Milker's nodule: an occupational infection and threat to the immunocompromised.

Milker's nodule virus, also called paravaccinia virus, is a DNA virus of the parapoxvirus genus transmitted from infected cows to humans. It results from contact with cattle, cattle by-products or fomites. Classified as an occupational disorder, those at risk of exposure include farmers, butchers and agricultural tourists. The viral infection begins 5-15 days after inoculation as an erythematous-purple, round nodule with a clear depressed centre and a surrounding erythematous ring. While familiar to those in farming communities, the presence of the nodule may be concerning to others, particularly the immunosuppressed. Milker's nodules are self-limited in immunocompetent individuals and heal without scarring within 8 weeks. Another member of the Parapoxvirus genus, the orf virus, is also transmitted from animals to humans by direct contact. While complications are rare, haematopoietic stem cell transplant recipients are at risk of graft-versus-host disease, as the parapoxvirus may trigger these complications in immunocompromised individuals. In addition, paravaccinia may serve as the antigen source for the development of erythema multiforme. The unique structure and replication process of viruses in the Poxvirus family, while includes the Parapoxvirus genus, have been a focus for treatment of infections and cancer. Manipulation of these viruses has demonstrated promising therapeutic possibilities as vectors for vaccines and oncologic therapy.

A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients.

BACKGROUND: For the treatment of a chronic disease like atopic dermatitis, sustained tolerability and efficacy of the applied medication are essential. OBJECTIVES: The present open-label, noncomparative study was conducted to obtain information on the long-term safety and efficacy of 0.1% tacrolimus ointment. METHODS: Patients aged 2 years or older with an affected body surface area of more than 5%, who previously participated in a clinical trial on tacrolimus ointment, were eligible for this study. The treatment area was defined by the investigator at study entry. Both children and adults applied continuously or intermittently 0.1% tacrolimus ointment twice daily during episodes of active disease plus an additional week after remission over a follow-up period of up to 4 years. RESULTS: The intent-to-treat population comprised 782 patients, with a median age of 22 years (range 2-72). Patients remained in the study for up to 4 years. Approximately half of the patients discontinued the study prematurely; the median follow-up was 1422 days. Median tacrolimus ointment use was 31.2 g during the first week; ointment use decreased during the first year and then remained stable for the remainder of the study. The median cumulative tacrolimus use was 271.5 g at month 6, 462.5 g at month 12, 739.9 g at month 24, 1029.3 g at month 36 and 1320.8 g at month 48. Altogether 51.8% of patients discontinued the study prematurely; the main reasons were withdrawal of consent (13.3%), loss to follow-up (11.3%) and lack of efficacy (9.4%). Adverse events led to study discontinuation in 3.7% of the patients. The most frequent application site events were skin burning and pruritus. These events were most often reported in adult patients during the initial treatment period; prevalence decreased after the first week and remained at a low level throughout the study. Nonapplication site events occurred with stable incidences throughout the study period. In general, calculated daily hazard rates did not indicate an increased risk of adverse events with prolonged treatment. The total affected body surface area decreased substantially upon onset of treatment and efficacy of treatment was maintained until the end of the study with smaller but continuous improvements throughout the follow-up period. Overall, 75% of the patients and 76% of the investigators rated their satisfaction with the treatment as excellent, very good or good at the end of the study or at the time of premature discontinuation. CONCLUSIONS: The safety profile of intermittent or continuous long-term application of 0.1% tacrolimus ointment for up to 4 years was consistent with that which has been established from shorter studies and gave no reason for concern. In addition, 0.1% tacrolimus ointment demonstrated sustained efficacy as reflected by the expression of high satisfaction with treatment by both patients and investigators.

Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group.

