Hair in psoriasis: A prospective, blinded scanning electron microscopic study

Hair in psoriasis: A prospective, blinded scanning electron microscopic study

P2703 P2705 Medicinal chemistry development of AN2728, a novel oxaborole in development for the topical treatment of psoriasis Stephen Baker, PhD, A...

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P2703

P2705

Medicinal chemistry development of AN2728, a novel oxaborole in development for the topical treatment of psoriasis Stephen Baker, PhD, Anacor Pharmaceuticals, Inc., Palo Alto, CA, United States; Virginia Sanders, PhD, Anacor Pharmaceuticals, Inc., Palo Alto, CA, United States; Tsutomu Akama, PhD, Anacor Pharmaceuticals, Inc., Palo Alto, CA, United States; Jacob Plattner, PhD, Anacor Pharmaceuticals, Inc., Palo Alto, CA, United States AN2728 is a novel anti-inflammatory agent in clinical development to treat psoriasis topically. We report the synthesis and structure-activity relationship that led to the selection of this compound. AN2728 derives from a class of small molecules known as phenoxy-2,1-dihydrobenzoxaboroles. These all contain a 5-membered boroncontaining ring fused to a phenoxy-substituted benzene ring. We discovered that these compounds have broad-spectrum anti-inflammatory activity. We synthesized a library of analogs to optimize the structure for potency. First, we investigated the importance of the 5-membered boron-containing ring. This included increasing ring size from 5 to 6 members, synthesizing a ring-opened form, replacing boron with carbon, and adding other substituents to the ring. Next we focused on the phenoxysubstituent, positioning this in different places on the benzoxaborole, replacing the oxygen with sulfur, replacing the phenyl group with pyridine and adding various substituents on the phenyl ring. These compounds were tested for their ability to inhibit the release of pro-inflammatory, Th-1 and Th-2 cytokines from human PBMC cells stimulated with phytohemaglutinin. From this study we found that the optimal structure contained an unsubstituted 5-membered oxaborole ring with a p-cyanophenoxy substituent at the 5-position of the benzoxaborole. This compound was AN2728. The IC50 values for AN2728 against TNF-a, IL-1b, IFN-g, and IL-4 were 0.19 g/mL, 4 g/mL 0.08 g/mL, and 2.3 g/mL, respectively. This compound was then tested for in vitro cytotoxicity against a mouse fibroblast cell line, L929, and showed a good level of safety at 100 M. These results led us to select AN2728 as our clinical candidate for the topical treatment of psoriasis.

Hair in psoriasis: A prospective, blinded scanning electron microscopic study Amrinder Jit Kanwar, MD, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Inderjeet Kaur, MD, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Sunil Dogra, MD, Postgraduate Institute of Medical Education and Research, Chandigarh, India Background: Psoriasis affects not only the cutaneous surface but also other ectodermal structures like nails, hair, and rarely mucous membranes. There are not many studies, which have described the changes in hair in detail. Various findings reported are reduced density of hair with dystrophic and telogen hair in the psoriatic plaques, thinning of hair shaft in unaffected areas, scarring alopecia in psoriatic lesions etc. In this study, we tried to expand these observations in a series of patients and normal controls.

This study was sponsored by Anacor Pharmaceuticals, Inc.

Methods: Hairs from the lesions of 30 patients aged 12-67 years (mean 37.6 6 9.2) and from the corresponding unaffected parts of these patients were examined. Hairs taken from similar sites in 15 normal adults (healthy controls) aged 18-62 years (mean 35.2 6 8.6) were also similarly examined. Patients who were using topical keratolytics or any cosmetic products for the last 4 weeks on the test area were also excluded. After their processing, 5 hairs from each subject were examined under scanning electron microscope (SEM) and the mean value of each type of change was used for analysis. The following features were counted on the hair segments examined in all 3 groups (lesional, non-lesional, control) - micropits/macropits, upturned edges of cuticular cells, dystrophy and transverse/longitudinal fissures. Results: Micropits/macropits (sharply demarcated defects on the cuticle \0.5/ [ 0.5), dystrophy (areas showing generalized roughness and ragged appearance of the cuticle), upturned edges of cuticular cells, transverse and longitudinal fissures were seen in varying frequency in all 3 groups. Micropits were significantly more in the lesional hair compared to those in the hair from non-lesional area and controls. Dystrophic changes were significantly more severe in lesional hairs as compared to the hair from the non-lesional areas. Upturning of cuticular edges was more frequent (but not significantly so) in hair from psoriatic plaques. Conclusion: The presence of micropits and hair dystrophy could contribute to the thinning and loss of hair in the psoriatic plaques. Commercial support: None identified.

