Personalized pathology maps to quantify diffuse and focal brain damage.

BACKGROUND AND OBJECTIVES: Quantitative MRI (qMRI) permits the quantification of brain changes compatible with inflammation, degeneration and repair in multiple sclerosis (MS) patients. In this study, we propose a new method to provide personalized maps of tissue alterations and longitudinal brain changes based on different qMRI metrics, which provide complementary information about brain pathology. METHODS: We performed baseline and two-years follow-up on (i) 13 relapsing-remitting MS patients and (ii) four healthy controls. A group consisting of up to 65 healthy controls was used to compute the reference distribution of qMRI metrics in healthy tissue. All subjects underwent 3T MRI examinations including T1, T2, T2* relaxation and Magnetization Transfer Ratio (MTR) imaging. We used a recent partial volume estimation algorithm to estimate the concentration of different brain tissue types on T1 maps; then, we computed a deviation map (z-score map) for each contrast at both time-points. Finally, we subtracted those deviation maps only for voxels showing a significant difference with healthy tissue in one of the time points, to obtain a difference map for each subject. RESULTS AND CONCLUSION: Control subjects did not show any significant z-score deviations or longitudinal z-score changes. On the other hand, MS patients showed brain regions with cross-sectional and longitudinal concomitant increase in T1, T2, T2* z-scores and decrease of MTR z-scores, suggesting brain tissue degeneration/loss. In the lesion periphery, we observed areas with cross-sectional and longitudinal decreased T1/T2 and slight decrease in T2* most likely related to iron accumulation. Moreover, we measured longitudinal decrease in T1, T2 - and to a lesser extent in T2* - as well as a concomitant increase in MTR, suggesting remyelination/repair. In summary, we have developed a method that provides whole-brain personalized maps of cross-sectional and longitudinal changes in MS patients, which are computed in patient space. These maps may open new perspectives to complement and support radiological evaluation of brain damage for a given patient.

Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: Drug survival is a marker for treatment sustainability in chronic diseases such as psoriasis. OBJECTIVE: The aim of these analyses was to assess survival of biologic treatments in the PSOriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a large, prospective, international, disease-based registry of patients with psoriasis receiving (or eligible for) systemic therapy in a real-world setting. Drug survival is defined as the time from initiation to discontinuation (stop/switch) of biologic therapy on registry. The number of patients who discontinued each treatment and the duration of therapy were recorded. Using Kaplan-Meier survival curves and Cox-regression analyses [hazard ratios (HR) and 95% confidence intervals (CIs)], time to discontinuation was compared across cohorts undergoing first-, second- or third-line treatment with ustekinumab, infliximab, adalimumab or etanercept. RESULTS: As of the 2013 data cut, 12 095 patients with psoriasis were enrolled in PSOLAR. Of the 4000 patients initiating any new biologic therapy, approximately 3500 started a first-line, second-line or third-line biologic therapy during the registry. Lack of effectiveness was the most common reason for discontinuation across biologic therapies. Based on the multivariate analysis, significantly shorter times to discontinuation were observed for infliximab [HR (95%CI) = 2.73 (1.48-5.04), P = 0.0014]; adalimumab [4.16 (2.80-6.20), P < 0.0001]; and etanercept [4.91 (3.28-7.35) P < 0.0001] compared with ustekinumab [reference treatment]) for first-line biologic use; results were similar for treatment effects for second/third-line therapies. Although limited in power, analyses in patients with concurrent psoriatic arthritis confirmed by a rheumatologist reflect observations in the overall psoriasis population. CONCLUSION: Drug survival was superior for ustekinumab compared with infliximab, adalimumab and etanercept in patients with psoriasis.

A multi-contrast MRI study of microstructural brain damage in patients with mild cognitive impairment.