OBJECTIVE: To investigate the safety and efficacy of using 0.1% tacrolimus ointment for long-term treatment of atopic dermatitis. DESIGN: Open-label, noncomparative study with 6 to 12 months of follow-up. SETTINGS: Outpatient departments in 30 study centers in 11 European countries. PATIENTS: We enrolled 316 patients aged 18 years and older with moderate to severe atopic dermatitis, 200 for 6 months and 116 for 12 months; 77.5% of patients completed the study. INTERVENTION: Twice-daily application of 0.1% tacrolimus ointment on all affected skin. Visits were scheduled on day 1; after 1, 2, and 4 weeks of treatment; and monthly thereafter. MAIN OUTCOME MEASURES: Safety assessments included monitoring of adverse events, clinical laboratory values, and tacrolimus blood concentrations. Efficacy end points included a combined score (modified Eczema Area and Severity Index) and an investigator's global assessment. RESULTS: Local irritation, adverse events such as burning sensation (47% of patients), pruritus (24% of patients), and erythema (12% of patients) were common but tended to occur only when initiating treatment. Laboratory values showed no marked changes over time. Systemic absorption was minimal, with the maximum tacrolimus blood concentration being less than 1 ng/mL in 76% of patients. All efficacy end points showed improvement. The mean (SD) modified Eczema Area and Severity Index score was 23.7 (12.6) at day 1, 13.5 (11.3) at week 1, 6.1 (9.2) at month 6, and 6.1 (8.1) at month 12. Marked or excellent improvement or clearance of disease was reported in 54%, 81%, and 86% of patients at week 1, month 6, and month 12, respectively. CONCLUSION: Up to 1 year of tacrolimus ointment use was safe and effective in patients with atopic dermatitis. Arch Dermatol. 2000;136:999-1006

Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study.

BACKGROUND: Cyclosporine for the treatment of psoriasis constitutes a new approach. Alternative systemic cyclosporine derivatives have been studied to find an immunosuppressive drug with fewer adverse effects. Tacrolimus is one of these new immunosuppressive drugs. Systematically, it has been proven effective in treating psoriasis. A topical formulation of tacrolimus is attractive because it has fewer adverse effects and is useful for a large group of patients. We report for the first time on the efficacy of nonocclusive topical tacrolimus in the treatment of psoriasis. OBSERVATIONS: After a washout phase of 2 weeks, patients were randomized to receive 0.005% calcipotriol ointment twice daily, placebo ointment once daily, or 0.3% tacrolimus ointment once daily. One psoriatic plaque was treated with a surface area of 40 to 200 cm2. Efficacy was estimated using the local psoriasis severity index. The reduction in the local psoriasis severity index score after 6 weeks was 62.5% in the calcipotriol group, 33.3% in the tacrolimus group, and 42.9% in the placebo group. CONCLUSIONS: There was no statistically significant difference between the efficacy of tacrolimus and placebo ointment (P = .77). Calcipotriol ointment, applied twice daily, had a better effect than tacrolimus ointment and placebo ointment once daily.

A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group.

BACKGROUND: Tacrolimus (FK 506) is an effective immunosuppressant drug for the prevention of rejection after organ transplantation, and preliminary studies suggest that topical application of tacrolimus is effective in the treatment of atopic dermatitis. METHODS: We conducted a randomized, doubleblind, multicenter study that compared 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus ointment with vehicle alone in patients with moderate to severe atopic dermatitis. The ointment was applied twice daily to a defined, symptomatic area of 200 to 1000 cm2 of skin for three weeks. The primary end point was the change in the summary score for erythema, edema, and pruritus between the first and last days of treatment. RESULTS: After three weeks of treatment, the median percentage decrease in the summary score for dermatitis on the trunk and extremities was 66.7 percent for the 54 patients receiving 0.03 percent tacrolimus, 83.3 percent for the 54 patients receiving 0.1 percent tacrolimus, 75.0 percent for the 51 patients receiving 0.3 percent tacrolimus, and 22.5 percent for the 54 patients receiving vehicle alone (P<0.001). The results for the face and neck were similar. The differences among the three tacrolimus groups were not statistically significant. A sensation of burning at the site of application was the only adverse event that was significantly more frequent with tacrolimus than with vehicle alone (P<0.001). Throughout the study, most patients in all three tacrolimus groups had blood concentrations of tacrolimus below 0.25 ng per milliliter. The highest concentration was 4.9 ng per milliliter, which was reported in the group receiving 0.3 percent tacrolimus. CONCLUSIONS: The short-term application of tacrolimus ointment is effective in the treatment of atopic dermatitis, with the sensation of burning being the main side effect.

Therapeutic options for erythroderma.

In this work we will discuss some of the dilemmas and therapeutic options in the treatment of patients with erythroderma. We will mention treatment modalities for psoriatic erythroderma and review briefly one illustrative case in which a new experimental approach was utilized.

