Itraconazole and terbinafine treatment of some nondermatophyte molds causing onychomycosis of the toes and a review of the literature.

BACKGROUND: Onychomycosis may be caused by dermatophytes (which form the majority of organisms), Candida species, and nondermatophyte molds. OBJECTIVE: To evaluate the efficacy and safety of itraconazole and terbinafine in the treatment of some nondermatophyte molds that cause toe onychomycosis and to review the literature on the treatment of nondermatophyte mold toe onychomycosis using the oral antifungal agents. PATIENTS AND METHODS: Patients with nondermatophyte mold toe onychomycosis were treated in an open, prospective manner with either itraconazole (pulse) or terbinafine therapy. In each instance, light microscopic examination was consistent with the diagnosis of a nondermatophyte mold. For each patient, mycological evaluation of the target nail resulted in 3 or more successive cultures yielding growth of the mold alone. RESULTS: All 15 patients had onychomycosis of the toes which was of the distal and lateral type. The patients were treated with itraconazole given as the standard 3 pulses with additional pulses administered depending upon the response exhibited by the toe onychomycosis in the patient. Similarly, terbinafine was given for 12 weeks with additional therapy administered as dictated by the response. Efficacy parameters were mycological cure (MC) and clinical cure (CC). Mycological cure was negative light microscopic examination (KOH) and culture. Clinical cure was the appearance of a completely normal-looking nail. At month 12 from the start of treatment, the response was as follows: Scopulariopsis brevicaulis: itraconazole (MC 4/4, CC 2/4) and terbinafine (MC 0/1, CC 0/1), Fusarium species: itraconazole (MC 1/1, CC 1/1) and terbinafine (MC 0/1, CC 0/1), Aspergillus species: itraconazole (MC 5/6, CC 3/6), Alternaria alternata: itraconazole (MC 0/1,CC 0/1), and Onychocola canadensis: itraconazole (MC 1/1, CC 0/1). There were no significant clinical or laboratory adverse effects. CONCLUSIONS: In the present series itraconazole demonstrated efficacy against onychomycosis of the toenails caused by S. brevicaulis and Aspergillus species. A review of the literature confirms our experience with itraconazole and further suggests that terbinafine may also demonstrate efficacy against cases of S. brevicaulis and Aspergillus toe onychomycosis. Additionally, reports in the literature suggest that pedal onychomycosis caused by Fusarium species may also show response to itraconazole and terbinafine. For the other species, there are fewer data, making it difficult to draw conclusions.

Single-blind, randomized, prospective study on terbinafine and itraconazole for treatment of dermatophyte toenail onychomycosis in the elderly.

