Recombinant human granulocyte-macrophage colony-stimulating factor applied locally in low doses enhances healing and prevents recurrence of chronic venous ulcers.

BACKGROUND: Chronic venous leg ulcers have a major medical and economic impact on the elderly worldwide. Healing of the large ulcers (>10 cm2) occurs only in two-thirds of the patients and reulceration of healed ulcers recurs in one-third within 1 year. Because both healing and relapse rate influence greatly a patient's quality of life and the overall cost of treatment, every effort should be made to improve these two parameters. OBJECTIVE: To determine the safety and efficacy of topical low-dose recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) for the treatment of venous ulcers, and to document any improvement in healing rates. METHODS: Thirty-eight patients (29 women, 9 men; median age, 74 years) with chronic venous insufficiency were treated with topical rhu GM-CSF (5 microg/mL 0.9% sodium chloride solution), followed by application of a compression dressing. All subjects were treated as outpatients. RESULTS: Complete healing was observed in 47 of the 52 ulcers (90.4%). The average healing time was 19 weeks. No systemic or local side-effects from the therapy were observed. Nine chronic ulcers, previously refractory to conventional treatment (pretreatment for more than 46 weeks), showed the same response rate (9/8, or 88.9%) and healing time (mean, 19 weeks). After 40 months, no reulceration of the healed ulcers was observed, but two patients developed new ulcers on the same leg. Healing remained stable, with excellent cosmetic results. CONCLUSIONS: In this first study, topically applied low-dose rhu GM-CSF was a safe treatment for chronic venous leg ulcers. Healing rates were significantly increased and relapse rates were minimal.

[Gamma 1 heavy chain disease with immune vasculitis and rheumatoid arthritis]. / Gamma-1-Schwerkettenkrankheit mit Immunvaskulitis und rheumatoider Arthritis.

We are reporting about a case of gamma heavy-chain disease (Franklin's disease) with immunovasculitis and rheumatoid arthritis. The diagnosis was confirmed by the results of immunoelectrophoresis of the patient's serum and also by evidence of stimulated lymphocytes without light chain, but having gamma heavy-chain surface proteins. The immunofixation of the serum showed two protein bands of gamma heavy-chains with different loads. These results are confirmed by a two dimensional electrophoresis and isoelectric focussing of the serum proteins. The pathologic protein consists of at least two different heavy-chain proteins (mol wt 40,000 and 80,000) with isoelectric points between pH 5.5 and 7.3. In the urine of the patient pathological gamma heavy chain-protein was found only in a very low concentration. The predominant clinical symptom of the patient was a necrotizing vasculitis which became a therapeutical problem. In the immunofluorescence examination of the skin biopsy specimens, immunoglobulins and C3-complement could be detected in the stratum papillare. This fact would be compatible with the development of antibodies or immune complexes against deposited heavy-chain proteins. The arthropathy and the positive rheumatoid factor could similarly be explained by an immune complex mechanism.

[UV-B phototherapy in psoriasis]. / UV-B-Phototherapie der Psoriasis.

67 patients, 41 with chronic plaque-psoriasis and 26 with acute eruptive or seborrhoic psoriasis, were treated in a stand-up unit equipped with UV-B fluorescent bulbs. 92 per cent of the latter group of patients showed satisfactory results (13 exposures, total UV-B dose: 464 mJ/cm2), whereas only 46 per cent of the patients with plaque psoriasis responded comparably (19 exposures, total UV-B dose: 994 mJ/cm2). A split comparison study of PUVA and UV-B on plaque-psoriasis revealed the superiority of PUVA in both initial treatment phase and duration of the remission. For certain types of psoriasis, UV-B phototherapy represents an alternative option. With regard to long-term hazards, however, as carcinogenicity in particular, UV-B has to be judged with the same scrutiny as PUVA.

Serum levels of 8-methoxypsoralen in two different drug preparations: correlation with photosensitivity and UV-A dose requirements for photochemotherapy.

