Targeted Therapy for Chronic Spontaneous Urticaria: Rationale and Recent Progress.

Chronic spontaneous urticaria (CSU) is characterized by the presence of wheals, angioedema, or both for at least 6 weeks. It may persist for a long time-up to 50% of the patients have been reported to be symptomatic 5 years after the onset. Some patients can suffer more than one episode of CSU during their lifetime. Considering the recurrences, disabling symptoms, and significant impact on quality of life, proper and effective treatment of CSU is critical. The use of antihistamines (AHs) is still the mainstay of treatment. However, given the low rates of response to AHs (38.6% and 63.2% to standard doses and higher doses, respectively), the complete control of symptoms seems difficult to attain. The use of omalizumab for CSU has been a major breakthrough in the care of patients with CSU. However, the partial response and lack of response to omalizumab in a subgroup of patients, as high as 70% in some studies, make the development of alternative treatments desirable. Ever-increasing knowledge on the pathogenesis is making new target molecules available and enabling drug development for CSU. In addition to drug repurposing as in anti-IL-4/13, IL-5, and IL-17 antibodies, novel targeted therapy options such as ligelizumab and Bruton's tyrosine kinase inhibitors are currently undergoing clinical trials and will be available in the near future. This article reviews the current challenges in the treatment of CSU, the pathogenesis and potential target molecules, and the rationale for novel treatments and their rapidly developing status.

Real-Life Study of Mepolizumab in Idiopathic Chronic Eosinophilic Pneumonia.

INTRODUCTION: Idiopathic chronic eosinophilic pneumonia (ICEP) is an orphan lung disease characterized by concomitant systemic and local eosinophilia, along with bilateral lung infiltrates. Symptoms include dyspnea of subacute/chronic onset, cough, and general systemic signs. Although all patients do respond to oral corticosteroids, relapse rate is very high, which highlights the need for alternative therapies in case of relapsing ICEP. Mepolizumab is a fully humanized antibody directed against interleukin 5, a key growth factor of eosinophils. In the present study, we retrospectively studied the effect of off-label use of mepolizumab for relapsing ICEP. MATERIALS AND METHODS: All data from patients treated with mepolizumab for relapsing ICEP were included in our database and diagnoses were reviewed. We analyzed the effect of treatment on relapse rate, oral corticosteroids (OCS) use, and lung lesions on high-resolution computed tomography (HRCT). RESULTS: We included ten patients in the final analysis, with a median follow-up of 9 months after initiation of mepolizumab. Beside its expected effect on circulating eosinophils, treatment with mepolizumab was associated with a significant reduction of annual rate of exacerbations and a reduced consumption of corticosteroids. We also observed a remission of lung lesions on follow-up HRCT. CONCLUSIONS: In this open-label retrospective study, treatment of ICEP with mepolizumab was associated with a reduction of relapses, OCS use, and the disappearance of lung infiltrates.

Targeted Anti-IL-5 Therapies and Future Therapeutics for Hypereosinophilic Syndrome and Rare Eosinophilic Conditions.

Eosinophilic inflammation is a component of many atopic diseases such as asthma, and biologics targeting eosinophils have been shown to be effective in subsets of these patients. However, there also are conditions in which eosinophils are the key inflammatory cells responsible for driving tissue damage. In these eosinophilic diseases such as hyper-eosinophilic syndrome, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis (EGPA), the development of biologics inhibiting eosinophilic inflammation have offered targeted therapeutic strategies for patients that have not responded well to typical first line drugs, which often have significant adverse side effects with poor disease modification or recurrent relapse with significant morbidity. IL-5 has long been recognized as the key inflammatory cytokine involved in the priming and survival of eosinophils and their proliferation and maturation in eosinophilic disease. There are a number of trials and case series demonstrating the immunomodulatory benefits of anti-IL-5 therapies in these diseases with good clinical responses. Yet, due to the heterogeneity and rarity of these conditions, anti-IL-5 therapies have not resulted in disease remission for all patients. Clearly, further research into the use of anti-IL-5 therapies in various eosinophilic diseases is needed and ongoing investigation into other immune mechanisms underlying chronic eosinophilic diseases may provide alternative therapies for these challenging conditions.

The use of biologic therapies for the management of pediatric asthma.