BACKGROUND: The 2 most common agents used to treat dermatophyte onychomycosis of the toe are terbinafine (continuous) and itraconazole (pulse). Although comparative studies have been performed evaluating the efficacy of these 2 agents in adults, no such studies have been reported specifically in the elderly subset. OBJECTIVE: This prospective, randomized, single-blind, non--industry-sponsored, comparative study evaluated the efficacy and safety of terbinafine (continuous) and itraconazole (pulse) therapies in the treatment of dermatophyte onychomycosis of the toe in the elderly population. METHODS: Elderly patients (> or =60 years old) with dermatophyte onychomycosis of at least 1 great toe were randomly assigned to receive either terbinafine 250 mg/day for 12 weeks or itraconazole (pulse) 200 mg twice a day for 1 week, given for 3 pulses. At month 6 from the start of therapy, if there was less than 50% reduction in the affected nail plate area compared with baseline, or if there was less than 3 mm outgrowth of unaffected nail plate as measured in midline, then patients who had been administered terbinafine (continuous) therapy were given an extra 4 weeks of the drug (total of 16 weeks of therapy), and those who had received itraconazole (pulse) therapy were given an extra pulse (fourth pulse). Patients were evaluated at 1.5, 3, 6, 12, and 18 months from the start of therapy. The efficacy measures included mycologic cure rate and clinical efficacy (mycologic cure plus clinical cure or clinical improvement so that 10% or less of nail plate was clinically involved). RESULTS: There were 101 elderly patients enrolled in the study with 50 and 51 patients receiving terbinafine and itraconazole, respectively. The terbinafine group consisted of 28 men and 22 women, age (mean +/- standard error [SE]) 68.0 +/- 0.9 years, duration of onychomycosis (mean +/- SE) 18.2 +/- 1.4 years, number of nails involved (mean +/- SE) 5.5 +/- 0.5, and percent baseline nail plate area involved (mean +/- SE) 67.5% +/- 4.2%. The corresponding figures for the itraconazole (pulse) group were 24 men and 27 women, age (mean +/- SE) 68.8 +/- 0.8 years, duration of onychomycosis (mean +/- SE) 16.1 +/- 1.7 years, number of nails involved (mean +/- SE) 6.0 +/- 0.7, and percent baseline nail plate area involved (mean +/- SE) 74.9% +/- 3.8%, respectively, with no significant difference between the groups. At month 6, the number of patients that required an extra 4 weeks of terbinafine in the allylamine group or an extra itraconazole pulse in the triazole group was 13 of 50 and 23 of 51, respectively. The mycologic cure rate and clinical efficacy at 18 months from the start of therapy for the terbinafine group were 64.0% and 62.0%, respectively. The corresponding figures for the itraconazole (pulse) group were 62.7% and 60.8%, respectively, with no significant difference between the 2 groups. There were no dropouts during therapy. For both groups the drug appeared safe with no significant adverse events (AEs) or clinically significant laboratory abnormalities. All the AEs were mild and transient. There was high compliance with both regimens. CONCLUSIONS: In the elderly, for the treatment of dermatophyte toe onychomycosis, both terbinafine (continuous) and itraconazole (pulse) therapies are effective, safe, and associated with high compliance.

Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared with terbinafine pulse for the treatment of toenail onychomycosis.

OBJECTIVE: Efficacy and safety of sequential pulse therapy with itraconazole and terbinafine were compared with pulse terbinafine alone in the treatment of toenail onychomycosis. METHODS: This was a 72-week prospective, single-blind, randomized, multicenter, comparative, parallel group, nonindustry-sponsored trial. A total of 190 patients were recruited from 3 outpatient dermatology offices in North America. Patients were at least 18 years old and had a clinical and mycologic diagnosis of dermatophyte toenail onychomycosis. Patients were randomly assigned to receive sequential pulse therapy (IIT) with 2 pulses of itraconazole followed by 1 or 2 pulses of terbinafine (itraconazole pulse is 200 mg twice daily for 1 week and terbinafine pulse is 250 mg twice daily for 1 week) versus 3 or 4 pulses of terbinafine (TTT). Main outcome measures at week 72 evaluated mycologic cure rate (negative light microscopy and culture), clinical cure (nail appears completely or totally normal), complete cure (clinical and mycologic cure), and effective therapy (mycologic cure and clinical response with at least 5 mm of new, uninvolved nail growth). RESULTS: At week 72, in the IIT versus TTT groups, the mycologic cure rate was 54 of 75 (72.0%) versus 44 of 90 (48.9%), clinical cure rate was 42 of 75 (56.0%) versus 35 of 90 (38.9%), effective therapy 49 of 75 (65.3%) versus 41 of 90 (45.6%), and complete cure 39 of 75 (52.0%) versus 29 of 90 (32.2%), respectively. Both regimens were well tolerated with no new adverse effects being identified. The rate of permanent discontinuation of therapy because of adverse effects was 2 of 81 (2.5%) with IIT and 2 of 95 (2.1%) with TTT. Each of the adverse effects normalized over time. The number of patients who reported an adverse effect in the 2 groups was 12 of 81 (14.8%) versus 22 of 95 (23.2%), respectively. All these adverse effects were reversible and mild to moderate in severity. CONCLUSION: Sequential pulse therapy with itraconazole and terbinafine is effective and safe for the treatment of dermatophyte toenail onychomycosis.

A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns.

BACKGROUND: Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. OBJECTIVE: A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. METHODS: A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. RESULTS: The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. CONCLUSION: Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America.

