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CONSENSUS STATEMENT “THE MANAGEMENT OF PSORIASIS” August 1996 By PERSATUAN DERMATOLOGI MALAYSIA (DERMATOLOGICAL SOCIETY OF MALAYSIA) Prepared by The Committee on Guidelines for Quality Care in Dermatology Chairman/Editor Dr Kim Weng Chow FRCP Secretary Dr Gangaram Hemandas MRCP Members Datin Dr Suraiya H Tun Hussein FRCP Dr Ain Tian Gan MRCP Dr Sushil K Ratti MRCP Dr Hon Nam Chew FAAD Dr Roshidah Baba MRCP Dr Kim Chye Yee MRCP CONTENTS 1. 2. Psoriasis Management of Psoriasis 1.1 Introduction 1.2 Definition 2.1 Rationale for Treatment 2.1.1 Scope of the Problem 2.1.2 Morbidity Issue 2.1.3 Mortality Issue 2.2 Diagnostic Criteria 2.2.1 Clinical Characteristics 2.2.2 Diagnostic Tests 2.2.3 Differential Diagnosis 2.3 Aims of Treatment 2.4 Principles of Management 2.5 Indications for referral to a Consultant Dermatologist 2.6 Levels of Care for Psoriasis Management 2.61 Office Treatment 2.62 Ambulatory (day care) Treatment 2.63 Hospitalisation (in-patient care) 2.7 Office Treatment 2.7.1 Topical Therapy 2.7.2 Summary of Topical Therapy 2.7.3 Physical Therapy 2.7.4 Systemic Therapy 2.7.5 Combination Therapy 2.8 Ambulatory Treatment (day care) 2.8.1 Introduction 2.8.2 Phototherapy (Ultraviolet B Irradiation) 2.8.3 Photochemotherapy (PUVA) 2.8.4 Combination Regimes with Phototherapy 2.8.5 Hand and Foot PUVA 2.8.6 Bath PUVA 2.8.7 Summary of Systemic and Physical Therapy 2.8.8 Additional services 2.9 Hospitalisation (in-patient care) 2.9.1 Indications for hospitalisation 2.9.2 Adjunctive Therapies 3. Patient Education 4. Use of Guidelines to Derive Audit Measures 5. Supporting Evidence 6. Disclaimer 7. List of References 1. PSORIASIS This Consensus Report reflects the best data available at the time of preparation. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report. 1.1 INTRODUCTION The Dermatological Society of Malaysia Committee on Guidelines for Quality Care is developing its guidelines of care for our profession. The development of guidelines will promote the continued delivery of quality care and assist those outside our profession in understanding the complexities and scope of care provided by dermatologists. 1.2 DEFINITION Psoriasis is a chronic skin disease that is classically characterized by thickened, red areas of skin covered with silvery scales. The extent of skin involvement can range from discrete, localized areas to generalised body involvement. The joints, nails and mucous membranes may also be affected with the disease. 2. MANAGEMENT OF PSORIASIS 2.1 RATIONALE FOR TREATMENT 2.1.1 Scope of the Problem Psoriasis affects 1% to 2% of the general population. It has no known cure and can affect all age groups and both sexes. It may be symptomatic throughout life and may be progressive with age or wax and wane in its severity. Physical and psychological disability produced by the disease may range from minor to total. In addition to classical plaque psoriasis, a severe inflammatory form of the disease, erythrodermic psoriasis, or generalised pustular psoriasis may produce involvement of the total body surface and may have associated systemic or constitutional manifestations. 2.1.2 Morbidity Issue Patients with psoriasis have a disease that may be readily apparent to others because of the redness, scaling and thickening of the skin. This disease can cause functional impairment, disfigurement of the skin and emotional distress. The skin may itch, burn, sting and easily bleed in the areas affected with psoriasis. Severe involvement of the hands, feet and nails may make even routine activities, such as walking or dressing difficult to perform. Up to 30% of patients with psoriasis may have arthritic symptoms. Five to ten percent of these patients may experience functional disability from arthritis of various joints. Persons with erythrodermic (generalised redness of the body surface) psoriasis usually have difficulty in controlling body temperature. These and other factors directly related to psoriasis may cause a person to have difficulty in work performance, problems with social rejection, sexual dysfunction and depression. Patients usually find their disease more disabling than that diagnosed by their doctors. 2.1.3 Mortality Issue Erythrodermic and generalised pustular psoriasis may be life-threatening because of systemic infections or cardiovascular or pulmonary complications. Severe social rejection and morbidity with the disease has led to suicide. 2.2 DIAGNOSTIC CRITERIA 2.2.1 Clinical Characteristics A history and complete total surface skin examination should be performed. The history, clinical appearance and location of lesions are the most reliable indicators of the disease. i. The amount of scale, thickness of the lesion and degree of redness may vary depending on the area of the body involved. The classic areas of involvement are scalp, face, elbows, knees, palms and soles, intertriginous folds and genitalia. The lesion morphology may also vary and include papules and plaques of various sizes as well as pustules. The surface area of skin affected may range from minimal to total body involvement. Severe cradle cap or diaper dermatitis may be forerunners of psoriasis. Approximately 30% of patients have a family history of the disease. ii. Aggravating/Precipitating Factors Infections may precipitate and exacerbate the disease. Drugs, predominantly lithium, beta-blockers, antimalarials, alcohol or nonsteroidal anti-inflammatory agents may aggravate the disease. iii. Nails Various degrees of nail deformity may be seen including pitting, onycholysis and subungual hyperkeratosis. iv. Joints Inflammatory changes can affect small or large joints either singly or in combination, producing a wide range of arthritic changes and joint deformity. v. Ears A moderate degree of scaling within the ear canals is common. In severe cases this may produce an impaction of scale within the ear canal causing hearing impairment. vi. Mucous Membranes Psoriasis frequently involves the genitalia and may involve the lips, buccal mucosa and other mucous membranes. 2.2.2 Diagnostic Tests Laboratory tests may include the following: i. Biopsy Histology is sometimes used to differentiate psoriasis from other conditions (see "differential diagnosis"). The pathology is usually, but not always confirmatory, particularly in guttate, palmoplantar or erythrodermic psoriasis. ii. Other tests Radiologic studies Serologic studies Culture for appropriate organisms Microscopic (potassium hydroxide) examinations HLA typing 2.2.3 Differential Diagnosis Many diseases mimic psoriasis. These may include but are not limited to dermatitis, fungal infections, discoid and subacute lupus erythematosus, lichen planus, mycosis fungoides, pityriasis rubra pilaris, Bowen's disease, parapsoriasis and secondary syphilis. 