F.M. Cunningham

Leukotriene B4-like material in scale of psoriatic skin lesions

1 Acidic lipid extracts of scale from the lesions of the skin disease, psoriasis, were purified by straight phase high performance liquid chromatography (h.p.l.c). Assay of fractions by an agarose microdroplet chemokinesis method showed the presence of biologically active material that co‐eluted with standard leukotriene B4 (LTB4). 2 LTB4‐like chemokinetic activity was also detected in fractions collected on reversed phase h.p.l.c. of psoriatic scale extracts that were initially purified by straight phase h.p.l.c. 3 No LTB4‐like activity was detected after similar purification of scale obtained by abrasion of large areas of normal skin. 4 The LTB4‐like material found in extracts of psoriatic scale may play a role in the pathogenesis of the neutrophil infiltrate which characterizes psoriasis.

Contrasting in vitro lymphocyte chemotactic activity of the hydroxyl enantiomers of 12-hydroxy-5,8,10,14-eicosatetraenoic acid

1 The chemotactic activity of 12(R)‐hydroxy‐5,8,10,14‐eicosatetraenoic acid (12(R)‐HETE), 12(S)‐HETE and leukotriene B4 (LTB4) for human mixed peripheral blood lymphocytes has been assessed in a 48‐well microchemotaxis assay. Responses to the standard lymphocyte chemoattractants, zymosan‐activated plasma, casein and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP) were also measured. 2 12(R)‐HETE was shown to be chemotactic for lymphocytes over the range 5 × 10−7 to 5 × 10−5 m. In contrast, negligible chemotactic responses to 12(S)‐HETE were obtained. 3 LTB4 was 200 times more potent than 12(R)‐HETE as a lymphocyte chemoattractant, although maximal responses to the two agonists were similar. 4 12(R)‐HETE and LTB4, which are present in extracts of samples from the skin lesions of psoriasis, may be, at least in part, responsible for the lymphocyte infiltrate which is a characteristic feature of this disease.

The role of chemo-attractant lipoxygenase products in the pathogenesis of psoriasis.

The histopathology of chronic, stable plaque psoriasis is characterized by acanthosis with mitotic figures in the lower epidermis, abnormalities of differentiation, vascular dilatation and tortuosity, and leukocyte infiltrates. These infiltrates are composed of neutrophils and mononuclear cells, the former apparently migrating from the dermal papilla, through the Malpighian layer and into the parakeratotic stratum corneum. Mononuclear cells are evident in the superficial dermis and in the lower half of the epidermis (Ragaz & Ackerman, 1979; Soltani & Van Scott, 1972; Helwig, 1958; Pinkus & Mehregan, 1966). The nature of the earliest histopathological change in developing psoriatic lesions is the subject of controversy with, for example, one group (Chowaniec et al, 1981) reporting infiltration of polymorphonuclear leukocytes into the epidermis to be the earliest change, another (Ragaz & Ackerman, 1979) finding a superficial perivascular lymphocyte infiltrate, and yet another (Brody, 1984a, b) reporting mast cell degranulation as the primary event in acute guttate psoriasis. In addition, Braun-Falco and Schmoeckel (1977) found macrophages to be the predominant infiammatory cells in initial psoriatic lesions. In postulating a role for an endogenously released chemical mediator in the genesis of a pathological change, it is important (i) to recover elevated levels of the mediator from the involved tissue in vivo at an appropriate time, (2) to reproduce at least in part the pathological change by introduction ofthe mediator into the tissue in vivo, in appropriate concentrations, (3) to demonstrate mechanisms for the release and removal of the mediator in the involved tissue, (4) to modify the pathological process by administration of specific enzyme inhibitors or receptor antagonists in vivo, (5) to determine the relative amounts of other chemical mediators with similar modes of action in the involved tissue in vivo and (6) to determine whether production ofthe mediator occurs in other lesions, i.e. whether it is specific to the pathological process under study. It is noteworthy that most ofthe above, which are an extension ofthe criteria of Dale (1934), can only be investigated by in vivo studies. We have chosen to examine the role of acidic lipid neutrophil chemo-attractants in the pathogenesis ofthe infiammatory changes in chronic plaque psoriasis. The evidence obtained to date is presented here in six sections, according to the above criteria.

Psoriatic skin lesions contain a novel lipid neutrophil chemokinetic compound which is distinct from known chemoattractant eicosanoids

1 Lipid extracts of scale from the lesions of the skin disease psoriasis were purified by high performance liquid chromatography (h.p.l.c.). Assay of fractions by an agarose microdroplet method showed the presence of a novel neutrophil chemokinetic compound which possessed the chromatographic properties of a monohydroxy fatty acid, yet was distinct from the chemoattractant eicosanoid, 12‐hydroxyeicosatetraenoic acid, previously isolated in psoriasis. 2 The novel material, termed compound X, was also detected in fractions collected on h.p.l.c. of extracts of chamber fluid samples obtained from abraded psoriatic lesions, but was not detectable in samples from clinically normal skin. 3 Comparison of the straight and reversed phase h.p.l.c. retention times of compound X with those of a range of standard monohydroxy fatty acids, together with further analysis by gas chromatography — mass spectrometry and assay of selected standards for neutrophil chemokinetic activity, failed to reveal the structural identity of compound X. 4 The finding of a further compound in psoriatic lesions, which stimulates neutrophil movement, highlights the complexity of inflammatory mediator production in this disease.

