per beneficiary in 2016. Exposures: Support by independent charity patient assistance programs. Main Outcomes and Measures: The primary outcomes were the characteristics of patient assistance programs, including assistance type, insurance coverage (vs uninsured), and income eligibility. The secondary outcomes were the cost of the drugs covered by the patient assistance programs and the coverage of expensive off-patent brand-name drugs vs substitutable generic drugs. Results: Among the 6 independent charity foundations included in the analysis, their total revenue in 2017 ranged from $24 million to $532 million, and expenditures on patient assistance programs ranged from $24 million to $353 million, representing on average, 86% of their revenue. Of the 274 patient assistance programs offered by these organizations, 168 (61%) provided only co-payment assistance, and the most common therapeutic area covered was cancer or cancer treatment-related symptoms (113 patient assistance programs; 41%). A total of 267 programs (97%) required insurance coverage as an eligibility criterion (ie, excluded uninsured patients). The most common income eligibility limit was 500% of the federal poverty level. The median annual cost of the drugs per beneficiary covered by the programs was $1157 (interquartile range, $247-$5609) compared with $367 (interquartile range, $100-$1500) for the noncovered drugs. Off-patent brand-name drugs (cost: >$10 000) were covered by a mean of 3.1 (SD, 2.0) patient assistance programs, whereas their generic equivalents were covered by a mean of 1.2 (SD, 1.0) patient assistance programs. Conclusions and Relevance: In 2018, among 274 patient assistance programs operated by the 6 independent charity foundations, the majority did not provide coverage for uninsured patients. Medications that were covered by the patient assistance programs were generally more expensive than those that were not covered.

Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy.

Active pulmonary tuberculosis (APTB) is associated with a failure of the host immune system to control the invading Mycobacterium tuberculosis (Mtb). The objective of this study was to quantify and assess the role of serum inflammatory cytokines in active pulmonary tuberculosis patients following anti-tuberculosis drug (ATD) therapy. Blood samples were collected from APTB patients and normal healthy subjects (NHS) (total n=204) at baseline and 2, 4 and 6 months post-therapy and the abundance of serum inflammatory cytokines were measured by cytokine specific ELISA. Compared to NHS, APTB patients at baseline had higher levels of serum pro-inflammatory cytokines IL-12p40 (P<0.001), IFN-γ (P<0.001), TNF-α (P<0.01), IL-1ß (P<0.001) and IL-6 (P<0.001) and anti-inflammatory cytokines IL-10 (P<0.001) and TGF-ß1 (P<0.001) while there was no change in the level of IL-4. In APTB patients, the serum levels of IFN-γ, TNF-α, IL-6 and TGF-ß1 directly relate to the bacterial load while the TNF-α, IL-1ß, IL-6 and TGF-ß1 relate to radiological severity. At baseline, the IL-6 level in NHS and APTB patients differed most and following ATD therapy, this level rapidly decreased and stabilized by 4-month in APTB patients. It is concluded that a subtle reduction in the serum level of IL-6 of the APTB patients following ATD therapy might play a vital role in immune-protection of the host against Mtb infection and hence the serum IL-6 level can be a useful marker to diagnose the effectiveness of therapy in the patients.

Role of hyperglycemia-mediated erythrocyte redox state alteration in the development of diabetic retinopathy.