P2706 P2704 Pustular psoriasis of the lip is mediated by skin-homing and not gastrointestinal-homing T-lymphocytes Harries Matthew, MBChB, The Dermatology Centre, The University of Manchester, Manchester, United Kingdom; Rachel Watson, PhD, The University of Manchester, Manchester, United Kingdom; Tamara Griffiths, MD, Department of Dermatology, Macclesfield District General Hospital, Macclesfield, United Kingdom; Christopher Griffiths, MBChB, MD, The University of Manchester, Manchester, United Kingdom A 38-year-old woman presented with a progressive, pustular rash involving the hands and feet that had been present for 18 years. It initially started on the right thumb and had spread to involve most of her fingers and both great toes. Eight years ago she developed a similar looking rash on her lower lip, which had a clinical course that paralleled that of the skin. Examination revealed erythematous and scaly plaques containing pustules on the distal phalanges of the hands and feet. There was marked nail plate dystrophy with a number of nails having already been shed. The appearance was entirely consistent with the diagnosis of acrodermatitis continua of Hallopeau (ACH). Interestingly the lower lip vermillion was also erythematous and scaly and was studded with numerous pinhead-sized pustules. The remaining skin and oral mucosa was normal. The appearance of the lip was suggestive of pustular psoriasis. Subsequent histology of the lip showed acanthosis and pustulosis in keeping with pustular psoriasis. As psoriasis is a T-lymphocyte mediated disease and mucosal lesions are rare, we performed immunohistochemistry on lesional skin of the lip and hand to try and demonstrate where the T-lymphocytes were derived. Immunohistochemistry showed positive staining on both lip and hand specimens for intercellular adhesion molecule-1 (ICAM-1), which is up-regulated on endothelial cells in psoriatic skin. Cutaneous lymphocyte-associated antigen (CLA), found on skin-homing memory T-lymphocytes, also showed positive staining in both lip and hand specimens. Alpha4Beta7 integrin staining, found on gastrointestinal-homing T-lymphocytes that migrate to normal and inflamed sites in the gastrointestinal tract, was negative in both samples. ACH is a chronic and progressive pustular eruption of unknown cause involving the distal phalanges of the hands and feet. Due to its histological features, most authors regard ACH as a form of acropustular psoriasis. Psoriasis of the lip is very rare with only a few reported cases in the literature. The diagnosis is best made when the clinical course of the oral lesions parallels that of the skin lesions and is supported by histological examination. We present a case of ACH with pustular psoriasis of the lip. The immunohistochemistry results show that psoriasis of the lip is mediated by skin-homing and not gastrointestinal-homing memory T-lymphocytes as demonstrated by CLA 1 and Alpha4Beta7-staining. Commercial support: None identified.

FEBRUARY 2007

Long-term efficacy of adalimumab for the treatment of psoriasis and psoriatic arthritis Marina Papoutsaki, MD, Department of Dermatology, University of Rome ‘‘Tor Vergata,’’ Rome, Italy; Maria Sole Chimenti, MD, Department of Rheumatology, University of Rome ‘‘La Sapienza,’’ Rome, Italy; Marina Talamonti, MD, Department of Dermatology, University of Rome ‘‘Tor Vergata,’’ Rome, Italy; Sergio Chimenti, MD, Department of Dermatology, University of Rome ‘‘Tor Vergata,’’ Rome, Italy Background: Adalimumab is a human, anti-TNF monoclonal antibody, genetically engineered using phage display technology and is structurally and functionally analogous to naturally occuring human immunoglobulin G1 (IgG1). This monoclonal antibody demonstrates a high specificity and affinity for TNFa but not other cytokines, such as lymphotoxin (LFb), and has a terminal half-life comparable to that of human IgG1 (about 2 weeks). The mechanism of action for adalimumab involves blocking the interaction of TNF with the p55 and the p75 TNF cell surface receptors. This drug is approved for the treatment of moderate to severe reumatoid arthritis and recently it has been approved also for psoriatic arthritis. Objectives: The aim of our study was to evaluate the efficacy and safety of monotherapy with adalimumab in patients affected by psoriasis and/or psoriatic arthritis for which previous conventional treatments have failed. Methods: We treated 43 patients (28 males, 15 females), 29 patients affected by psoriatic arthritis, 10 patients affected by plaque type psoriasis, and 4 patients affected by erythrodermic psoriasis. All patients were required to have a history of an inadequate response or intolerance to conventional (MTX, cyclosporin, retinoids, PUVA) systemic treatments. Adalimumab was administered at a dosage of 40 mg, subcutaneously, once a week. The efficacy was evaluated in all patients every 4 weeks by the determination of the psoriasis area and severity index (PASI), the dermatology life quality index (DLQI), the psoriasis disability index (PDI), and the health assessment questionaire (HAQ) scores. At the present, 12 patients have reached 6 months of treatment and 15 patients have reached 1 year of continuative treatment. Adalimumab was generally well tolerated. There were no reports of severe adverse events during the treatment period. Results: Adalimumab treatment was effective and considerably improved patients PASI score and quality of life, as assessed by all three measures (DLQI, PDI, HAQ), already at week 12 and its efficacy continued to improve at week 24. Conclusions: Our results suggest that among the new biologic therapies, adalimumab can be considered as a valuable alternative therapy for the treatment of psoriasis and psoriatic arthritis. Commercial support: None identified.

J AM ACAD DERMATOL

AB175