The clinical and pharmacological effect of lonapalene (RS‐43179), a 5‐lipoxygenase inhibitor, applied topically in psoriasis

33 increased in psoriatic cells (011410014) compared with normal cells (003710001) (P < o 001). There was greater conversion both of total PI and individual PI fractions in samples from psoriatics, implying increased PLC activity. In addition, there was a correlation between MNL PDE activity and MNL cytosol PLC activity (r = o-9). These studies suggest a link between cyclic nucleotide and phosphoinositide regulatory abnormalities which may lead to immune and proliferative aspects of cell dysfunction in psoriasis.

261 Tissue and circulating microRNA co-expression analysis reveals potential involvement of miRNAs in the pathobiology of frontal fibrosing alopecia

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The Inflammatory Properties of Eicosanoids in Human Skin

Arachidonic acid metabolites have been implicated as mediators of both the vascular and cellular components of inflammatory processes. The importance of prostaglandins as pro-inflammatory agents was highlighted by the discovery that non-steroid anti-inflammatory drugs are cyclo-oxygenase inhibitors (1–3). Research into the role of eicosanoids as mediators of inflammation has been extended in recent years following the characterisation of biologically active products of arachidonate lipoxygenase systems. The formation of these lipoxygenase products is not significantly inhibited by conventional non-steroid anti-inflammatory drugs in doses which inhibit the cyclo-oxygenase system.

Retrospective review of 18 British South Asian women with frontal fibrosing alopecia

Retrospective review of 18 British South Asian women with frontal fibrosing alopecia Frontal fibrosing alopecia (FFA) was first described in 1994. While FFA was initially described exclusively in postmenopausal Caucasian women, it has since been reported in Hispanic, African, Afro-Caribbean, and Asian individuals, premenopausal women, and men. There is no epidemiological data on the incidence or prevalence of FFA in the general population, but anecdotal evidence from multiple specialist centers suggests that the incidence is increasing. Despite the high prevalence of South Asians in the United Kingdom (5%, UK Census 2011), there is paucity of published information about South Asians with FFA. We conducted a retrospective review of 578 FFA patients from four hair specialist units in the United Kingdom. We identified 18 women of Indian, Pakistani, and Bangladeshi origin (3.1%). The mean age at diagnosis was 52 (range 41–71). Ten of 18 (56%) were premenopausal. Eleven (60%) had perifollicular erythema and/or hyperpigmentation over the affected areas on the scalp. Fourteen (77%) had associated eyebrow loss, and nine (50%) had body hair loss. Eight of the 18 women (44%) had facial hyperpigmentation clinically consistent with lichen planus pigmentosus (LPPigm), and this was confirmed histologically in four patients. The hyperpigmentation affected the face and neck, and the pattern was diffuse in six cases, speckled in one, and there were multiple macules in two cases (Fig. 1). One patient presented with facial papules. Interestingly, the majority of South Asians with FFA (56%) were premenopausal in contrast to a much smaller proportion of premenopausal Caucasian women with FFA (14–17%). The coexistence of FFA with facial hyperpigmentation due to LPPigm was first described 4 years ago. Hyperpigmentation due to LPPigm seems to be a unique feature of FFA seen in darker skin types, as seen in our cohort (44%) and in previously published cohorts from South Africa (54%), although the background prevalence of LPPigm (without FFA) in this population is poorly-defined. Study limitations include the retrospective design, potential skewing of numbers due to access or referral practices, and the fact that not all of our patients with facial hyperpigmentation had skin biopsies or patch testing to exclude alternative diagnoses. There is growing evidence that lichenoid/pigmented contact dermatitis is associated with leave-on facial cosmetics, patch test reactions, and FFA pathogenesis. Also, hydroxychloroquine-induced pigmentation may mimic LPPigm clinically and dermoscopically, as antimalarials are commonly prescribed for FFA. There are limited data about the coexistence of FFA and hyperpigmentation. The question that arises from these observations is whether LPPigm is part of the spectrum of FFA or whether LPPigm is a distinct entity which occurs coincidently with FFA in darker skin types. Supporting the same spectrum theory is that both have histological similarities, LPPigm seems more common in South Asian individuals with FFA, and both conditions are more common in women. On the other hand, LPPigm is less common than FFA and is extremely rare in Caucasians, while FFA is more common in Caucasians. Finally, FFA is more common in postmenopausal women, while LPPigm affects younger premenopausal women more frequently. This retrospective review has demonstrated that LPPigm is seen in a high proportion of patients of South Asian origin with FFA – this seems to be a unique feature in darker skin types given the similar finding in South African patients. In addition, a greater majority of Asian patients with FFA are premenopausal compared with Caucasian cohorts – this ideally needs validation with larger series. Given that almost half of all women in our series had coexistent LPPigm, we would strongly advocate that careful clinical examination of the frontal hairline should be considered in South Asian patients presenting with LPPigm to look for coexisting FFA. We would also consider patch testing and skin biopsies in patients with FFA and LPPigm to exclude other causes of pigmentation. Figure 1 These photos show a Pakistani woman with frontotemporal recession, eyebrow loss, and facial and temporal hyperpigmentation in a diffuse pattern. Histology showed lichenoid changes consistent with lichen planus pigmentosus