Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND: PF-04965842 is an oral Janus kinase 1 inhibitor being investigated for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the efficacy, safety and tolerability of PF-04965842 in patients with moderate-to-severe plaque psoriasis. METHODS: Patients in this phase II, placebo-controlled study (NCT02201524) were randomized to receive placebo, 200 mg once daily (OD), 400 mg OD or 200 mg twice daily (TD) PF-04965842 for 4 weeks. The primary endpoint was change from baseline in Psoriasis Area Severity Index (PASI) at week 4. Study enrolment was discontinued on 25 June 2015 due to changes in the sponsor's development priorities. RESULTS: Fifty-nine patients were randomized and received at least one dose of PF-04965842 or placebo. The estimated treatment effect (active -placebo PASI change from baseline) and 90% confidence interval at week 4 was -5·1 (-9·2 to -1·0), -5·6 (-9·6 to -1·6) and -10·0 (-14·2 to -5·8) for the 200 mg OD, 400 mg OD and 200 mg TD groups, respectively. At week 4, the proportion of patients achieving PASI 75 was 17% for the placebo and 200 mg OD groups, 50% for the 400 mg OD group and 60% for the 200 mg TD group. There were more abnormal laboratory test results of clinical interest (low neutrophil, reticulocyte and platelet counts) in the 200 mg TD group compared with the OD treatment groups. No serious infections or bleeding events related to neutropenia or thrombocytopenia, respectively, were reported. CONCLUSIONS: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.

Interrelationship between ultraviolet light and recurrent herpes simplex infections in man.

In humans, epicutaneous application of a universally sensitizing dose (2000 micrograms) of dinitrochlorobenzene (DNCB) to skin exposed to 4 consecutive daily doses (144 mJ/cm2) of ultraviolet-B radiation (UVB) induces contact hypersensitivity (CH) in approximately 56% of normal, adult individuals (UVB-resistant--UVB-R), but not in the remaining 44% (UVB-susceptible--UVB-S). In patients with biopsy proven basal/squamous cell cancer, the frequency of the UVB-S trait exceeds 90%, indicating that this phenotype may be a risk factor for sunlight-induced skin cancer. Since many patients with recurrent herpes labialis complain that lip lesions are precipitated by acute sun exposure, we wondered whether the UVB-S trait might be associated with this recurrent disease. A group of 31 volunteers was selected, each with a history of numerous episodes of labialis secondary to reactivated herpes simplex virus-1 infection. Subjects were questioned carefully concerning factors, including sun exposure, thought to be important in precipitating lip lesions. Each individual was then subjected to the UVB plus DNCB protocol. When forearm skin of these individuals was assayed for CH after 30 days, 20 (65%) proved to be UVB-S (approximately 1.5 times the expected frequency), while the remainder displayed vigorous DNCB-specific CH. A strong history of sun-induced recurrent herpes simplex labialis did not predict the UVB phenotype. A subset of these subjects was exposed to 2 MEDs of UVB to their faces. None of the UVB-R subjects developed recurrent herpes labialis while 6 of 8 UVB-S subjects developed recurrent lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Cumulative sunlight exposure and the risk of developing skin cancer in Florida.

Epidemiologic evidence suggests that the risk of developing skin cancer is higher in certain geographic regions where sunlight is excessive. Even in such high risk regions, two distinct populations of long-term residents exist: people with, and people without skin cancer. We have compared the quantitative lifetime sunlight exposure between 11 nonmelanoma skin cancer patients who have lived in South Florida for 23.7 +/- 5.1 years and 9 age-matched normal, healthy individuals who have lived in South Florida for 23.4 +/- 4.1 years. An estimation of personal cumulative sunlight exposure was determined for each subject from data collected through detailed interviews. We found that there was no detectable, significant quantitative difference in cumulative sunlight exposure during life between these two groups. Because these individuals had previously been phenotyped for the effects of ultraviolet-B (UVB) radiation on induction of contact hypersensitivity, our results suggest that UVB-susceptibility may be a better indicator of skin cancer risk than cumulative lifetime sunlight exposure. Thus, although there is little doubt that sunlight exposure is an important factor in the development of skin cancer, our results emphasize the importance of host genetic factors in the pathogenesis of this disease.

