A.V. Powles

The effects of cyclosporin A on T lymphocyte and dendritic cell sub-populations in psoriasis

Sequential skin biopsies from six patients with severe psoriasis were studied during treatment with cyclosporin. Four of the patients cleared completely and the remaining two showed a marked improvement. A subset of dendritic cells, HLA‐DR+ but lacking the T6 antigen characteristically expressed by Langerhans cells (DR+ 6‐), was observed in lesional epidermis. They disappeared during treatment, before clinical improvement was apparent and at a rate which correlated with clearance of psoriasis. These cells were not found in normal or uninvolved psoriatic epidermis and their number in lesional skin appeared to be related to the clinical severity of the disease. Total numbers of CD4 and CD8, and HLA‐DR+ CD8 T cells were substantially reduced in both epidermis and dermis prior to clinical improvement. In contrast, there was generally no decrease in the number of HLA‐DR + CD4 T cells in the epidermis during resolution, whereas these cells were reduced by an average of 68% in the dermis. The beneficial effects of cyclosporin in psoriasis further support the hypothesis that T cells play a central role in the pathogenesis of psoriasis. The cellular changes observed in the skin during cyclosporin treatment may help to elucidate the effects of this drug on immunoregulatory mechanisms in man.

Restricted T-cell receptor Vβ gene usage in the skin of patients with guttate and chronic plaque psoriasis

A strong association between acute guttate psoriasis and group A, β‐haemolytic streptococcal infections is well established. Furthermore, streptococcal M proteins and toxins have been shown to act as superantigens, stimulating subpopulations of T lymphocytes expressing particular Vβ families.

Immunofluorescent studies in ocular cicatricial pemphigoid.

Twenty nine patients with cicatrizing conjunctivitis were studied; 17 with a clinical diagnosis of cicatricial pemphigoid, five with a clinical diagnosis of pseudopemphigoid caused by long‐term application of topical medication and seven who had a cicatrizing conjunctivitis from other causes. Biopsies from clinically uninvolved bulbar conjunctiva were taken for direct immunofluorescence and blood was taken for indirect immunofluorescence using normal human conjunctiva, oral mucosa and skin as substrates.

Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions.

A strong association exists between guttate psoriasis and group A, β‐haemolytic streptococcal infections. To demonstrate the presence of streptococcal‐specific T cells in psoriatic skin, T‐cell lines (TLs) were established from biopsies of lesions from five patients with guttate psoriasis, and compared with TLs from five patients with eczema, five with lichen planus, two with pityriasis rosea and three with nickel contact dermatitis. TLs from purified protein derivative (PPD)‐induced delayed hypersensitivity sites in three normal individuals were also studied. All five of the psoriatic TLs responded in a proliferation assay to heat‐killed isolates of group A streptococci, compared with only one eczema, two lichen planus and one pityriasis rosea. The response of one nickel contact dermatitis and two PPD TLs to group A streptococci was markedly less than to nickel and PPD, respectively. One of the psoriatic TLs was cloned in the presence of type 5 streptococcal M protein. The nine clones obtained were all CD3+, CD4+, CD45RO+, TCR α,β+, γ,δ−. However, they were all unreactive with antibodies to TCR V β 5, 6, 8 or 12. Eight of the nine clones reacted, to a varying extent, to one or two of three preparations of group A streptococci expressing different M proteins. The streptococcal response of four consistently reactive clones from this patient was HLA‐DR‐restricted and inhibited by anti‐HLA‐DR antibody in a dose‐dependent manner. On stimulation these four clones secreted high levels of γ‐interferon and detectable levels of IL‐2, IL‐10 and granulocyte/macrophage colony stimulating factor (GM‐CSF) depending upon the nature of the stimulus, but no IL‐4 or TNF‐α production was detected.

Long-term cyclosporin for psoriasis

Thirteen patients with severe persistent psoriasis, intolerant of, or unresponsive to, other current treatments have been treated with cyclosporin (Cys) for periods varying from 12–25 (mean 18) months. The dose ranged from 1–4 mg/kg/day (mean 2.8 mg). There was a 72% reduction in the mean PASI score at 4 weeks, and at the end of the study, an 81% reduction. Adjuvant therapy with topical steroids was used in 11 of the 13 patients after the first 3 months of Cys treatment to persistent patches on an intermittent basis with beneficial effect. Six patients developed mild to moderate hypertension, in three this was controlled by a reduction in the dose of Cys, and in the other three by hypotensive agents. The mean serum creatinine rose from 72 to 90μM/1 during the study. Hypertrichosis occurred in seven of the 13 patients. Low dosage Cys is an effective treatment for clearing psoriasis and maintaining improvement on a long‐term basis.

