Serum Haptoglobin as a Predictor of Treatment Response in Patients With Chronic Spontaneous Urticaria

Experience-based advice on stepping up and stepping down the therapeutic management of chronic spontaneous urticaria: Where is the guidance?

The haptoglobin promoter polymorphism rs5471 is the most definitive genetic determinant of serum haptoglobin level in a Ghanaian population

Haptoglobin (HP) 2-2 phenotype has been suggested as a risk factor for cardiovascular disease (CVD) and to modulate fenofibrate benefit on CVD risk in Type 2 diabetes. However, little is known as to whether HP levels modulate CVD risk and fenofibrate response. Haptoglobin phenotype and levels were determined in 8047 Fenofibrate Intervention and Event Lowering in Diabetes trial participants at baseline and randomization (after a 16 week run-in period, including a 6 week fenofibrate therapy) and their association with new on-trial total CVD events over 5 years was assessed. Higher baseline HP levels were associated with total CVD events in the placebo group {n = 4030, hazard ratio [95% confidence interval (CI)] = 1.30 [1.02-1.66] for HP level Tertile 3 vs. Tertile 1, P = 0.035}. This was driven by participants with HP 1-1 phenotype (P for interaction = 0.011). Participants with the lowest baseline HP level tertile and HP 1-1 phenotype tended to have the lowest CVD risk, whereas CVD risk was similar in other participants, regardless of HP phenotype and levels. Fenofibrate benefit on total CVD events did not differ significantly by HP phenotypes, baseline HP level tertiles, or tertiles of change in HP levels by fenofibrate during active run-in. Higher baseline HP levels were associated with a higher CVD risk, especially in participants with HP 1-1 phenotype. A lower CVD risk is found only in Type 2 diabetes participants with both the HP 1-1 phenotype and low baseline HP levels. Fenofibrate benefits on CVD risk reduction did not differ by HP levels or phenotype. We evaluated the relationship of different forms or phenotypes of the blood protein, haptoglobin, and its circulating levels with the risk of developing CVD and fenofibrate benefit in patients with Type 2 diabetes, and showed that both HP phenotype and levels are important to assess CVD risk in patients with Type 2 diabetes, although fenofibrate did not modulate CVD risk via HP phenotype or level.Higher baseline HP levels were associated with higher CVD risk, especially in participants with HP 1-1 phenotype.Fenofibrate benefit on CVD did not differ by HP phenotype and baseline or change in HP levels.

The association between gut microbiota and circulating zonulin level, a marker of intestinal permeability, has not been studied yet. The aim of the study is the assessment of plasma zonulin, haptoglobin and proinflammatory cytokines (TNF-α and IL-6) levels in relation to composition of gut microbiota in obese and normal weight subjects. Circulating inflammation markers, such as TNF-α, sTNFR1, sTNFR2, IL-6, zonulin, and haptoglobin levels were measured and semiquantitative analysis of gut microbiota composition was carried out in 50 obese and 30 normal weight subjects without concomitant diseases. Higher circulating zonulin, TNF-α, sTNFR1, sTNFR2, and IL-6 levels were found in the obese subjects. Plasma zonulin level correlated positively with age (r = 0.43, P < 0.001), body mass (r = 0.30, P < 0.01), BMI (r = 0.33, P < 0.01), fat mass and fat percentage (r = 0.31, P < 0.01 and r = 0.23, P < 0.05, resp.). Positive correlations between bacterial colony count and sTNFR1 (r = 0.33, P < 0.01) and plasma zonulin (r = 0.26, P < 0.05) but not haptoglobin levels were found. Additionally, plasma zonulin level was proportional to daily energy intake (r = 0.27, P < 0.05) and serum glucose concentration (r = 0.18, P < 0.05) and inversely proportional to diet protein percentage (r = −0.23, P < 0.05). Gut microbiota-related systemic microinflammation in the obese is reflected by circulating zonulin level, a potential marker of interstitial permeability.