OBJECTIVES: The aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI). METHODS: Forty-two MCI patients and 77 healthy controls (HC) underwent T1/T2* relaxometry as well as Magnetization Transfer (MT) MRI. Between-groups comparisons in MRI metrics were performed using permutation-based tests. Using MRI data, a generalized linear model (GLM) was computed to predict clinical performance and a support-vector machine (SVM) classification was used to classify MCI and HC subjects. RESULTS: Multi-parametric MRI data showed microstructural brain alterations in MCI patients vs HC that might be interpreted as: (i) a broad loss of myelin/cellular proteins and tissue microstructure in the hippocampus (p ≤ 0.01) and global white matter (p < 0.05); and (ii) iron accumulation in the pallidus nucleus (p ≤ 0.05). MRI metrics accurately predicted memory and executive performances in patients (p ≤ 0.005). SVM classification reached an accuracy of 75% to separate MCI and HC, and performed best using both volumes and T1/T2*/MT metrics. CONCLUSION: Multi-contrast MRI appears to be a promising approach to infer pathophysiological mechanisms leading to brain tissue alterations in MCI. Likewise, parametric MRI data provide powerful correlates of cognitive deficits and improve automatic disease classification based on morphometric features.

Improvement of scalp and nail lesions with ixekizumab in a phase 2 trial in patients with chronic plaque psoriasis.

BACKGROUND: Scalp and nail psoriasis have a major impact on quality of life and are traditionally resistant to therapy. Ixekizumab is a monoclonal antibody that targets IL-17A, a key cytokine in psoriasis pathogenesis. OBJECTIVE: Changes in nail and scalp psoriasis associated with ixekizumab treatment were evaluated in a post hoc analysis of a phase 2 study comprising a 20-week randomized, placebo-controlled (RCT) period and 48 weeks of an open-label extension (OLE) period. METHODS: There were 142 patients with moderate-to-severe plaque psoriasis at baseline of the RCT. Patients were randomized to receive placebo, 10, 25, 75 or 150 mg of ixekizumab injected subcutaneously at weeks 0, 2, 4, 8, 12 and 16. In the OLE, all patients received 120 mg ixekizumab every 4 weeks. Nail Psoriasis Severity Index (NAPSI) and Psoriasis Scalp Severity Index (PSSI) were used to evaluate nail and scalp psoriasis respectively. Fifty-eight (41.0%) patients had nail psoriasis (NAPSI > 0) and 105 (74.0%) had scalp psoriasis (PSSI > 0) at baseline; these cases were evaluated for the present analyses. RESULTS: At RCT week 20, patients with scalp psoriasis in the 25-, 75- and 150-mg groups had significant mean change and percent improvement from baseline PSSI of -16.3 (75.3%; P = 0.001), -11.6 (83.7%; P = 0.001) and -18.2 (82.2%; P < 0.001) respectively compared to -6.0 (18.8%) in placebo. Patients with nail psoriasis in the 75- and 150-mg groups had significant improvements from baseline NAPSI of -26.3 (63.8%; P = 0.003) and -23.1 (52.6%; P = 0.009) respectively compared to 0.4 (-1.7%) in placebo. By OLE week 48, 78.0% of patients with scalp psoriasis and 51.0% of patients with nail psoriasis experienced complete resolution of lesions (PSSI = 0 or NAPSI = 0). CONCLUSIONS: Ixekizumab monotherapy improved scalp psoriasis quickly with maintenance of clinical response and complete resolution of plaques in the majority of patients. Additionally, over 50.0% of patients with nail psoriasis experienced complete resolution of nail lesions by OLE week 48.

Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up.

