Comparison of three methods for measuring psoriasis severity in clinical studies (Part 2 of 2): use of quality of life to assess construct validity of the Lattice System Physician's Global Assessment, Psoriasis Area and Severity Index and Static Physician's Global Assessment.

BACKGROUND: Systems for determining psoriasis severity in clinical trials have not been sufficiently validated against patients' perceived quality of life. OBJECTIVE: To validate three systems of physician-determined psoriasis severity (the Lattice System Physician's Global Assessment [LS-PGA], Psoriasis Area and Severity Index [PASI] and static Physician's Global Assessment [sPGA]). METHODS: Data were from a 24-week randomized, double-blind, placebo-controlled, multicenter trial of therapy with oral calcineurin inhibitors in 445 patients. Construct validity was measured by correlations of the three severity scores with patients' self-reported quality of life (QoL) from the Dermatology Life Quality Index (DLQI) and a DLQI item about psoriasis symptoms. RESULTS: All severity systems were moderately and positively correlated with QoL, indicating construct validity. QoL was most consistently related to physicians' assessments of body surface area involved with psoriasis (iBSA) followed by, in the order of consistency, plaque elevation, erythema and scale. CONCLUSIONS: The LS-PGA weights iBSA and aspects of plaque morphology in concert with their relative effects on QoL. The LS-PGA, sPGA and PASI are validated by their relationship to QoL in a clinical trial.

Comparison of three methods for measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and Severity Index, Static Physician's Global Assessment and Lattice System Physician's Global Assessment.

BACKGROUND: Accurate and reliable assessment of changes in psoriasis severity is critical in clinical trials of therapies. OBJECTIVE: To compare Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment (sPGA), and the Lattice System Physician's Global Assessment (LS-PGA) in a trial of systemic treatments for plaque psoriasis vulgaris and to assess whether they measure change in psoriasis induced by therapy. METHODS: Patients were randomized to voclosporin or cyclosporine for 24 weeks (the '24-week-treatment' group, n = 366), or placebo for 12 weeks followed by voclosporin for 12 weeks (the 'initial-placebo' group, n = 89). RESULTS: All scoring systems changed in concert and were sensitive enough to detect reductions in severity during placebo therapy as well as with active therapy (P < 0.01 for each measurement). At study onset, there were poorer correlations of sPGA with PASI (r = 0.45) and LS-PGA (r = 0.39) than between PASI and LS-PGA (r = 0.68). After therapy, all correlations were stronger, but sPGA continued to be less well correlated (with PASI, r = 0.85; with LS-PGA, r = 0.79) than LS-PGA with PASI (r = 0.90). Two- or three-step improvements in LS-PGA showed very good to excellent accuracy in corresponding to PASI-50 and PASI-75, respectively, and were more accurate than comparable changes in sPGA. CONCLUSION: PASI, sPGA and LS-PGA are responsive to the varying degrees of improvement in psoriasis induced by either placebo or active therapy. While the three systems capture similar information, each has different reasons for use in a clinical trial.

Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Assessment of comparative skills between hand-assisted and straight laparoscopic colorectal training on an augmented reality simulator.

PURPOSE: The aim of this study was to compare skills sets during a hand-assisted and straight laparoscopic colectomy on an augmented reality simulator. METHODS: Twenty-nine surgeons, assigned randomly in 2 groups, performed laparoscopic sigmoid colectomies on a simulator: group A (n = 15) performed hand-assisted then straight procedures; group B (n = 14) performed straight then hand-assisted procedures. Groups were compared according to prior laparoscopic colorectal experience, performance (time, instrument path length, and instrument velocity changes), technical skills, and operative error. RESULTS: Prior laparoscopic colorectal experience was similar in both groups. Both groups had better performances with the hand-assisted approach, although technical skill scores were similar between approaches. The error rate was higher with the hand-assisted approach in group A, but similar between both approaches in group B. CONCLUSIONS: These data define the metrics of performance for hand-assisted and straight laparoscopic colectomy on an augmented reality simulator. The improved scores with the hand-assisted approach suggest that with this simulator a hand-assisted model may be technically easier to perform, although it is associated with increased intraoperative errors.

Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells.