2.3 AIMS OF TREATMENT The majority of patients with psoriasis may be able to control their disease with treatment either prescribed or delivered in a dermatologist's office. However, a significant number of patients may require specialized treatments and experienced nursing care that would necessitate the use of an ambulatory treatment centre or admission to the hospital. Some of the treatment periods may be prolonged because of the severity and extent of the disease. Psoriasis is a chronic and recurrent disease that can be psychologically and physically disabling. The aims of therapy are: i) Suppressive ii) Preventive and iii) Supportive 2.4 PRINCIPLES OF MANAGEMENT The principles of management include: Confirmation of diagnosis - usually clinical and only rarely is a biopsy required Counselling of patient - on disease process, treatment options, importance of compliance and follow-up including the non-contagious and non-cancerous nature of the disease Counselling of others as necessary, eg. spouses, employers, friends etc Use of anti-psoriatic medications For successful management it is important to establish a good rapport with the patient from the outset. Management should then be a two-way process with the patient as much involved as the doctor in the decision making process as each have their own views about severity and importance of treatment. 2.5 INDICATIONS FOR REFERRAL TO A CONSULTANT DERMATOLOGIST Diagnostic difficulty Request for patient counselling or education, or both, including initial demonstration of topical treatment Failure of topical treatment used appropriately for three months Need for increasing amounts or potencies of topical corticosteroids Need for systemic drugs Generalised pustular or erythrodermic psoriasis (emergency referral) 2.6 LEVELS OF CARE FOR PSORIASIS MANAGEMENT The management of psoriasis can be delegated via 3 levels of care 2.6.1 Office Treatment 2.6.2 Ambulatory Treatment (day care) and 2.6.3 Hospitalisation (in-patient care) By and large the majority of patients are managed by levels 2.6.1 and 2.6.2. Hospitalisation is only required for specific indications. 2.7 OFFICE TREATMENT This can usually be done on an outpatient basis and can be broadly divided into 3 main groups: 2.7.1 Topical Therapy - tar, dithranol, calcipotriol, corticosteroids and others 2.7.2 Physical Therapy - ultraviolet radiation (UVA/UVB) - PUVA (Psoralen, Ultraviolet A Treatment) 2.7.3 Systemic Therapy - methotrexate retinoids sulphasalazine and others hydroxyurea cyclosporin corticosteroid (only for specific indications) 2.7.4 Various combinations of 2.7.1, 2.7.2 and 2.7.3 This sequence generally defines not only the risk-benefit ratio but also the progression of therapy. Topical agents are safest while systemic agents carry the greatest risk. Initial therapy is usually with topical agents followed by ultraviolet radiation if the disease responds poorly and finally systemic agents. Some extensive cases may need phototherapy or systemic agents from the beginning. The more severe cases such as erythrodermic psoriasis or acute generalised pustular psoriasis will need inpatient treatment with close monitoring as it can be fatal. Often patients are on a combination of treatment. 2.7 OFFICE TREATMENT 2.7.1 Topical i. ii. iii. iv. v. vi. Emollient Tar Anthralin Vitamin D3 and derivatives Keratolytics Corticosteroids i. Emollients Emollients are topical agents that smoothen and soften the stratum corneum. They have their effect, not by hydration of the stratum corneum, but by a trapping mechanism that slows down the rate of transepidermal water loss. Emollients are an important component of therapy for psoriasis. They are particularly valuable in patients with dry skin and skin dryness aggravated by frequent bathing and phototherapy. They appear to enhance the efficacy of phototherapy, possibly by altering the optical and UV- transmitting characteristics of the stratum corneum. There is great personal patient preference for different emollients; it is advised that several names or samples be given and patients be allowed to find the emollient that they are willing and able to use on a regular basis. Examples Vaseline Petrolatum Mineral oils Urea Glycerine Others ii. Tars Coal tar suppresses DNA synthesis in the epidermis within the first few hours after its application. It has antiinflammatory and anti-pruritic effects. Forms : Crude tar in ointment or solution 1 - 10% Purified tar Treatment Regimen Tar alone - Tar bath. - Apply tar ointment on psoriatic plaques, face and flexures to be spared. Tar with phototherapy (Goeckerman Regimen) - Tar bath for 15 - 30 niinutes. - Followed by suberythemogenic UVB dosage or natural sunlight. Tar ointment to psoriatic plaques at an initial dose of 1% and gradually step up every 2 - 3 days if patient tolerates. - Leave tar ointment for 12 - 24 hours. Scalp Tar containing preparations eg Ung Cocois Co Side Effects Folliculitis Skin irritation Aggravation of Acne iii. Anthralin Anthralin slows proliferative rate of stem cell population; therefore it allows normal keratinisation. Although it is an effective agent, it is not an ideal drug because of its irritating and staining properties. Regardless of these shortcomings, it is an effective treatment for plaque psoriasis. Treatment Regimen Routine Anthralin Therapy Anthralin 0.1 per cent cream is applied to the affected areas daily at bedtime. Continue therapy until the lesion clears and then taper the application. Short Contact Therapy Anthralin 0.5 to 4 per cent cream is rubbed into the plaques. After 30 to 60 minutes the anthralin is removed by washing or showering. An emollient or suitable corticosteroid may be applied after the treatment. Treatment is scheduled daily and continues until the plaques have cleared. This regimen is for convenient anthralin therapy; increased effectiveness of anthralin and it causes less staining of clothes Anthralin treatment of the scalp Anthralin pomade is massaged on to the scalp at night and left in place overnight. Remove by shampooing in the morning. This treatment can be daily initially but twice weekly is often sufficient. It is important to warn patients to avoid eye contamination. Side Effects of Anthratin Skin irritation Some patients cannot tolerate strengths as low as 0.1% while others may tolerate more than 4%. Skin staining Patients should be encouraged to identify staining as a sign of progress in treatment. The brown staining usually clears 2 - 3 weeks after stopping treatment. Keratolytic agent such as salicylic acid can help to hasten the removal of this stain. iv. Calcipotriol Trial It promotes differentiation of keratinocytes and inhibits proliferation leading to