Tomasz Hawro

Interleukin‐31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge

The most intriguing function attributed to interleukin‐31 (IL‐31) is its ability to induce pruritus in pathologic conditions, such as atopic dermatitis (AD). As of today, this feature of IL‐31 was tested in vivo only in animal models.

The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders

Interleukin-33 (IL-33) is a recently discovered cytokine that belongs to the IL-1 superfamily and acts as an important regulator in several allergic disorders. It is considered to function as an alarmin, or danger cytokine, that is released upon structural cell damage. IL-33 activates several immune cells, including Th2 cells, mast cells and basophils, following its interaction with a cell surface heterodimer consisting of an IL-1 receptor-related protein ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP). This activation leads to the production of a variety of Th2-like cytokines that mediate allergic-type immune responses. Thus, IL-33 appears to be a double-edged sword because, in addition to its important contribution to host defence, it exacerbates allergic responses, such as allergic rhinitis and asthma. A major purported mechanism of IL-33 in allergy is the activation of mast cells to produce a variety of pro-inflammatory cytokines and chemokines. In this review, we summarize the current knowledge regarding the genetics and physiology of IL-33 and IL-1RL1 and its association with different allergic diseases by focusing on its effects on mast cells and basophils.

Impact of psoriasis severity on family income and quality of life

Psoriasis is a common disease and the costs of its therapy, medical care and loss of productivity are a major financial burden for patients and society. The financial status of psoriasis patients and its relationship with disease severity and quality of life (QoL) remains ill characterized.

Intractable headaches, ischemic stroke, and seizures are linked to the presence of anti-β2GPI antibodies in patients with systemic lupus erythematosus.

Background Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common and potentially fatal manifestation of SLE. Antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA), anticardiolipin (aCL) and antibodies to β2glycoprotein I (anti-β2GPI), the most important aPL antigen, are thought to play a role in some forms of NPSLE. As of yet, their specific roles in NPSLE manifestations remain to be elucidated. Methodology/Principal Findings 57 SLE patients (53 women) were assessed for LA, aCL and anti-β2GPI twice, to determine persistent positivity. All patients were examined by neurology and psychiatry specialists. 69 healthy subjects were assessed as controls. NPSLE was diagnosed in 74% of patients. Headaches were the most prevalent manifestation of NPSLE (39%), followed by cerebrovascular disease (CVD) (23%), depressive disorders (19.0%), and seizures (14%). NPSLE and non-NPSLE patients showed comparable SLE activity and corticosteroid use. In 65% of patients neuropsychiatric manifestations preceded SLE diagnosis. aPL profiles of NPSLE patients and non-NPSLE patients were similar. Headaches and ischemic stroke were independently associated with anti-β2GPI-IgM (OR=5.6; p<0.05), and seizures were linked to anti-β2GPI-IgG (OR=11.3; p=0.01). Conclusions In SLE patients, neuropsychiatric manifestations occur frequently and early, often before the disease is diagnosed. Autoantibodies to β2GPI are linked to non-specific headaches, ischemic stroke and seizures, and show a better predictive value than aCL and LA. These findings may help to improve the diagnosis of NPSLE and should prompt further studies to characterize the role of anti-β2GPI in the pathogenesis of this condition.

Substance P Is Upregulated in the Serum of Patients with Chronic Spontaneous Urticaria