Because the immunosuppressant rapamycin (sirolimus) blocks T cell proliferation in G1 phase, it has been proposed as a potential treatment for psoriasis, a skin disease characterized by T cell activation and keratinocyte stem cell hyperproliferation. To determine another potentially important mechanism through which rapamycin can act as an antipsoriatic agent, we tested its direct effect on keratinocyte stem cell proliferation in vitro as well as in vivo. In vivo cell cycle quiescent (G0 phase) stem cell keratinocytes in primary culture sequentially express de novo cyclin D1 and proliferating cell nuclear antigen (PCNA), prior to S phase entry, and upregulate beta1 integrin. Rapamycin inhibited the growth of keratinocytes that were leaving quiescence as well as those already in cell cycle without affecting cell viability. Although beta1 integrin(bright) expression was not affected, the number of beta1 integrin(bright) cells entering S/G2/M was significantly lowered by rapamycin. Cells treated with rapamycin exhibited decreased PCNA expression while cyclin D1 expression, which precedes PCNA expression in the cell cycle, was not affected. We found similar effects on stem cell keratinocytes in patients with psoriasis treated systemically with rapamycin. Because PCNA is required for cell cycle progression from G1 to S phase, our data indicate that inhibition of PCNA protein synthesis may be an important regulatory element in the ability of rapamycin to exert a G1 block.

Short-term changes in renal function, blood pressure, and electrolyte levels in patients receiving cyclosporine for dermatologic disorders.

We compared the changes in renal function, blood pressure (BP), and concentrations of serum potassium, magnesium, and urate (uric acid) in two groups of patients not given transplants. Group 1, comprising 21 psoriatic patients, was treated with 14 mg/kg per day of oral cyclosporine for 4 weeks in a prospective, placebo-controlled study; group 2, comprising 28 patients with diverse cutaneous diseases, was given 6 mg/kg per day of oral cyclosporine for 1 to 3 months in a prospective, open-labeled study. Renal function (determined by serum urea nitrogen [SUN] and creatinine levels and urinalysis), BP, serum electrolyte levels (potassium and magnesium), and urate level were measured weekly for the first 4 weeks in both groups, and then, after 2 and 3 months of therapy, in group 2 only. During the first 4 weeks in group 1 patients, there were significant increases in values of SUN, creatinine, BP, potassium, and urate, and a significant decrease in the serum magnesium value. When data for the two groups were combined, the changes from pretherapy values in each of the above measures (except systolic BP) during the first 4 weeks correlated significantly with cyclosporine trough levels. In group 2, the changes that occurred in the first 4 weeks in the SUN value, SUN/creatinine ratio, and BP were magnified over the subsequent 8 weeks of treatment. In the combined group for the first 4 weeks of therapy, duration of therapy, independent of cyclosporine trough levels, correlated with changes in SUN, creatinine, and urate levels, but not with changes in the potassium or magnesium level or in BP. We conclude that the cyclosporine blood level was a better discriminant than cyclosporine dosage in the analysis of renal dysfunction and hypertension in these patients.

Determination of 5,12, and 15-lipoxygenase products in keratomed biopsies of normal and psoriatic skin.

Keratomed epidermal tissue from normal individuals and from the lesional and non-lesional skin of psoriasis patients served as source materials for the extraction, separation, and quantitation of eicosanoids that may be important to cutaneous function and pathophysiology. The eicosanoids were extracted in ethanol and buffer, partially purified on SEP-PAKs, separated by reverse phase microbore high-performance liquid chromatography, and quantitated by radioimmunoassay or integration of absorbency peaks obtained by high performance liquid chromatography. The involved areas from psoriasis patients contained a statistically significant seven- to 11-fold increase in the levels of leukotriene B4, 13-hydroxyoctadecadienoic acid-like compound, 15-hydroxyeicosatetraenoic acid compound and 12-hydroxyeicosatetraenoic acid in comparison to normal samples and a three- to sevenfold increase in comparison to uninvolved tissue. The uninvolved areas contained 40% to 100% increases in the levels of these compounds in comparison to normal tissue; these increases were statistically significant except for 13-hydroxyoctadecadienoic acid-like compound. From a single keratome biopsy, multiple eicosanoids can be separated and quantitated; in addition, levels before, during, and after therapy for psoriasis may be compared.