Once weekly fluconazole is effective in children in the treatment of tinea capitis: a prospective, multicentre study.

In an open, multicentre evaluation carried out in Brazil, Canada and South Africa we have demonstrated that fluconazole 8 mg kg-1 once weekly is effective in tinea capitis caused by Trichophyton and Microsporum species. There were 61 children, aged (mean +/- SE) 5.0 +/- 0.3 years; weight (mean +/- 5.6) 20.0 +/- 0.9 kg; 41 males, 20 females; one Asian, 57 Black, one Caucasian and two Hispanic. The organisms were Trichophyton violaceum (33 patients), T. tonsurans (11) and Microsporum canis (17). The extent of tinea capitis at pretherapy was: mild (18 patients), moderate (30) and severe (13). Patients with tinea capitis due to Trichophyton species were initially treated for 8 weeks with an extra 4 weeks of fluconazole if clinically indicated. All 44 patients with tinea capitis due to Trichophyton species were completely cured (clinically and mycologically) when evaluated 8 weeks after completion of active treatment, following 8 weeks of once weekly dosing in 35 patients and 12 weeks of once weekly dosing in nine patients. In Microsporum canis tinea capitis, an extra 4 weeks was administered at week 12 in patients where it was clinically indicated at the time. Sixteen of 17 patients with M. canis tinea capitis were completely cured (clinically and mycologically) when evaluated 8 weeks following the end of treatment when given for 8, 12 and 16 weeks in 12, one and three patients, respectively. Overall, complete cure (clinical and mycological) occurred in 60 of 61 patients at follow-up 8 weeks from the end of therapy. The duration of once weekly fluconazole in the 60 patients was 8 weeks (47 patients), 12 weeks (10 patients) and 16 weeks (three patients), respectively. Clinical adverse effects consisted of a mild, reversible gastrointestinal complaint in three (4.9%) of 61 children. A laboratory abnormality with elevated liver function tests was observed in one (5.9%) of 17 patients; this was asymptomatic, and reversible. No patient discontinued therapy. The data suggest that once weekly fluconazole dosing is effective, safe and associated with high compliance when used to treat tinea capitis.

The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease.

BACKGROUND: Onychomycosis is a relatively common condition the aetiology of which appears to be multifactorial, with both genetic and acquired factors being responsible. In our clinical practice we have observed that smokers and individuals with peripheral arterial disease may have an increased prevalence of onychomycosis compared to normal individuals. PATIENTS AND METHODS: Patients attending a vascular clinic in a hospital were asked about a history of smoking and peripheral arterial disease. The lower extremity was assessed for peripheral arterial disease. Material was obtained from toenails for mycological evaluation. RESULTS: Two hundred and fifty-four patients (male 146, female 108; age, mean +/- standard error, 66.6 +/- 0.8 years) were enrolled. Abnormal-appearing nails and onychomycosis were present in 49.2% and 22.4% of patients, respectively. Factors associated with onychomycosis included, increasing age (risk odds ratio [ROR] 1.05, P = 0.002), male gender (ROR 1.7, P = 0.09), smoking (packs per day) (ROR 1.9, P = 0.02) and peripheral arterial disease (ROR 4.8, P = 0.02). CONCLUSIONS: The factors predisposing to the development of onychomycosis are multifactorial. Both smoking (number of packs of cigarettes consumed per day) and peripheral arterial disease are independent predictors of onychomycosis. Awareness of these factors may help in the prevention of onychomycosis and the optimal management of this disease.

Onychomycosis: predisposed populations and some predictors of suboptimal response to oral antifungal agents.

The population groups predisposed to onychomycosis and factors associated with a poor response to antifungal therapy may be subdivided into (a) genetic, (b) environmental, (c) systemic conditions, (d) local nail characteristics, and (e) other miscellaneous items. By paying attention to the scenarios that may lead to a suboptimal response to the therapy and a higher probability of relapse of the onychomycosis, it may be possible to improve the overall cost-effectiveness of treatments for onychomycosis. Besides attempting to achieve a cure when treating onychomycosis it is important to take steps to prevent reinfection with fungal organisms.