normalisation of the epidermal cells. Calcipotriol is effective for mild to moderate chronic plaque psoriasis as it clears the psoriasis in 6 - 8 weeks. Improvement is seen within 2 weeks. For some patients, further improvement is observed if treatment with calcipotriol is extended up to 16 weeks. Preparation Calcipotriol 50 mcg/g Ointment/Cream Application Twice a day to psoriatic lesions. Weekly dose of Calcipotriol should not exceed 100 gms. Face and body folds to be avoided. Calcipotriol has been used for up to one year without significant side effects. Calcipotriol has also been used in combination therapy with UVB, PUVA, cyclosporin, methotrexate and retinoids in moderate and severe psoriasis. Side Effects Transient skin irritation. Potential hypercalcemia if recommended dose is exceeded. v. Keratolytics Keratolytics are agents that help to remove diseased scales or hyperkeratosis in psoriasis. They work by breaking down and peeling off excess scales in the psoriatic areas. Topical salicylic acid is the most frequently used keratolytic agent. It may be used alone or in conjunction with other forms of therapy. The concentration range is between 2% and 10%. Caution is to be exercised when this agent is applied extensively to body, particularly in children, since use may result in salicylism. vi. Corticosteroids Corticosteroids are thought to work by vasoconstriction decreased cell turnover and by their anti-inflammatory action. Topical corticosteroids are of value for the treatment of psoriasis but as psoriasis is a chronic disease, long term use may have untoward side effects. Therefore caution needs to be exercised in its usage. The most common complications are systemic absorption, cutaneous atrophy and striae formation, and flare-ups, which may occur after the discontinuation of treatment. Corticosteroids are the treatment of choice for psoriasis involving the face, hairline, and postauricular and flexural areas. More potent corticosteroids should be reserved for the treatment of the palms and the soles. Choosing a steroid Topical steroid is an adjunct to other accepted forms of topical therapy. Selection of steroid depends on: Site of lesions to be treated Severity of lesions Age of patient Steroid's inherent potency Scalp Steroid lotions, sprays and gels can be rubbed into the scalp more easily than cream and ointment and are to be recommended in the treatment of scalp psoriasis. Face When psoriasis occurs on the face, mild steroid is recommended; the use of potent steroids on the face is to be avoided. Extremities Lesions on the extremities, particularly the lower extremities, are at times notoriously difficult. Potent steroids can be used to treat a limited area and if necessary under occlusion. Trunk Topical steroid can be combined with anthralin or tar to reduce irritation or topical steroid cream can be applied in the morning and anthralin or tar at night. How much Topical Steroids to use? Body Area to Treat Your prescription for twice daily applications for seven days. Adult One arm One leg Hand and Foot Trunk (front and back) Head and Neck 14 g 28 g 14 g 56 g 14 g As a rough guide, 1% surface area requires 0.5 gm per day based on twice a day application. Children The smaller the child the lesser topical steroid you use. Never continue the use of topical steroid to prevent relapse. Side Effects of Topical Steroids General Pituitary - adrenal axis suppression (rare) Cushing's Syndrome Local Atrophy Striae Echymoses Rosacea like dermatitis Perioral dermatitis Acne Glaucoma Secondary infection especially fungal Rebound phenomenon Body Folds Since the skin in the body folds tends to be thin, one can treat areas like axillae, groins, genitalia etc. with low potency steroids. Cream or gel is often better accepted than ointments. Palms and Soles Topical steroids are only mildly effective in the treatment of psoriasis on the palms and soles. Nail Folds The use of topical steroids on nail folds is often unrewarding. While Intralesional Kenacort is effective it is often painful and should not be encouraged when lesions are many. Intralesional Steroid Intralesional therapy is rarely used in psoriasis except in experienced hands. Triamcinolone acetonide, 2.5 to 10 mg per ml in a quantity of 0.1 to 1 ml, is used to infiltrate lesions on the scalp on fingernails, or any small, stubborn plaques. Wait 6 to 8 weeks before retreating. Summary of Topical Therapy Table I - Topical Therapy Emollients Tar Anthralin Calcipotriol Keratolytics Topical corticosteroids - mild potency - mid potency - maximum potency Effectiveness + ++ ++ ++ + Remission + ++ ++ ++ + Possible side effects +A +ADE ++ADE +AF +AE Comments d,e,f d,f d,f c,d + ++ +++ + +/++ ++ +AB ++AB +++AB a,b a,b,c,d a,b,c,d,f Effectiveness : + Mild ++ Moderate +++ High Remission : + < 1 month ++ 1 - 3 months +++ > 3 months Possible side effects : + Mild ++ Moderate +++ Severe A : Inconvenience. B : Topical corticosteroid side effects may be local and/or systemic and may include burning, irritation, itching, stinging, erythema, folliculitis, skin atrophy, telangiectasia, hypertrichosis, acneiform eruptions, maceration, hyperglycemia, hyperglycuria and manifestations of Cushing's syndrome; side effects tend to increase with increased potency. C : Pain, discomfort, atrophy, telangiectasia and hypopigmentation. D : Staining. E : Irritation. F : Potential hypercalcaemia if recommended dose is exceeded. Comments a. Tachyphylaxis b. Increased risk of steroid side effects with increased potency, duration of treatment, and total dosage. c. Possibility of systemic absorption may limit use in children. d. Avoid eye contact and intertriginous use in children. e. Increased photosensitivity. f. Avoid use in body folds. 2.7.2 Physical Therapy (Refer Table II) Phototherapy - UVA UVB Refer to section 2.8 Photochemotherapy (PUVA) 2.7.3 Systemic Therapy Systemic treatment should only be used by dermatologists or physicians familiar in its use in the treatment of psoriasis i. Indications for Systemic Treatment Failure of adequate trial of topical treatment Repeated hospital admissions for topical treatment Extensive chronic plaque psoriasis in elderly or infirm people Generalised pustular or erythrodennic psoriasis Severe psoriatic arthropathy ii. Available Systemic Treatment Methotrexate - Oral - Intramuscular - Intravenous Retinoid - Acitretin Sulfasalazine Hydroxyurea Cyclosporin Corticosteroids In the vast majority of cases, this is not the treatment of choice because of a potential severe rebound of psoriasis and steroid side effects. It is contraindicated except for certain selected cases, disabling psoriasis or psoriatic arthritis and is usually limited to short-term use. Antibiotics Useful in patients with evidence of cutaneous or