In a quantitative study we have compared the serum levels, the time course and the photosensitizing capacity of a conventional crystalline 8-methoxypsoralen brand and an investigational liquid formula. Evidence is presented showing that the liquid preparation is superior to the crystalline form: it peaks earlier after ingestion, it produces higher and more constant degree of photosensitization, it is eliminated more rapidly from the blood, and it requires a lower UV-A dose for eliciting photosensitivity reactions aiming at a reduction of the total cumulative UV-A dose required for clearing psoriasis.

Selective accumulation of lipid within melanocytes during photochemotherapy (PUVA) of psoriasis.

In patients undergoing photochemotherapy (PUVA) a selective accumulation of lipid droplets was observed within the cytoplasm of melanocytes. Keratinocytes did not develop lipid droplets. Within 2 months after clearing of psoriasis the droplets gradually vanished and did not reappear even during maintenance PUVA therapy. Increased intracellular lipid deposits are usually taken to herald cell degeneration. Since the maximum lipid accumulation coincided with the end of the clearing phase when melanin production was at its height, the intramelanocytic lipid may have been a morphological sign of over-stimulation of melanocytes, which could eventually result in melanocyte destruction. Since excess melanin may be cytotoxic for melanocytes this may explain the irreversible hypopigmentation which develops in some patients treated with PUVA.

[Hydroa vacciniforme - action spectrum. UV - tolerance following photochemotherapy]. / Hydroa vacciniforme - Aktionsspektrum. UV-Toleranz nach Photochemotherapie.

In a 14-year-old boy with hydroa vacciniforme by UV-testing was found to be the provoking wave band region. Tolerance to artificial UV-and sunlight was achieved by inducing pigmentation with oral methoxsalen photochemotherapy (PUVA).

[Netherton syndrome: weakened immunity, generalized verrucosis and carcinogenesis]. / Netherton-Syndrom: Abwehrschwäche, generalisierte Verrukose und Karzinogenese.

Two patients with Netherton's syndrome are presented who, in addition to the classical triad of trichorrhexis invaginata, ichthyosis linearis circumflexa and atopy, exhibit signs of reduced cellular immunity (negative skin tests to a battery of microbial antigens, impaired stimulation of lymphocytes with various mitogens and widespread viral warts resembling epidermodysplasia verruciformis). One patient had a squamous cell carcinoma possibly arising from a viral wart. It is suggested that Netherton's syndrome is part of the group of immunodeficiency syndromes with atopy-like symptoms.

Long-term photochemotherapy: histopathological and immunofluorescence observations in 243 patients.

Skin biopsies of 243 patients treated with photochemotherapy (PUVA) for 1--4 years were examined histologically. Two hundred and six patients were examined retrospectively after total cumulative UV-A doses of 579 . 6 +/- 598 . 0 J/cm2 (mean +/- s.d.). An eosinophilic homogenization and a reduction of elastic fibres at the dermo--epidermal junction, and an increase of dermal macrophages were found as possible abnormalities. However, except for the increase of melanophages there was no statistically significant correlation between the incidence of these changes, the total UV-A dose applied and the skin type of the patients. Neither were such correlations found in thirty-seven patients biopsies twice after 394 . 8 +/- 267 . 6 J/cm2 and 808 . 5 +/- 458 . 9 J/cm2 (mean +/- s.d.), respectively. Studies with direct immunofluorescence techniques revealed no immunoglobulin deposits in PUVA treated skin in fifty-six patients after 469 . 2 +/- 370 . 2 J/cm2; antinuclear antibodies were observed in 4 . 6% of 129 patients after 169 J/cm2 (mean); in 11% of fifty-three patients reexamined after 381 J/cm2 (mean) and in 13 . 6% of twenty-two patients reexamined a second time after 643 J/cm2 (mean). Thirteen out of a total of 572 patients developed a peculiar mottling of skin in areas previously overdosed by PUVA. Subepidermal homogenization and reduction of elastic fibres were found in 45% of the patients, indicating that these changes indeed are a consequence of PUVA. Nuclear and cellular irregularities were found in 45% of the biopsies and 63% showed a disturbed epidermal architecture, but no carcinomas were observed. PUVA-induced mottling was reversible in 31%, partially reversible in 15%, but continued to be present in 54%.

