Charles N. Ellis

Treatment of Chronic Plaque Psoriasis by Selective Targeting of Memory Effector T Lymphocytes

BACKGROUND Psoriatic plaques are characterized by infiltration with CD4+ CD45RO+ and CD8+ CD45RO+ memory effector T lymphocytes. The recombinant protein alefacept binds to CD2 on memory effector T lymphocytes, inhibiting their activation. METHODS In a multicenter, randomized, placebo-controlled, double-blind study, we evaluated alefacept as a treatment for psoriasis. Two hundred twenty-nine patients with chronic psoriasis received intravenous alefacept (0.025, 0.075, or 0.150 mg per kilogram of body weight) or placebo weekly for 12 weeks, with follow-up for 12 additional weeks. Before treatment, the median scores on the psoriasis area-and-severity index were between 14 and 20 in all groups (0 denotes no psoriasis and 72 the most severe disease possible). RESULTS Alefacept was well tolerated and nonimmunogenic. The mean reduction in the score on the psoriasis area-and-severity index two weeks after treatment was greater in the alefacept groups (38, 53, and 53 percent in the groups receiving 0.025, 0.075, and 0.150 mg per kilogram, respectively) than in the placebo group (21 percent, P<0.001). Twelve weeks after treatment, 28 patients who had received alefacept alone were clear or almost clear of psoriasis. Three patients in the placebo group were clear or almost clear; all three had received additional systemic therapy for psoriasis. Alefacept reduced peripheral-blood memory effector T-lymphocyte (CD45RO+) counts, and the reduction in the number of memory-effector T lymphocytes was correlated with the improvement in psoriasis. CONCLUSIONS Treatment with alefacept for 12 weeks is associated with improvement in chronic plaque psoriasis; some patients have a sustained clinical response after the cessation of treatment. Alefacept selectively targets CD45RO+ memory effector T lymphocytes, suggesting that they have a role in the pathogenesis of psoriasis.

Cyclosporine for plaque-type psoriasis: Results of a multidose, double-blind trial

BACKGROUND Severe plaque-type psoriasis has been successfully treated with orally administered cyclosporine, but there has been no comparative, controlled evaluation of various dosages and their efficacy and side effects. METHODS In a 16-week, double-blind trial, we randomly assigned 85 patients with severe psoriasis to receive 3, 5, or 7.5 mg of cyclosporine per kilogram of body weight per day or a placebo consisting of the vehicle for the drug. After eight weeks the dose could be adjusted to improve safety or efficacy while maintaining blinding. RESULTS The psoriasis improved in a dose-dependent fashion. After eight weeks of fixed-dose therapy, 36, 65, and 80 percent of the patients receiving 3, 5, and 7.5 mg of cyclosporine per kilogram per day, respectively, were rated as being clear or almost clear of psoriasis; each group had significant improvement (P less than 0.0001) as compared with the group receiving vehicle, in which none of the patients were rated as clear or almost clear. The patients who received 5 mg per kilogram were the least likely to require dosage adjustments because of side effects or a lack of efficacy. The glomerular filtration rate, measured in a subgroup of 34 patients receiving cyclosporine, decreased by a median of 16 percent. Higher doses of cyclosporine had greater adverse effects on systolic blood pressure, glomerular filtration rate, and serum levels of creatinine, uric acid, bilirubin, and cholesterol. Delayed-type hypersensitivity reactions to skin-test antigens were reduced by cyclosporine administration. Cyclosporine appears to become concentrated in skin. CONCLUSIONS Cyclosporine therapy leads to a rapid and thorough clearing of psoriasis; an initial dose of 5 mg per kilogram per day seems to be appropriate. However, the safety of cyclosporine for the long-term treatment of psoriasis remains to be determined.

Suicidal ideation in psoriasis.

Background. Psoriasis has been associated with depressive disease and case reports of completed suicide.

International Consensus Conference on Atopic Dermatitis II (ICCAD II): clinical update and current treatment strategies

C . E L L I S * A N D T . L U G E R † O N B E H A L F O F T H E I C C A D I I F A C U L T Y : D . A B E C K , R . A L L E N , R . A . C . G R A H A M B R O W N , Y . D E P R O S T , L . F . E I C H E N F I E L D , C . F E R R A N D I Z , A . G I A N N E T T I , J . H A N I F I N , J . Y . M . K O O , D . L E U N G , C . L Y N D E , J . R I N G , R . R U I Z M A L D O N A D O A N D J H . S A U R A T

Topical tretinoin (retinoic acid) improves melasma. A vehicle‐controlled, clinical trial

Melasma is a common disorder of cutaneous hyperpigmentation predominantly affecting the faces of women. Little is known about the aetiology of melasma, and treatment is frequently disappointing. Topical tretinoin is of benefit in treating other forms of hyperpigmentation, for example liver spots, and we therefore investigated its effectiveness in melasma. Thirty‐eight women completed a randomized, vehicle‐controlled study, in which they applied 0.1 % tretinoin (n=19) or vehicle cream (n=19) once daily to the face for 40 weeks.

Effect of topical cyclosporine rinse on oral lichen planus. A double-blind analysis.

