Persistence with Early-Line Abatacept versus Tumor Necrosis Factor-Inhibitors for Rheumatoid Arthritis Complicated by Poor Prognostic Factors.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling and destruction that leads to severe disability. There are no clear guidelines regarding the order of therapies. Gathering data on treatment patterns outside of a clinical trial setting can provide useful context for clinicians. Objectives: To assess real-world treatment persistence in early-line abatacept versus tumor necrosis factor-inhibitors (TNFi) treated patients with RA complicated by poor prognostic factors (including anti-cyclic citrullinated peptide antibodies [ACPA] and rheumatoid factor [RF] seropositivity). Methods: We performed a multi-center retrospective medical record review. Adult patients with RA complicated by poor prognostic factors were treated with either abatacept or TNFis as the first biologic treatment at the clinic. Poor prognostic factors included ACPA+, RF+, increased C-reactive protein levels, elevated erythrocyte sedimentation rate levels, or presence of joint erosions. We report 12-month treatment persistence, time to discontinuation, reasons for discontinuation, and risk of discontinuation between patients on abatacept versus TNFi. Select results among the subgroup of ACPA+ and/or RF+ patients are presented. Results: Data on 265 patients (100 abatacept, 165 TNFis) were collected. At 12 months, 83% of abatacept patients were persistent versus 66.1% of TNFi patients (P=0.003). Median time to discontinuation was 1423 days for abatacept versus 690 days for TNFis (P=0.014). In adjusted analyses, abatacept patients had a lower risk of discontinuing index treatment due to disease progression (0.3 [95% confidence interval (CI): 0.1-0.6], P=0.001). Among the subgroup of ACPA+ and/or RF+ patients (55 abatacept, 108 TNFis), unadjusted 12-month treatment persistence was greater (83.6% versus 64.8%, P=0.012) and median time to discontinuation was longer (961 days versus 581 days, P=0.048) in abatacept versus TNFi patients. Discussion: Patients with RA complicated by poor prognostic factors taking abatacept, including the subgroup of patients with ACPA and RF seropositivity, had statistically significantly higher 12-month treatment persistence and a longer time to discontinuation than patients on TNFis. Conclusions: In a real-world setting, RA patients treated with abatacept were more likely to stay on treatment longer and had a lower risk of discontinuation than patients treated with TNFis.

Risk and cost of infection-related hospitalizations in medicare beneficiaries with comorbid rheumatoid arthritis treated with abatacept versus other targeted disease-modifying anti-rheumatic drugs.

OBJECTIVE: This study evaluated infection-related hospitalization risk and cost in tumor necrosis factor inhibitor (TNFi)-experienced and targeted DMARD (tDMARD) naïve rheumatoid arthritis (RA) patients that were treated with abatacept, TNFi, or other non-TNFi. METHODS: This retrospective study used 100% Medicare Fee-for-Service claims to identify patients ≥65 age, diagnosed with RA, and were either 1) TNFi-experienced, who switched from a TNFi to another tDMARD (subsequent tDMARD claim served as index), or 2) tDMARD naïve (first therapy claim served as index), who initiated either abatacept, TNFi, or non-TNFi as their first tDMARD, between 2010 and 2017. Follow-up ended at the date of disenrollment, death, end of study period, or end of index treatment, whichever occurred first. Infection-related hospitalizations included pneumonia, bacterial respiratory, sepsis, skin and soft tissue, joint or genitourinary infections. A Cox proportional hazard model and two part generalized linear model were developed to estimate adjusted infection-related hospitalization risk and costs. Costs were normalized to per-patient-per-month (PPPM) and inflated to 2019 US$. RESULTS: The infection-related hospitalizations rate was lower during follow-up than during baseline periods for abatacept users, but was reversed for both TNFi and other non-TNFi users in both TNFi-experience and tDMARD naïve (p value < .001 based on Breslow-Day test for homogeneity of odds ratios). Infection-related hospitalization PPPM cost was significantly lower in abatacept treated patients compared to TNFi (TNFi-experienced: by $74; tDMARD naïve: $42) and other non-TNFi (TNFi-experienced: by $68; tDMARD naïve: $60). The adjusted infection-related hospitalization risk was significantly higher for RA patients treated with TNFi (TNFi-experienced HR: 1.48; 95% CI: 1.26-1.75, p < .0001; tDMARD naïve HR:1.59; 95% CI: 1.43-1.77, p < .0001) and other non-TNFi (TNFi-experienced HR:1.46; CI:1.28-1.66; tDMARD naïve HR:1.63; 95% CI: 1.44-1.83) than with abatacept. CONCLUSION: RA Medicare Fee-For-Service beneficiaries who either switched or initiated abatacept have a lower infection-related hospitalization risk and cost compared to patients who switched to or initiated other tDMARDs.