USE OF CYCLOSPORIN IN PSORIASIS

In the treatment of severe psoriasis, cyclosporin may achieve improvement or remission at low doses, but relapse usually occurs on withdrawal of treatment. An initial dose of 3 mg/kg per day is recommended. Complete remission should not be the objective, and the role of long-term maintenance cyclosporin therapy is uncertain because of potential side-effects--especially nephrotoxicity, hypertension, and a predisposition to malignancy. Guidelines are proposed for the assessment of such treatment.

Renal function and biopsy findings after 5 years' treatment with low-dose cyclosporin for psoriasis.

Renal biopsies were performed in eight patients with chronic plaque psoriasis who had been treated with low‐dose cyclosporin (CyA) (range 1–6 mg/kg/day; average dose 3.3 mg/kg/day) for an average period of 5 years. In six of the eight patients biopsies showed features consistent with CyA nephrotoxicity. Tubular atrophy and arteriolar hyalinosis were present in all six, four had an increase in interstitium. and two showed an increased incidence of glomerular obsolescence. Two of the patients showed all of these features, two patients had three features, and the remaining patients had two features. Renal function was assessed by glomerular liltration rate (CFR) and serum creatinine. Both a fall in the GFR and a rise in the serum creatinine correlated with the severity of the features of CyA nephrotoxicity seen on biopsy. However, the best predictor of the biopsy findings was a failure of renal function to show significant improvement when CyA was discontinued for a month.

Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid

One‐hundred and sixty‐eight cases of dermatitis herpetiformis were reviewed to compare the clinical response to and incidence of side‐effects from dapsone and sulphamethoxypyridazine. Thirty‐seven received sulphamethoxypyridazine (0·25–1·5 g/day) as a single agent therapy at some stage during their care and 161 had dapsone only (50–450 mg/day). Thirty of these patients received both drugs, but at different times. Both were highly effective in controlling the skin disease in 97% of patients on dapsone and 89% on sulphamethoxypyridazine. While 36 (22%) of dapsone‐treated subjects had intolerable side effects warranting a change in therapy, this occurred in only five (13·5%) of those treated with sulphamethoxypyridazine. Sulphamethoxypyridazine was also effective as a single agent in three patients with linear IgA disease who had suffered adverse effects from dapsone, and in 10 out of 15 patients with oral and cutaneous lesions of cicatricial pemphigoid.

Cytokine expression in psoriatic skin lesions during PUVA therapy

To determine whether an improvement in skin lesions as a result of PUVA therapy may be correlated with changes in cytokine patterns, RT-PCR amplification was used to compare the levels of IL-2, IL-6, IL-8, IL-10, TNF-α and IFN-γ cytokine mRNA expression in serial biopsies from three chronic plaque psoriatic patients. In each case, 3-mm punch biopsies were taken from lesional skin before and during 2–28 days of treatment with PUVA. Total mRNA was extracted from each biopsy, cDNA synthesized, and then amplified by 35 cycles of PCR using cytokine-specific primers. The specificity of the PCR products was confirmed by the Southern blot technique. Substantial levels of specific mRNA for each of the cytokines studied was present in the lesions prior to treatment. In two of the three patients who responded well to PUVA, a reduction in all the cytokines including IL-10 was observed compared with baseline levels. In contrast, PUVA proved to be ineffective in clearing the psoriasis of the third patient whose skin lesions worsened during the course of treatment. This was accompanied by an increase in IFN-γ but not of the other cytokines investigated, above the pretreatment level. This study showed an association between PUVA-induced resolution and decreases in the levels of various cytokines highly expressed in psoriatic lesions.

Altered cell‐mediated immunity to group A haemolytic streptococcal antigens in chronic plaque psoriasis

The proliferative lymphocyte response to sonicated group A, β‐haemolytic streptococci (Strep‐A) was measured by thymidine incorporation in 78 patients with psoriasis (guttate, chronic plaque or both). Lymphocytes from 72 of these patients were also cultured with streptokinase/streptodornase (SK/SD), and 20 of the patients with chronic plaque psoriasis were further tested with PPD, Candida albicans and sonicated Streptococcus mutans, a bacterial type not associated clinically with psoriasis. The median stimulation index (SI) of the psoriasis group to the Strep‐A preparation was significantly higher than that of a group of 27 non‐psoriatic individuals (P < 0·05). Within this group, only the patients with chronic plaque psoriasis (n = 42) showed a significantly increased proliferative response compared to the non‐psoriatic controls (median SI = 123·8 and 31·9, respectively, P < 0·01). Although the lymphocyte response of the chronic plaque group to SK/SD was also markedly higher than that of the control group, this difference did not reach statistical significance. In addition, these patients did not show significantly increased responses to any of the other antigens tested, including S. mutans.