Mechanisms of cyclosporine A inhibition of antigen-presenting activity in uninvolved and lesional psoriatic epidermis.

To elucidate how cyclosporine A affects antigen-presenting cell subsets and their function in human skin, we studied patients with psoriasis undergoing a therapeutic trial of cyclosporine A. Immunologic parameters abnormal in psoriatic epidermis were evaluated before and early in the course of therapy. We quantitated function and numbers of skin biopsy-derived epidermal cells with potential antigen-presenting cell (APC) activity. The antigen-presenting capacity of epidermal cells from normal-appearing skin to activate allogeneic T cells was profoundly inhibited (81% decrease) 7 d after the onset of therapy (p less than 0.05). Thus, cyclosporine A therapy inhibited T-cell activation mediated by Langerhans cells in uninvolved skin. By contrast, in lesional skin epidermal allo-antigen presenting activity was only partially inhibited at this early time point (55 +/- 7% decrease) (p less than 0.01, n = 8). The percentage decrease in allo-antigen-presenting cell activity correlated with reduced clinical activity of the lesions, r = 0.84. In three patients also examined at 14 d, we found an additional 42 +/- 5% decrease between day 7 and 14. Decreased allo-antigen-presenting activity in lesional skin was not associated with a decrease in the number of CD1+ Langerhans cells or epidermal cell release of detectable amounts of cyclosporine A or other soluble factors that abrogate T-cell alloreactivity. The time course and degree of inhibition of antigen-presenting capacity within involved psoriatic skin correlated best with a significant (p less than 0.01) reduction in non-Langerhans cell DR+ leukocytes (from 3.0 +/- 1.2% to 1.0 +/- 0.6% at day 7) (r = 0.71). Cyclosporine A therapy was associated with a rapid and complete loss of HLe1-DR+ keratinocytes (94% decrease at 7 d) in lesional skin despite the skin still being quite involved with psoriasis at this point and antigen-presenting cell activity being only 60% reduced. In conclusion, cyclosporine A interferes with T-cell activation by human epidermis through at least two mechanisms: 1) in uninvolved skin, rapid inhibition of Langerhans cell-mediated activation of T cells, and 2) in lesional skin, delayed inhibition of antigen-presenting activity which appears to correlate with the time course and level of reductions in non-Langerhans cell DR+ leukocytes. The antigen-presenting activity of the latter cells appears to be cyclosporine A resistant. In psoriatic lesions, early and complete loss of DR expression on lesional keratinocytes during cyclosporine A therapy is likely due to decreased lesional T-cell lymphokine production critical for keratinocyte DR expression.(ABSTRACT TRUNCATED AT 400 WORDS)

Levels of cyclosporin in epidermis of treated psoriasis patients differentially inhibit growth of keratinocytes cultured in serum free versus serum containing media.

Cyclosporin A, which is a specific immunosuppressive compound, has recently been demonstrated to be of significant benefit in the treatment of psoriasis. Because hyperplasia is a major feature of psoriasis, we have investigated whether this drug acts directly to inhibit keratinocyte growth. We have determined the concentration range of cyclosporin in the epidermis of psoriatic patients undergoing cyclosporin therapy and the effect of this concentration range on the growth of cultured keratinocytes. After 7 days of treatment, psoriatic involved epidermis contained 1.1 +/- 0.3 ng cyclosporin/micrograms DNA. Based on tissue wet weight this is approximately 2.8 micrograms cyclosporin/ml. This value was 10 times that of trough blood samples. On day 3 of treatment, involved epidermis contained 7 times more cyclosporin than scale, while on day 7 this ratio was reduced to 2. This suggests that cyclosporin was initially associated with the lower layers of the epidermis and distributed upward with time. Exposure of adult human keratinocytes, cultured on collagen in the presence of human serum, to cyclosporin (0.1-30 micrograms/ml, 0.4-13-fold higher than lesional cyclosporin) for 2-6 d had no effect on the rate of incorporation of thymidine into DNA. Cyclosporin (1-30 micrograms/ml) also had not effect on the reinitiation of DNA synthesis of quiescent cells subsequent to the reintroduction of serum. In contrast, cyclosporin (1-10 micrograms/ml) inhibited growth of keratinocytes cultured on plastic culture dishes in serum free media (MCDB 153). For a given dose of cyclosporin, cell associated drug was 2-3 times greater in serum free compared to serum containing media. This may contribute in part to the sensitivity of keratinocytes in serum free media to growth inhibition by cyclosporin. These data demonstrate that human epidermis contains a high concentration of cyclosporin after oral administration, and that, under certain conditions, concentrations of cyclosporin within the range found in vivo can inhibit growth of cultured keratinocytes. Because cyclosporin regulates lymphocyte function in vivo and in vitro, the demonstrated antiproliferative effects of cyclosporin on psoriatic keratinocytes in vivo may be due to inhibition of a mononuclear leukocyte-derived keratinocyte growth factor(s) in combination with direct inhibition of keratinocyte growth.