A Cost per Responder Model for Abatacept versus Adalimumab Among Rheumatoid Arthritis Patients with Seropositivity.

PURPOSE: The primary objective of this study was to compare the cost per responder (CPR) between abatacept and adalimumab among seropositive rheumatoid arthritis (RA) patients. PATIENTS AND METHODS: CPR analysis was conducted from a US payer perspective over 24 weeks for early moderate-to-severe seropositive RA patients. Efficacy data (American College of Rheumatology [ACR] improvement criteria [ACR20/50/70] and DAS28-C reactive protein <2.6) for abatacept and adalimumab were sourced from the post hoc analysis of the Early AMPLE trial (NCT02557100). Medication costs were considered assuming complete adherence. A 30% rebate was applied for adalimumab in the base case. RESULTS: At week 24, the total per patient pharmacy cost was $26,273.34 and $21,731.18, whereas the CPR (using ACR70 as the responder definition) was $46,337.46 and $74,935.10 (difference of -$28,597.64) for abatacept and adalimumab, respectively. The CPR was consistently lower for abatacept compared to adalimumab across all clinical measures, with differences ranging from -$7099.32 to -$43,608.97. CONCLUSION: While the pharmacy cost was higher for abatacept compared to adalimumab, due to its higher clinical efficacy, the CPR was consistently lower for seropositive RA patients treated with abatacept. The results may be useful for healthcare decision-makers in understanding how to optimize treatment for seropositive RA patients while minimizing costs in today's budget-constrained health environment.

Comparison of infection-related hospitalization risk and costs in tumor necrosis factor inhibitor-experienced patients with rheumatoid arthritis (RA) treated with abatacept or other targeted disease-modifying anti-rheumatic drugs (tDMARDs).

Background: Evidence on the cost and risk of infection-related hospitalizations associated with targeted disease-modifying anti-rheumatic drugs (tDMARDs) in patients with RA previously treated with a tumor necrosis factor inhibitor (TNFi) is limited. This study compared the risk and cost of infection-related hospitalizations in commercially insured TNFi-experienced RA patients receiving abatacept, TNFi, or another non-TNFi.Methods: A retrospective observational study was conducted using 2 large insurance claims databases (1 January 2009-30 June 2017). Adult TNFi-experienced RA patients initiating a subsequent tDMARD (initiation date of tDMARD = index date) with 12 months of continuous enrollment pre-index date, and who had ≥1 inpatient or ≥2 outpatient medical RA claims on 2 different dates were included. Abatacept was compared to TNFis (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) and other non-TNFis (tocilizumab, rituximab, and tofacitinib). Cox proportional hazards models estimated the adjusted risk for infection-related hospitalization; costs were calculated on a per-member-per-month (PMPM) and per-patient-per-month (PPPM) basis using generalized linear models.Results: More patients in the abatacept cohort had an infection-related hospitalization at baseline (4.5%) vs TNFis (2.0%, p < .0001) and other non-TNFis (3.6%, p = .2619). However, during follow-up abatacept patients had fewer infection-related hospitalizations (abatacept: 2.8%, TNFi: 3.7% and other non-TNFis: 5.2%; p < .05). Regression results indicated that compared to patients on abatacept, patients receiving a TNFi [HR: 1.6 (95% CI: 1.1, 2.2)] and other non-TNFis [HR: 1.9 (95% CI: 1.3, 2.8)] had a significantly higher risk of infection-related hospitalization. Abatacept PMPM costs were lowest ($0.25 vs $0.39 and $0.43 for TNFi and other non-TNFi respectively). Mean PPPM (95% CI) cost in the follow-up was lower for abatacept compared to TNFi ($73 vs. $115; p = .042), and other non-TNFi ($73 vs. $125; p = .039).Conclusions: There were significantly lower infection-related hospitalizations and associated costs in TNF-experienced RA patients treated with abatacept than TNFis and other non-TNFis.