BACKGROUND Oral lichen planus is a relatively common disorder of the mouth that can be debilitating. It is frequently palliated with topical or systemic corticosteroids and retinoids. These treatments require prolonged use, however, and are not always effective. METHODS In a double-blind trial, 16 patients with symptomatic oral lichen planus were randomly assigned to receive either topical cyclosporine or its vehicle. The patients swished and expectorated 5 ml of medication (containing 100 mg of cyclosporine per milliliter) three times daily. RESULTS After eight weeks, the eight recipients of cyclosporine had marked improvement in erythema (P = 0.003), erosion (P = 0.02), reticulation (presence of white lacelike lesions; P = 0.007), and pain (P = 0.002), whereas the eight recipients of vehicle had no change or minimal improvement. After a switch to cyclosporine for eight weeks, the vehicle-treated patients had improvement similar to that seen in the patients who initially received cyclosporine. There were no systemic side effects. In most cases blood cyclosporine levels were low or undertectable. Cyclosporine levels present in specimens of oral mucosa at the end of therapy four hours after the patients swished were similar to the levels previously reported in psoriatic lesions after treatment with systemic cyclosporine (14 mg per kilogram of body weight per day). CONCLUSIONS As a topical preparation, cyclosporine may be useful in the treatment of oral lichen planus and possibly other cutaneous disorders.

Oral cyclosporine for the treatment of alopecia areata: A clinical and immunohistochemical analysis

Cyclosporine inhibits the activation of helper T cells that may be pathogenic in alopecia areata. Therefore we treated six patients with alopecia areata (five men, one woman) with oral cyclosporine, 6 mg/kg/day for 12 weeks. Three patients had alopecia universalis, one had alopecia totalis, and two had patchy alopecia areata of the scalp. Hair regrowth in the scalp of all patients occurred within the second and fourth weeks of therapy, followed by hair regrowth of the face and chest (in the male patients), pubic area, extremities, and axillae. Overall, the site of best response was the scalp. Cosmetically acceptable terminal hair regrowth on the scalp occurred in three of six patients. Significant hair loss, however, occurred in all patients within 3 months of discontinuation of cyclosporine treatment. Clinical response correlated with changes in immune cell infiltration of the hair follicles. The number of leukocytes per hair follicle was quantified in transverse scalp biopsy sections stained with a panel of monoclonal antibodies. The degree of terminal hair regrowth correlated significantly with decreases in follicular epithelial human lymphocyte antigen-DR and intercellular adhesion molecule-1 expression, T cells, helper/inducer (CD4) T cells, suppressor/cytotoxic (CD8) T cells and Langerhans cells (CD1+DR+) from the hair follicles during cyclosporine therapy. A significant decrease in the CD4/CD8 ratio occurred early in the course of treatment and was maintained throughout the therapy. This decrease suggests that cyclosporine not only cleared immune cells from the hair follicles but also altered the balance of regulatory lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topical tretinoin in the treatment of aging skin

We review the use of topical tretinoin (all-trans-retinoic acid) in the treatment of aging skin. We have found topical tretinoin capable of improving aged-appearing skin in both a double-blind, vehicle-controlled trial and our clinic patients. The most impressive improvement occurs after application of tretinoin 0.1% cream for 8 to 12 months. Side effects have been limited to a mild, transient, and clinically insignificant burning sensation in the eyes and mild irritation of tretinoin-exposed skin.

A double-blind evaluation of topical capsaicin in pruritic psoriasis

BACKGROUND Substance P, an undecapeptide neurotransmitter, has been implicated in the pathophysiology of psoriasis and pruritus. OBJECTIVE Safety and efficacy of topical capsaicin, a potent substance P depletor, were evaluated in patients with pruritic psoriasis. METHODS Patients applied capsaicin 0.025% cream (n = 98) or vehicle (n = 99) four times a day for 6 weeks in this double-blind study. Efficacy was based on a physicians global evaluation and a combined psoriasis severity score including scaling, thickness, erythema, and pruritus. RESULTS Capsaicin-treated patients demonstrated significantly greater improvement in global evaluation (p = 0.024 after 4 weeks and p = 0.030 after 6 weeks) and in pruritus relief (p = 0.002 and p = 0.060, respectively), as well as a significantly greater reduction in combined psoriasis severity scores (p = 0.030 and p = 0.036, respectively). The most frequently reported side effect in both treatment groups was a transient burning sensation at application sites. CONCLUSION Topically applied capsaicin effectively treats pruritic psoriasis, a finding that supports a role for substance P in this disorder.

Topical Tretinoin (Retinoic Acid) Therapy for Hyperpigmented Lesions Caused by Inflammation of the Skin in Black Patients

BACKGROUND AND METHODS Irregular disfiguring skin hyperpigmentation due to inflammation may develop in black persons. We investigated the treatment of this hyperpigmentation with topical tretinoin (0.1 percent retinoic acid cream). Fifty-four subjects completed a 40-week randomized, double-blind, vehicle-controlled study. Twenty-four subjects applied tretinoin daily to the face, arms, or both areas, and 30 subjects applied vehicle cream. At base line and after 40 weeks of treatment, each subjects post-inflammatory hyperpigmented lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. RESULTS The facial post-inflammatory hyperpigmented lesions of the tretinoin-treated subjects were significantly lighter after the 40 weeks of therapy than those of the vehicle-treated subjects (P < 0.001); overall improvement was first noted after four weeks of tretinoin treatment. At the end of treatment, colorimetry demonstrated a 40 percent lightening of the lesions toward normal skin color in the tretinoin-treated lesions, as compared with an 18 percent lightening in vehicle-treated lesions (P = 0.05). The epidermal melanin content in the lesions decreased by 23 percent with tretinoin and by 3 percent with vehicle (P = 0.24). Normal skin was minimally lightened by tretinoin as compared with vehicle, according to both clinical evaluation (0.1 vs. -0.1 unit change on an 8-point scale; P = 0.055) and colorimetry (P < 0.001). Retinoid dermatitis developed in 12 of the 24 tretinoin-treated subjects who completed the study (50 percent) and in 1 tretinoin-treated subject who withdrew from the study, but diminished as the study progressed. CONCLUSIONS Topical application of tretinoin significantly lightens post-inflammatory hyperpigmentation and, to a clinically minimal but statistically significant degree, lightens normal skin in black persons.