With better understanding of the role of type 2 inflammation in allergic asthma, there has been progress made in the development of new biologic therapies targeting these specific pathways. This review will consider diagnostic criteria for using biologic therapies for pediatric asthma with special emphasis on populations that are likely to benefit the most from particular therapies. With the exception of the anti-immunoglobulin E, omalizumab, very few studies have been published on the efficacy and safety of biologic therapies in children, particularly anti-interleukin-5 (IL5) and anti-IL4/IL13 therapies. The review will highlight the scarcity of published data in pediatric-specific populations. In addition, we will consider the cost-effectiveness as well as potential long-term consequences of biologic therapies in pediatric asthma.

Reslizumab Compared with Benralizumab in Patients with Eosinophilic Asthma: A Systematic Literature Review and Network Meta-Analysis.

BACKGROUND: The interaction of IL-5 with its receptor on eosinophils increases the activation and maintenance of eosinophils; blocking this interaction reduces asthma symptoms in patients with the eosinophilic phenotype. Reslizumab, which binds to IL-5, and benralizumab, which targets the IL-5 receptor α subunit, have not been compared in head-to-head trials. OBJECTIVE: To indirectly compare reslizumab with benralizumab in similar patient populations using a network meta-analysis. METHODS: A systematic literature review was conducted and a network meta-analysis was performed on eligible studies using the Markov Chain Monte-Carlo simulation method and a Bayesian statistical framework. RESULTS: Eleven studies were identified, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. To control for population differences, subgroups were selected for the base-case efficacy analysis: a benralizumab subgroup with blood eosinophil levels of greater than or equal to 300 cells/µL (n = 1537) and a reslizumab subgroup in Global Initiative for Asthma step 4/5 with 2 or more previous exacerbations and greater than or equal to 400 eosinophils/µL (n = 318). Safety was analyzed in the full population (N = 3462). Reslizumab significantly improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores compared with benralizumab once every 4 weeks and there were reasonably high posterior probabilities that reslizumab is superior to benralizumab once every 4 weeks and once every 8 weeks for ACQ score, AQLQ score, FEV1, and clinical asthma exacerbations. CONCLUSIONS: This indirect comparison suggests that reslizumab may be more efficacious than benralizumab in patients with eosinophilic asthma in Global Initiative for Asthma step 4/5 with elevated blood eosinophil levels (benralizumab, ≥300/µL; reslizumab, ≥400/µL) and 2 or more exacerbations in the previous year.

Pistacia integerrima ameliorates airway inflammation by attenuation of TNF-α, IL-4, and IL-5 expression levels, and pulmonary edema by elevation of AQP1 and AQP5 expression levels in mouse model of ovalbumin-induced allergic asthma.

BACKGROUND: Natural products are considered as an essential source for the search of new drugs. Pistacia integerrima galls (PI) have been used for the treatment of asthma and cough in traditional system of medicine. AIM/HYPOTHESIS: Current study investigates the immunomodulatory and anti-inflammatory activities of P. integerrima in mouse model of ovalbumin-induced allergic asthma. METHODS: Mice were intraperitoneally sensitized and subsequently challenged intranasally with ovalbumin to induce allergic asthma. Experimental group mice were treated with methanol extract of P. integerrima extract (200mg/kg b. w.) and Methylprednisolone (MP) (15mg/kg b. w.) for 07 consecutive days, alongside intranasal challenge. Lung tissues were stained with Hematoxyline and Eosin (H & E), and Periodic Acid-Schiff (PAS) stains for histopathological evaluation. Lung wet/dry weight ratio was measured as an index of lung tissue edema. Albumin was injected in the right ear 24h before sacrificing the mice and difference of weight was taken as a degree of delayed type hypersensitivity (DTH). mRNA expression levels of TNF-α, IL-4, IL-5, Aquaporin-1 (AQP1), and AQP5 were evaluated using reverse transcription polymerase chain reaction (RT-PCR) followed by gel electrophoresis. RESULTS: The data showed both PI extract and MP significantly alleviated DTH and nearly normalized total leukocyte count and differential leukocyte count in both blood and BALF. We found significantly suppressed goblet cell hyperplasia and inflammatory cell infiltration after treatment with both PI extract and MP. Expression levels of TNF-α, IL-4, and IL-5 were also found significantly reduced after treatment with both PI extract and MP, which might have resulted in the amelioration of airway inflammation. Current study displayed that both PI extract and MP significantly decreased lung wet/dry ratio, suggesting reduction in pulmonary edema. RT-PCR analysis showed significant increase in AQP1 and AQP5 expression levels after treatment with both PI extract and MP, which might have caused the alleviation of pulmonary edema. CONCLUSION: Our study displays that P. integerrima possesses significant anti-asthmatic activity which may be attributed to reduction in TNF-α, IL-4, and IL-5 expression levels, and increase in AQP1 and AQP5 expression levels.