Cyclosporin A rapidly inhibits epidermal cytokine expression in psoriasis lesions, but not in cytokine-stimulated cultured keratinocytes.

To better understand the cellular target(s) of cyclosporin action in psoriasis, we have studied the effects of systemic short-term (7 d), low-dose (3-7.5 mg/kg) cyclosporin A administration on the expression of the cytokines interleukin (IL)-8 and IL-1 beta in psoriatic lesions. RNA blot hybridization analysis of pretreatment keratome biopsies revealed that expression of both cytokine mRNAs was highly variable from patient to patient. Significant covariation of both cytokine mRNA levels was noted (r = 0.86, p < 0.0001). However, there was no significant correlation between expression of either cytokine and clinical severity, as measured by the pretreatment Psoriasis Area and Severity Index (PASI). IL-1 beta protein levels measured by enzyme-linked immunosorbent assay (ELISA) were highly correlated with IL-1 beta mRNA levels, indicating that the differences in transcript levels accurately reflect differences in epidermal cytokine protein. Significant reductions in both cytokine transcripts and in IL-1 beta immunoreactive protein were noted in the high expression subgroup after 1 week of cyclosporin A therapy, prior to detectable clinical improvement. In contrast to its pronounced effects on epidermal cytokine expression in vivo and the allogeneic mixed lymphocyte reaction in vitro, cyclosporine A did not inhibit the induction of intercellular adhesion molecule (ICAM)-1 or IL-8 mRNAs by cultured keratinocytes in response to IL-1 beta or the combination of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. These data suggest that epidermal keratinocytes respond to signals produced by activated T cells by coordinate expression of multiple cytokines, and that cyclosporin A acts primarily through blockade of T cells, rather than through keratinocyte activation.

Psoriatic epidermal cells demonstrate increased numbers and function of non-Langerhans antigen-presenting cells.

The recent findings that the immunosuppressant cyclosporine A (CsA) improves psoriasis raises the possibility that cellular immune processes play a major role in the pathogenesis of psoriasis. We therefore investigated the phenotype and function of cells within psoriatic epidermis that can play a role in cellular immunologic reactivity. Double fluorescence microscopic studies with monoclonal antibodies of epidermal cells in suspension (EC) and of histologic sections demonstrated that involved psoriatic skin contained a significantly increased number of non-Langerhans cell T6-DR+ EC (4.9 + 2.1%) relative to uninvolved (0.3 +/- 0.1%), p less than 0.01. This non-Langerhans cell population was comprised of DR+ monocytes, DR+ activated T lymphocytes, a few DR+RFD1+ antigen-presenting cells (APC), and DR+ keratinocytes. Langerhans cell (LC) levels in EC suspension were not different between involved and uninvolved psoriatic epidermis. Functional studies demonstrated that involved psoriatic epidermal cells had an increased capacity to induce T-cell activation and proliferation relative to uninvolved EC (p less than 0.04). This increased APC activity was due to the non-LC T6-DR+HLe1+ APC population and not to DR+ keratinocytes. These results demonstrate that involved psoriatic epidermal cells contain both an increased number and function of antigen-presenting cells. The pathogenetic mechanisms in psoriasis may be related to ongoing cellular immune responses in the skin, and the effect of CsA may be mediated through a suppressive effect on the enhanced antigen-presenting cell activity.

Changes in photo-aged human skin following topical application of all-trans retinoic acid.