systemic microbial infection or colonization especially in guttate psoriasis associated with streptococcal pharyngitis. i. Methotrexate Methotrexate (MTX) is an effective antipsoriatic agent especially in acute generalised pustular psoriasis, erythrodermic psoriasis, psoriatic arthropathy and extensive chronic plaque psoriasis in the elderly or infirm patients. It is to be used by dermatologists and physicians who are familiar with its use in psoriasis. Indications The decision to administer MTX for the treatment of psoriasis should be individualized. It should be based on the severity, amount of discomfort, degree of incapacity and general medical and psychological conditions. MTX is indicated in the symptomatic control of recalcitrant psoriasis not responsive to topical therapy. Specific clinical indications include the following: Psoriatic erythroderma Psoriatic arthritis Acute pustular psoriasis of Von Zumbusch Localized pustular psoriasis Psoriasis which is physically disabling eg. that of palms and soles Extensive plaque psoriasis Relative Contraindications Significant abnormalities in liver chemistry Significant abnormalities in renal function Pregnancy or nursing mothers (absolute contraindication) Male or female infertility Hepatitis active or recent Cirrhosis Severe anaemia, leucopenia and thrombocytopenia Excessive alcohol consumption Active infectious diseases eg TB Overt or laboratory evidence of immunodeficiency syndromes Patient who is unreliable/non compliant In deciding the use of MTX, one must always keep in mind the risk benefit ratio. Dosage - The drug may be administered orally, IM or IV. The dose must be individually assessed. It may be given as a single or three divided doses weekly orally, intramuscularly or intravenously. A test dose of 2.5-5 mg may be administered to avoid early toxicity. The range of oral dosages ordinarily is 7.5-25 mg/week The range of IM/IV is 7.5-50 mg/week. There must be appropriate monitoring of the blood counts weekly initially and monthly whilst on maintenance therapy. Side Effects The main side effects are bone marrow suppression and a long-term risk of hepatic fibrosis and cirrhosis, which is related to a cumulative lifetime dosage. Conception must be avoided during the course of treatment and for one menstrual cycle after stopping the drug. Monitoring Full blood count, measurement of blood urea, electrolytes, and creatinine concentrations; liver function tests; and clinical examination of liver should be done weekly. The need for estimation should then be extended to two to three monthly intervals and or when clinical need arises. There may be a transient rise of liver enzymes occurring in the first few days after administering the dose. Liver Biopsy It is now established beyond all doubts that MTX is hepatotoxic, causing hepatic fibrosis and cirrhosis, the incidence of which has varied in different series. The incidence is however low if the cumulative dose is less than 1.5 gms. In patients with persistently deranged liver biochemistry or abnormal results on liver imaging, liver biopsy should be considered before starting or continuing treatment. It is therefore recommended that a liver biopsy should be performed on patients who have to be on long term MTX and this should be done soon after or before starting treatment and repeated after a cumulative dose of 1.5 gms. Exceptions are made for those who are given short term treatment. Drug Interactions The following drugs may interact with MTX and increase its activity: alcohol, salicylates, cotrimoxazole, trimethoprin, probenecid, phenytoin, retinoids, pyrimethanine and frusemide. Patients must be warned of concominant administration of these drugs. ii. Retinoids This drug is available only to dermatologists and physicians licensed by the Drug Control Authority of Malaysia. Indications Generalised pustular psoriasis (Von Zumbusch type) - treatment of choice Acrodermatitis continua of Hallopeau - treatment of choice Palmoplantar pustulosis - as combined therapy when other treatments inadequate Erythrodermic (Exfoliative) psoriasis - treatment of choice Extensive plaque psoriasis - as combined therapy when standard treatment ineffective - only considered under special circumstances Psoriatic arthropathy - monotherapy - to reduce dose of NSAIDS Contraindications All female patients of reproductive age because retinoids are teratogenic Exceptions: - other treatments are ineffective or not feasible - effective contraceptive used Raised serum lipids Liver disease - cirrhosis, HBS Ag positive, abnormal liver function tests Synthetic Retinoids Used Acitretin (Trade name: Neotigason) Dosage and Duration of Treatment Acitretin 0.5 - 1 mg/kg/day - 1 mg/kg preferable as initial dose. When condition is controlled, the dose is reduced to 0.25 - 0.5 mg/kg as maintenance for 3 months after which discontinuation is considered. - For combination treatment e.g. with UVB or PUVA, a lower dose of 0.25 - 0.5 mg/kg is used. Side Effects Cheilitis (chapped lips), dry nasal mucosa, hair loss, dry skin, skin fragility, palm/sole peeling, bruising, fingertip peeling, thirst, nosebleed, sticky/clammy skin, bone/joint pain, myalgia, irritation of eyes, paronychia, pyogenic granuloma, hyperlipidaemia, hepatitis. TERATOGENICITY : The retinoids are highly teratogenic SKELETAL TOXICITY: There is concern that long term etretinate therapy is associated with skeletal and ligamentous calcification and hyperostosis (DISH syndrome: Diffuse Interstitial Skeletal Hyperostosis). These appears to be a cumulative threshold dose of 25 - 30 gms Acitretin below which skeletal toxicity is not seen radiographically. Management Protocol Signed consent - Both female and male patients. Pre-treatment Tests - Full blood count, Liver function tests, Fasting serum lipid. Treatment Tests - Repeat every 2 weeks during first 6 weeks' clearing doses. - Repeat every 8 weeks when on low-dose maintenance dosages. Pregnancy Test - Female patients: Pre-treatment pregnancy test or treatment started immediately after menses. Pregnancy test repeated every month of therapy. Skeletal X-rays - To exclude hyperostosis and ligamentous calcification if patient needs continued treatment after 12 months. Then repeat yearly. iii. Salazopyrine Sulphasalazine Salazopyrine is a useful second-line drug in rheumatoid arthritis as well as in psoriatic arthropathy. It also appears to be useful in moderate-to-severe plaque-type psoriasis. Its effectiveness is probably less than other systemic modalities such as PUVA, methotrexate, or retinoids although 25% of patients have comparable efficacy. Its advantage is that although adverse effects are relatively common, these are often not severe and generally reversible. Salazopyrine is also relatively