A budget impact analysis for making treatment decisions based on anti-cyclic citrullinated peptide (anti-CCP) testing in rheumatoid arthritis.

Aim: Given that rheumatoid arthritis (RA) patients with high anti-citrullinated protein antibodies (ACPA) titer values respond well to abatacept, the aim of this study was to estimate the annual budget impact of anti-cyclic citrullinated peptide (anti-CCP) testing and treatment selection based on anti-CCP test results.Materials and methods: Budget impact analysis was conducted for patients with moderate-to-severe RA on biologic or Janus kinase inhibitor (JAKi) treatment from a hypothetical US commercial payer perspective. The following market scenarios were compared: (1) 90% of target patients receive anti-CCP testing and the results of anti-CCP testing do not impact the treatment selection; (2) 100% of target patients receive anti-CCP testing and the results of anti-CCP testing have an impact on treatment selection such that an increased proportion of patients with high titer of ACPA receive abatacept. A hypothetical assumption was made that the use of abatacept would be increased by 2% in Scenario 2 versus 1. Scenario analyses were conducted by varying the target population and rebate rates.Results: In a hypothetical health plan with one million insured adults, 2,181 patients would be on a biologic or JAKi treatment for moderate-to-severe RA. In Scenario 1, the anti-CCP test cost was $186,155 and annual treatment cost was $101,854,295, totaling to $102,040,450. In Scenario 2, the anti-CCP test cost increased by $20,684 and treatment cost increased by $160,467, totaling an overall budget increase of $181,151. This was equivalent to a per member per month (PMPM) increase of $0.015. The budget impact results were consistently negligible across the scenario analyses.Limitations: The analysis only considered testing and medication costs. Some parameters used in the analysis, such as the rebate rates, are not generalizable and health plan-specific.Conclusions: Testing RA patients to learn their ACPA status and increasing use of abatacept among high-titer ACPA patients result in a small increase in the total budget (<2 cents PMPM).

IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM.

Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) in humans is often described as asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that mucosal secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and taxa-specific antibody coating of the gut microbiota in 15 sIgAd subjects and matched controls. Despite the secretion of compensatory IgM into the gut lumen, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls. These alterations were characterized by a trend towards decreased overall microbial diversity as well as significant shifts in the relative abundances of specific microbial taxa. While secretory IgA in healthy controls targeted a defined subset of the microbiota via high-level coating, compensatory IgM in sIgAd subjects showed less specificity than IgA and bound a broader subset of the microbiota. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community.

Antibiotics and autoimmune and allergy diseases: Causative factor or treatment?

The newborn infant emerges from an almost sterile environment into a world of bacteria. Bacteria colonize the infant's skin, lungs, and, of most importance, the gut. The process of bacterial colonization is coordinated, and each body niche acquires a unique composition of bacteria. In the gut, most bacteria belong to the Firmicutes and Bacteroidetes phyla, while Actinobacteria and Proteobacteria are far less abundant. Some of these bacteria possess strong immunoregulatory properties. Bacterial colonization is essential to skew the newborn's immune response away from the allergy-favoring Type-2 response towards a Type-1 immune response, which is essential for pathogen elimination. Imbalance between Type 1 and Type 2 responses, however, can promote autoimmunity. In addition, the microbiota shapes immune responses in adults. Autoimmune and allergic diseases are commonly associated with an altered composition of resident bacteria, which is known as dysbiosis. Perhaps the most common cause of disruption and alteration of the bacterial colonization of newborns is the use of antibiotics. It is not known whether the dysbiosis precedes or is the consequence of allergic and autoimmune disorders, and whether antibiotics can be a trigger for these disorders, depending on the type of antibiotic used and the maturity of immune system. In this review, we discuss the development of the microbiota in different body niches and their immunomodulatory potential. We evaluate the impact of antibiotics, both in mice and in humans, on microbial communities and how that may impact the development and manifestation of diseases through all stages of life: the prenatal period, childhood, and adulthood.

Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model.

