SUMMARYLesions of the common inflammatory skin disease psoriasis are characterized by epidermal hyperproliferation, leucocyte adhesion molecule expression and leucocyte infillralion. The local release of proinflammatory cytokines. such as TNF-a, may play an iniporiant role in the induction of these events. We have, therefore, analysed aqueous extracts of lesional and uninvolved (clinically normal) stratum corneum for lhe presence of TNF-a immunoreactivity and biological activity. TNF-a immunoreactivity and bioactivity were consistently higher in lesional compared wilh uninvolved samples. By using an anti-TNF-a neutralizing antibody it was demonstrated that the biological activity measured was due to the presence of TNF-a alone. Concentrations of soluble TNF receptors {p55 and p75) were aiso higher in lesional stratum corneum extracts, with Ihe p55 form predominating. The plasma of psoriatic palients was also found to contain elevated concentrations of soluble p55 compared with normal controls. These results confirm the presence of inimunoreactive TNF-a and, for the fust time, conclusively demonstrate TNF-a biological activity and quantifiable concentrations ofsoluble TNF receptors (p55 and p75) in lesional psorialic samples. TNF-a recovery from stratum corneum probably reflects synthesis in deeper, viable layers, where il is likely lo exert its biological effects. Local and systemic release ofsoluble TNF receplors, in particular p55, may serve to regulate the effects of TNF-a in psoriasis.

Histamine releasing autoantibodies play a central role in the pathogenesis of chronic urticaria (CU) in approximately 30% of affected patients. We investigated the therapeutic effect of high-dose intravenous immunoglobulin (IVIG) on disease activity in patients with severe CU of autoimmune aetiology. Autoimmune urticaria was diagnosed by the development of a weal-and-flare reaction to the intradermal injection of autologous serum and by serum-induced histamine release from the basophil leucocytes of healthy donors in vitro. Ten patients with severe, autoimmune CU, poorly responsive to conventional treatment, were treated with IVIG 0.4 g/kg per day for 5 days. The outcome on cutaneous wealing and itch was monitored using urticaria activity scores, visual analogue scales and autologous intradermal serum tests. Clinical benefit was noted in nine of 10 patients: three patients continue in prolonged complete remissions (3 years follow-up), two had temporary complete remissions, and symptoms in four patients improved subsequent to treatment. There was significant improvement in the urticaria activity scores and visual analogue scores at 2 (P < 0.01) and 6 weeks (P < 0.01) post-IVIG compared with the baseline values (Wilcoxon matched pairs). The diminution in urticarial activity in the majority of patients corresponded with a reduced weal-and-flare response to the intradermal injection of autologous post-treatment serum compared with the pretreatment serum. Minor side-effects were common, but there were no serious or long-term adverse effects. IVIG represents a novel therapeutic option in selected patients with recalcitrant CU associated with histamine releasing autoantibodies.

The major histocompatibility complex (MHC) acts as a marker for self during T-cell ontogeny and is associated with the pathogenesis of many autoimmune diseases. Recent investigations have shown about 30% of patients with chronic idiopathic urticaria (CIU) have IgG autoantibodies against the high-affinity IgE receptor, FcepsilonRI, or IgE. A link between MHC class II alleles and CIU has not been reported previously. DNA was extracted from blood of 100 Caucasian patients with CIU, and the MHC class II type determined using the polymerase chain reaction with sequence-specific primers, testing for DRB and DQB1 alleles. The frequency of alleles in CIU patients was compared with that found in 603 controls. Further human leucocyte antigen (HLA) typing on patient subsets, classified by the patients' responses to intradermal injection of autologous serum and their serum-induced histamine release from basophil leucocytes of healthy donors, was undertaken. HLA DRB1*04 (DR4) and its associated allele, DQB1*0302 (DQ8), are raised in CIU patients compared with a control population (P = 2 x 10-5 and P = 2 x 10-4, respectively). HLA DRB1*15 (DR15) and its associated allele, DQB1*06 (DQ6), are significantly less frequently associated with CIU. The HLA DRB1*04 association is particularly strong (corrected P = 3.6 x 10-6) for patients whose serum has in vivo and in vitro histamine-releasing activity. HLA class II typing is consistent with the concept that CIU is a heterogeneous disease, and supports an autoimmune pathogenesis in a subset of patients.

We performed high resolution computed tomography (HRCT) on the lungs of 20 patients with RA and clinical and radiological evidence of interstitial lung disease (ILD). A case control group of patients with RA but without evidence of ILD were similarly studied and all patients underwent detailed pulmonary function testing. Clinical findings, drug therapy, smoking status, the presence/absence of SS and disease activity were also assessed. HRCT showed a range of abnormalities among patients thought to have ILD. Interstitial fibrosis was confirmed in 16 but was frequently associated with emphysema. Ground glass opacification was present in seven, while basal honey-combing was also evident in seven patients. Both these features were present in two patients with ILD. Bronchiectasis was identified in six patients and was the predominant finding in two patients previously thought to have ILD. Among the control patients, HRCT was normal in only five. Clinically unsuspected ILD was present in four patients, while a further four had bronchiectasis. Pleural disease was identified in seven controls. Pulmonary function tests were generally poor predictors of HRCT findings, although a reduced residual volume (RV) [> 1 S.D.] was 83% specific for the presence of ILD and a raised RV [> 1 S.D.] was 64% specific for emphysema. Smoking did not correlate with the presence of either ILD or emphysema and there were no correlations between disease activity and HRCT findings. RA patients with evidence of ILD have abnormalities on HRCT which cannot be confidently predicted on any other non-invasive test.(ABSTRACT TRUNCATED AT 250 WORDS)

1The ability of intradermally injected leukotrienes C4 (LTC4), LTD4 and LTB4 to produce inflammatory changes in human skin alone and in combination with prostaglandin E2 (PGE2) has been investigated. 2 LTC4 and D4 (0.012-0.38 nmol) caused dose-related erythema and wealing. No evidence of synergism between PGE2 and LTC4 or LTD4 was detected, although only single dose combinations were studied. 3 LTB4 (0.15-1.5 nmol) caused areas of induration which persisted for more than 4 h and which showed perivascular neutrophil infiltrates on histological examination. Only slight synergism between PGE2 and LTB4 was found. 4 It was concluded that these pro-inflammatory properties of LTC4, LTD4 and LTB4 are consistent with their proposed roles as mediators of inflammation in the skin and other tissues.

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1 Clinically normal human abdominal skin was irradiated with three minimal‐erythema doses of ultraviolet B irradiation, (u.v.B). 2 Erythema was assessed visually, and exudate recovered by a suction bulla technique from normal skin, and at 10 min, 2, 6, 18, 24 and 48 h after irradiation. 3 Erythema was barely visible at 2 h, but increased to maximum at 24 h, which was maintained at 48 h. 4 Increased arachidonic acid and prostaglandin E2, F2 alpha and D2 concentrations in the exudate, measured by gas chromatography‐mass spectrometry, accompanied the developing erythema, with the maximal rise of arachidonic acid, prostaglandin E2 and D2 occurring at the height of the erythema at 24 h. 5 At 48 h, still at the height of the erythemal response, arachidonic acid and PGE2 levels had returned to near normal. 6 Concentrations of arachidonic acid and of its products from the cyclo‐ oxygenase pathway, parallel the development of i.u.B. erythema in the first 24 h.