TO THE EDITOR Chronic spontaneous urticaria (CSU) is characterized by short-lived itchy wheals, angioedema, or both for more than 6 weeks. Symptoms of CSU are mainly mediated by the release of histamine from mast cells, but as of yet it is not entirely understood how mast cells get activated in CSU. In most CSU patients, underlying causes such as intolerance to foodstuff, chronic infections, or autoreactivity (ie due to circulating IgG anti-FceRI, IgG anti-IgE, or IgE antibodies to autoantigens) can be identified (Grattan et al., 1986; Gruber et al., 1988; Hide et al., 1993; Wedi et al., 1998; Magerl et al., 2010; Altrichter et al., 2011; Hatada et al., 2013; Zuberbier et al., 2014). Why some people in whom these potential causes are found develop urticaria and others don’t is unclear, as is the question why CSU shows spontaneous remission at some point. Disease activity of CSU is assessed using the UAS (urticaria activity score) and the AAS (angioedema activity score), and the impact of CSU on quality of life is assessed using the CU-Q2oL (chronic urticaria quality of life questionnaire) and the AE-QoL (angioedema quality of life questionnaire) (Zuberbier et al., 2014). The recently introduced urticaria control test (UCT) enables a quick assessment of treatment efficacy and disease control (Weller et al., 2014). All of these tools are, however, based on the subjective assessment of symptoms by the patient, and there is currently no objective measure to assess disease activity or severity. We and others have tried in the past to identify biomarkers in CSU. Among these, D-dimer has been shown to correlate with disease severity and to be especially high in antihistamine-resistant urticaria (Asero et al., 2008; Asero, 2013). However, plasma D-dimer concentrations are known to be rather nonspecific as they are known to be elevated in various inflammatory processes. A good biomarker in CSU should be elevated (only) in CSU patients and correlate with disease activity. As of yet, no good biomarker has been reported and confirmed by independent studies (Metz et al., 2013). We hypothesized that Substance P (SP), an 11-amino-acid peptide that acts primarily via the G-protein-coupled receptor neurokinin-1, could be both a biomarker and a factor involved in the pathogenesis of CSU since (1) at high concentrations, SP can induce the degranulation of mast cells in vitro (Kulka et al., 2008); (2) SP induces a wheal and flare response in vivo, which is more pronounced in patients with CSU as compared to healthy controls (Borici-Mazi et al., 1999); and (3) low concentrations of SP, ie, concentrations that are likely to occur in the skin of patients, can increase the responsiveness of mast cells to activating signals (Janiszewski et al., 1994; Forsythe and Bienenstock, 2012). To assess whether SP is a good biomarker in CSU, we first compared serum concentrations of SP in samples from 30 healthy subjects with 118 CSU patients from two independent urticaria clinics in Germany and observed a significant and more than fourfold increase in SP levels in patients with CSU (491±24 pg ml ) compared to healthy controls (105±28 pg ml , Po0.0001, Figure 1a). Additionally, we have assessed SP levels in the serum of 20 patients with cold urticaria. Here, SP levels are also increased (280.3±24 pg ml ), but significantly lower than in CSU patients (Figure 1a). All analyses have been carried out in adherence to the Helsinki Guidelines and after institutional approval with written and informed patient consent. Next, using the UAS7 as activity marker, we found a significant correlation between SP and disease activity (Figure 1b). Furthermore, very high levels of SP (4800 pg ml ) were absent in healthy subjects and in mild CSU but found in every fourth patient with severe CSU (26%), while low levels of SP were predominant in healthy controls (77%) and rarely found in severe CSU patients (13%, Figure 1c). It has been shown that mast cells can be a source of SP (Katsuno et al., 2003); hence it can be speculated that elevated SP is due to massive mast cell degranulation in patients with high UAS. To address this possibility, we have correlated SP level with urticaria activity at the day of blood withdrawal, which did not reveal significant differences (Figure 1d), indicating that elevated SP levels in CSU patients are not due to SP released from mast cells. It has been hypothesized that SP is involved in the pathogenesis of angioedema in CSU (Akcali et al., 2008). We, therefore, compared patients with (n1⁄4 48) or without (n1⁄411) angioedema and did not detect differences in SP levels between these groups (Figure 2a). Furthermore, comparison of SP levels among CSU patients based on the underlying etiology of CSU showed no differences between these groups (Figure 2b). LETTER TO THE EDITOR

The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change

Omalizumab is an effective and well‐tolerated treatment for chronic spontaneous urticaria (CSU). Markers and predictors of response are largely unknown, but needed to optimize omalizumab treatment. Omalizumab targets IgE, and IgE levels may be linked to the effects of treatment. We evaluated whether response rates to treatment with omalizumab in patients with CSU are linked to their baseline IgE levels, their IgE levels after omalizumab treatment, and the ratio of on treatment IgE and baseline IgE levels.