BACKGROUND: Medical advances in the field of infection therapy have led to an increasing use of antibiotics, which, apart from eliminating pathogens, also partially eliminate naturally existing commensal bacteria. It has become increasingly clear that less exposure to microbiota early in life may contribute to the observed rise in "immune-mediated" diseases, including autoimmunity and allergy. OBJECTIVE: We sought to test whether the change of gut microbiota with the broad spectrum antibiotic enrofloxacin will modulate contact sensitivity (CS) in mice. METHODS: Natural gut microbiota were modified by oral treatment with enrofloxacin prior to sensitization with trinitrophenyl chloride followed by CS testing. Finally, adoptive cell transfers were performed to characterize the regulatory cells that are induced by microbiota modification. RESULTS: Oral treatment with enrofloxacin suppresses CS and production of anti-trinitrophenyl chloride IgG1 antibodies. Adoptive transfer experiments show that antibiotic administration favors induction of regulatory cells that suppress CS. Flow cytometry and adoptive transfer of purified cells show that antibiotic-induced suppression of CS is mediated by TCR αß+CD4+CD25+FoxP3+ Treg, CD19+B220+CD5+ IL-10+, IL-10+ Tr1, and IL-10+ TCR γδ+ cells. Treatment with the antibiotic induces dysbiosis characterized by increased proportion of Clostridium coccoides (cluster XIVa), C coccoides-Eubacterium rectale (cluster XIVab), Bacteroidetes, and Bifidobacterium spp, but decreased segmented filamentous bacteria. Transfer of antibiotic-modified gut microbiota inhibits CS, but this response can be restored through oral transfer of control gut bacteria to antibiotic-treated animals. CONCLUSIONS: Oral treatment with a broad spectrum antibiotic modifies gut microbiota composition and promotes anti-inflammatory response, suggesting that manipulation of gut microbiota can be a powerful tool to modulate the course of CS.

Epicutaneous immunization with ovalbumin and CpG induces TH1/TH17 cytokines, which regulate IgE and IgG2a production.

BACKGROUND: Subcutaneous allergen-specific immunotherapy is a standard route for the immunotherapy of allergic diseases. It modulates the course of allergy and can generate long-term remission. However, subcutaneous allergen-specific immunotherapy can also induce anaphylaxis in some patients, and therefore additional routes of administration should be investigated to improve the safety and tolerability of immunotherapy. OBJECTIVE: We sought to determine whether epicutaneous treatment with antigen in the presence of a Toll-like receptor 9 agonist can suppress TH2-mediated responses in an antigen-specific manner. METHODS: Epicutaneous immunization was performed by applying a skin patch soaked with ovalbumin (OVA) plus CpG, and its suppressor activity was determined by using the mouse model of atopic dermatitis. Finally, adoptive cell transfers were implemented to characterize the regulatory cells that are induced by epicutaneous immunization. RESULTS: Epicutaneous immunization with OVA and CpG reduces the production of OVA-specific IgE and increases the synthesis of OVA-specific IgG2a antibodies in an antigen-specific manner. Moreover, eosinophil peroxidase activity in the skin and production of IL-4, IL-5, IL-10, and IL-13 are suppressed. The observed reduction of IgE synthesis is transferable with T-cell receptor (TCR) αß(+)CD4(+)CD25(-) cells, whereas IgG2a production is dependent on both TCRαß(+) and TCRγδ(+) T cells. Further experiments show that the described phenomenon is myeloid differentiation primary response 88, IFN-γ, and IL-17A dependent. Finally, the results suggest that epicutaneous immunization with OVA and CpG decreases the synthesis of OVA-specific IgE and skin eosinophil peroxidase activity in mice with ongoing skin allergy. CONCLUSION: Epicutaneous application of protein antigen in the presence of adjuvant could be an attractive needle-free and self-administered immunotherapy for allergic diseases.