Intermittent short duration therapy with fluconazole is effective for tinea capitis.

We have demonstrated in an open multicentre investigation that oral fluconazole 6 mg/kg daily for 2 weeks, followed, if clinically indicated four weeks from the start of therapy, by an extra week of treatment at the same dosage, may be effective and safe in the treatment of tinea capitis. Of a total of 48 patients, there were 42 evaluable children < 18 years old (19 boys, 23 girls; mean age 6.2 years, range 1.5-16). The causative organisms were Trichophyton tonsurans (38 subjects) and T. violaceum (four). In the 42 evaluable patients, a 2-week course of fluconazole was administered in 21, with the remainder requiring 1 additional week of therapy. At follow-up 12 weeks from the start of therapy, mycological and clinical cure was recorded in 37 of the 42 evaluable patients (88.1%, 95% confidence interval 83.1-93.1%). The treatment was well tolerated, with no clinical adverse effects. This regimen appears to be effective and safe, and is associated with high compliance. The preliminary results of the investigation need to be evaluated in a larger sample of patients, and in tinea capitis caused by zoophilic species.

Wegener's granulomatosis: case report and literature review.

Wegener's granulomatosis (WG) is a necrotizing granulomatous vasculitis usually affecting the upper and lower respiratory tracts and kidneys. Any organ system can be affected by the pathologic process, which remains an etiologic enigma. Limited forms of the disease are recognized in which few extrapulmonary and no renal lesions occur. Cutaneous manifestations occur in 40% to 50% of patients with WG (1). Early diagnosis is imperative because treatment regimens reduce morbidity and mortality in this potentially fatal disease. We report WG in a 10-year-old boy whose upper respiratory tract symptoms began at age 8 years. The case is illustrative of the difficulties that can be encountered in attempting to make this diagnosis. Skin is an easily accessible organ for biopsy, thus an increasing familiarity with the typical biopsy specimen findings within a consistent clinical setting may aid in earlier diagnosis of WG.

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail.

BACKGROUND: Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS: In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS: At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION: The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.

Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail.

BACKGROUND: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. OBJECTIVE: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. METHODS: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. RESULTS: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. CONCLUSION: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.

Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey.

The number of individuals diagnosed with diabetes mellitus is increasing. The diabetic may present with complications involving all systems of the body. While onychomycosis is often observed in diabetics, there have been no large studies on the prevalence of the condition in this patient group. We examined the prevalence of onychomycosis in diabetics attending diabetes and dermatology clinics in London, Ontario, Canada and Boston, MA, U.S.A. Diabetic subjects seen in dermatology offices were for unrelated dermatoses; those referred specifically for the management of onychomycosis were excluded from the sample. A total of 550 diabetic subjects was evaluated (283 males and 267 females), age 56.1 +/- 0.7 years (mean +/- SEM). Patients with type I diabetes constituted 34% of the sample. The racial origin was: 531 Caucasians, 17 Asians, one African-American and one American-Indian. Abnormal-appearing nails and mycological evidence of onychomycosis (mostly due to dermatophytes) were present in 253 (46%) and 144 (26%), respectively, of 550 subjects. The development of onychomycosis was significantly correlated with age (P < 0.0001) and male gender (P < 0.0001). Males were 2.99 times more likely to have onychomycosis compared with females (95% confidence interval, CI 1.94-4 61). After controlling for age and sex, the risk odds ratio for diabetic subjects to have toenail onychomycosis was 2.77 times compared with normal individuals (95% CI 2.15-3.57). After controlling for age and sex, a stepwise logistic regression demonstrated that significant predictors for onychomycosis included a family history of onychomycosis (P = 0.0001), concurrent intake of immunosuppressive therapy (P = 0.035) and peripheral vascular disease (P = 0.023). Toenail onychomycosis was present in 26% of the sample and is projected to affect approximately one-third of subjects with diabetes. Predisposing factors include increasing age, male gender, family history of onychomycosis, concurrent intake of immunosuppressive agents and peripheral vascular disease.