BACKGROUND: Evaluation of the dosing flexibility and long-term efficacy of biological agents is limited. OBJECTIVES: To evaluate the long-term efficacy and safety of ustekinumab with and without dosing adjustment in the 5-year PHOENIX 2 study. METHODS: Patients were randomized to placebo or ustekinumab (45 or 90 mg) at weeks 0, 4, then every 12 weeks; patients receiving placebo crossed-over at week 12. Dosing adjustments were permitted at/beyond week 28 for early adjusters (weeks 28 or 40 per response); late adjusters (during long-term extension per investigator judgement); and nonadjusters (maintained randomized treatment throughout the study). Efficacy and safety were evaluated through weeks 244 and 264, respectively. RESULTS: In the overall population, 70% (849 of 1212) of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45-mg and 90-mg doses, respectively: 75% improvement in Psoriasis Area and Severity Index (PASI 75) (76·5% and 78·6%) and PASI 90 (50·0% and 55·5%). Approximately 20% of patients were early adjusters, 30% were late adjusters and 50% were nonadjusters. Approximately half of the late adjusters initiated adjustments after already achieving PASI 75. Improved response was generally observed following dosing adjustments. Through week 264, safety event rates did not increase and event rates were generally comparable between dose groups and between patients with and without dosing adjustment. CONCLUSIONS: Treatment with ustekinumab for up to 5 years was safe and effective. Improved response was generally demonstrated following dosing adjustments; further investigations are required to quantify actual incremental benefits. The results also suggest that some patients may desire treatment goals beyond PASI 75.

Patient satisfaction with treatments for moderate-to-severe plaque psoriasis in clinical practice.

BACKGROUND: Treatment satisfaction among patients with moderate-to-severe psoriasis has not been studied and compared across treatments using a validated instrument. OBJECTIVES: To assess patient-reported satisfaction with systemic and phototherapy treatments for moderate-to-severe psoriasis in clinical practice and to correlate satisfaction with disease severity and quality-of-life measures. METHODS: This was a cross-sectional study of 1182 patients with moderate-to-severe psoriasis in the Dermatology Clinical Effectiveness Research Network in the U.S.A. Patients receiving either topical therapies only; monotherapy with oral systemic therapies, biologics or narrowband ultraviolet B phototherapy; or combination therapy with biologics and methotrexate completed the Treatment Satisfaction Questionnaire for Medication version II. RESULTS: Median unadjusted overall satisfaction scores were highest for patients receiving biologic monotherapies, biologic-methotrexate combinations, or phototherapy (83.3); scores were lowest for those receiving topical therapies only or acitretin (66.7). In fully adjusted models, compared with patients receiving methotrexate monotherapy, those receiving adalimumab, etanercept, ustekinumab, phototherapy or adalimumab with methotrexate had significantly higher median overall satisfaction scores by 7.2-8.3 points, while those receiving topical therapies only had significantly lower overall satisfaction by 8.9 points. Adjusted convenience scores were lowest for patients receiving topical therapies only or infliximab. Modest but significant correlations were found between the overall satisfaction subscale and both the Psoriasis Area and Severity Index (ρ = -0.36, P < 0.001) and the Dermatology Life Quality Index (ρ = -0.47, P < 0.001). CONCLUSIONS: Discernible differences were found in treatment satisfaction among therapies, particularly regarding treatment effectiveness and convenience. Further application of treatment satisfaction measures may inform treatment decisions and guideline development.

Diagnosing and treating psoriatic arthritis: an update.

Psoriatic arthritis (PsA) is an inflammatory arthritis of uncertain pathogenesis, affecting approximately one in four patients with psoriasis. Onset of psoriasis typically precedes the development of PsA. Therefore, the dermatologist is ideally positioned to recognize the early signs and symptoms of PsA for diagnosis and subsequent treatment. The role of the dermatologist in early diagnosis and treatment is essential for preventing pain and functional disabilities, as well as the joint deterioration that accompanies progressive forms of PsA. Diagnosis of PsA is a key aspect of the clinical decision process for the dermatologist, as psoriasis plus PsA requires a different therapeutic approach from that required for psoriasis alone. Furthermore, PsA is associated with an increased risk of cardiovascular comorbidities that present significant health concerns. In this review, the pathogenesis and comorbidities of PsA are discussed. In addition, screening and imaging tools that aid in the diagnosis of PsA, as well as tools used for efficacy assessment, are reviewed. Available therapies are presented, with a focus on targeted biologics and emerging treatments.

Migraineurs without aura show microstructural abnormalities in the cerebellum and frontal lobe.