[Multilocular Paget's disease--a case report (author's transl)]. / Multilokulärer Morbus Paget--Fallbericht.

The simultaneous occurrence of Paget's disease in five different regions in a 76-year old woman is reported. Only one lesion exhibited the typical clinical appearance of this condition, whereas the others were diagnosed histologically. After radical surgical treatment of all lesions the patient has remained free from recurrence for more than three years.

5-Methoxypsoralen (Bergapten) in photochemotherapy of psoriasis.

5-Methoxypsoralen (5-MOP, Bergapten) was evaluated as a potential photosensitizing drug in oral photochemotherapy of psoriasis. Treatment results indicate that (1) 5-MOP is as effective as, and in high doses more effective than, 8-methoxypsoralen in clearing psoriatic lesions; (2) therapeutic doses of 5-MOP do not lead to erythema; the acute side-effects of 8-MOP PUVA therapy--erythema, blistering, pruritus--are thus avoided; (3) even high doses of 5-MOP are not followed by nausea. 5-MOP PUVA therapy thus represents a real alternative to 8-MOP PUVA, its advantages over 8-MOP PUVA being greater safety and patient acceptance.

[Hyperkeratotic variant of Darier's disease. Successful oral treatment using an aromatic retinoid (Ro 10-9395)]. / Hypertroph verhornende Variante des Morbus Darier. Erfolgreiche orale Behandlung mit einem aromatischen Retinoid (Ro 10-9359).

Oral aromatic retinoid (Ro 10-9359) in the treatment of a patient with hyperkeratotic Darier's disease yielded excellent results, which could be maintained over a period of 14 months by continuous administration of the drug. No serious side effects occurred which would have necessitated discontinuation of the therapy.

Epidermolytic hereditary palmoplantar keratoderma. Report of a family and treatment with an oral aromatic retinoid.

This study describes a family of 30 people in which 14 members have hereditary epidermolytic palmoplantar keratoderma. Four patients were treated with an oral aromatic retinoid for up to 5 months. They responded in a uniform and dramatic way: 10-14 days after the onset of therapy, the hyperkeratotic horny layer was sequestered in large sheets resulting in normal appearing skin and restoration of normal surface sensitivity. Biopsies revealed that the underlying disorder of keratinization had remained unchanged. Treatment with the retinoid had to be discontinued as the sensitivity and vulnerability restricted normal function of hands and feet.

[Photochemotherapy of psoriasis: increasing its effectiveness with an oral aromatic retinoid (clinical results in 134 patients) (author's transl)]. / Photochemotherapie bei Psoriasis: Steigerung der Wirksamkeit durch ein orales aromatisches Retinoid. Klinische Erfahrungen bei 134 Patienten.

The effectiveness of photochemotherapy can be substantially increased by the concomitant administration of an oral aromatic retinoid. 134 patients with severe plaque-type or palmoplantar psoriasis were given various combined treatment schedules. In the initial (clearing) phase a significant synergistic effect was achieved if retinoid administration was started before photochemotherapy, and if the dose was 1.0 mg/kg body-weight. This shortened by half the time required in a control group given photochemotherapy alone (7.7 +/- 4.5 irradiation sessions within 14.1 +/- 8.6 days), and reduction of the total UVA energy necessary for complete clearing to one third (32.4 +/- 40.0 J/cm2). After clearing the patients received standard photochemotherapy maintanance treatment. The incidence of relapses observed during a 10-month follow-up was the same as that in patients cleared and maintained with photochemotherapy alone. Short courses of retinoid treatment in addition to photochemotherapy were highly effective in clearing patients who had failed to do so or had not been maintained in a cleared state on standard photochemotherapy.