Relationship between glycemic control and diabetes-related hospital costs in patients with type 1 or type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus requires continuous medical care and patient self-management in order to prevent short-term complications and decrease the risk of long-term complications, which can result in substantial increases in the total economic burden of the disease. Findings from randomized clinical trials have shown that improved glycemic control may reduce the risk of long-term complications as long as a target for hemoglobin A1c is not set below 7% for intensive glycemic control. However, limited data from clinical practice are available regarding the relationship between glycemic control and medical costs associated with diabetes care. OBJECTIVE: To assess the potential relationships between glycemic levels, diabetes-related hospitalizations, and hospital costs among adult patients with either type 1 or type 2 diabetes mellitus who were assigned to a primary care provider (PCP) in a clinic that was affiliated with a managed care organization (MCO). METHODS: A retrospective cohort analysis was conducted using data from approximately 200,000 members of the Fallon Clinic Health Plan who were assigned to a clinic PCP at any time during a 5-year study period beginning January 1, 2002, and ending December 31, 2006. Patients aged 30 years or older with at least 2 medical claims with any listed diagnosis of diabetes mellitus (ICD-9-CM code 250.xx) during the study period and 2 or more A1c values within 1 year of each other during the study period (mean 7.6 tests over 39 months; median=6.8), were identified and stratified into 1 of 5 groups defined by 1% increments of A1c, based on their mean A1c values during the entire study period. A1c data were available only for tests ordered by a clinic provider; tests ordered by other specialists in the MCO's network were absent from the database. The study follow-up period started with each patient's first A1c test (index date) and continued until plan disenrollment, death, or December 31, 2006, whichever was earlier (end date), regardless of when the diagnosis of diabetes mellitus was made. Study measures included the proportion of patients with 1 or more diabetes-related hospitalizations, number of diabetes-related inpatient stays, and the associated estimated hospitalization costs over the follow-up period. Diabetes-related hospitalizations were identified based on a diagnosis, in any of 10 diagnosis fields, for 1 of 16 selected complications of diabetes identified by the authors. Hospital costs were estimated using discharge data (diagnoses and costs calculated from cost-to-charge ratios) contained in the 2004 Healthcare Cost and Utilization Project (HCUP) database and inflated to 2007 dollars using the medical care component of the Consumer Price Index. Multivariate models controlled for age, sex, number of A1c tests, diagnosis of cancer, and follow-up time. A multivariate logistic regression analysis was conducted with the occurrence of at least 1 diabetes-related hospital admission as the dependent variable. In the logistic regression analysis, follow-up time was defined as time from the index date to the date of the first diabetes-related hospitalization, plan disenrollment, death, or the study end date, whichever occurred first. A generalized linear model with a Poisson distribution and a log link was employed to estimate the rate of hospital admissions. In the Poisson regression analysis, follow-up time was defined as duration of the entire study follow-up period and was an offset variable. Costs were estimated using a 2-part model: first, we calculated the probability of having a hospitalization, as determined by the logistic regression above; second, a generalized linear model with a negative binomial distribution and a log link was used to predict the mean cost of diabetes-related hospitalizations only for patients with an inpatient stay, with the duration of the entire study follow-up period as an offset variable. We calculated the mean per patient cost of diabetes-related hospitalizations by multiplying the probability of having a hospitalization (as determined by the first part of the model) by the mean costs for patients who had such admissions (as determined by the second part of the model). RESULTS: 9,887 patients met study selection criteria. Mean A1c level was < 7% for 5,649 (57.1%) patients, 7% to < 8% for 2,747 (27.8%), 8% to < 9% for 1,002 (10.1%), 9% to < 10% for 312 (3.2%), and 10% or more for 177 (1.8%). Over a mean (median) 40 (40) months of follow-up (interquartile range = 30-50 months), 28.7% (n = 2,838) of patients had 1 or more diabetes- related hospital admissions. In the logistic regression analysis, odds of having at least 1 diabetes-related hospital stay did not significantly differ for patients with mean A1c of < 7% compared with patients in most higher mean A1c categories (7% to < 8%, 8% to < 9%, or 9% to < 10%); however, odds of having a diabetes-related hospitalization were significantly higher for patients with mean A1c of 10% or more compared with patients with mean A1c of < 7% (odds ratio = 2.13, 95% confidence interval = 1.36-3.33). In the negative binomial regression analysis of those with at least 1 hospital admission, estimated costs per hospitalized patient increased by mean A1c level. In the Poisson regression analysis, the rate of diabetes-related hospitalizations significantly increased by A1c level (13 per 100 patient-years for patients with mean A1c of < 7% vs. 30 per 100 patient-years for mean A1c of 10% or more when covariates were held at mean levels, P<0.001). In the 2-part model results, adjusted mean estimated costs of diabetes-related hospitalizations per study patient were $2,792 among those with mean A1c of < 7% and $6,759 among those with mean A1c of 10% or more. CONCLUSIONS: In this managed-care plan, the odds of having at least 1 diabetes-related hospitalization were not significantly associated with higher mean A1c except for patients with mean A1c of at least 10%. However, higher mean A1c levels were associated with significantly higher estimated hospitalization costs among those with at least 1 hospitalization and with higher rates of diabetes-related hospital utilization per 100 patient-years.