The involvement of the cerebellum in migraine pathophysiology is not well understood. We used a biparametric approach at high-field MRI (3 T) to assess the structural integrity of the cerebellum in 15 migraineurs with aura (MWA), 23 migraineurs without aura (MWoA), and 20 healthy controls (HC). High-resolution T1 relaxation maps were acquired together with magnetization transfer images in order to probe microstructural and myelin integrity. Clusterwise analysis was performed on T1 and magnetization transfer ratio (MTR) maps of the cerebellum of MWA, MWoA, and HC using an ANOVA and a non-parametric clusterwise permutation F test, with age and gender as covariates and correction for familywise error rate. In addition, mean MTR and T1 in frontal regions known to be highly connected to the cerebellum were computed. Clusterwise comparison among groups showed a cluster of lower MTR in the right Crus I of MWoA patients vs. HC and MWA subjects (p = 0.04). Univariate and bivariate analysis on T1 and MTR contrasts showed that MWoA patients had longer T1 and lower MTR in the right and left pars orbitalis compared to MWA (p < 0.01 and 0.05, respectively), but no differences were found with HC. Lower MTR and longer T1 point at a loss of macromolecules and/or micro-edema in Crus I and pars orbitalis in MWoA patients vs. HC and vs. MWA. The pathophysiological implications of these findings are discussed in light of recent literature.

Safety results from a pooled analysis of randomized, controlled phase II and III clinical trials and interim data from an open-label extension trial of the interleukin-12/23 monoclonal antibody, briakinumab, in moderate to severe psoriasis.

BACKGROUND: Anti-interleukin-12/23 treatment (anti-IL-12/23) has recently demonstrated significant efficacy for moderate to severe psoriasis, yet potential safety signals warrant further investigation. OBJECTIVES: Expand safety findings for the anti-IL-12/23, briakinumab, beyond individual phase II and III clinical trials. METHODS: Safety data pooled from five phase II and III clinical trials (parent studies) and an open-label extension study (OLE), through 22 October 2010; patients with ≥ 1 dose of briakinumab in a parent study or the OLE are included. All parent study briakinumab treatment groups were combined with the OLE population, which received 100-mg briakinumab every 4 weeks. Adverse events (AEs) were collected from the first dose of briakinumab, whether in a parent study or the OLE, through 45 days post-last dose. RESULTS: Two thousand five hundred and twenty patients (4704 patient-years drug exposure) received ≥ 1 dose of briakinumab during the interim period: 5.6% withdrew due to AEs. Serious infections occurred in 1.3% and malignancies in 2.6% (including 1.0% basal cell carcinoma, 0.8% squamous cell carcinoma). Twenty-seven major adverse cardiovascular events (MACE) occurred, seven in one parent study and 20 in the OLE (incidence = 0.57 events/100 PY). Four cardiovascular risk factors were retrospectively found to be significant predictors for MACE during briakinumab exposure: history of cardiovascular disease, diabetes, body mass index (≥ 30) and baseline blood pressure (systolic ≥ 140 or diastolic ≥ 90). CONCLUSIONS: Pooled briakinumab safety results from five parent studies and an OLE suggest increased rates of infections, malignancies and MACE, and that patients receiving anti-IL-12/23 treatment for moderate to severe psoriasis should be monitored for these potential safety signals.

A multi-center study: intra-scan and inter-scan variability of diffusion spectrum imaging.

The objective of this study was to investigate whether it is possible to pool together diffusion spectrum imaging data from four different scanners, located at three different sites. Two of the scanners had identical configuration whereas two did not. To measure the variability, we extracted three scalar maps (ADC, FA and GFA) from the DSI and utilized a region and a tract-based analysis. Additionally, a phantom study was performed to rule out some potential factors arising from the scanner performance in case some systematic bias occurred in the subject study. This work was split into three experiments: intra-scanner reproducibility, reproducibility with twin-scanner settings and reproducibility with other configurations. Overall for the intra-scanner and twin-scanner experiments, the region-based analysis coefficient of variation (CV) was in a range of 1%-4.2% and below 3% for almost every bundle for the tract-based analysis. The uncinate fasciculus showed the worst reproducibility, especially for FA and GFA values (CV 3.7-6%). For the GFA and FA maps, an ICC value of 0.7 and above is observed in almost all the regions/tracts. Looking at the last experiment, it was found that there is a very high similarity of the outcomes from the two scanners with identical setting. However, this was not the case for the two other imagers. Given the fact that the overall variation in our study is low for the imagers with identical settings, our findings support the feasibility of cross-site pooling of DSI data from identical scanners.

