Current topical and systemic therapies for itch.

Itch is a common distressing symptom which may be caused by multifactorial aetiologies including inflammatory skin diseases, systemic diseases, neuropathic conditions and psychogenic disorders. Itch is a term used synonymously with pruritus and is defined as acute if it lasts less than 6 weeks or chronic if it persists for more than 6 weeks. It can have the same impact on the quality of life as chronic pain and shares many of the same pathophysiological pathways. Depending on the aetiology of the itch, different pathogenic mechanisms have been postulated with a number of mediators identified. These include histamine, leukotrienes, proteases, neuropeptides, cytokines and opioids, which may activate peripheral itch-mediating C-fibres via receptors on the nerve terminals and central neuronal pathways. Therefore, there is no single universally effective anti-itch treatment available. First-line treatments for itch include topical therapies, such as emollients, mild cleansers (low pH), topical anaesthetics, steroids, calcineurin inhibitors and coolants (menthol). Treatment with systemic therapies can vary according to the aetiology of the chronic itch. Non-sedating antihistamines are helpful in conditions such as urticaria where the itch is primarily histamine mediated. Although the itch of eczema is not mediated by histamine, sedating antihistamines at night are helpful to break the itch-scratch cycle. Chronic itch may also be treated with other systemic therapies, such as anticonvulsants, antidepressants as well as mu-opioid antagonists, kappa-opioid agonists and phototherapy, depending on the cause of the itch. This article summarises the topical and systemic therapies available with our current understanding of the pathophysiology of itch.

Pathology and classification of urticaria.

Chronic urticaria is defined as daily or almost daily urticaria for more than 6 weeks. Chronic urticaria is normally subdivided into physical urticaria (wheals evoked by a physical stimulus such as pressure friction or cold contact) and spontaneous urticaria. A patient with a history of less than 6 weeks is traditionally designated as having acute urticaria. Patients with chronic spontaneous urticaria have an increased frequency of HLA-DR and HLA-DQ alleles characteristically associated with autoimmune disease. Some of these patients have functional anti-FceR1 and/or anti-IgE autoantibodies which are considered to be the cause of the urticaria.

Detection of refractive index changes in individual living cells by means of surface plasmon resonance imaging.

Real time imaging of living cell activation is an increasing demand in disciplines of life science and medicine. We previously reported that surface plasmon resonance (SPR) sensors detect large changes of refractive index with living cells, such as mast cells, keratinocyte, human basophils and B-cells activated by biological stimuli. However, conventional SPR sensors detect only an average change of refractive index with thousands of cells at detectable area on a sensor chip. In this study, we developed an SPR imaging (SPRI) sensor with a CMOS camera and an objective lens in order to analyze refractive index of individual living cells and their changes upon stimuli. The SPRI sensor could detect reactions of individual rat basophilic leukemia (RBL-2H3) cells, mouse keratinocyte (PAM212) cells, and human epidermal carcinoma (A431) cells in response to either specific or non-specific stimuli, such as antigen, phorbol ester or epidermal growth factor, with or without their inhibitors, resembling signals obtained by a conventional SPR sensor. Moreover, we distinguished reactions of different type cells, co-cultured on a sensor chip, and revealed that the increase of refractive index around nuclei is rapid and potent as compared to that in peripheries in the reaction of RBL-2H3 cells against antigen. This system may be a useful tool to investigate the mechanism of refractive index-changes evoked in near-membrane fields of living cells, and to develop a system of high-throughput screening for clinical diagnosis.

Pathogenesis and treatment of pruritus.

Classification of itch into four categories-pruritoceptive, neurogenic, neuropathic, and psychogenic-has proven to be of utility to clinicians and investigators. Itch is recognized to be transmitted by dedicated afferent neurons, and a matrix of cerebral cortical loci involved in perception and the desire to scratch has been recognized. This highlights the multidimensional nature of the itch sensation. Some of the many mediators of itch, especially relevant in pruritogenic itch, are the result of cross-talk between dermal mast cells and adjacent cutaneous afferents. Keratinocytes of the epidermis express many neuropeptides, and their receptors are far from passive bystanders in the neurophysiology of itch. Mediators can also act centrally (eg, opioid peptides that act on micro receptors in the central nervous system). The pathophysiology of pruritus in neurogenic itch caused by common systemic diseases is gradually being elucidated, especially in the itch of cholestasis, although the molecular basis of itching in chronic renal failure remains elusive. Better understanding of the mediators of itch and their receptors has led to the imminent development of novel anti-itch compounds, including interleukin-31 inhibitors, histamine H4-receptor antagonists, and neurokinin-1 receptor antagonists.