Zingiber mioga (Thunb.) Roscoe attenuates allergic asthma induced by ovalbumin challenge.

Zingiber mioga (Thunb.) Roscoe (ZM) is a traditional medicine, used to treat inflammatory diseases. The present study aimed to evaluate the inhibitory effects of ZM on the inflammatory response in lipopolysaccharide (LPS)­stimulated RAW264.7 murine macrophage cells and in a mouse model of ovalbumin (OVA)­induced allergic asthma. Mice received OVA sensitization on day 0 and 14, and were challenged with OVA between days 21 and 23. ZM was administered to the mice at a dose of 30 mg/kg, 1 h prior to OVA challenge. In LPS­stimulated RAW264.7 cells, ZM significantly decreased nitric oxide (NO) and tumor necrosis factor (TNF)­α production in a concentration­dependent manner, and mRNA expression of inducible NO synthase (iNOS), TNF­α and matrix metalloproteinase (MMP)­9 was reduced. In addition, treatment with ZM decreased the inflammatory cell count in bronchoalveolar lavage fluid from the mice, and reduced the expression of interleukin (IL)­4, IL­5, IL­13, eotaxin and immunoglobulin E. ZM also reduced airway hyperresponsiveness in OVA­challenged mice, and attenuated the infiltration of inflammatory cells and mucus production in the airways, with a decrease in the expression of iNOS and MMP­9 in lung tissue. In conclusion, the results of the present study indicate that ZM effectively inhibits inflammatory responses. Therefore, it may be that ZM has potential as a therapeutic agent for use in inflammatory diseases.

Novel therapies for hypereosinophilic syndromes.

BACKGROUND: Conventional therapies (corticosteroids, cytotoxic agents or interferon-a) or newer compounds such imatinib are used specifically in subsets of hypereosinophilic syndromes (HES). However other therapies are still needed in this condition. OBJECTIVE: To review the novel therapies for HES discussing their advantages and shortcomings. METHODS AND RESULTS: Preclinical and clinical data on novel tyrosine kinase inhibitors, anti-IL -5 antibodies or anti-CD52 antibodies (alemtuzumab) are analysed. The former might represent appropriate options in case of imatinib resistance; the efficacy of anti-IL-5 monoclonal antibodies therapy is limited by the occurrence of rebound eosinophilia and alemtuzumab might be a promising anti-eosinophil therapy for all HES subsets. CONCLUSION: Some of the novel therapies might become appropriate therapeutic options for HES.

Current strategies in the management of hypereosinophilic syndrome, including mepolizumab.

BACKGROUND: Patients with hypereosinophilic syndrome (HES) vary considerably in their clinical presentation with regard to the severity and pattern of end-organ involvement. Clinical manifestations range from nonspecific symptoms to life-threatening, multisystem damage caused by eosinophil infiltration and local release of proinflammatory mediators and toxic granule products from these invading cells. The primary objective of treatment is to reduce blood and tissue eosinophilia and prevent eosinophil-mediated tissue damage as safely as possible. Systemic corticosteroids, such as prednisone, are first-line therapy for the management of patients with symptomatic HES who lack the Fip1-like 1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) gene fusion mutation. The tyrosine kinase inhibitor, imatinib, is first-line treatment for FIP1L1-PDGFRA-positive patients). Because of the toxicity and serious side-effects that can occur with oral corticosteroids, alternative therapies may need to be introduced to reduce the cumulative corticosteroid exposure while maintaining disease control. SCOPE: Among corticosteroid-sparing agents are cytotoxic drugs and interferon-alpha; anti-interleukin-5 (IL-5) monoclonal antibodies are also currently under investigation for the treatment of HES. This manuscript reviews the available treatments for HES and the range of side-effects associated with long-term corticosteroid use, and then focuses on the anti-IL-5 monoclonal antibodies, mepolizumab and reslizumab. Of these, only mepolizumab has been studied in a randomized, placebo-controlled trial. Literature search methodology utilized www.pubmed.gov and www.clinicaltrials.gov with search terms including hypereosinophilic syndrome and corticosteroid side-effects coupled with search terms including eosinophils, mepolizumab and reslizumab through March 2010. FINDINGS: Three case studies are presented that demonstrate the limitations of corticosteroid therapy in terms of tolerability and quality of life, and the subsequent use of mepolizumab as a corticosteroid-sparing agent in these individuals. CONCLUSION: Targeted eosinophil-directed therapy with an anti-IL-5 neutralizing monoclonal antibody reduced the need for corticosteroids in these three HES patients without disease exacerbations.