inexpensive. Indications Psoriasis not responding to topical therapy but not severe enough to warrant other more potentially toxic systemic modalities. Contraindications G6PD deficiency and allergies to sulpha drugs. Dosage Initially 500 mg three times a day for 3 days, if no adverse effects increase dose to 1 gm three times daily. Maximum dose 4 gm/day. Dosages for psoriatic arthritis can be lower - 2 to 3 gm/day. Discontinue salazopyrine if no response by week 8. Monitoring Baseline - Full blood counts (FBC), liver function tests, urea, creatinine. Repeat blood counts at 2 nd and 4th week and the rest at 4 weeks and periodically. A drop in haemoglobin during therapy is well documented. Discontinue treatment if there is a drop of more than 2 gm haemoglobin at any stage; 50% or more reduction in total white cell count or neutropenia of less than 3,000/mm3, platelet count less than 100,000/mm3. Side Effects The incidences vary between 5 - 50% but are generally mild. (Watkinson 1986) These include gastrointestinal upsets, cutaneous eruptions, and haematological changes. Slow acetylators are more likely to develop adverse effects with sulpha drugs. Only 15% of Asians are slow acetylators compared to 50% - 60% of Caucasians. iv. Hydroxyurea Although the role of hydroxyurea in the treatment of psoriasis has diminished in recent years, it has several advantages. It is relatively inexpensive; dose schedules are simple, and has few contraindications and subject side effects. Patients with hyperlipidemia, mild renal insufficiency, and cardiopulmonary disease who may tolerate other systemic therapy may be managed with hydroxyurea. Its efficacy however is probably less than the other agents above, with a favourable outcome of up to 63%. Indications - Patients unresponsive to topical therapies or UVB - Patients not acceptable for PUVA, methotrexate, acitretin, cyclosporin A. Contraindications Absolute : Pregnancy/lactation, Drug allergy. Relative : Blood dyscrasias, ongoing infection, unstable / fulminant psoriasis, psoriatic arthropathy (ineffective), and hepatic / renal / cardiopulmonary disease Dosage Initial - 500 mg two to three times/day with food. Maintenance - 0.5 to 1.5 gm/day Monitoring Baseline During Therapy Discontinue therapy if - Full blood count (FBC), liver function tests, urea & electrolytes, urinalysis. - FBC's weekly for the first month, then every 2-4 weeks thereafter (A drop of 1-2 gm/dl of haemoglobin is expected, as well as a rise in MCV). Periodic estimations of the renal and liver function tests. - Haemoglobin falls by 3 gm/dl or more; White cell < 5000; platelet count < 100,000/mm3; No response after 8 weeks; Concurrent infection. Adverse Effects Hydroxyurea is usually well tolerated. Older patients are more prone to side effects: Hemopoetic System - this is the main limiting adverse effect, but irreversible bone marrow suppression has not been reported with above doses Gastrointestinal - nausea and vomiting, occasionally mild hepatitis but no irreversible hepatic damage or fibrosis Teratogenicity - seen in animal models. Females of reproductive age will require adequate contraception Cutaneous - hyperpigmentation especially in sun-exposed areas; transient alopecia Neoplasia - rarely, second tumours with long term use. v. Cyclosporin A The efficacy of Cyclosporin A (CyA) in psoriasis is well established with clearance rates of over 90%. Provided that strict guidelines are followed using dermatologic doses (< 5 mg/kg/day) it has been used with relative safety as monotherapy for up to 2 years. However, long-term safety is still a concern especially with regards to nephrotoxicity and neoplasia. It should only be used by dermatologists with expertise in its use. Careful monitoring is mandatory, preferably in consultation with an experienced nephrologist. As with most therapies, severe psoriasis recurs after cessation of therapy, often within 2 months. It can be used as a 'crisis buster' for very inflammatory disease, and as part of rotational therapies in an effort to limit toxicities from the different systemic modalities. Indications Patients who have failed with: topical treatment ultraviolet radiation (UVL) treatment systemic treatment Contraindications Patients with: concomitant therapy with nephrotoxic or cytotoxic agents concomitant immunosuppressive or radiation (UVB and PUVA) therapy previous or concomitant malignancies infections of any type primary or secondary immunodeficiency severe organ dysfunction drug or alcohol abuse abnormal renal function uncontrolled hypertension poor compliance history Dosimetry guidelines Induction base : The starting dose should be 3 to 4 mg/kg/body weight/day in one single dose or two divided doses. If there is no improvement within one month the dose can be increased, but not exceeding 5 mg/kg/day. Maintenance Phase : With good improvement the dose can be lowered in steps of 0.5 - 1 mg/kg to the minimum maintenance dose, often 2.5 - 3 mg/kg/day. The duration of treatment should not be more than 2 years. Discontinue if there is poor response to CyA at doses of 5 mg/kg/day within 6 weeks. In general, patients who go into remission with lower CyA doses eg. 2.5 mg/kg/day (good responders) have better control whilst on maintenance. Those requiring higher induction doses, up to 5 mg/kg/day, (poorer responders) are more difficult to maintain on lower maintenance doses. Side Effects The major adverse effects are nephrotoxicity, hypertension, second tumours, hyperlipidemia and the minor ones are tremor, hypertrichosis, gingival hyperplasia and nausea. Monitoring The major adverse effects are nephrotoxicity, hypertension, second tumours, hyperlipidemia; and the minor ones are tremor, hypertrichosis, gingival hyperplasia and nausea. Baseline 12-hour fasting creatinine (3 separate occasions) 12-hour fasting lipids serum bilirubin liver enzymes serum potassium serum magnesium serum uric acid urinary protein Glomerular filtration rate (GFR) - ideally this should be done as serum creatinine is an unreliable indicator of decreased renal function. First 3 months: every 2 weeks serum creatinine blood pressure Subsequently: monthly serum creatinine blood pressure Periodically liver enzymes serum electrolytes, uric acid, lipids If serum creatinine rises beyond 30% of baseline level, CyA dosage should be reduced for one month and continued if it stays below this level, otherwise CyA should be discontinued. Present experience suggests that even dermatologic doses of CyA can produce morphologic changes on renal biopsy and reduced GFR. These nephrotoxic effects are correlated with dose and duration of therapy. Fortunately, the renal abnormalities are generally not progressive after CyA withdrawal and are at least partially reversible although not