Chronic urticaria: recent advances.

Chronic urticaria is an umbrella term, which encompasses physical urticarias, chronic "idiopathic" urticaria and urticarial vasculitis. It is important to recognize patients with physical urticarias as the investigation and treatment differs in important ways from patients with idiopathic chronic urticaria or urticarial vasculitis. Although relatively uncommon, urticarial vasculitis is an important diagnosis to make and requires histological confirmation by biopsy. Underlying systemic disease and systemic involvement, especially of the kidneys, should be sought. It is now recognized that chronic "idiopathic" urticaria includes a subset with an autoimmune basis caused by circulating autoantibodies against the high affinity IgE receptor (FceR1) and less commonly against IgE. Although the autologous serum skin test has been proven useful in prompting search for and characterization of circulating wheal-producing factors in chronic urticaria, its specificity as a screening test for presence of functional anti-FceR1 is low, and confirmation by demonstration of histamine-releasing activity in the patient's serum must be the benchmark test in establishing this diagnosis. Improved screening tests are being sought; for example, ability of the chronic urticaria patient's serum to evoke expression of CD 203c on donor human basophils is showing some promise. The strong association between autoimmune thyroid disease and autoimmune urticaria is also an area of ongoing research. Drug treatment continues to be centered on the H1 antihistamines, and the newer second-generation compounds appear to be safe and effective even in off-label dosage. Use of systemic steroids should be confined to special circumstances such as tapering regimens for acute flare-ups. Use of leukotriene antagonists is becoming popular, but the evidence for efficacy is conflicting. Cyclosporin is also effective and can be used in selected cases of autoimmune urticaria, and it is also effective in non-autoimmune cases, although less so.

Recent advances in pathophysiology and current management of itch.

The neurophysiology of itch, the dominant symptom of skin disease, has previously received scant attention. Recent advances in the neurophysiology and molecular basis of itch include the use of microneurography to demonstrate the existence of a subset of itch-dedicated afferent C neurons distinct from neurons which transmit pain; use of functional positron emission tomography (PET) and magnetic resonance imaging (MRI) of the brain to reveal an itch-specific activation matrix, and new evidence of a functional "dialogue" between C neuron terminals and dermal mast cells in which recently described proteinase-activated receptor type 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors, proteases and endovanilloids play a major role. As a necessary prerequisite to diagnosis and management, a pathophysiologically based classification of itch is proposed. Recent advances in understanding of the pathomechanisms of itch of cholestasis include the role of opioids and opioid antagonists. Focusing on neurogenic itch (itch without visible rash), common causes are reviewed and guidelines for laboratory and radiological investigation are proposed. A stepwise approach to management of generalised itch is recommended, including broadband or narrow band ultraviolet (UV), tricyclics such as doxepin, opioid antagonists including naltrexone and selective serotonin reuptake inhibitors (SSRIs) such as paroxetine. For troublesome localised itches such as insect bite reactions, physical urticaria, lichen simplex chronicus or, less commonly, notalgia paraesthetica, brachioradial pruritus, local cooling devices which rely on the cooling action of dimethyl ethers on thermosensitive TRP voltage-sensitive ion channels are now commercially available for shortterm relief.

Cutaneous mast cell receptors.

Two types of mast cells, MC(T) and MC(TC), exist in humans. MC(T) and MC(TC) are different in their granular neutral proteases, tissue localizations, and functions. This article describes the differences between the cutaneous mast cell receptors.

Clinical classification of itch: a position paper of the International Forum for the Study of Itch.

