Autoimmune bullous diseases (AIBD) are a constellation of skin diseases. Their common pathophysiology is an autoimmune response to the adhesion structures of the epidermis, dermoepidermal basement membrane and anchoring fibrils of the dermis. Clinically they vary in presentation and may involve blistering and erosions of the skin and mucous membranes. They include pemphigus, the pemphigoids, epidermolysis bullosa acquisita, dermatitis herpetiformis and linear IgA dermatosis. Each of these diseases has subtly different target antigens and immunological responses. Pruritus is a common, although not invariable, aspect of the clinical presentation of the AIBD.

There is a spectrum of prevalence of pruritus in AIBD. In some pruritus is uncommon; in others it is universal and severe. That spectrum may be summarised as:

AIBD where pruritus is rare—pemphigus vulgaris
AIBD where pruritus is common and may be mild to severe in presentation—bullous pemphigoid, epidermolysis bullosa acquisita and linear IgA disease
AIBD where pruritus is both characteristically present and severe—dermatitis herpetiformis and pemphigoid gestationis

While the prevalence of pruritus in AIBD is acknowledged, there has been little research on its pathogenesis. The literature on AIBD concentrates on the autoimmunity of the disease, its pathological manifestations and management. The symptom of pruritus, where it is mentioned, is described as an aspect of its clinical presentation. A detailed analysis of the pathophysiology of pruritus itself, its assessment and management in AIBD has yet to occur.

69.2 The Pathophysiology of Pruritus as a Symptom

In the skin, there are nociceptive sensory nerve endings that transmit signals through sensory nerves via the spinal cord and on to the somatosensory cortex. A and C fibres transmit sensory modalities. Of the C fibres, 5–10 % are dedicated to the transmission of itch. Of these itch fibres, only 10 % are histamine dependent; 90 % are histamine independent. A growing number of histamine-independent itch receptors have been identified on terminal afferent fibres. Various pruritogens have been described. These pruritogens, cytokines and other inflammatory markers are secreted by skin cells (including keratinocytes, mast cells, lymphocytes, eosinophils and basophils) in a complex cross-talking between these cells and the afferent nerve endings. The itch signal is transmitted by peripheral nerves to the dorsal horn of the spinal cord. At the dorsal horn, there are several receptors that transmit the itch signal to fibres that decussate and ascend to the cortex in the spinothalamic pathway. In addition to this pathway of positive signalling, there is an inhibitory mechanism reducing the intensity of the itch signal: cold and cannabinoid receptors in the skin and kappa receptors at the dorsal horn. There is also thought to be an inhibitory pathway descending from the periaqueductal grey matter to the dorsal horn.

69.3 The Prevalence of Pruritus in Various Forms of AIBD

Each of the AIBD is described elsewhere in this book. In pemphigus, skin lesions are often painful but rarely pruritic [1]. On the other hand, pruritus is common in bullous pemphigoid and HG.

69.3.1 Bullous Pemphigoid (BP)

The severity of this commonly occurring pruritus varies from mild to severe [2]. Pruritus may manifest early as part of the erythematous papular or urticarial lesions prior to bullae formation. Occasionally, as a prodrome of BP, generalised pruritus may develop without blisters. Ishiuji and Fleischer stated that “Elderly patients with severe or persistent unexplained generalized pruritus may merit immunofluorescence biopsy to exclude BP as the cause of the generalized pruritus” [1].

Bullous pemphigoid is characterised by autoantibodies against hemidesmosomal proteins BP180 and BP230. Bullous pemphigoid involves both IgG and IgE. IgG antibodies against BP180 result in complement activation and neutrophil recruitment leading to an interference in the adhesion of basal epidermal keratinocytes to the dermoepidermal basement membrane [1]. IgE antibodies to the basement membrane have also been described. They activate the infiltration and activity of mast cells and eosinophils. Those cells are significantly implicated in producing tissue damage via the release of proteases and proinflammatory mediators, such as TNF alpha, IL-5 and eotaxin [2]. IgE autoantibodies to BP180 also amplify the inflammatory response by directly stimulating keratinocytes to express IL-8 [3]. To Dresow and colleagues, “subepidermal vesiculation in BP is often preceded by the development of urticarial plaques, with marked itching, further indicating possible involvement of IgE autoantibodies in the pathogenesis of BP by causing mast cell and basophil histamine release” [1].