in all cases. If hypertension develops (diastolic > 95 mm) it should be treated with calcium antagonists such as nifedipine or isradipine but not diltiazem or verapamil (interference with CyA blood) Diuretics should not be used. Withdraw CyA if hypertension cannot be controlled with these measures. Drug interactions with CyA Care should be taken with the following medications: Nephrotoxic drugs - aminoglycosides, amphotericin B, ciprofloxacin, trimethoprim Non-steroidal anti-inflammatory drugs - potentiates adverse effects on renal function. Lovastatin and colchicines - increased risk of muscular toxicity. Agents increasing blood CyA levels - ketoconazole, erythromycin, doxycycline, oral contraceptives, some calcium channel blockers (diltiazem, nicardipine, verapamil) Agents decreasing blood CyA levels - phenobarbitone, phenytoin, carbamazepine, rifampicin. vi. Systemic Corticosteroids Systemic corticosteroids are not used routinely because it may precipitate erythrodermic or generalised pustular psoriasis, or very unstable psoriasis on withdrawal. Therefore it should only be used by dermatologists if absolutely necessary. Indications It is indicated only for these 3 rare and specific conditions: Persistent, or otherwise uncontrollable, erythrodenna causing metabolic complications. Generalised pustular psoriasis of Von Zumbusch type if other drugs are contraindicated or ineffective (including impetigo gestationis - a form of pustular psoriasis in pregnancy). Hyperacute psoriatic polyarthritis that threatens irreversible joint damage. Systemic corticosteroids are used for a short period only so as to allow the slower systemic drugs e.g. methotrexate or retinoids started at the same time to work. Dosage Start with high dose oral steroids l mg/kg per day and tail off slowly. Monitoring Blood sugar, electrolytes Blood pressure, peptic ulcer disease Side Effects This can be divided into 2 categories - those resulting from: Withdrawal Acute adrenal insufficiency Pseudotumour cerebri with papilloedema - rare Precipitate pustular or erythrodermic psoriasis And those from continued use of large doses Hypothalamic-pituitary-adrenal axis suppression Fluid and electrolyte disturbances - hypokalaemic alkalosis and oedema Hyperglycaemia and glycosuria Increased susceptibility to infections including tuberculosis and candidiasis Peptic ulcer Osteoporosis and vertebral compression fractures Proximal myopathy Behavioral disturbances - nervousness, insomnia, change in mood or psyche, manic-depressive psychosis or schizophrenia Posterior subcapsular cataracts Cushing's syndrome 2.7.4 Combination Therapy The rationale for combination therapy is to try to reduce the side effect profile of individual treatments and to improve efficacy. Some examples of useful combination therapy are: i. Retinoids + PUVA (RePUVA) Reduces total UVA dose and number of treatments for clearance with lower risks of UVL-induced carcinogenesis. ii. PUVA-UVB (ReUVB) As with RePUVA, better clearance with fewer treatments and less cumulative UVB. iii. Calcipotriol + PUVA (D-PUVA) As above, less treatments and cumulative UVA dose for clearance. iv. PUVA + Methotrexate Rapid clearance possible even with recalcitrant disease. v. Calcipotriol + UVB No significant improvement seen in Kragballe's study although later as yet unpublished data suggests synergistic effects as with RePUVA. Photosensitive reactions can occur. vi. Calcipotriol + Cyclosporin A Clearance in 50% of patients with very low dose cyclosporin (2 mg/kg/day) compared to 12% clearance with cyclosporin 2 mg/kg/day alone. 2.8 AMBULATORY TREATMENT (DAY CARE) 2.8.1 Introduction Ambulatory treatment centres provide specialized combination therapies such as Goeckerman and Ingram, in addition to standard office treatments for psoriasis. Traditional treatment plans may vary depending on the individual centre and they allow for extended periods of care under the supervision of a physician. The basic components of each treatment are listed. Approximately 20% of psoriasis patients require more than topical therapy to improve their skin. Phototherapy with UVB or PUVA (Psoralens plus Ultraviolet A) is often the next recommended choice of treatment. Proper patient selection and pre-treatment assessment, good dosimetry and protocol and regular monitoring will result in good therapeutic index. 2.8.2 UVB Phototherapy (Ultraviolet B Irradiation) UVB is used in psoriasis usually in the Goeckerman or Ingram's Regimes, i.e. in combination with either coal tar or anthralin. UVB alone is used regularly only in guttate psoriasis. UVB wavelength is in sunburn range of 300 - 320 nm. Goeckerman Regime : Coal tar bath UVB exposure (minimal erythemogenic doses) Coal tar application Ingram Regime : Coal tar bath UVB exposure (minimal erythemogenic doses) Application of dithranol in Lassar's paste Indication for Treatment : 1. Failed topical treatment alone 2. Chronic stable plaque psoriasis 3. Guttate psoriasis 2.8.3 Photochemotherapy (PUVA) Photochemotherapy combines the photosensitising drug methoxsalen with Ultraviolet A Phototherapy (i.e wavelength range of 320 - 400 nm) The drug is given in a dosage of 0.6 mg/kg of body weight, 2 hours before UVA exposure. UV protective eyeglasses must be worn after ingestion of drug for 12 hours The dosage of UVA is determined by the patient's skin type (i.e. the sensitivity of the skin to UVA radiation) or preferably by prior determination of the minimum phototoxic dose (MPD) Treatments are usually given 3 times weekly 85% of patients go into remission after 20 - 30 treatments. Total duration of treatment may take about 6 - 10 weeks Relapse may occur within 6 to 12 months Maintenance treatment may be required for frequent relapses Benefits of PUVA - High likelihood of response - Absence of need for topical except perhaps emollients - Simplicity of therapeutic schedules PUVA Contraindications Absolute Xeroderma pigmentosum Gorlin's syndrome Hereditary dysplastic naevus syndrome Systemic lupus erythematosus Dermatomyositis Trichothiodysdrophy Bloom's syndrome Cockayne's syndrome Previous malignant melanoma Relative Major Age less than 10 years* Previous or current non-melanoma skin cancer Previous exposure to arsenic or ionizing radiation Current premalignant skin lesions Concomitant immunosuppressive therapy Pregnancy Porphyria Minor Age less than 16 years* Cataracts + Bullous pemphigoid Pemphigus Previous or concomitant treatment with methotrexate Significant hepatic dysfunction + Previous internal malignancy * A lower age limit may be acceptable where topical psoralen is used + Oral psoralen only Problems with PUVA Side effects - short term (nausea, burning, dryness, pruritus) - long term (increased risk of photodamage wrinkling, irregular pigmentation, lentigenes, benign keratosis, premalignant keratosis and skin cancers) Inconvenience - need to visit clinic 3 times/week - need to wear UV protective eyeglasses for up to 12 hours after ingestion of psoralen - must protect from further sun exposure during day of treatment. Comments: The therapeutic index of this treatment is high if the cumulative dose of UVA is less than that likely to cause skin cancer or severe photodamage. As a general guide, it is recommended that one should receive not more than 200 treatments or not more than 1000 – 1500 joules/cm2 cumulative dose of UVA. A careful and permanent record of the total number of treatment sessions and cumulative UVA dosage is essential, and supervision by dermatologists with special PUVA experience is desirable. In addition, annual review of patients, when possible up to 10 years is advisable to check for premalignant and malignant skin cancers. 