Chronic itch is a common and distressing symptom that arises from a variety of skin conditions and systemic diseases. Despite this, there is no clinically based classification of pruritic diseases to assist in the diagnosis and cost-effective medical care of patients with pruritus. The proposed classification focuses on clinical signs and distinguishes between diseases with and without primary or secondary skin lesions. Three groups of conditions are proposed: pruritus on diseased (inflamed) skin (group I), pruritus on non-diseased (non-inflamed) skin (group II), and pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis (group III). The next part classifies the underlying diseases according to different categories: dermatological diseases, systemic diseases including diseases of pregnancy and drug-induced pruritus, neurological and psychiatric diseases. In some patients more than one cause may account for pruritus (category "mixed") while in others no underlying disease can be identified (category "others"). This is the first version of a clinical classification worked out by the members of the International Forum for the Study of Itch. It is intended to serve as a diagnostic route for better evaluation of patients with chronic pruritus and aims to improve patients' care.

Papel de los anticuerpos en la urticaria autoinmune / Antibodies role in autoimmune urticaria

Autoimmune urticaria occurs in patients in whom there are functional autoantibodies directed against FcepsilonR1 and IgE. The antibodies concerned are of subtypes IgG1 and IgG3. It is generally more severe and treatment-resistant. The significance of diagnosing autoimmune urticaria is that patients can be offered an explanation for an otherwise unremitting and puzzling condition. It also opens up the prospect of effective treatment by immunomodulatory treatment in selected patients with autoimmune urticaria. The utologous serum skin test is used as a screening test for autoimmune urticaria. The sensitivity and specificity are about 80% respectively. The diagnosis can be confirmed by demonstrating release of histamine from target basophils or dermal mast cells. Treatment of autoimmune urticaria involves the use of low sedation H1 antihistamines in licensed dosages. Off-label dosages are used if the condition is still poorly controlled. Prednisolone can be used in acute and severe flare-ups. Immunomodulatory treatment with cyclosporin can be considered in recalcitrant cases.

La urticaria autoinmune aparece en pacientes que generan autoanticuerpos funcionales contra el FcepsilonR1 y la IgE. Los anticuerpos involucrados pertenecen al subtipo IgG1 e IgG3. Generalmente es una forma de urticaria más grave y resistente al tratamiento. La importancia de diagnosticar urticaria autoinmune radica en que al hacerlo los enfermos pueden recibir una explicación acerca de una enfermedad desconcertante y que habitualmente no remite. En casos seleccionados de urticaria autoinmune también se abre un espectro de tratamientos eficaces que incluyen terapias inmunomuduladoras. La prueba de suero autólogo se utiliza como estudio de rastreo para esta patología. La sensibilidad y especificidad son cercanas al 80%. El diagnóstico puede confirmarse mediante la demostración de liberación de histamina de basófilos o células cebadas de dermis. El tratamiento de la urticaria autoinmune consiste en la utilización de antihistamínicos H1 con escaso efecto sedante en las dosis recomendadas. Las dosis superiores a las habituales se utilizan en pacientes en quienes la enfermedad se controla escasamente. En casos agudos y durante las exacerbaciones puede administrarse prednisolona. El tratamiento inmunomodulador con ciclosporina puede considerarse en casos refractarios.

Itch in systemic disease: therapeutic options.

A new pathophysiologically based classification of itch is proposed, which should help the clinician adopt a rational approach to diagnosis and management of generalized itch. Focusing on neurogenic itch (itch without visible rash), common causes are reviewed and guidelines for laboratory and radiologic investigation are proposed. A stepwise approach to the management of generalized itch resulting from systemic disease is recommended. Specifically, the relative merits of broad versus narrowband ultraviolet B (UVB) are discussed and the pros and cons of doxepin, opioid antagonists, and selective serotonin reuptake inhibitors (SSRIs) such as paroxetine are considered. Attention is drawn to some novel approaches, including bright-light phototherapy and molecular adsorbent recirculating system (MARS) for selected patients with intractable itch caused by hepatic failure, and mirtazapine for nocturnal itch.

Angioedema.