Quercetin regulates Th1/Th2 balance in a murine model of asthma.

Quercetin is found to be the most active of the flavonoids in studies and many medicinal plants owe much of their activity to their high Quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation. However, its anti-allergic effect in the Th1/Th2 immune response was poorly understood. Recently, it was shown that T-bet and GATA-3 were master Th1 and Th2 regulatory transcription factors. In this study, we have attempted to determine whether Quercetin regulates Th1/Th2 cytokine production, T-bet and GATA-3 gene expression in OVA-induced asthma model mice. Quercetin reduced the increased levels of IL-4, Th2 cytokine production in OVA-sensitized and -challenged mice. The other side, it increased IFN-gamma, Th1 cytokine production in Quercetin administrated mice. We also examined to ascertain whether Quercetin could influence Eosinophil peroxidase (EPO) activity. The administration of Quercetin before the last airway OVA challenge resulted in a significant inhibition of all asthmatic reactions. Accordingly, this study may provide evidence that Quercetin plays a critical role in the amelioration of the pathogenetic process of asthma in mice. These findings provide new insight into the immunopharmacological role of Quercetin in terms of its effects in a murine model of asthma, and also broaden current perspectives in our understanding of the immunopharmacological functions of Quercetin.

21-Methylmelianodiols from Poncirus trifoliata as inhibitors of interleukin-5 bioactivity in Pro-B cells.

Interleukin (IL)-5 plays an important role in the progression of allergic inflammation. Here, we have isolated 21alpha-methylmelianodiol and 21beta-methylmelianodiol from Poncirus trifoliata (L.) Raf., a plant of the Rutaceae family, as the inhibitors of IL-5-dependent growth of Y16 pro-B cells by bioassay-guided fractionation. 21alpha-Methylmelianodiol and 21beta-methylmelianodiol inhibited IL-5-dependent growth of Y16 cells in a dose-dependent manner with IC (50) values of 17 microM and 15 microM, respectively. A positive control, tyrphostin AG-490, exhibited an IC (50) value of 23 microM on IL-5 bioactivity. Further, we have documented that 21alpha-methylmelianodiol and 21beta-methylmelianodiol cause G1 arrest of IL-5-induced cell cycle progression of Y16 cells, and also reduce IL-5-dependent survival of the cells by apoptosis. This study could provide a pharmacological potential for P. trifoliata in treatment of IL-5-associated inflammatory disorders.

Clara cell 16-kd protein downregulates T(H)2 differentiation of human naive neonatal T cells.

BACKGROUND: Levels of the Clara cell 16-kd protein (CC16) are lower in plasma and bronchoalveolar lavage fluid from adults with asthma relative to those seen in healthy control subjects, and CC16 inhibits the T(H)2 cytokine production from murine T cells. OBJECTIVE: We sought to determine the plasma levels of CC16 in infants and to investigate whether CC16 might inhibit the T(H)2 cytokine production from neonatal T cells. METHODS: Cord blood and blood samples at 4, 18, and 36 months of age were taken from 64 children prospectively, and CC16 levels were analyzed in plasma. Cord monocyte-derived dendritic cells (DCs) were pulsed with birch allergen extract alone or together with CC16 or prostaglandin D(2) receptor inhibitors, after which autologous naive CD4(+) T cells were added to the DCs. The production of IL-5, IL-13, and IFN-gamma was measured by means of ELISA and flow cytometry. RESULTS: The plasma levels of CC16 in children peaked at 4 months. CC16 did not directly affect the cytokine production from human T(H)2 cells. However, CC16 inhibited birch pollen extract-stimulated T(H)2 differentiation of naive T cells through the DC. Inhibition of the prostaglandin D(2) receptors did not consistently result in suppressed T(H)2 differentiation. CONCLUSION: The production of CC16 seems to peak early in life, and CC16 has an inhibitory effect on T(H)2 cell differentiation from human infants by affecting DCs. CLINICAL IMPLICATIONS: CC16 is an immunoregulatory protein, and its inhibitory effect on T(H)2 cell differentiation might be of importance in the pathogenesis of allergy in infants.

IgE and non-IgE-mediated food allergy: treatment in 2007.