Effects of topical erythromycin on ecology of aerobic cutaneous bacterial flora.

We have demonstrated previously that application of topical erythromycin, an antibiotic commonly used for the treatment of acne, results in an increased density of cutaneous erythromycin-resistant (Emr) coagulase-negative staphylococci; however, it is unknown if this increase results in an overall higher density of total cutaneous staphylococci or if upon cessation of erythromycin use, Emr coagulase-negative staphylococci remain at an increased density compared with the pretreatment density. To investigate this, 2% erythromycin or vehicle was applied to each subject's forehead (n = 225) twice a day by laboratory personnel for a period of 6 weeks. Samples were obtained for culture from the forehead, anterior nares, and back of the subjects at baseline and at weeks 6, 9, and 12 of the study. Cultures were performed on differential media. Plates into which erythromycin was incorporated (8 micrograms/ml) were used to identify Emr coagulase-negative staphylococci. The species of all Emr coagulase-negative staphylococci were determined, and an antibiogram for 16 antibiotics was obtained. The baseline prevalence of Emr coagulase-negative staphylococci on the forehead and nose was about 80% at the two study sites, whereas that on the back was 50%. The baseline density of Emr coagulase-negative staphylococci on the forehead, nose, and back was approximately 20% of the total flora. Following 6 weeks of erythromycin treatment, the prevalence of Emr coagulase-negative staphylococci on the forehead and nose was nearly 100% and the densities were 73 and 62%, respectively; the prevalence and density for the back were 78 and 42%, respectively. The most prevalent erythromycin resistance gene expressed by the Emr coagulase-negative staphylococci was ermC. There was no increase in the numbers of Staphylococcus aureus, gram-negative rods, or yeasts, nor was there increased resistance to any other antibiotic except clindamycin. The density of total aerobic organisms also remained static. There were no changes in the prevalence or density of Emr coagulase-negative staphylococci in the vehicle group. A statistically significant decrease in the prevalence and density of Emr coagulase-negative staphylococci in the erythromycin group was observed within 3 weeks posttreatment and by 6 weeks posttreatment, the prevalence and density returned to baseline values. These data demonstrate that the increased prevalence and density of Emr coagulase-negative staphylococci as a result of topical 2% erythromycin use are transient on both population and individual levels.

Eruptive epidermal cysts and multiple squamous cell carcinomas after therapy for cutaneous T-cell lymphoma.

Both topical nitrogen mustard and psoralen photochemotherapy may induce benign and malignant alterations in the skin. We describe the explosive appearance of multiple epidermal cysts and squamous cell carcinomas in a patient whose cutaneous T-cell lymphoma was treated sequentially with these two types of therapy. This is the first report of both processes in the same patient with cutaneous T-cell lymphoma. It strongly supports the concept of lesion induction, while raising the question of an additive or even synergistic effect of these types of therapy.

Elevated plasma interleukin-1 levels in humans following ultraviolet light therapy for psoriasis.

Interleukin-1 (IL-1) is a potent cytokine with a wide range of biologic activities including induction of several acute phase responses. Ultraviolet radiation (UVR) is widely used as a therapeutic modality to treat many chronic skin diseases, including psoriasis. In the present study, we investigated whether ultraviolet B (UVB) radiation induced circulating IL-1 in the plasma of patients undergoing chronic UVB therapy. In order to remove plasma proteins which inhibit IL-1-induced T-cell proliferation, each plasma sample was chromatographed and each fraction was assayed for IL-1 activity. There was no detectable IL-1 before and 1 h after UVB radiation; IL-1 appeared 4 h after treatment and was absent after 24 h. Plasma IL-1 was neutralized by antibodies to recombinant human IL-1 beta and alpha. The anti-IL-1 alpha, but not anti-IL-1 beta, antibodies partially neutralized the IL-1 activity present in a keratinocyte cell line supernate. These results demonstrate that UVB therapy induces circulating IL-1 and that this IL-1 may originate from both keratinocyte and non-keratinocyte sources.