2.8.4. Combination Regimes with Phototherapy PUVA may be combined with concomittant use of retinoids and methotrexate PUVA may also be used in conjunction with topical agents such as calcipotriol and topical steroids The potential advantage includes reduction in number of PUVA sessions and/or cumulative UVA dosage and clearance of psoriasis in patients unresponsive to PUVA alone. This may reduce the long term skin cancer risk of PUVA therapy Combination with retinoids may be considered in patients who have reached 50 treatment sessions or relapsed within 6 months of previous PUVA therapy Acitretin dosage of 0.25-0.5 mg/kg is recommended If associated prolonged risk of teratogenicity is unacceptable, isotretinoin may be substituted due to its shorter period of teratogenicity risk upon cessation of treatment Retinoids may be started together with PUVA or one week prior to PUVA PUVA and methotrexate are effective but is recommended only for very severe psoriasis due to possibility of further increasing skin cancer risk Concomittant use of topical steroids, although producing more rapid clearance is associated with earlier relapse PUVA and cyclosporin appear to confer little therapeutic advantage and skin cancer risk is likely to be potentiated PUVA and calcipotriol appears superior to PUVA. The duration of treatment, number of radiations and cumulative UVA dose has been known to reduce 2.8.5 Hand and Foot PUVA Local PUVA using oral or topical psoralen delivery is a useful and effective second line treatment for hand and foot psoriasis or palmoplantar psoriasis 2.8.6 Bath PUVA Bath PUVA is effective and an increasingly popular alternative to oral PUVA. Advantages include shorter irradiation time due to greater photosensitization, lack of GIT, nephrotoxic or other systemic adverse effects. Data concerning ocular risks with bath PUVA are still lacking, hence it is still recommended to wear eye protection for at least 12 hours after treatment. Requires closer patient supervision. 2.8.7 Summary of Systemic and Physical Therapy Table II - Systemic, UVB/UVA Phototherapy, and Photochemotherapy (PUVA) Phototherapy UVB Photochemotherapy (PUVA) Methotrexate Hydroxyurea Retinoids Effectiveness and Remission +++ ++++ ++++ ++ +++ Patient Monitoring ++ ++ + I,II ++ II + II Clinical Indications All forms G All forms G All forms All forms All forms Comments d,e,f,g a,b,c,d,e,f a,b,c,e a,b,c,e a,b,c,e Effectiveness and Remission : + ++ +++ ++++ Partial clearing Partial clearing and short remission (1 month) Total clearing and short remission (1 month) Total clearing and long remission (months to years) Patient Monitoring (patient and laboratory) : + ++ I II weekly to monthly monthly to every 6 months Roenigk HH Jr, Auerbach R, Maibach HI, et al. Methotrexate in psoriasis; revised guidelines, J Am Acad Dermatol 1988; 19: 145-56 Physicians’ Desk Reference – thorough familiarization needed Clinical Indications : G Reduce frequency when active, inflammatory phase is over Comments : a. b. c. d. e. f. Should not be used in children except rare circumstances Contraindicated in pregnant patients Should be used with caution in female patients of childbearing potential Recommended periodic evaluation for skin cancer May be combined with other treatment modalities Unsupervised UV light, including use of tanning booths is inappropriate. Likewise home phototherapy should only be used with great caution under the direction of the patient's physician. PUVA (Photochemotherapy) should not be attempted in the home unless under direct physician supervision UVB alone more effective than UVA alone g. 2.8.8 Additional services may include the following: a) b) c) d) Specialized scalp treatments Nail treatment Patient education sessions Psychological support groups 2.9 HOSPITALIZATION (IN-PATIENT CARE) 2.9.1 Indications for hospitalization Some patients may require inpatient treatment. The criteria for admission may include the following: i. Acute erythrodermic psoriasis ii. Acute generalised pustular psoriasis iii. Hyperacute psoriatic polyarthritis that threatens irreversible joint damage iv. Psoriasis not controlled with outpatient treatment v. Complications from previous treatment such as topical, systemic, phototherapy or photochemotheraphy, not controlled with outpatient therapy vi. Psoriasis that is physically or emotionally disabling enough to limit activities of daily living 2.9.2 Adjunctive Therapies i. Antihistamines/antibiotics ii. Occlusive dressings and/or suits iii. Wet dressings iv. Antifungal creams/antibacterial creams v. Specialized baths vi. Psychiatric counselling vii. Others 3. PATIENT EDUCATION This is an important part of any treatment plan and should include information on the disease and the effects that trauma, alcohol, infection and stress may have on psoriasis. Expectations of the results of therapy and interactions that are possible between phototherapy and drugs and the disease are to be considered part of patient education. It is very important for patients to be partners in treatment. At diagnosis the following should be provided: i. ii. iii. Booklet on psoriasis Counselling to patients and or relatives Patient taught on side effects, possible provoking factors and warned on harmful treatments e.g. colonic washout. 