PURPOSE: To evaluate erythrocyte redox state and its surrogates in patients with different stages of diabetic retinopathy and their association with cellular metabolic derangement developed in retinal microvascular cells. METHODS: Sixty type 2 diabetic patients with nonproliferative diabetic retinopathy (NPDR), 85 patients with proliferative diabetic retinopathy (PDR), and 70 patients with diabetes but without retinopathy were considered as diabetic control (DC) for the study. In addition, 65 normal individuals without diabetes were enrolled as healthy control in this study. Erythrocyte oxidized nicotinamide adenine dinucleotide phosphate / reduced nicotinamide adenine dinucleotide phosphate (NADP / NADPH), oxidized nicotinamide adenine dinucleotide / reduced nicotinamide adenine dinucleotide (NAD / NADH) glutathione, plasma and vitreous lactate, and pyruvate levels were determined by enzymatic reaction-based spectrophotometric assay for the patients and individuals. RESULT: Erythrocyte NADP+ to NADPH ratio to NADPH ratio was found to be significantly higher among NPDR and PDR patients compared with DC subjects (P < 0.0001). Erythrocyte-reduced glutathione was significantly decreased in patients of NPDR (P = 0.0004) and patients of PDR (P = 0.0157) compared to DC. Erythrocyte NAD to NADH ratio was also significantly decreased in patients of NPDR (P < 0.0001) and PDR (P < 0.0001) compared to DC subjects. Lactate to pyruvate ratio of plasma was elevated significantly in patients with NPDR compared with DC (P < 0.0001) and those having PDR (P = 0.0046). In the vitreous fluid, the lactate to pyruvate ratios were found to be significantly lower in normal individuals without diabetes compared with patients having PDR (P < 0.0001). CONCLUSION: Hyperglycemia-mediated erythrocyte redox state alterations might be a potential risk factor for the development of NPDR in poorly controlled diabetic subjects.

Association of vascular endothelial growth factor, transforming growth factor beta, and interferon gamma gene polymorphisms with proliferative diabetic retinopathy in patients with type 2 diabetes.

PURPOSE: Chronic hyperglycemia and hypoxemia are believed to be causal factors in the development of proliferative diabetic retinopathy (PDR) among individuals with type 2 diabetes. It is hypothesized that formation of new blood vessels in the retina due to prolonged hypoxia is associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we investigated the association of genetic polymorphisms in vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-ß), and interferon γ (IFN-γ) genes, which may be responsible for the hypoxia-induced VEGF-mediated neovascularization pathway for the pathogenesis of PDR. METHODS: Our case-control association study composed of 493 ethnically matched volunteers (253 with PDR [cases] and 240 diabetic controls [DC]). Gene polymorphisms were determined with Taqman-based real-time PCR and amplification refractory mutation analysis system PCR. RESULTS: The VEGF-460C (rs833061C; p=0.0043) and IFN-γ +874T (rs2430561T; p=0.0011) alleles were significantly associated with PDR. CONCLUSIONS: Genetic variations at VEGF-460C and IFN-γ +874T might accelerate the pathogenesis of retinal neovascularization in PDR.

Intermittent iron folate supplementation: impact on hematinic status and growth of school girls.

UNLABELLED: In view of high iron needs for adolescent growth, this paper studied the impact of daily vs. intermittent (once and twice weekly) iron folic acid (IFA) supplementation on hemoglobin levels and pubertal growth among primary school girls in early adolescence (9-13 years) of Vadodara, India. Methods. Hemoglobin (Hb), height and weight of the girls were assessed using standard methods. In three experimental schools (ES) IFA tablets in a dose of 100 mg Fe + 0.5 mg folic acid was given either daily, once weekly or twice weekly for one year. The fourth school (control: CS) did not receive any intervention. Results. Hb levels significantly improved (P < 0.01) in all ES compared to CS. Body Mass Index (BMI) increment in ES vs CS was significant (P < 0.05) in twice weekly IFA and daily IFA. Within ES groups, mean Hb and BMI increments were comparable between twice weekly IFA and daily IFA. Anemic ES girls showed higher Hb and BMI increments vs. non-anemic girls. Better the Hb response, greater was the benefit on BMI. CONCLUSION: Twice-weekly IFA supplementation was comparable to daily IFA as regards impact on Hb and growth; at less cost and greater feasibility. Once-weekly dose was inadequate to significantly improve growth.

Association of tumor necrosis factor α, interleukin 6, and interleukin 10 promoter polymorphism with proliferative diabetic retinopathy in type 2 diabetic subjects.