Role of TLR ligands in epicutaneously induced contrasuppression.

Our previous work showed that epicutaneous (EC) immunization in mice with protein antigen (Ag) induced an Ag-independent unresponsiveness mediated by suppressor CD4(+)8(+) T cells (Ts), which inhibited contact hypersensitivity (CS). Simultaneous EC immunization with Ag and various Toll-like receptor (TLR) ligands reversed skin-induced suppression. Our present study shows that this process activates Ag-specific T contrasuppressor (Tcs) cells and leads to the protection of CS effector T cells from suppression. Epicutaneous immunization with Ag and the TLR4 ligand lipopolysaccharide (LPS) led to a significant increase in IFN-gamma production by lymph node and spleen cells. Ag and TLR ligands, like LPS, CpG or lipoteichoic acid did not need to be applied concomitantly to the skin. An identical contrasuppressive effect was observed when the Ag and TLR ligands were deposited on distant skin areas, suggesting that both the generation of Ts and Tcs are independent. To corroborate this finding, we used a model system that uses macrophages (Mf) as Ag-presenting cells. Mf labeled in vitro with Ag (Mf-Ag) induced, upon intravenous (iv) administration, an unresponsiveness reaction that was mediated by Ts cells. When treated simultaneously with LPS-treated Mf (Mf-Ag-LPS), a TLR-ligand could induce CS. Both the Ag and the LPS signal could be uncoupled i.e., Mf-Ag and Mf-LPS given at separate time points (with an 1 h interval between injections) induced immunity.We also found that LPS-treated Mf also produced significant amounts of IL-12, a cytokine that has well-known anti-tolerogenic properties. Our experiments suggest that reversal of EC-induced suppression by TLR-ligands may be a potential tool to increase the immunogenicity of weakly immunogenic antigens.

Epicutaneous immunization with protein antigen in the presence of TLR4 ligand induces TCR alpha beta+CD4+ T contrasuppressor cells that reverse skin-induced suppression of Th1-mediated contact sensitivity.

Our previous work showed that epicutaneous (EC) immunization of mice with different protein Ags applied on the skin in the form of a patch induces a state of subsequent Ag-nonspecific unresponsiveness due to suppressor CD4+8+ T cells (Ts) that inhibit Th1-mediated contact sensitivity (CS) reactions via released TGF-beta. In the present work we show that EC immunization with Ag together with the TLR4 ligand LPS induced cells that could prevent suppression by the Ag-nonspecific Ts. These up-regulatory cells, called contrasuppressor T cells (Tcs), belong to a population of Ag-specific TCRalphabeta CD4+ lymphocytes and are different from Th1 CD4+ cells that mediate the CS reaction. Experiments using knockout mice showed that EC induced contrasuppression is MyD88, INF-gamma, and IL-12 dependent, whereas IL-6 is not involved in this phenomenon. Additional experiments with anti-IFN-gamma mAb showed that IFN-gamma is required for induction of Tcs cells but does not play a crucial role in the effector phase of contrasuppression. Additionally, treatment of CS effector cells with rIL-12 makes them resistant to EC induced suppression without affecting Ts cells, whereas IL-12 neutralization in vitro abrogates contrasuppression. These data show that IL-12 is indeed involved in the effector phase of EC induced contrasuppression and that this cytokine does not act directly on Ts cells. The mechanism of action of Tcs protects Th1 effector cells mediating CS from the nonspecific Ts, leaving suppression to other Ags intact. Ts and Tcs cells do not influence each other and can be induced simultaneously in the same animal.

What do physicians know about normal pressure hydrocephalus and when did they know it? A survey of 284 physicians.

Normal pressure hydrocephalus (NPH) is a relatively new neurologic disorder first described by Salamon Hakim of Bogotá, Colombia, in 1965. NPH is characterized by three symptoms - impaired gait, incontinence and dementia - and an anatomic abnormality, i.e., enlargement of the cerebral ventricles, which can be seen on computerized tomographic or magnetic resonance imaging. Surprisingly, the intracranial pressure is normal. The first author of this article, a Yale Medical School faculty member, developed NPH over the decade from 1992 to 2002, during which it was erroneously diagnosed as cerebral atrophy and/or Parkinson's disease. On recognizing the lack of awareness of NPH by physicians, he initiated a survey to explore this problem. He interviewed 166 practicing physicians who graduated from 50 American and 33 foreign medical schools, using a one-page, 10-point questionnaire (Part I). Almost one-third of the physicians had never heard of NPH. One-fifth had learned of NPH in medical school, and about half learned of it after medical school. Because there were insufficient physicians surveyed from 1986 to 2005, we recruited 118 additional physicians from the 20 Yale Medical School graduating classes from 1986 through 2005 (Part II). Two-thirds of them had learned of NPH in medical school, and one-fourth during residency and fellowship. Seven percent had never heard of NPH. The significance of these studies is discussed.