Although topical applications of retinoids on rodents and humans have been shown to cause epidermal hyperplasia, a detailed study of the influence of retinoids on epidermal differentiation in vivo has not been performed. In order to assess the pharmacologic effects of chronic topical tretinoin application used to improve the appearance of patients with photoaged skin, cutaneous biopsies from 25 patients in a controlled clinical study were examined histologically and immunocytochemically. Chronic application of tretinoin causes epidermal thickening (25 of 25 samples), stratum granulosum thickening (15 of 25), parakeratosis (13 of 25), a marked increase in the number of cell layers expressing epidermal transglutaminase (13 of 25), and focal expression of two keratins, K6 (12 of 25) and K13 (8 of 25), not normally expressed in the epidermis. The morphologic changes correlated with immunohistochemical abnormalities; neither of these correlated with the subjective cosmetic response. Three major epidermal differentiation products, keratins K1, K10, and K14 were not altered, within the limits of the methods used. Thus, chronic topical tretinoin reprograms some, but not all, aspects of human epidermal differentiation in vivo.

Decreased urinary polyamines in patients with psoriasis treated with etretinate.

Oral administration of the aromatic retinoid etretinate is effective therapy for psoriasis and other epidermal hyperproliferative disorders. Since polyamine metabolism is known to be important in cell growth and differentiation, we measured urinary levels of the polyamines putrescine, spermidine, and spermine as a reflection of cutaneous polyamine metabolism in 19 psoriatic patients treated with etretinate for 16 weeks. Using thin-layer chromatography, polyamine determinations were performed on urine collected pretherapy, during therapy, and 8 weeks after therapy was concluded. Good to excellent clearing of psoriasis occurred in 18 of 19 patients. All urinary polyamines showed a downward trend in the first week of therapy, prior to significant clinical improvement. At week 16 of therapy, the greatest reduction in mean urinary polyamine content occurred. Mean putrescine levels decreased from pretherapy to week 16 by 27% (p less than 0.001), mean spermidine values fell by 34% (p less than 0.001), and mean spermine levels declined by 37% (p = 0.005). These data are consistent with the hypothesis that etretinate inhibits polyamine biosynthesis.

The erythromycin breath test as a predictor of cyclosporine blood levels.

The daily dose of cyclosporine required to attain a desired blood level can vary greatly among patients. Because elimination of cyclosporine depends on its metabolism in the liver by an enzyme (cytochrome P-450IIIA) that also demethylates erythromycin, we reasoned that the ability of patients to demethylate a test dose of erythromycin might be useful in estimating their appropriate daily doses of cyclosporine. Accordingly, the [14C-N-methyl] erythromycin breath test was administered to 32 patients before they received 3.0, 5.0, or 7.5 mg/kg/day cyclosporine to treat psoriasis. We found that a simple mathematical equation incorporating just the 14CO2 production, the age of the patient, and the daily dose of cyclosporine accounted for almost 80% (R2 = 0.78) of the interpatient variability in cyclosporine blood levels we observed. Our data indicate that P-450IIIA activity largely accounts for the relationship between dose of cyclosporine and blood levels for an individual patient. We conclude that the erythromycin breath test may be a convenient guide for cyclosporine dosing.

Relation of renin status to neurogenic vascular resistance in borderline hypertension.

The relation of renin-angiotensin status to general hemodynamics and to neurogenic vascular resistance was studied in patients with border-line hypertension. Plasma renin activity during standing was referred to a standard renin-urinary sodium nomogram derived from 18 normal subjects. Among 22 patients with borderline hypertension the renin level was high in 8, low in 4 and within normal limits in the remaining 10. In patients with borderline hypertension and high or normal levels of plasma renin activity, the blood pressure elevation was due to increased total peripheral vascular resistance. In contrast, in patients with low renin borderline hypertension, total peripheral resistance was not significantly elevated; the blood pressure elevation reflected a cardiac index 12 percent higher than that in normal subjects. The neurogenic contribution to total peripheral vascular resistance was assessed by studying the effects of alpha adrenergic blockade with phentolamine, after prior autonomic blockade of the heart with atropine (0.04 mg/kg body weight) and propranolol (0.2 mg/kg). Phentolamine (15 mg) produced an immediate reduction in total peripheral resistance of 12.0 +/- 6.7 percent in patients with high renin borderline hypertension (P less than 0.01) but no change in normal subjects or those with borderline hypertension and normal or low renin levels. Normalization of the blood pressure followed "total" autonomic blockade with atropine, propranolol or phentolamine only in patients with high renin borderline hypertension. It is concluded from these preliminary data that in high renin borderline hypertension the blood pressure elevation is sustained by neurogenic mechanisms. The elevated renin level in these patients is probably an expression of increased sympathetic nervous activity. Although the elevated plasma renin level may possibly be contributing to the generation of higher sympathetic tone, or data do not support a direct role of circulating angiotensin in the maintenance of the elevated vascular resistance.