Haptoglobin (HP) phenotype has been reported to modulate fenofibrate benefit on coronary artery disease in type 2 diabetes. It is unknown whether HP phenotype and levels modulate fenofibrate benefit on sight-threatening diabetic retinopathy (STDR). In plasma from 8,047 Australasian adults with type 2 diabetes in the FIELD trial, HP phenotype was determined, and HP levels were measured at baseline and after six-week fenofibrate run-in. There were 307 new first on-trial STDR events over five years. Baseline HP levels and phenotype were not related to STDR risk. Fenofibrate benefit on STDR vs. placebo (-32% overall), was greatest in participants with the lowest baseline HP level tertile (hazard ratio [95% CI] 0.41 [0.26-0.65], vs. 0.82 [0.56-1.21] and 0.84 [0.56-1.27] for tertiles 2 and 3 respectively, P for heterogeneity=0.019). During run-in, fenofibrate reduced HP levels by 20.7%. However, fenofibrate benefit on STDR did not differ significantly by HP phenotype or change in HP levels during run-in after adjustment for confounding factors. Regarding STDR, fenofibrate benefit is greatest in type 2 diabetes patients with the lowest baseline HP levels, which may reflect patients more susceptible to oxidative retinal injury. All HP phenotypes benefit from fenofibrate.

Introduction: Omalizumab is a humanized anti-IgE monoclonal antibody, which is effective in the treatment in patients with chronic spontaneous urticaria (CSU) who are unresponsive to antihistamine therapy. There are few studies in the literature evaluating omalizumab treatment response in patients with symptomatic dermographism (SDerm). The aim of this study was to compare the response to omalizu­mab treatment in patients with CSU and SDerm. Methods: Patients treated with omalizumab for the diagnosis of CSU and SDerm were evaluated retrospectively. Treatment response to omalizumab was evaluated with the urticaria control test (UCT). Quality of life was evaluated with the dermatology quality of life questionnaire (DLQI). Baseline UCT and DLQI were compared with UCT and DLQI after omalizumab treatment. Results: Evaluation was made of a total of 116 patients (CSU: 92, SDerm: 24), comprising 36 (31%) males and 80 (69%) females with a mean age of 38.95 ± 13.64 years. The most common accompanying comorbid disease was allergic rhinitis (n = 40, 34.5%). There was no statistically significant difference between patients with CSU and SDerm in respect of response to omalizumab treatment (p = 0.890). After omalizumab treatment, the increase in UCT and decrease in DLQI was statistically significant in all patient groups (p < 0.001; p < 0.001, respectively), patients with CSU (p < 0.001; p < 0.001, respectively) and SDerm (p < 0.001; p < 0.001, respectively). There was no statistically significant difference between baseline (before omalizumab treatment) UCT (p = 0.804) and UCT after omalizumab treatment (p = 0.933) between patients with CSU and patients with SDerm. There was no statistically significant difference between baseline (before omalizumab treatment) DLQI (p = 0.356) and DLQI after omalizumab treatment (p = 0.145) between patients with CSU and patients with SDerm. Conclusion: Omalizumab treatment improved disease control and quality of life in patients with SDerm. The findings of this study should be supported by randomized placebo-controlled studies.

Introduction and Objective: Haptoglobin (HP) is a circulating glycoprotein with antioxidant and anti-inflammatory properties. It scavenges toxic free hemoglobin. Cardiovascular disease (CVD) risk in Type 2 diabetes (T2D) patients may differ by HP phenotype. It is unknown if CVD risk and fenofibrate benefits differ by HP levels. Methods: HP phenotype and levels were measured in baseline plasma from 8047 T2D adults in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial by ELISA and immunoturbidimetric assay, respectively. Results: Frequencies of HP 1-1, 2-1 and 2-2 phenotypes were 15.6%, 47.6% and 36.9% respectively. Higher HP level tertiles, but not HP phenotype, were associated with a higher risk of total CVD events, especially coronary heart disease events (P=0.019) and CVD mortality (P=0.003) in placebo group, after adjustment for CVD risk factors (overall P for trend =0.032, Fig. 1A). The HP level association was independently significant only in the HP 1-1 phenotype (P for level/phenotype interaction =0.039, Fig. 1B). Participants with both HP 1-1 phenotype and the lowest HP tertile levels tended to have the lowest CVD risk (Fig. 1C). Fenofibrate benefits on total CVD events did not differ by HP phenotype or levels. Conclusion: HP levels and phenotype help to identify T2D patients at high CVD risk for treatment, especially those with HP 1-1 phenotype. Disclosure K. Ong: None. A.S. Januszewski: None. H. Francis: None. R.L. O'Connell: None. A. Mangani: None. L. Li: None. P.G. Colman: None. D. Sullivan: Other Relationship; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Other Relationship; Novartis Pharmaceuticals Corporation, Merck Sharp &amp; Dohme Corp. Research Support; Ionis Pharmaceuticals. J.D. Best: None. R.S. Scott: None. A. Jenkins: Advisory Panel; Abbott. Speaker's Bureau; GlaxoSmithKline plc. Research Support; Abbott, Metronics, Ypsomed AG, Insulet Corporation, Jaeb Center for Health Research, Endogenex, Hemsley Charitable Trust. Speaker's Bureau; CSL Seqirus. Research Support; AbbVie Inc, National Institutes of Health, Juvenile Diabetes Research Foundation (JDRF). A.C. Keech: Research Support; Abbott, Amgen Inc, ASPEN Australia, Mylan. Speaker's Bureau; Novartis AG, Pfizer Inc. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sanofi. Research Support; AbbVie Inc, Viatris Inc. Funding Laboratoires Fournier, Dijon, France and the National Health and Medical Research Council of Australia (457103, 1024105, 1037786, 1105467, 1121272, 1137071 and 2018537)