Temporal SNR characteristics in segmented 3D-EPI at 7T.

Three-dimensional segmented echo planar imaging (3D-EPI) is a promising approach for high-resolution functional magnetic resonance imaging, as it provides an increased signal-to-noise ratio (SNR) at similar temporal resolution to traditional multislice 2D-EPI readouts. Recently, the 3D-EPI technique has become more frequently used and it is important to better understand its implications for fMRI. In this study, the temporal SNR characteristics of 3D-EPI with varying numbers of segments are studied. It is shown that, in humans, the temporal variance increases with the number of segments used to form the EPI acquisition and that for segmented acquisitions, the maximum available temporal SNR is reduced compared to single shot acquisitions. This reduction with increased segmentation is not found in phantom data and thus likely due to physiological processes. When operating in the thermal noise dominated regime, fMRI experiments with a motor task revealed that the 3D variant outperforms the 2D-EPI in terms of temporal SNR and sensitivity to detect activated brain regions. Thus, the theoretical SNR advantage of a segmented 3D-EPI sequence for fMRI only exists in a low SNR situation. However, other advantages of 3D-EPI, such as the application of parallel imaging techniques in two dimensions and the low specific absorption rate requirements, may encourage the use of the 3D-EPI sequence for fMRI in situations with higher SNR.

Ustekinumab improves health-related quality of life in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial.

Background PHOENIX 1 was a phase III, randomized, double-blind, placebo-controlled study that demonstrated the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis. Objectives To assess the effect of ustekinumab maintenance therapy on health-related quality of life (HRQoL) in PHOENIX 1 patients. Patients and methods Patients (n = 766) were randomized to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and every 12 weeks thereafter, or placebo (n = 255) at weeks 0 and 4 with crossover to ustekinumab at week 12. Ustekinumab-randomized patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI) 75 at weeks 28 and 40 were re-randomized at week 40 to continue ustekinumab or be withdrawn until loss of therapeutic effect. HRQoL was assessed using the SF-36 and Dermatology Life Quality Index (DLQI). Results At baseline, more than 97% had a DLQI > 1 and the average DLQI was > 10, indicating a significant impact on patients' HRQoL. Significantly greater proportions of patients receiving ustekinumab 45 and 90 mg achieved a normalized DLQI score (< or = 1) compared with placebo (53.2%, 52.4% and 6.0%, respectively, both P < 0.001) at week 12 and achieved a clinically meaningful improvement (increase of at least five points) in SF-36 physical (23.1%, 33.7% and 15.6%) and mental (25.5%, 31.3% and 14.8%) component summary scores. At week 12, changes in individual DLQI and SF-36 domains were significantly better in each ustekinumab group vs. placebo (P < 0.001). The magnitude of improvement across SF-36 scales was greatest for the bodily pain and social functioning domains. Improvements in HRQoL were sustained with maintenance ustekinumab therapy through at least 1 year. Regression analysis showed that, after adjustment for improvement in PASI or Physician's Global Assessment (PGA), ustekinumab-treated patients demonstrated significant improvements in DLQI. Conclusions Ustekinumab improves HRQoL in patients with moderate-to-severe psoriasis. Patient-reported outcomes measured a treatment effect beyond that indicated by clinical measures.

Plaque thickness and morphology in psoriasis vulgaris associated with therapeutic response.