Analysis of effects of ultraviolet B radiation on induction of primary allergic reactions.

Acute, low-dose exposure to UVB light reveals a genetic polymorphism in humans with respect to the ability of irradiated skin to support the induction of contact hypersensitivity (CH) to dinitrochlorobenzene (DNCB). In healthy adult caucasians, as well as in humans with deeply pigmented skin, approximately 45% fail to develop CH when DNCB is painted on UVB-irradiated skin; these individuals are termed "UVB susceptible" (UVB-S), whereas those who develop CH at the challenge site are termed "UVB resistant" (UVB-R). The UVB-S trait is characteristic of virtually all patients with biopsy-proved basal/squamous cell cancer, and may therefore be a risk factor for this disease. We have investigated the effects of UVB on expression of primary allergic reactions (PAR) in healthy caucasian and black-skinned adults, as well as patients with skin cancer. Among UVB-R caucasians, very few (less than 25%) developed PAR at site exposed to UVB, whereas among black-skinned UVB-R subjects, all displayed a PAR at the UVB irradiated site. To determine whether the lack of PAR in UVB-R caucasian subjects was systemic or local in origin, DNCB was applied to UVB-exposed buttock skin, and each individual was then challenged with dilute DNCB on forearm skin twice: 11 and 30 d thereafter. When inflammatory responses were evaluated at the original hapten application site, as well as both challenge sites, complete concordance was observed between positive challenge reactions at 30 d (UVB-R) and positive challenge reactions at 11 d, whereas only one caucasian subject displayed a PAR at 12 d. Thus, UVB-R caucasians can display CH as early as 11 d following hapten application to UVB-treated skin, indicating that their failure to display PAR is a local, rather than a systemic, effect of UVB. Because UVB-induced phototoxicity was significantly greater in caucasian than in deeply pigmented skin, it is anticipated that phototoxicity leads to rapid hapten "washout" from UVB-exposed caucasian skin. We propose that PAR usually do not occur in UVB-treated caucasian skin because insufficient hapten remains at the site to trigger a spontaneous inflammation when systemic hapten-specific immunity emerges.

Effects of ultraviolet B light on cutaneous immune responses of humans with deeply pigmented skin.

The incidence of skin cancers of the basal and squamous cell types is extremely low among genetically black-skinned human beings, whereas these types of skin cancers are common among Caucasians, especially those who live in geographic areas of high sun exposure. Ultraviolet B light (UVB) is thought to be the primary oncogenic agent in sunlight. We have recently demonstrated that acute, low-dose exposure of Caucasian skin to UVB impairs the induction of contact hypersensitivity to dinitrochlorobenzene (DNCB) in approximately 40% of normal individuals. Importantly, this trait--termed UVB susceptibility--was found to be a characteristic of virtually 100% of patients with a history of biopsy-proved skin cancer, implying that UVB susceptibility may be a risk factor for this disease. Because melanin pigment is thought to be protective of some of the deleterious effects of UVB radiation, we have examined the capacity of a low-dose regimen of UVB to alter induction of contact hypersensitivity in individuals with genetically melanized or heavily tanned skin. Our results indicate that UVB radiation depletes heavily pigmented skin of Langerhans cells, just as it does in Caucasian skin. Moreover, UVB-susceptibility exists as a polymorphic trait in individuals with genetically determined black skin, as well as in individuals with heavily tanned skin, and the incidence of this trait is similar to that found among normal Caucasian subjects. Thus, melanin does not appear to protect against the deleterious effects of an acute, low-dose regimen of UVB on induction of cutaneous immunity, and the UVB susceptibility trait is equally well-represented in both black- and Caucasian-skinned individuals. We conclude that although UVB susceptibility may function as a risk factor for skin cancer in Caucasians, it does not function similarly in black-skinned human beings, probably because melanin effectively protects against the mutagenic properties of UVB radiation.