Background: Chronic urticaria (CSU) is a chronic inflammatory mast cell-driven disorder of which reliable clinical data in Belgium are lacking. This study focusses on clinical characteristics of CSU patients presenting at an urban Immunology-Allergology department. Methods: Outpatients with CSU were included from 2018 to 2021. Clinical characteristics, Dermatology Life Quality Index (DLQI) and Urticaria activity score (UAS7) were collected by thorough anamnesis and questionnaires. Furthermore, patients underwent provocational testing, an autologous serum skin test (ASST) and a blood analysis. Results: The study included 49 CSU patients and 20 non-CSU subjects. CSU was distributed differently with age and sex, showing higher numbers in female patients below the age of 46 years. 67% of CSU patients had accompanying angioedema of which 9% were reported genital. CSU patients scored a mean 8/30 on their DLQI questionnaire. There was no significant difference in immunoglobulin E (IgE), C-reactive protein, and tryptase levels between CSU patients and controls. Oral glucocorticosteroids were prescribed in 23% of CSU patients during their disease course though only half of these patients had a severity grade 4 CSU. In 82% of the included CSU patients, Urticaria Control Test (UCT) scores were below 12. When we hypothetically considered low IgE levels and high IgG anti-thyroid peroxidase levels as differentiation marker for autoimmune (ai)CSU and non-aiCSU, we found that 4% of all included CSU patients could be considered aiCSU. Conclusion: Generally, the inner-city population displayed the same clinical characteristics, as previous cohorts from Northern Europe. The relatively high rate of CSU patients receiving oral glucocorticosteroid treatment for their disease though not always classified as severe, underlines the need to train doctors of various specialties in the treatment algorithms of CSU. Furthermore, by looking at potential autoimmune characteristics, our findings open perspectives on the identification of new routinely used clinical parameters for the detection of aiCSU, a relatively small immunological subtype of CSU.

Colorectal cancer (CRC) is a widespread and serious global malignancy. This study aimed to investigate the clinical relevance of galanin (GAL) and haptoglobin (HP) as new diagnostic CRC biomarkers. An enzyme-linked immunosorbent assay was used to determine the GAL and HP levels in the serum of 88 patient with CRC and 88 healthy controls. The carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) contents were quantitatively evaluated via electrochemiluminescence assay. Receiver operating characteristic (ROC) curves were created to identify the diagnostic importance of single and combined CRC detection. The patients' relevant diagnostic and treatment data were collected from their medical records. Statistical analysis methods were employed to examine the relationship between these indicators and the clinical pathological parameters. Patients with CRC exhibited significantly decreased and increased serum GAL and HP levels, respectively, compared with the healthy controls (P < 0.0001 for both). Furthermore, the HP level was positively correlated with tumor T stage (P = 0.0124). The area under the curve (AUC) of the ROC values for GAL and HP was 0.744 and 0.712, respectively, indicating their diagnostic efficiency. The combination of GAL and HP increased the AUC to 0.753, and when both were integrated with CEA and CA19-9, the AUC further increased to 0.893. This study shows that serum GAL and HP can be used as potential noninvasive diagnostic biomarkers for CRC.