The impact of psoriasis on health care costs and patient work loss.

BACKGROUND: There are few comprehensive estimates of the cost of psoriasis in the United States. OBJECTIVE: We sought to quantify the incremental direct medical and indirect work loss costs associated with psoriasis. METHODS: A de-identified claims database from 31 self-insured employers during the period 1998 to 2005 was used. Patients with at least two psoriasis diagnosis claims (N = 12,280) were compared with 3 control subjects (matched on year of birth and sex) without psoriasis. Multivariate two-part regression analysis was used to isolate the incremental cost of psoriasis by controlling for comorbidities and other confounding factors. RESULTS: After multivariate adjustment, the incremental direct and indirect costs of psoriasis were approximately $900 and $600 (P < .001) per patient per year, respectively. LIMITATIONS: The database used in this study does not contain information on patient out-of-pocket costs or loss of productivity costs at work. CONCLUSION: The incremental cost of psoriasis is approximately $1500 per patient per year, with work loss costs accounting for 40% of the cost burden.

The direct and indirect cost burden of atopic dermatitis: an employer-payer perspective.

The goal of this study was to quantify the incremental direct medical and indirect work-loss costs associated with patients diagnosed with atopic dermatitis (AD). A de-identified administrative claims database was used comprising 5.1 million covered beneficiaries from 31 Fortune 500 self-insured employers between 1998 and 2005. Patients with at least two AD diagnosis claims (N = 13,749) were compared with three matched controls (based on yr of birth and gender) with no AD diagnosis (N = 41,247). In addition, a multivariate two-part regression analysis was used to isolate the cost increase attributable to AD by controlling for confounding factors such as age, gender, health plan type, comorbidities, organ transplantation, industry of employer, region, and year. Direct medical and indirect work-loss costs for the AD group were higher on average by $88 and $64 per patient per month, respectively (both P< .001). After multivariate adjustment, the total incremental cost per patient per month for the AD group was $83 (direct: $52, P< .001; indirect: $31, P< .001). Employer-payers experience a significant annual cost burden of $991 per patient attributable to AD. Employee disability and increased sick days account for 38% of the cost burden.

Addressing the issue of channeling bias in observational studies with propensity scores analysis.

Randomized Clinical Trials (RCTs) remain the gold standard for determining the utility of pharmaceuticals especially from a safety and efficacy standpoint. However, restrictive entry criteria and stringent protocols can be barriers to generalizing RCT findings to real world practices and outcomes. Observational studies overcome these limitations of RCTs since they are representative of real world populations and practices. Nonetheless, attributing causality remains a major limitation in observational studies, due to the non-random assignment of subjects to treatment. Non-random assignment can lead to imbalances in risk-factors between the groups being compared and thus bias the estimates of the treatment effect. Non-random assignment can be particularly problematic in observational studies comparing older versus newer pharmaceuticals from similar therapeutic classes due to the phenomenon of channeling. Channeling occurs when drug therapies with similar indications are preferentially prescribed to groups of patients with varying baseline prognoses. In this manuscript we discuss the phenomenon of channeling and the use of a statistical technique known an propensity scores analysis which potentially adjusts for the effects of channeling. During the course of this manuscript we discuss tests for determining the quality of the derived propensity score, various techniques for utilizing propensity scores, and also the potential limitations of this technique. With the increasing availability of high quality pharmaceutical and medical claims data for use in observational studies, increased attention must be given to analytic techniques that adjust optimally for non-random assignment and resulting channeling bias. For research studies using observational study designs, propensity score analysis offers a reasonable solution to address the limitation of non-random assignment, especially when RCTs are too costly, time-consuming or not ethically feasible.

Amprenavir-induced maculopapular exanthem followed by desensitization in a patient with late-stage human immunodeficiency virus.

