Jaakko Karvonen

Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish patients with psoriasis.

It has been suggested that trioxsalen bath and ultraviolet (UV) A (PUVA) is associated with a very low or no risk of non‐melanoma skin cancer, but the numbers of patients in individual studies have been limited. In order to attain statistically relevant information about the cancer risk associated with trioxsalen bath PUVA, two follow‐up studies were combined and the joined cancer incidence was analysed among 944 Swedish and Finnish patients with psoriasis. The mean follow‐up time for skin cancer was 14.7 years. Standardized incidence ratios (SIR) were calculated as a ratio of observed and expected numbers of cases. The expected numbers of cases were based on the national cancer incidence rates in the respective countries. There was no excess of squamous cell skin carcinoma [SIR 1.1, 95% confidence interval (CI) 0.2–3.2] or malignant melanoma (SIR 0.9, 95% CI 0.1–3.2) in the combined cohort. Basal cell skin carcinoma was not studied. The incidence of all non‐cutaneous cancers was not increased (SIR 1.1, 95% CI 0.8–1.4). A threefold excess risk of squamous cell skin carcinoma after trioxsalen bath PUVA could therefore be excluded, which is a markedly lower risk than that associated with oral 8‐methoxypsoralen PUVA. The result needs to be confirmed in a future follow‐up, however, as the number of patients with high PUVA exposures was low.

Trioxsalen bath plus UVA effective and safe in the treatment of psoriasis

Seventy‐four patients with psoriasis were treated using a trioxsalen bath (50 mg/150 1 of water) and long wave ultraviolet light (UVA) given in an ordinary PUVA‐cabin. Good or excellent results were observed in 92% of the patients in the initial phase and in 63% during the maintenance treatment. Because of local side‐effects the therapy was discontinued in two patients. One of them developed contact hypersensitivity to trioxsalen and the other developed blisters with such low doses of UVA that it was difficult to maintain the proper dose. The therapy was started with 0‐28 J/cm2 of UVA and after an average of 18 treatments, when the average dose was 1.70 J/cm2, the patients were moved to maintenance treatment which took place at 1‐4 week intervals. The therapy was well tolerated and cosmetically very acceptable. The final tan was even on all but the face, which remained untanned.

HLA risk haplotype Cw6,DR7, DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris

Psoriasis vulgaris has HLA associations. We have previously defined HLA-Cw6,DR7,DQA1*0201 as the central element of the risk haplotypes for psoriasis. On the other hand, Cw6 as a single gene has the strongest association with psoriasis. The aim of this study was to determine whether the risk haplotype and Cw6 correlate with the clinical parameters of the disease. The series consisted of 64 patients and the clinical parameters were age at onset, family history of psoriasis, arthritis and the frequency of inpatient treatment. The HLA risk haplotype Cw6,DR7,DQA1*0201 had previously been found in 30% and Cw6 alone in 54% of the patients. The presence of Cw6 correlated with early age at onset (Pc=0.01). The presence of the risk haplotype correlated with a positive family history of psoriasis among the first-degree relatives (Pc=0.02) and an overall positive family history (Pc=0.04), but Cw6 had a stronger correlation with an overall positive family history (Pc=0.01). There were no positive correlations with arthritis or the number of inpatient treatment periods. Only type I psoriasis was associated with Cw6 (Pc=0.0006). In conclusion, Cw6 and the haplotype Cw6,DR7,DQA1*0201 are important in the heredity of psoriasis vulgaris, but the presence of Cw6 alone is sufficient to indicate a clinically significant risk for psoriasis.

Cancer incidence among Finnish psoriasis patients treated with 8-methoxypsoralen bath PUVA

BACKGROUND Long-term oral 8-methoxypsoralen (8-MOP) and UVA (PUVA) therapy increases the risk of nonmelanoma skin cancer and possibly also of cutaneous malignant melanoma. Topical application of 8-MOP PUVA induces malignant tumors in rodent skin, but little is known about its carcinogenicity in human skin. OBJECTIVE Our purpose was to investigate the carcinogenicity of 8-MOP bath PUVA in humans. METHODS This was a cohort study of 158 patients with psoriasis, for whom 8-MOP bath PUVA had been initiated during 1979 to 1992. The average number of 8-MOP bath PUVA treatments was 36 (range, 6 to 204) and the mean cumulative UVA dose was 92 J/cm2 (range, 3 to 884 J/cm2) by the end of 1995. The patients were not treated with any other forms of PUVA. Cancer incidence subsequent to 8-MOP bath PUVA up to the end of 1995 was determined by linking the cohort with the records of the Finnish Cancer Registry. The standardized incidence ratios (SIR) were calculated for skin cancer and some common internal cancers, using the expected numbers of cases based on the regional cancer incidence rates. RESULTS There was one case of basal cell carcinoma, but no cases of other types of skin cancer. A total of 6 noncutaneous cancers were observed (SIR, 1.3; 95% confidence interval, 0.5 to 2.8). CONCLUSION No association between cutaneous cancer and 8-MOP bath PUVA was found, but the statistical power of this study alone is not adequate to warrant definite conclusions. The results can be used in a meta-analysis as soon as other studies on the carcinogenicity of 8-MOP bath PUVA are published.

