Psoriasis

Psoriasis is a common chronic inflammatory disease characterized by recurrent exacerbations and remissions of thickened, erythematous, and scaling 

Once T cells are activated, they migrate from lymph nodes and the bloodstream into skin and secrete various cytokines (e.g., interferon j, interleukin 2 [IL-2]) that induce the pathologic changes of psoriasis. Local keratinocytes and neutrophils are induced to produce other cytokines, such as tumor necrosis factor-a (TNF-ce), lL-8, and others. 

As a result of pathogenic T-ceU production and activation, psoriatic epidermal cells proliferate at a rate sevenfold faster than normal epidermal cells. Epidermal proliferation is also elevated in apparently normal skin of psoriatic patients. 

There is a significant genetic component in psoriasis. Studies of histocom-patibflity antigens in psoriatic patients indicate a number of significant associations, especially with HLA-Cw6, where the relative likelihood for developing psoriasis is 9 to 15 times normal. 

Psoriatic lesions are relatively asymptomatic, but about 25% of patients complain of pruritus. 

Psoriasis is a disease of the immune system that involves T lymphocytes. The etiology and pathogenesis of psoriasis results from complex communications that cause activation of T lymphocytes and trafficking to the skin. Further reactivation causes inflammation and overproduction of skin, resulting in lesions and plaques. In psoriatic skin, there is an upregulation of intracellular adhesion molecule-1 (ICAM-1) on endothelium and keratinocytes. 

Efalizumab is a humanized IgGlK antibody produced by recombinant DNA technology. It exhibits immunosuppressive function. It binds to CDlla, which is the a-subunit of leukocyte function antigen (LFA)-l. Efalizumab decreases the cell 

Efalizumab is administered weekly by subcutaneous injections to treat psoriasis, where a steady state is reached after 4 weeks. Its side effects include serious infections, thrombocytopenia, hemolytic anemia and the probability of malignancies due to its immunosuppressive effects. Other common side effects produced by efalizumab within 2 weeks of administration are nausea, fever, chills and headache. Furthermore, it can produce symptoms associated with hypersensitivity reaction. 

Psoriasis is a chronic inflammatory skin disease affecting about 1% of the population. The condition is characterized by hyperproliferation of keratinocytes. Cell turnover in the epidermis is increased with cells reaching the surface in as few as 3 days instead of the normal 21-28 days. This results in a thickened epidermis with immature keratinocytes containing nuclei piling up on the surface. The keratinocytes produce excessive amounts of keratin and form typical silvery scales. There are dilated blood vessels in the upper dermis and the skin bleeds easily if scratched. Leucocytes infiltrate into the epidermis and can form microabsesses. 

All parts of the skin can be involved including mucous membranes and nails, but more usually isolated patches of skin are affected, particularly at the elbows and knees with clear demarcation between the plaques of psoriasis and normal skin. Plaque psoriasis is the most common form, accounting for 80% of cases. 

Psoriasis occurs in several other forms. A form particularly difficult to treat is palmo-plantar psoriasis (PPP), which manifests as pus-fllled spots (pusmles) on the hands and feet. Pustular and erythrodermic psoriasis are two rare forms of the disease, which present as medical emergencies. Both types cover the entire body, as either pus-fllled spots (pustular) or red patches with skin shedding (erythrodermic). 

The disease appears to have a genetic basis with environmental factors, such as infections, emotional trauma or mechanical trauma, causing outbreaks in susceptible individuals. Psoriasis should be regarded as a chronic systemic disease, which can be associated with other chronic diseases such as heart disease, hypertension and diabetes and may reduce life expectancy. About 15% of people with psoriasis also have psoriatic arthritis (see Chapter 7, page 173). 

Sometimes psoriasis can occur in response to drugs such as lithium (Chapter 11), chloroquine and NSAIDs (Chapter 7), beta-blockers and ACE inhibitors (Chapter 4). 

Psoriasis is an inflammatory skin disease characterized by red, scaly, raised plaques. Usually, the psoriasis lesions are several centimeters in diameter and separated by normal-appearing skin [239, 240]. Psoriasis involves a chronic cutaneous pathologic process, driven by interactions between infiltrating leukocytes (Tcells, dendritic cells, macrophages, neutrophils), cytokines, chemokines and keratinocytes, the cells from the epidermis. The disease is initiated or exacerbated by infections, physical and/or emotional stress, antigenic stimuli and various medications (e.g., lithium, P-block-ers [241, 243]). Psoriatic plaques can revert back to symptomless skin spontaneously or after treatment vdth selective immune-targeted agents [239, 240, 242-244]. 

About 2.1% of the U.S. population has psoriasis or more than 4.5 million adults in the U.S. Diagnosis usually is between ages 15 and 35. 