Multiple carcinoma in patients with psoriasis caused by psoralen-ultraviolet A therapy, natural killer cell insufficiency, or intensified sun exposure?

A case is presented of a patient with psoriasis in whom squamous cell carcinoma most likely occurred due to the interaction of various factors (psoralen-ultraviolet A therapy, sun exposure, and suppression of natural killer cell function). Therapy consisted of 1 mg/kg/daily of etretinate (Tegison), which resulted in clearing of psoriatic lesions in one month's time. New carcinomas did not develop and natural killer function improved.

[Development of multiple spinocellular cancer of the skin in a patient with psoriasis]. / Razvitie mnozhestvennogo spinotselliuliarnogo raka kozhi u bol'nogo psoriazom.

A rare case of multiple spinocellular carcinoma is described, that developed in a patient suffering from psoriasis after PUVA therapy in the presence of a reduced function of the peripheral blood killer cells.

Subpopulations of T lymphocytes in psoriasis patients and their changes during immunotherapy.

The content of T-lymphocytes and their basic subpopulations T-helpers and T-suppressors have been studied by means of monoclonal antibodies in the peripheral blood of 104 patients with different forms of psoriasis (56 patients with psoriasis vulgaris, 25 with exudative psoriasis, 10 with psoriasis arthropathica, and 13 with erythrodermic psoriasis). In all forms of psoriasis with a slight alteration in T-lymphocyte content a significant dysbalance of T-helpers and T-suppressors was found that brought about a decrease in the correlation ratio T-helpers/T-suppressors (T-helpers/T-suppressors in patients suffering from psoriasis vulgaris, 1.55 +/- 0.12; in those with exudative psoriasis, 1.24 +/- 0.16; with psoriasis arthropathica, 1.33 +/- 0.16; with erythrodermic psoriasis, 1.33 +/- 0.18; the control showed 1.82 +/- 0.08). The decrease in T-helpers/T-suppressors to 1.2 and lower that corresponded to a more severe clinical course of the disease was revealed in 27 patients having psoriasis vulgaris, in 13 with exudative psoriasis, in 7 with psoriasis arthropathica, and in 9 with erythrodermic psoriasis. The dysbalance in T-helpers/T-suppressors was due to a decrease in T-helpers and an increase in T-suppressors. To normalize T-helpers/T-suppressors, 27 psoriatics (20 with psoriasis vulgaris, 6 with exudative psoriasis, 1 with erythrodermic psoriasis) received immunomodulators Thymalinum and Natrii nucleinas in addition to antipsoriatic therapy, which resulted in an increase in T-helper/T-suppressor ratio, on the average up to 1.74 +/- 0.16 (prior to treatment T-helper/T-suppressor ratio in these patients was 1.0 +/- 0.14) and was followed by a favorable clinical course (shorter periods of skin rash regression, prolonged remissions).(ABSTRACT TRUNCATED AT 250 WORDS)

[Imbalance of T lymphocyte subpopulations in patients with psoriasis and its immune correction]. / Dysbalance der T-Lymphozyten-Subpopulationen bei Psoriasis-Patienten und ihre Immun-Korrektion.

We investigated the levels of T-lymphocytes and their subpopulations-T-helper cells (TH) and T-suppressor cells (TS)-in the peripheral blood of 57 patients suffering from various clinical forms of psoriasis. Considerable decrease of the TH/TS rate (0.2 to 1.2) was found in 29 patients (15 with vulgar, 8 with arthropatic, and 6 with exudative psoriasis). The total number of T-lymphocytes was normal in 20 of these patients. In 8 patients showing a marked disbalance of TH and TS immunomodulators, thymalin and natrii nucleinas were included in the complex schedule of antipsoriatic therapy. As a result of the immunocorrective therapy, the disbalance normalized in 6 cases accompanied by regression of the psoriatic rash. The disbalance of TH and TS in the peripheral blood of the patients has a certain pathogenic significance in the development of psoriasis, and immunocorrection becomes necessary for successful therapy in severer forms of the disease.

[Clinicopathogenetic significance of K and NK blood lymphocytes in psoriasis]. / Kliniko-pathogenetische Bedeutung der K- und NK-Blutlymphozyten bei Psoriasis.

The activity of killer lymphocytes and natural killer cells was impaired in the peripheral blood especially of such patients whose psoriasis was progressive or resistant to therapy.