The content of tumor DNA as an indicator of prognosis in patients with T1N0M0 and T2N0M0 carcinoma of the breast.

To determine if the flow cytometric measurement of the content of the tumor DNA could provide prognostic information in T1N0M0 and T2N0M0 carcinoma of the breast, we isolated nuclei from paraffin-embedded tumor specimens from 128 consecutive patients who underwent modified radical mastectomy and were found to have a T1 or T2N0M0 carcinoma of the breast. The content of DNA of the nuclei was determined by flow cytometry. Although the average tumor size was not significantly different, 17 of 56 patients with aneuploid tumors died of cancer compared with 2 of 72 with euploid tumors. The 10-year overall actuarial survival rate of the euploid and aneuploid groups was 72% and 67%, respectively (p less than 0.02). A hazards model of the data shows that the DNA content of the tumor is the most significant indicator of prognosis, with a 2.25-fold increased risk of death for patients with aneuploid tumors. These data show that the tumor DNA content can be used to identify a group of patients with T1 or T2N0M0 carcinoma of the breast with the same prognosis as a group of patients without carcinoma of the breast that would be unlikely to benefit from adjuvant therapy.

A controlled clinical trial of a new formulation of betamethasone dipropionate cream in once-daily treatment of psoriasis.

In a multicenter, evaluator-blind, parallel group study of 244 patients with moderate to severe psoriasis, a once-daily application of a new formulation of beta-methasone dipropionate 0.05% cream, augmented formulation (AF), and a twice-daily application of fluocinonide 0.05% cream were compared, with respect to safety and efficacy. Results significantly favored betamethasone dipropionate AF over fluocinonide, as indicated by improvements in signs of erythema, induration, and scaling, as well as the physicians' and patients' global evaluations of response after 14 days of treatment. As a result of adverse experiences, treatment had to be discontinued in three patients on fluocinonide. No patient on betamethasone dipropionate AF had to discontinue treatment.

Antidepressant drugs in dermatology. An update.

Recent studies indicate that antidepressant medications may be effective treatments for dermatologic disorders such as chronic urticaria and angioedema, nocturnal pruritus in atopic eczema, and postherpetic neuralgia, even in the absence of coexisting psychopathologic conditions. Their efficacy may be related to their antihistaminic, anticholinergic, and centrally mediated analgesic effects and appears to be independent of their antidepressant effect. It is likely, therefore, that more dermatologists will be prescribing these drugs without a psychiatric consultation.

Treatment of cutaneous sarcoidosis with isotretinoin.

A patient with chronic cutaneous and pulmonary sarcoidosis, unresponsive to oral corticosteroid therapy, was treated with isotretinoin. The patient's cutaneous manifestations of sarcoidosis showed consistent improvement during the course of retinoid therapy. The lesions that responded earliest either resolved or showed the greatest reduction in size. The patient's WBC count increased and her angiotensin-converting enzyme level decreased during the first two months of isotretinoin therapy; both returned to pretreatment levels during the third month of therapy. Pulmonary function tests were unchanged after four months of treatment. Isotretinoin may be a useful therapeutic agent for cutaneous sarcoidosis. However, the possibility of spontaneous remission of the disease during the course of therapy cannot be excluded.

Scurvy. A case caused by peculiar dietary habits.

A 9-year-old girl had the insidious development of lethargy, gingival erosions, and follicular hyperkeratosis with perifollicular hemorrhage. A dietary history disclosed that she consumed only one kind of sandwich and beverage and took no other foods. A skin biopsy specimen was consistent with the diagnosis of scurvy, and marked improvement occurred with ascorbic acid therapy. Although it is an uncommon disorder in the United States, scurvy may occur in persons with prolonged and peculiar dietary habits.