PURPOSE: New blood vessel formation in the retina because of prolonged hypoxia is believed to be directly associated with increased expression of several growth factors and angiogenic cytokines. In the present study, we made an attempt to investigate the possible association of the promoter polymorphisms of interleukin 6, tumor necrosis factor α, and interleukin 10 for the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS: This case-control study comprised 493 volunteers (253 PDR cases and 240 diabetic controls). Cases and controls were ascertained such that age, sex, nutrition, and glycemic status were matched. Genotypes were determined by polymerase chain reaction-based methods. RESULTS: Interleukin 10-1082GG (P = 0.0037; odds ratio [OR] = 2.232), tumor necrosis factor α-238AA (P = 0.0001; OR = 5.791), and GA (P = 0.0015; OR = 1.909) genotypes were significantly associated with PDR occurrence. The interleukin 10-1082G allele (P = 0.0048, OR = 1.4442) and the tumor necrosis factor α-238A allele (P = 0.0001; OR = 2.2897) were significantly increased among PDR cases. CONCLUSION: From our study, it may be concluded that the genetic variation, that is, tumor necrosis factor α-238A and interleukin 10-1082G alleles are the potent risk factors for the pathogenesis of PDR.

Impact of interleukin-6 promoter polymorphism and serum interleukin-6 level on the acute inflammation and neovascularization stages of patients with Eales' disease.

PURPOSE: To evaluate the role of interleukin-6 (IL-6) in the inflammatory and proliferative stages of Eales' disease (ED) and to determine the influence of IL-6-174G/C polymorphism in the IL-6 and IL-6-regulated protein expression, as well as the development of ED. METHODS: One hundred and twenty-one patients diagnosed with ED, 223 matched healthy controls, and 16 control patients with macular holes were recruited from the eastern Indian population. Serum and vitreous levels of IL-6 and vascular endothelial growth factors (VEGF) were measured by enzyme-linked immunosorbent assay. Serum levels of high-sensitivity C-reactive protein (hsCRP) were measured by enzyme immunoassay. Subjects were genotyped for the IL-6-174G/C polymorphism (rs1800795) by a custom TaqMan single-nucleotide polymorphism (SNP) Genotyping Assays system. RESULTS: Serum IL-6 (p<0.0001), hsCRP (p<0.0001), and VEGF (p=0.0031) levels were significantly higher in the inflammatory stage of ED than in healthy controls. Serum IL-6 also significantly correlated with hsCRP (Spearman's correlation coefficient; r=0.4992, p=0.0009), but not with VEGF in this stage in ED patients. At the proliferative stage of ED, significantly higher levels of vitreous IL-6 (p=<0.0001) and VEGF (p=<0.0001) were found compared with the vitreous of patients with macular holes. A significant correlation was observed between vitreous IL-6 and VEGF in ED patients (Spearman's correlation coefficient; r=0.5834, p=0.0087). A statistically significant association was found between the -174GG genotype (p=0.006) and occurrence of ED. Mean serum and vitreous concentrations of IL-6 were also higher in the subjects with the GG genotype than in those with the GC or CC genotype in this population. CONCLUSIONS: IL-6 expression, regulated by the allelic distribution of -174 loci and the enhanced level of IL-6, modulates CRP and VEGF concentration depending respectively on the acute inflammatory stimulation at the initial stage and angiogenic stimulation at the advanced stage of ED.

Assessment of gelatinase and tumor necrosis factor-α level in the vitreous and serum of patients with Eales disease: role of inflammation-mediated angiogenesis in the pathogenesis of Eales disease.