Th 2 lymphocytes predominate within lesional tissue and in the sera of patients with BP. The blister fluid of patients with BP shows an increase in cytokines produced by Th 2 lymphocytes including IL-4, IL-5, IL -6 and soluble Il-2 receptors.

Anna Cynkier and her colleagues examined the presence of potential pruritogens and receptors in the lesional skin of bullous pemphigoid and dermatitis herpetiformis [4]. In patients with BP they found no statistical difference in the expression of substance P, calcitonin gene-related peptide (CGRP) or neurokinin B in lesional skin compared to perilesional skin and controls. However, they found a statistically significant increase in the expression of corticotrophin-releasing factor (CRF), which modulates the expression of cell surface adhesion molecules and the expression of cytokines. In other studies, the blister fluid of BP patients has shown an increased expression of known pruritogens such as prostaglandin E2 and leukotriene B4 [5].

The pathogenesis of pruritus in BP has not been determined. Almost certainly it involves a complex mechanism involving pruritogens released by mast cells, basophils, eosinophils, keratinocytes and Th2 lymphocytes stimulating itch receptors on afferent nerve fibres.

The standard management for BP are corticosteroids. Other immunosuppressive agents have been shown to be efficacious and potentially preferable when seeking a steroid-sparing approach. In a trial comparing azathioprine and dapsone, both were found to be efficacious. Pruritus was controlled by both medications after 4 weeks of treatment [6].

69.3.2 Pemphigoid Gestationis (PG)

Pemphigoid gestationis is a variant of BP. It is a vesicobullous eruption that develops in the third trimester of pregnancy or in the postpartum period. PG is associated with severe pruritus. Classically there is an eosinophilic infiltrate in the subepidermal area with eosinophils in the blister fluid and dermal oedema with a mixed perivascular infiltrate of eosinophils and lymphocytes.

In PG there are various changes that may account for the intense itch present. There is a preponderance of Th2 lymphocytes, a marked increase in IL-1 and eosinophilic infiltrate.

Various agents have been described to manage this pruritus—emollients, topical corticosteroids, topical tacrolimus and those antihistamines that are considered safe in pregnancy [1].

69.3.3 Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is the most common AIBD in early to middle adulthood. DH is frequently associated with gluten intolerance in the small intestine. It is characterised by a symmetrical papulovesicular eruption at the dermal-epidermal junction that are intensely itchy.

The pathogenesis of DH is as follows. Gluten is ingested. Digestive enzymes process this into gliadin peptides. IgA antibodies are mounted against these peptides. Concurrently, in the epidermis, keratinocytes produced tissue transglutaminase-3 (TG3). This diffuses into the dermis. IgA-anti-TG3 antibodies reach the dermis and complex with the TG3 locally in the papillary dermis. In DH there is an IgA deposition within the papillary dermis. This leads to neutrophil infiltration of the upper dermis, apoptosis of basal and suprabasal keratinocytes and proteolytic cleavage of the lamina lucida culminating in subepidermal blister formation.

The Cynkier study examined the presence of potential pruritogens and receptors in the lesional skin of dermatitis herpetiformis [4]. They found no statistical difference in the expression of substance P, calcitonin gene-related peptide (CGRP) or neurokinin B in lesional skin compared to perilesional skin and controls. However, they found a statistically significant increase in the expression of corticotrophin-releasing factor (CRF) and the receptor of endothelin B.

Only gold members can continue reading. Log In or Register to continue