BACKGROUND: The Utah Psoriasis Initiative (UPI) is an expanding database that is being used to identify and characterize phenotypic variants of psoriasis and explore genotype-phenotype relationships. We recently reported distinct morphological variants of psoriasis that are characterized by thickness of lesions (induration) in the untreated state. OBJECTIVES: To explore the clinical relevance of these morphological variants. METHODS: For these analyses, we used the phenotypic data from 282 additional subjects gathered at enrollment into the UPI and compared their phenotype with that of the original 500 patients reported previously. The analysis was further expanded via a longitudinal follow-up of 286 subjects from the original 500 case cohort. RESULTS: Firstly, the initial findings were confirmed. Expansion of the cohort used for the original observation by about 50% and reanalysis showed that there was no alteration in the proportions of patients expressing thin- and thick-plaque disease phenotypes. Secondly, analysis of the larger cohort showed that this morphological phenotype had clinical relevance: those patients with thin-plaque disease were more likely to report a complete therapeutic response to topical corticosteroids and phototherapy. In contrast, plaque thickness did not appear to be a factor in response to systemic agents. CONCLUSIONS: Using a patient's baseline plaque morphology to choose a primary treatment modality may result in earlier disease improvement and reduce the cost of therapy.

Investigations on spinal cord fMRI of cats under ketamine.

Functional magnetic resonance imaging (fMRI) of the spinal cord has been the subject of intense research for the last ten years. An important motivation for this technique is its ability to detect non-invasively neuronal activity in the spinal cord related to sensorimotor functions in various conditions, such as after spinal cord lesions. Although promising results of spinal cord fMRI have arisen from previous studies, the poor reproducibility of BOLD activations and their characteristics remain a major drawback. In the present study we investigated the reproducibility of BOLD fMRI in the spinal cord of cats (N=9) by repeating the same stimulation protocol over a long period (approximately 2 h). Cats were anaesthetized with ketamine, and spinal cord activity was induced by electrical stimulation of cutaneous nerves of the hind limbs. As a result, task-related signals were detected in most cats with relatively good spatial specificity. However, BOLD response significantly varied within and between cats. This variability was notably attributed to the moderate intensity of the stimulus producing a low amplitude haemodynamic response, variation in end-tidal CO(2) during the session, low signal-to-noise ratio (SNR) in spinal fMRI time series and animal-specific vascular anatomy. Original contributions of the present study are: (i) first spinal fMRI experiment in ketamine-anaesthetized animals, (ii) extensive study of intra- and inter-subject variability of activation, (iii) characterisation of static and temporal SNR in the spinal cord and (iv) investigation on the impact of CO(2) end-tidal level on the amplitude of BOLD response.

Detailed genetic characterization of the interleukin-23 receptor in psoriasis.

Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (>2800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR(common)=0.67; P(comb)=4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P(Het)=0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.

Variants in the 5q31 cytokine gene cluster are associated with psoriasis.

A multitiered genetic association study of 25 215 single-nucleotide polymorphisms (SNPs) in three case-control sample sets (1446 patients and 1432 controls) identified three IL13-linked SNPs (rs1800925, rs20541 and rs848) associated with psoriasis. Although the susceptibility effects at these SNPs were modest (joint allelic odds ratios (ORs): 0.76 to 0.78; P(comb): 1.3E-03 to 2.50E-04), the association patterns were consistent across the sample sets, with the minor alleles being protective. Haplotype analyses identified one common, susceptible haplotype CCG (joint allelic OR=1.27; P(comb)=1.88E-04) and a less common, protective haplotype TTT (joint allelic OR=0.74; P(comb)=7.05E-04). In combination with the other known genetic risk factors, HLA-C, IL12B and IL23R, the variants reported here generate an 11-fold psoriasis-risk differential. Residing in the 5q31 cytokine gene cluster, IL13 encodes an important T-cell-derived cytokine that regulates cell-mediated immunity. These results provide the foundation for additional studies required to fully dissect the associations within this cytokine-rich genomic region, as polymorphisms in closely linked candidate genes, such as IRF1, IL5 or IL4, may be driving these results through linkage disequilibrium.