BACKGROUND: Eales disease (ED) is an idiopathic, inflammatory, venoocclusive disorder of peripheral retina resulting in retinal angiogenesis and vitreous hemorrhage. The objective of the present study is to investigate the expression and activation of gelatinase associated with the retinal neovascularization in ED and the relation between the levels of gelatinase and the cytokine tumor necrosis factor-α, known to upregulate matrix metalloproteinase (MMP) expression on various cells. METHODS: Vitreous and serum samples from 19 patients with ED who underwent retinal surgery were estimated for levels of MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, and tumor necrosis factor-α by enzyme-linked immunosorbent assay method. Matrix metalloproteinase-2 and MMP-9 activities in serum and vitreous samples were evaluated by gelatin zymography method. Vitreous samples from 16 patients with macular hole undergoing vitrectomy were used as controls. RESULTS: Among the 2 gelatinase examined in vitreous and serum samples, only level and activity of MMP-9 were significantly higher in serum (P = 0.0001) and vitreous (P = 0.0002) samples of patients with ED than those of control subjects. Simultaneously, a positive correlation was found between intraocular tumor necrosis factor-α and MMP-9 concentration (Spearman correlation coefficient, r = 0.7040, P = 0.0023) in patients with ED. CONCLUSION: Increase in MMP-9 activity and its concentration in serum and vitreous of patients with ED compared with that of control subjects and correlation between intraocular levels of MMP-9 and tumor necrosis factor-α in patients with ED seem to provide a plausible explanation for inflammation-mediated angiogenesis during the development of this condition.

Association of interferon-gamma, interleukin-10, and tumor necrosis factor-alpha gene polymorphisms with occurrence and severity of Eales' disease.

PURPOSE: Eales' disease (ED) is an idiopathic retinal vasculitis characterized by capillary nonperfusion and neovascularization. Previous reports on ED demonstrated that T-cell-mediated immunoresponse and differential cytokine production in inflammatory and angiogenic stage seem to influence the extent and severity of this disease. Therefore, the purpose of this study is to investigate the influence of cytokine gene polymorphisms on occurrence and severity of ED. METHODS: One hundred twenty-one patients with ED were recruited from an Eastern Indian population and compared with 223 matched healthy control subjects. Genotyping of IFN-γ, IL-10, and TNF-α were performed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). RESULTS: A statistically significant association was found between the IL-10 -1082AA (P = 0.002), TNF-α -308AA (P = 0.0017) genotypes and the IL-10 ATA haplotype (P = 0.0123) and the occurrence of ED. In addition IL-10 -1082GG (P = 0.0005), TNF-α -308GG (P < 0.0001) genotype were found to be protective against disease occurrence. A synergistically low IL-10/high TNF-α genotype increased the risk of development (P < 0.0001) and the severity (P = 0.019) of ED. CONCLUSIONS: These data suggest that a low IL-10-expressing and high TNF-α-expressing genotype of the host can influence the occurrence and severity of outcome of ED.

Impact of iron-folic acid supplementation on cognitive abilities of school girls in Vadodara.

OBJECTIVES: To assess impact of daily and intermittent iron-folate (IFA) supplementation on cognition of underprivileged primary schoolgirls in Vadodara. DESIGN: Experimental-control longitudinal study. SETTING: Municipal primary schools. PARTICIPANTS: Schoolgirls (n=161) in the age group of 9 - 13 years. INTERVENTION: Participants at three randomly selected schools were given IFA tablets (100 mg elemental iron + 0.5 mg folic acid) either once weekly or twice weekly or daily for one year. The fourth was the control school. OUTCOME MEASURES: Digit span, maze test, visual memory test, and clerical task scores. RESULTS: IFA supplementation given daily and twice-weekly significantly improved cognition in most tests; the effect was not seen in once-weekly or control groups. In daily and twice weekly IFA groups, positive change in cognition test scores was relatively higher in girls with good compliance(< 70 % dose) vs. poor compliance; in anemic (hemoglobin < 11 g/dL) vs non-anemic girls and in those with higher hemoglobin (Hb) gain (< 1g/dL) vs. lower Hb gain. CONCLUSION: Twice weekly IFA supplementation is comparable to daily IFA in terms of beneficial effects on cognition in young adolescent girls.