MultiSys tern Invol vemen t vdth Emphasis on Neurologic Involvement 

Psoriasis generally appears at the joints, limbs and scalp but may appear anywhere on the body. At least 10% those with psoriasis develop psoriatic arthritis, a degenerative disease of the joints and connective tissue. Approximately 1 million people in the U.S. have psoriatic arthritis. Psoriatic arthritis usually develops between the ages of 30 and 50 but can develop without the lesions characteristic of psoriasis (Natl Psoriasis Foundation, 2005, Specific forms of psoriasis, psoriasis.org). Of those with psoriatic arthritis, about 20% will develop spinal involvement. The inflammation associated with spinal involvement can lead to vertebral fusion as in alkylosing spondylitis. 

Those patients who develop psoriatic arthritis with spinal involvement are most likely to test positive for the HLA-B27 genetic marker also implicated in alky losing spondylitis and Reiter s syndrome. 

The type of lesion and whether the patient also has psoriatic arthritis are important issues in cleterinining therapy. Steroid topical creams, cyclosporine andmethotraxate are useful in treatment of psoriasis. Oral tazarotene, a non-biologic retinoid is pending FDA approval for moderate to severe psoriasis. As with most autoimmune disorder s, different patients respond differently and newer more targeted therapies are important goals. 

Multi System Involvement with Emphasis on Neurologic Involvement 

Ca shows a twofold or even higher increase in the stratum granulosum region compared to normal skin, but in contrast to the Ca distribution in normal skin, that of psoriasis follows the mass distribution more closely. In many sections there is an additional Ca peak in the vicinity of the basal cell layer, but the full significance of this is not clear. 

The trace element distributions of uninvolved psoriatic skin merit special comments. The main Fe peak appears closer to the mass distribution peak than in normal skin. Also, there are obvious variations in the Fe content in different strata (cell layers), and the lowermost values are consistently at least twice as high as those in normal skin. Our PIXE investigation substantiates the previously reported finding that psoriatic patients lose Fe through the shedding of stratum corneum cells in lesional areas by demonstrating that clinically normal skin of psoriatic patients contains higher than normal amounts of Fe.36,37 

The Zn content of the uninvolved psoriatic skin is increased in the stratum spinosum especially, except in one single section where the Zn follows suit with Fe distribution. Such variations are likely to occur as a function of the cell cycle position of a particular cell. 

2 Elemental Distributions in Different Strata of Psoriatic Normal-Looking Skin — Horizontal 

In comparison to the control skin there are high mean values and prominent variations in the trace elements, notably Fe and Zn, in the upper level of the epidermis. However, the mass distribution pattern essentially follows that of normal control skin with some variations in the upper layer. 

This appears as areas of reddened and flaky skin and can be a lifelong condition although it tends to flare up in the teens and twenties and then again in old age. About 1 person in 50 suffers from psoriasis at some time in their life. Why it occurs is still not understood. Psoriasis is caused by over-reactive skin cells in the lower layer of the epidermis dividing 20 times faster than normal. A normal skin cell takes around 4 weeks to mature and reach the surface of the skin, there to be shed. Psoriatic cells go through this process in only two days and they accumulate at the surface as a layer of dead skin. Skin affected by psoriasis has a thickened epidermis with an excessive growth of blood vessels, and there are clusters of immune cells. Plaque psoriasis is the most common and occurs on the knees, elbows, lower back, and scalp. 

44 Better Looking (II) and Better Living (I) Medical Advances 

Medicines related to vitamin D are also effective but an unwanted side effect of the early ones was to cause the body to retain too much calcium, which is detrimental. More than 1500 different compounds have been synthesised to try and find one that would act on the psoriasis without raising the level of calcium in the blood. Calcipotriol cream was the one that performed best and is now widely used. Another chemical, etretinate, was introduced in 1975 and found to be just as effective. It was eventually superseded by acitretin when it was discovered that the body converted etretinate to acitretin and it was the latter which was the active agent. Acitretin is now the prescribed drug and it is very effective with three quarters of those treated reporting noticeable improvement and for about a third of patients their psoriasis cleared up completely. Psoriasis can also be treated with successive oral doses of methoxsalen followed by UV irradiation of the affected area. 

Psychological treatments may even be effective because the condition seems to be caused by stress. Deep breathing, meditation, and even listening to relaxation CDs can help develop a positive attitude that can speed recovery. 

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Anthralin [1143-38-0] is acetylated using acetyl chloride in toluene and a pyridine catalyst to furnish 1,8-dihydroxy-lO-acetylanthrone [3022-61-5], an intermediate in the preparation of medications used in treating skin disorders, such as warts, psoriasis, and acne (38). Sugar esters can be similarly prepared from acetyl chloride under anhydrous conditions (39). 

The conditions whereby dandmff, seborrheic dermatitis, and psoriasis dmg products are generally recognized as safe and effective and are not misbranded is available (70). Specific active iagredients that can be used as well as the statement of identity, iadications for use, and required warnings, are identified. Products that do not meet all of these requirements are considered new dmgs and must have an approved NDA for the nonmonograph conditions. 