Community‐acquired pneumonia (CAP) commonly causes acute respiratory failure with high mortality. Here, we report that in contrast to the serum HP, levels of Trx1 is significantly decreased in serum from patients with CAP, especially in serum from female CAP patients. The levels for Trx1 in serum samples from patients with CAP compared to healthy controls using an indirect ELISA assay method. We assess the correlations of Trx1 with haptoglobin (HP), a well‐known biomarker for CAP. The CAP detection ability of Trx1 and HP were evaluated using receiver‐operating characteristic (ROC) curve. Analysis of the ROC curves indicates that CAP detection ability of Trx1is comparable to that of HP. At the cut‐off point 0.3964 at A540nm on the receiver operating characteristic curve, Trx1 could well discriminate CAP from normal female controls with a sensitivity of 72.5%, specificity 89.8%, and area under the curve (AUC) 0.877+/−0.0395. Decreased serum levels of the Trx1 in female CAP patients were reversely correlated with the elevated serum levels of HP (P&lt;0.05). Considering that elevated serum levels of Trx1 and HP in various diseases including carcinomas, the decreased serum Trx1 in case of female CAP patients may be helpful for the CAP‐specific diagnosis for female subjects. *This work was financially supported by project B0009735) funded by the Ministry of Knowledge Economy of Korea.

We previously found, using microarray, haptoglobin (HP) expression signal was 5.1-fold increased in peripheral blood mononuclear cells (PBMCs) from methotrexate (MTX)-resistant rheumatoid arthritis (RA) patients. To investigate whether serum levels of HP are associated with the response of 12weeks MTX therapy in recent-onset RA patients. Sixty-nine active RA patients with recent onset (<24months) were treated with MTX. Clinical variables, levels of HP messenger RNA (mRNA) in PBMCs and HP serum levels were tested at week 0 and week 12. After 12weeks of MTX treatment, 34.7% of RA patients were categorized as responders according to European League Against Rheumatism (EULAR) response criteria (Week 12 Disease Activity Score of 28 joints [DAS-28]≤3.2 and decrease >1.2) and all others (65.2%) were defined as non-responders. The baseline HP mRNA in PBMCs from non-responders is significantly higher than those in responders (P<0.05). Similar to mRNA expression, non-responders showed significantly elevated serum HP levels at baseline (369.9±159.8mg/dL) compared to those in responders (255.3±143.9mg/dL) (P=0.01). Serum HP levels were decreased significantly from 255.3±143.9mg/dL at baseline to 186.4±108.5mg/dL at week 12 (P=0.04) in responders, but remained at high levels in non-responders. High serum levels of HP at baseline are associated with inadequate response of 12weeks MTX treatment in recent-onset RA patients. Further replication studies in larger samples are needed to validate HP as a potential predictive biomarker for response to MTX therapy in RA.

Introduction: Biomarkers that could reliably anticipate the effectiveness of antihistamines and omalizumab in treating chronic spontaneous urticaria (CSU) have not been conclusively identified. Our objective was to examine how eosinophilic cationic protein (ECP), tryptase, D-dimer, and total Immunoglobulin E (IgE) impact the response to antihistamine and omalizumab treatments in individuals with CSU. Methods: In this cross-sectional retrospective study, CSU patients that had undergone treatment with either antihistamines or omalizumab for a minimum of 12 weeks between 2015 and 2021 at an Allergy and Immunology Department were analyzed. Several demographic and laboratory parameters including eosinophil counts, mean platelet volüme (MPV), sedimentation, C-reactive protein (CRP), antinuclear antibodies (ANA) and Anti-thyroperoxidase (Anti-TPO) and total IgE, tryptase, ECP and D-dimer were retrived from patient files. The association of these biomarkers with Urticaria Control Test (UCT) and the effect of these biomarkers on treatment response were evaluated. Treatment response was assessed using the UCT, with a score of UCT ≥ 12 indicating a responder and UCT < 12 indicating a non responder. Results: The patients in the omalizumab group were older, had a longer disease duration and had worse urticaria control (lower baseline UCT scores). 421 patients were treated with antihistamines and 88 patients were treated with omalizumab. ECP was found to be inversely correlated with baseline UCT (p < 0.001 r=−0.268). ECP and D-dimer levels of non-responder patients in the antihistamine group were significantly higher than in responder patients (ECP: 49 ng/mL vs 28.1 ng/mL, p < 0.001) (D-dimer: 0.60 mg/L vs 0.30 mg/L, p < 0.001), while there were no significant difference in terms of tryptase and total IgE. These four biomarkers were similar, in omalizumab responders and non responders. Conclusion: In this study with CSU, we looked at predictors of responses to treatments. ECP can serve as a marker of poor urticaria control and may predict antihistamine refractoriness along with D-dimer.

Validation of the Urticaria Control Test (UCT) in Children With Chronic Urticaria

BackgroundAmong the several available DMARDs, Methotrexate (MTX) is currently the most widely used drug in clinical practice. About 30-40% of the patients could experience an adequate response to MTX alone;...

Increased serum IL-31 levels in chronic spontaneous urticaria and psoriasis with pruritic symptoms