Trioxsalen baths plus UV‐A in the treatment of lichen planus and urticaria pigmentosa

Local photochemotherapy with trioxsalen baths and long‐wave ultraviolet radiation (UV‐A) was used in nineteen patients with lichen planus and five patients with urticaria pigmentosa. Widespread papular lichen planus healed totally in all sixteen patients. Hypertrophic lichen planus was more resistant to therapy; two out of three patients recovered completely and in one the result was good. The average total UV‐A dose in papular lichen planus was only 6 J/cm2. In urticaria pigmentosa good results were gained in all five patients treated with respect to whealing, itching and dermographism, and in one patient the lesions disappeared completely.

Pityriasis rubra pilaris

In a clinical study, 27 of 31 cases of pityriasis rubra pilaris (PRP) had two or more of the following clinical features: erythroderma, well-confined healthy islands inside the inflammatory areas, ker

Immunogenetic profile of psoriasis vulgaris: Association with haplotypes A2, B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201

Psoriasis vulgaris is a skin disease with an immunological and genetic background present in 1–3% of the population. We studied the genetic susceptibility to psoriasis vulgaris in Finns with serological HLA typing and genomic HLA class II typing of the DQ and DP loci to evaluate the risk of developing psoriasis. The haplotypes most frequently distinguishing between psoriatics and controls were those that carried Cw6 (P<10−8), DQA1*0201 (P=9.3×10−6) and DR7 (P=3.9×10−5). The two most frequent marker haplotypes were A2,B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201, which were not found among the control subjects. A deficit of haplotype B8,DR3,DQ2 (2 out of 124 in the patients versus 15 out of 106 in the controls,P=1.5×10−4) was found, and this was in accordance with a slightly decreased frequency of DQA1*0501 (P=3.1×10−2), which was usually linked with this haplotype. These results stimulate the search for a genetic resistance factor in psoriasis. Thus, this report sheds further light on the immunogenetic background of psoriasis in Finland. We conclude that the inheritance of psoriasis has a polygenic mode, in which the Cw6,DR7,DQA1*0201 combination seems to be important (P=7.5×10−7, relative risk 24.4, aetiological factor 0.29).

Expression of p53 protein before and after PUVA treatment in psoriasis.

We investigated the effect of the potentially carcinogenic psoralen plus UVA radiation (PUVA) therapy on the expression of p53 in skin of psoriatic patients. p53 antibodies DO7 and Pab240, antibodies against PCNA and Ki67 and the avidin-biotin immunoperoxidase complex method were used in the immunohistochemical staining of biopsy samples from non-lesional and lesional skin of 23 patients who received either trioxsalen bath PUVA or oral 8-methoxypsoralen PUVA. Biopsies were taken before and after a PUVA course. A modest expression of p53 was seen in psoriatic lesions in 17/21 patients before any treatment, probably as a physiological reaction to the hyperproliferation. Both p53 and the proliferation markers Ki67 and PCNA followed the same pattern, being more frequent in psoriatic lesions than in non-lesional skin. Exposure to PUVA induced an increase in p53 expression in non-lesional skin in 14/19 patients, putatively as a response to DNA damage caused by PUVA. In psoriatic lesions about half of the patients showed increased and half decreased expression of p53. The latter finding might be explained by decreased proliferation activity of the healing epidermis. In conclusion, p53 nuclear positivity in non-lesional skin after PUVA treatment is likely to be induced by DNA damage caused by PUVA, while in psoriatic lesions it could be a result of the combined effect of decreasing epidermal proliferation and DNA-damage.

Mononuclear cell subsets in the nickel-allergic reaction in vitro and in vivo

Nickel is the major cause of metal-induced contact allergy. To understand the mechanism of its immune reaction, we studied changes in lymphocyte surface markers during nickel challenge in both allergic and healthy subjects using an in vitro nickel reaction in which the lymphocytes of allergic subjects divide when they are stimulated with nickel sulfate. The lymphocytes were labeled with monoclonal antibodies (MAbs) to cell-surface antigens and studied by flow cytometry. Mononuclear cells from the nickel reaction in vivo were studied from skin biopsy specimens using MAbs and avidin-biotin immunohistochemistry. Nickel-induced lymphoblast transformation occurred in vitro only in cells from nickel-allergic subjects. CD4+ cells and CD45RO+ cells were overrepresented among the lymphoblasts of nickel-sensitive subjects, whereas CD8+ and CD8+CD11b+ and CD4+CD45R+ cells were underrepresented. The lymphoblasts contained T cells with the following activation markers: CD25, HLA-DR, CD26, CD71, Ki-67, and activation-associated antigen detected by the MAb, M21C5, but they were CD30-. CD16+ cells were overrepresented among the lymphoblasts. Nickel-reacting T cells used predominantly the T cell receptor, alpha beta-heterodimer, but no preferential selection of either V beta 5, V beta 6, or V beta 8 was observed. The phenotypes of nickel-reacting cells from cutaneous biopsy specimens were in agreement with the in vitro results.

Aminoterminal propeptide of type III procollagen in methotrexate-induced liver fibrosis and cirrhosis

Twenty‐four psoriatic patients on methotrexate were studied with liver biopsies and serum measurements of aminoterminal propeptide of type III procollagen (PHI NP). All but one of nine patients with scrum levels of PHI NP above the normal range had liver fibrosis or cirrhosis and no normal liver biopsies were obtained in this group. In contrast, nine normal liver biopsies and two biopsies with minimal fibrosis were found among the 15 patients with normal serum levels of PHI NP. The study indicates that aminoterminal propeptide of type III procollagen can be utilized as a valuable non‐invasive marker of fibrogenesis in the liver. This analysis is not specific for the liver, but it seems that the number of liver biopsies probably can be reduced in psoriatics on methotrexate who have normal levels of PHI NP.