PURPOSE OF REVIEW: Our understanding of the mechanism of food allergy has substantially increased over the past decade. Food allergies can be classified into those that are IgE mediated and those that are non-IgE mediated. RECENT FINDINGS: Various advances have been made in treating IgE-mediated food allergies. A phase II clinical trial of a second anti-IgE antibody, omalizumab, was recently initiated in subjects with peanut allergy, but was stopped as a result of safety concerns after severe reactions occurred during initial oral challenges. Oral immunotherapy is showing promise in various studies on patients with IgE-mediated food allergies. Gastrointestinal food allergic disorders involving non-IgE-mediated food allergies have recently received attention, particularly eosinophilic esophagitis. Although amino acid-based formula therapy remains the most successful in controlling inflammation and symptoms in these disorders, other therapeutic options including various dietary elimination protocols and swallowed fluticasone are showing success. Anti-IL-5 therapy may prove to be a promising future therapeutic option for refractory patients. SUMMARY: Although there are no specific therapeutic recommendations for many IgE-mediated and non-IgE-mediated food allergic disorders besides allergen avoidance, various novel approaches are currently being investigated and may influence treatment approaches in the future.

[Treatment of ANCA-associated vascularitides]. / Traitement des vascularites systémiques associées aux ANCA.

Treatment for ANCA-associated vasculitides is now well defined, but must be adjusted for each patient according to the type of vasculitis, its precise form (e.g., limited versus systemic Wegener's granulomatosis) and severity, and patients' characteristics, such as age and renal function. The therapeutic decision must also take into account the risk of adverse events inherent to each treatment. The efficacy of adequate induction treatment has been demonstrated: more than 80% of patients now achieve remission. Relapse rates nonetheless remain high, especially in Wegener's granulomatosis. Patients with microscopic polyangiitis or Churg-Strauss syndrome with no poor prognostic factors can be treated with corticosteroids alone, with immunosuppressants added only in case of treatment failure. Patients with Wegener's granulomatosis or microscopic polyangiitis or Churg-Strauss syndrome and one or more poor prognostic factors must receive a combination of corticosteroids and immunosuppressants, mainly intravenous pulsed cyclophosphamide. Plasma exchange is indicated as an adjuvant therapy for patients with severe renal involvement. Once remission is achieved, maintenance therapy can replace cyclophosphamide by a less toxic immunosuppressive drug, such as azathioprine or methotrexate. For these latter patients, the optimal duration of induction therapy remains to be determined, but should not be shorter than 18 months. Conversely, there is no need to prescribe high-dose corticosteroids for months. Prednisone must be started at 1 mg/kg/d then rapidly tapered so that patients are not receiving more than 15 mg/d after 3-4 months of therapy. Biological therapies also appear to have a place in the therapeutic armamentarium for ANCA-associated systemic vasculitides, at least for patients whose disease is refractory to conventional therapy. However, the precise indications for anti-TNFalpha or anti-CD20 monoclonal antibodies and their optimal regimens (doses and durations) have not yet been defined. Anti-IL5, interferon-alpha and anti-IgE monoclonal antibodies might also be useful for Churg-Strauss syndrome. These biologics must be prescribed extremely cautiously and only in trial settings, especially in view of the adverse effects, few but severe, recently been reported with them.

Structural requirement of chalcones for the inhibitory activity of interleukin-5.

Novel chalcones were found as potent inhibitors of interleukin (IL)-5. 1-(2-Benzyloxy-6-hydroxyphenyl)-3-(4-hydroxyphenyl)-2-propen-1-one (2b, 78.8% inhibition at 50microM, IC(50)=25.3microM) was initially identified as a potent inhibitor of IL-5. This shows the compatible activity with budesonide or sophoricoside. To identify structural requirements, 26 chalcones were prepared and their inhibitory activities were tested against IL-5. Among them, compound 4-[(E)-3-(2-cyclohexylmethoxy-6-hydroxyphenyl)-3-oxoprop-1-enyl]benzenesulfonamide (2w, 99.5% inhibition at 50microM, IC(50)=1.8microM) shows the most potent activity. The important structural requirements of these chalcone analogs exhibiting the inhibitory activity against IL-5 were recognized as the following. (1) The hydrophobic group such as benzyloxy or cyclohexylmethoxy at 6-position of A ring is necessary. (2) The existence of phenolic hydroxyl at 6-position of A ring is critical. (3) Propenone unit as alpha,beta-unsaturated ketone is essential. (4) Electron withdrawing groups with hydrogen acceptor property at 4-position of B ring enhance the activity and quantitative structure-activity relationship of 2 regarding these substituents was determined.