BACKGROUND: Amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is approved for the treatment of HIV infection in combination with other antiretroviral agents in treatment-naive and experienced patients. Amprenavir is generally well tolerated. However, cutaneous hypersensitivity reactions to amprenavir occur in up to 28% of patients, with treatment discontinuation required in 3% of cases. OBJECTIVE: To report successful desensitization to amprenavir after the occurrence of a maculopapular exanthem in an HIV-infected patient with late-stage disease and limited antiretroviral treatment options. METHODS: Incremental doses of 0.025, 0.1, 0.25, 1, 2.5, 7.5, 25, 50, 100, 300, 600, and 1,200 mg of amprenavir oral solution were administered via percutaneous endoscopic gastrostomy tube at 20- to 30-minute intervals. RESULTS: The patient successfully tolerated amprenavir desensitization and has continued therapy without recurrence of rash at 19 months of follow-up. CONCLUSION: Desensitization may permit the continued use of amprenavir in HIV-positive patients with a history of amprenavir-induced maculopapular eruptions who have limited alternate treatment options.

Toll-like receptor ligands reverse suppression of contact hypersensitivity reactions induced by epicutaneous immunization with protein antigen.

BACKGROUND: Epicutaneous (EC) immunization with protein antigens has been shown to induce antigen nonspecific suppression of subsequent T cell-dependent contact hypersensitivity (CS) reactions after active immunization. The aim of this work was to test if EC application of Toll-like receptor (TLR) ligands together with protein antigen could reverse suppression of CS. METHODS: Mice were EC immunized by applying gauze patches soaked with a solution of protein antigen alone or in the presence of crude bacterial material (bacterial lysates or heat-killed bacteria) or purified TLR ligands and then tested for CS response. To test if reversal of EC-induced suppression is antigen-specific, mice were patched with TNP- or OX-substituted mouse Ig alone or together with LPS and then tested for CS with corresponding or non-cross-reacting hapten. Influence of EC immunization on cytokine production by lymph node cells was measured by ELISA. RESULTS: EC immunization with protein antigen induces antigen nonspecific suppression that can be reversed by crude bacterial material as well as purified TLR-2, TLR-3, TLR-4, and TLR-9 ligands. The effect of TLR-4 ligand LPS was not observed in the Tlr-4 mutant C3H/HeJ mouse, indicating that this effect was dependent upon intact TLR-4 signaling. Unlike the antigen nonspecific suppression of CS by EC immunization with antigen alone, the reversal of suppression by TLR ligands was specific for the protein antigen applied in the EC protocol. CONCLUSIONS: Our results strongly suggest that EC immunization with protein antigen together with TLR ligands induces a particular antigen-specific cell population, akin to previously described contrasuppressor cells, which protects immune cells against the action of suppressor cells but have no direct influence on antigen nonspecific suppressor cells induced by antigen alone.

Estimation and comparison of derived preference scores from the SF-36 in lung transplant patients.

The purpose of this study was to estimate and compare preference scores derived from MOS Short Form-36 (SF-36) data for a sample of lung transplant patients using three methodologies: Fryback et al. (Med Decis Making 1997; 17: 1-9), Nichol et al. (Med Decis Making 2001; 21: 105-112) and Brazier et al. (J Health Econ 2002: 21: 271-292). Data were gathered from 99 lung transplant recipients using a mail survey, which included the SF-36 and other health-related quality of life (HRQL) measures. The mean preference score for the sample was 0.643 (range 0.43-0.83), 0.765 (range 0.36-1.0), and 0.697 (range 0.33-1.00) for Fryback, Nichol and Brazier methods, respectively. Correlations between the derived scores and visual analogue ratings of health (0.58-0.68) and pulmonary symptoms (-0.59 to -0.62) were moderate to good and in the expected directions. The mean preferences of patients grouped by levels of dyspnea, depression symptoms, illness burden, and self-rated general health differed significantly with all methods and supported the construct validity of the derived scores as measures of preference. The Nichol and Brazier scores, both derived with standard gamble utilities, were generally higher than Fryback scores, which are not utility-based. Given the popularity of the SF-36, these three methods could be useful where direct elicitation of preferences is not feasible. Researchers must be cognizant of the derivation method used, as absolute preference levels, hence quality adjusted life years (QALYs), will differ by method.