Responsiveness and minimal important difference of the urticaria control test

This study demonstrates the responsiveness of the Urticaria Control Test (UCT). Changes of its score by 3 points or more reflect a clinically relevant change of disease control (minimal important difference).

Successful omalizumab treatment in chronic spontaneous urticaria is associated with lowering of serum IL-31 levels

Funding sources: None declared. References 1 Tey HL, Yosipovitch G, Bernhard JD. Pruritus. In: Singh AK, ed. Scientific American Medicine. Decker publishing, Ontario, 2014: 1–12. 2 Pleet AB, Massey EW. Notalgia paresthetica. Neurology 1978; 28(12): 1310–1312. 3 Ellis C. Notalgia paresthetica: the unreachable itch. Dermatol Pract Concept 2013; 3(1): 3–6. doi:10.5826/dpc.0301a02. 4 Yeo B, Tey HL. Effective treatment of notalgia paresthetica with amitriptyline. J Dermatol 2013; 40(6): 505–506. 5 Tan ES, Tan AS, Tey HL. Effective treatment of scrotal lichen simplex chronicus with 0.1% tacrolimus ointment: an observational study. J Eur Acad Dermatol Venereol. 2014, doi: 10.1111/jdv.12500 [Epub ahead of print Mar 25]. 6 Pereira U, Boulais N, Lebonvallet N, Pennec JP, Dorange G, Misery L. Mechanisms of the sensory effects of tacrolimus on the skin. Br J Dermatol 2010; 163(1): 70–77. 7 St€ander S, Sch€ urmeyer-Horst F, Luger TA, Weisshaar E. Treatment of pruritic diseases with topical calcineurin inhibitors. Ther Clin Risk Manag 2006; 2(2): 213–218.

Polidocanol inhibits cowhage - but not histamine-induced itch in humans.

Polidocanol is a local anaesthetic and antipruritic compound that is used in the treatment of itching skin conditions such as eczema. Its mechanisms of action are largely ill defined. This study has compared the antipruritic efficacy of topical polidocanol in histamine‐induced itch and a histamine‐independent, cowhage‐induced model of pruritus. Polidocanol (3%) or vehicle was applied topically under occlusion for 1 h to the forearms of 45 healthy volunteers before itch was provoked by rubbing in 40–45 spicules of cowhage or skin prick testing with 10 mg/ml histamine. Itch was recorded at 1‐min intervals for 30 min on a 100‐mm visual analogue scale. Polidocanol significantly reduced the area under the curve for cowhage‐induced itch by 58% (P < 0.05), but had no significant effect on histamine‐induced itch. This result underlines the importance of histamine‐independent itch models in the development of topical antipruritic agents.

Lesions on the back of hands and female gender predispose to stigmatization in patients with psoriasis

Background Psoriasis vulgaris is characterized by disfiguring and stigmatizing skin lesions. The links among lesions distribution, severity, and stigmatization remain unclear. Objective We sought to investigate if the involvement of visible and sensitive areas is linked to stigmatization. Methods In all, 115 patients with psoriasis vulgaris were assessed for disease severity, skin lesions distribution, itch, and stigmatization using the Feelings of Stigmatization Questionnaire. Quality of life was assessed with the Dermatology Life Quality Index and the World Health Organization Quality of Life‐BREF. Results The localization of psoriatic lesions on the back of hands was related to higher stigmatization levels (P = .011, total score of the Feelings of Stigmatization Questionnaire), but not the involvement of nails, the palms, the face, or the genital area nor overall disease severity. All patients reported some level of stigmatization, regardless of the localization of lesions and type of psoriasis. Higher levels of stigmatization characterized patients who claimed not to be able to hide their lesions by clothing (P = .025), women (P = .001), and the unemployed (P = .004). Stigmatization was the strongest predictor of quality of life impairment. Limitations Only hospitalized patients were included. Conclusions Psoriatic lesions on the back of hands are debilitating and warrant effective treatment. Special attention should be paid to female patients, who are more sensitive to stigmatization.