UNLABELLED: Although first described more than 130 years ago, the pathophysiology, origin, and management of the several types of angioedema are poorly understood by most dermatologists. Although clinically similar, angioedema can be caused by either mast cell degranulation or activation of kinin formation. In the former category, allergic and nonsteroidal anti-inflammatory drug-induced angioedema are frequently accompanied by urticaria. Idiopathic chronic angioedema is also usually accompanied by urticaria, but can occur without hives. In either case, an autoimmune process leading to dermal mast cell degranulation occurs in some patients. In these patients, histamine-releasing IgG anti-FcepsilonR1 autoantibodies are believed to be the cause of the disease, removal or suppression by immunomodulation being followed by remission. Angiotensin-converting enzyme inhibitor-induced angioedema is unaccompanied by hives, and is caused by the inhibition of enzymatic degradation of tissue bradykinin. Hereditary angioedema, caused by unchecked tissue bradykinin formation, is recognized biochemically by a low plasma C'4 and low quantitative or functional C'1 inhibitor. Progress has now been made in understanding the molecular genetic basis of the two isoforms of this dominantly inherited disease. Recently, a third type of hereditary angioedema has been defined by several groups. Occurring exclusively in women, it is not associated with detectable abnormalities of the complement system. Angioedema caused by a C'1 esterase inhibitor deficiency can also be acquired in several clinical settings, including lymphoma and autoimmune connective tissue disease. It can also occur as a consequence of specific anti-C'1 esterase autoantibodies in some patients. We have reviewed the clinical features, diagnosis, and management of these different subtypes of angioedema. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of the classification, causes, and differential diagnosis of angioedema, the molecular basis of hereditary and non-hereditary forms of angioedema, and be able to formulate a pathophysiology-based treatment strategy for each of the subtypes of angioedema.

Antihistamines in dermatology.

Along with antibiotics, antihistamines are the most widely used systemic drugs in dermatology. This is attributable to the major role played by histamine in common diseases such as urticaria and atopic eczema. Of the currently recognised four subtypes of G protein-coupled histamine receptors, only the H1 and H2 subtypes have been positively identified in human skin. Traditionally believed to be competitive antagonists of histamine, H1 and H2 antihistamines are now considered to behave as inverse agonists. By consensus, H1 antihistamines are classified as 'first generation' (associated with troublesome side-effects including somnolence, anti-adrenergic and atropine-like actions) and 'second-generation' compounds (in which these side-effects are reduced or absent). The main indications for H1 antihistamines in skin are suppression of pruritus in urticaria and atopic eczema, both of which are associated with increased mast cell numbers and tissue histamine levels. However the evidence basis for use in atopic eczema is ambiguous and controversial, even though these drugs are widely used in practice. Currently, significant side-effects are mainly confined to the first-generation compounds and are especially troublesome in the elderly. Psychomotor impairment may persist throughout the day following administration. Anti-cholinergic and anti-alpha-adrenergic blockade and cardiotoxicity (torsade de pointes) may also occur with first-generation antihistamines. Two early low-sedation second-generation antihistamines caused arrhythmias in a small number of patients but these compounds have now been withdrawn. Generally, the second-generation H1 antihistamines are well tolerated.

Itch: more than skin deep.

Recent research in neurophysiology of itch has indicated the existence of itch-dedicated nociceptor neurones. The perception of itch is regulated by tonically inhibitory descending neuronal pathways and nociceptor spinal neuronal circuits. There is at present no convincing evidence of an 'itch centre' in the brain. A classification of itch has been proposed, based on neurophysiological considerations, which stresses the importance of neurogenic and neuropathic itch, and assists in differential diagnosis and selection of treatment. However, more than one class of itch can occur concurrently in the same patient. The importance of cross- talk between dermal mast cells and nociceptor nerve terminals, involving cleavage of proteinase-activated receptor 2 by mast cell tryptase, is highlighted. The pruritus of cholestasis is mediated at least in part by opioid peptides synthesized by the liver, and elevated levels of these mediators are found in the plasma and skin of patients with itch due to cholestasis. The combined use of both mu-receptor antagonists and kappa-receptor agonists (anti-pruritic) is worth exploring.