New impetus was given to photomedicine by development of lasers that are compatible with the clinical environment. These include HeNe, Ar ion, mby, and tunable dye lasers operating in the continuous wave (cw) mode. Prior to the advent of lasers in medicine, only the treatment of newborn jaundice, and the appHcation of long wavelength uv irradiation in conjunction with adininistration (or topical appHcation) of psoralen class sensitizers to treatment of skin diseases (86), principally psoriasis, were clinically important phototherapies. 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

Sahcyhc acid USP, EP, and other pharmacopeia grades are used medically as antiseptic, disinfectant, antifungal, and keratolytic agents. Sahcyhc acid is formulated in lotion or ointment formulations for the treatment of dandmff, eczema, psoriasis, and various parasitic skin diseases. Because the keratolytic property of this aromatic acid has use in the safe removal of dead skin cells from the surface of healthy skin, the acid is used in concentrated sahcyhc acid solutions or suspensions to remove warts and corns. In more dilute form, sahcyhc acid preparations have found use in dandmff and eczema treatment. Sahcyhc acid has been considered and found effective by the Advisory Committees to the FDA in various over-the-counter (OTC) dmg regulated uses. Among these are acne products, dermatitis, dry skin, dandmff and psoriasis products, and foot care products (24). 

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

Selective AR agonists are undergoing clinical trials for cardiac arrhythmias and pain (Ai) cardiac imaging and inflammation (A2a) colon cancer, rheumatoid arthritis, psoriasis, and dry eye (A3). Selective AR antagonists are either in or advancing toward clinical trials for kidney disorders (Ax) Parkinson s disease (A2a) diabetes and asthma (A2B) cancer and glaucoma (A3). 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

VX-765 Vertex Caspase-1 (irreversibly) IC50 0.8 nM Psoriasis Phase Ila... 

Vertex also put in clinical trial VX-765, another caspase-1 -specific, YVAD-derived peptidomimetic that is in vitro slightly more potent then pralnacasan (IC50 0.8 nM). Evaluation of VX-765 in a mouse model of oxazolone-induced dermatitis showed a dose-dependent (10-100 mg/kg) inhibition of ear inflammation. Consequently, VX-765 was enrolled in a 4-week phase Ila safety and pharmacokinetic study for psoriasis. However, Vertex has not communicated any results yet. 

CXCR3 Tularik II T487 MS Psoriasis Failed in Psoriasis... 

The antibodies are used to treat Crohn s disease, Psoriasis (including Psoriasis arthritis), Spondylitis ankylosans, and rheumatoid arthritis. Side effects... 

In the pathogenesis of many chronic inflammatory diseases (e.g., rheumatoid arthritis, glomerulonephritis, colitis ulcerosa, Morbus Crohn, atopic dermatitis, psoriasis) autoimmune processes play an important role, too. Although first of all nonsteroidal antiinflammatory agents or glucocorticoids should be applied, immunosuppressive agents may also be indicated. 

For the topical treatment of some chronic inflammatory skin diseases (like atopic dermatitis) immunosuppressive macrolides (like TRL and pimecrolimus) that permeate the inflamed epidermis are of benefit for patients. Severe side effects comparable to those after systemic application of TRL in transplanted patients (see above) have not been observed so far. For the treatment of psoriasis vulgaris these drugs are less effective. The CD2 antagonist alefacept may be a suitable alternative to allergic reactions. 

PB T1 T01.010 Proteasome catalytic subunit 1 Potential use in cancer, rheumatoid arthritis and psoriasis that are characterized by these processes... 

KC706 stabilizes the inactive conformation of the mitogen-activated protein kinase p38a, a protein kinase involved in inflammatory reactions and cardiovascular functions. KC706 therefore holds the potential to treat conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and cardiovascular disease. This compound is currently being tested in phase II clinical trials with patients suffering from rheumatoid arthritis. 

RAR 3 > RARy > > RARa. It does not bind to any of the RXRs. This retinoid derivative is said to have lower cytotoxic effects than other retinoids while achieving sustained therapeutic efficacy in the treatment of plaque type psoriasis. 

The topical and oral use of retinoids for treatment of hyperkeratotic disorders such as psoriasis and Darier s disease has long been established. Systemic retinoid therapy is often combined with topical diugs such as corticosteroids, dithranol, tar, and also UVA/UVB phototherapies where synergistic effects have been reported. 

Etretinate 0 i COOR Oral 0.25-1.0 mg/kg/d Generalized pustular psoriasis, exfoliative psoriasis, plaque psoriasis ... 

Combinations of retinoids with ultraviolet A or B radiation (and other drugs). For example, RePUVA-therapy (retinoids and psoralen and UVA combination) is currently one of the most effective regimens for recalcitrant severe psoriasis. 

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