4. USE OF GUIDELINES TO DERIVE AUDIT MEASURES Diagnosis, assessment and initial management (1) Is the diagnosis in clinical doubt? (2) Is the patient receiving any treatment likely to precipitate or aggravate psoriasis? (3) What in the patient's view is the most distressing or disabling aspect of psoriasis? (4) Has the nature of psoriasis been explained to the patient? (5) Have the treatment options been discussed in the light of (4)? (6) Has the patient had an adequately documented 8 - 12 week trial of topical treatment? (7) If topical steroids are included in the regimen is the potency and quantity used appropriate? (8) Is referral to a consultant dermatologist appropriate? Phototherapy (9) Has the minimal erythema dose been estimated? (10) Is the patient receiving an appropriate treatment regimen? Systemic treatment (11) Are the indications to move to systemic treatment appropriate? (12) Have the options and side effects of possible regimens been fully discussed with the patient? (13) If appropriate, has the need for contraception been fully discussed and appropriate provision arranged if required? (14) Has the patient been given a psoriasis systemic treatment card? (15) If yes, does the patient show this card to the general practitioner when receiving prescriptions for unrelated problems? Photochemotherapy (PUVA) (16) Has the patient been given advice about appropriate eye protection? (17) Have men been given advice about screening genitalia during PUVA? (18) Has the minimal phototoxic dose been estimated? (19) Is there a clear record of individual treatment and cumulative Ultraviolet A dosage? (20) Is the patient receiving an appropriate review and follow up programme? Methotrexate (21) Have pretreatment investigations excluded haemotological, biochemical and hepatic contraindications? (22) Is the patient taking any drug known to have an adverse interaction with methotrexate? (23) Are the arrangements for regular review and haemotological and biochemical monitoring appropriate? Yes/No Yes(What)/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Yes/No Acitretin (24) For women has the need for prolonged contraception (two years) after withdrawal of drug been fully discussed? (25) Is the dosage regimen appropriate? (26) Are review arrangements adequate? Yes/No Yes/No Yes/No Cyclosporin (27) Has the serum creatinine concentration been measured? (28) Have potential drug interactions been considered? (29) Is the current dose of cyclosporin appropriate? Yes/No Yes/No Yes/No 5. SUPPORTING EVIDENCE Refer to list of references 6. DISCLAIMER Adherence to these guidelines will not ensure successful treatment in every situation. Further, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgement regarding the propriety of any specific procedure must be made by the physician in the light of all the circumstances presented by the individual patient. Other modalities of treatment used by patients such as traditional medicaments, herbs and nutritional supplements lack concrete scientific proof of their effectiveness. 7. LIST OF REFERENCES GENERAL 1. 2. 3. 4. 5. REA Williams. Guidelines for management of patients with psoriasis. Regular review. Br Med J 1991; 303, 829-835. Louise S Goodman & Alfred Gilman. The Pharmacological Basis of Therapeutics 1990; 8th edition, 1431-1462. Treatment of Psoriasis. New England Journal of Medicine 1995; 332(9): 582-588. British Photodermatology Group Guidelines for PUVA. Br J Dermatology (1994); 130, 246-255. Guidelines of care for psoriasis. Journal of the American Academy of Dermatology (1993); 28: 632-7 TOPICAL AND INTRALESIONAL THERAPY Tar 1. 2. 3. 4. 5. 6. 7. 8. Chapman RS, Finn OA, An assessment of high and low temperature tars in psoriasis. Br J Dermatol 1976: 94: 71-4. Finlay AY, Young DW. Short contact coal tar therapy for psoriasis. Clin Exp Dermatol 1985; 10: 371-4. Lavker RN, Grove GL, Kligman Am. The atrophogenic effect of crude coal tar on human epidermis. Br J Dermatol 1981; 105: 77-82. Lin AN, Moses K Tar revisited. Int J Dermatol 1985: 24: 216-8. Lowe NJ, Wortzman MS, Breeding J, et al. Coal tar phototheraphy for psoriasis reevaluated: erythemogenic versus suberythemogenic ultraviolet with tar extract in oil and crude coal tar. J Am Acad Dermatol 1983; 8: 781-9. Petrozzi JW, Barton JO, Kaidbey KH, et al. Updating the Goeckerman regimen for psoriasis. Br J Dermatol 1978; 98: 437-44. Stern RS, Gange RW, Parrish JA, et al. Contribution of topical tar oil to ultraviolet B phototherapy for psoriasis. J Am Acad Dermatol 1986; 14: 742-7. Young E. The external treatment of psoriasis: a controlled investigation of the effects of coal tar. Br J Dermatol 1970; 82: 510-5. Anthralin 1. Abel EA, O'Connel BM, Farber EM. Psoriasis day care centre at Stanford: part-time and full-time programmes. Int J Dermatol 1987; 26: 500-7. 2. Ashton RE, Andre P, Lowe NJ, et al. Anthralin: historical and current perspectives. J Am Acad Dermatol 1983; 9: 17392. 3. Ingram JT. The approach to psoriasis. Br Med J 1953; 591-4. 4. Lowe NJ, Ashton RE, Koudsi H, et al, Anthralin for psoriasis: short-contact anthralin therapy compared with topical steroids and conventional anthralin. J Am Acad Dermatol 1984; 10: 69-72. 5. Ryatt KS, Statham BN, Rowell NR. Short-contact modification of the Ingram regimen. Br J Dermatol 1984; 111: 455-9. Calcipotriol 1. Murdoch D et al. Calcipotriol - A Review of its Pharmacological Properties and Therapeutic Use in Psoriasis Vulgaris 2. Jones JB et al. A multi-centre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol (1992), 127, 266-271 3. Cork M. Economic considerations in the treatment of psoriasis. Dermatol Pract 1993; 1(3): 16-20 4. Tham SN et al. A comparative study of calcipotriol ointment and tar in chronic plaque psoriasis. Br J Dermatol 1994; 131, 673-677 5. Frappaz A et al. Calcipotriol in combination with PUVA: A randomised double blind placebo study in severe psoriasis. Eur J Dermatol 1993; 3: 351-4 6. Speight EL et al. Calcipotriol improves the response of psoriasis to PUVA. Br J Dermatol 1993; Suppl 42: 32-33 7. Poyner T et al. Long-term treatment of chronic plaque psoriasis with calcipotriol. Journal of Dermatological Treatment (1993), 4: 173-177 8. Ramsay CA et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology (1994), 189: 260-264 9. Highton A et al. Calcipotriene ointment 0.005% for psoriasis: A safety and efficacy study. J Am Acad Dermatol 1995; 32: 67-72 10. Grossman RM et al. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: Results of a multi-centre placebo controlled study. J Am Acad Dermatol 1994; 31: 68-74 11. Kragballe K, Gjersten BT, De Hoop D, Karlsmark T, Van De Kerkhof PCM, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 337: 193-196. 12. Cunliffe WJ, Berth-Jones J, Claudy A et al. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26: 736-43. Keratolytics 1. Davies MG, Briffa DV, Greeves MW. Systemic toxicity from topically applied salicylic acid. Br Med J 1979; 1: 661. 2. Going SM, Guyer BM, Jarvie DR, et al. Salicylic acid gel for scalp psoriasis. Clin Exp Dermatol 1986; 11: 260-2. 3. Goldsmith LA. Salicylic acid. Int J Dermatol 1979; 18: 32-6. 4. Hulsebosch HJ, Ponec-Waelsch M. The interaction of anthralin, salicylic acid and zinc oxide in pasters. Dermatologica 1972; 144: 287-93. 5. Van Scott EJ, Yu RJ. Alpha hydroxy acids: procedures for use in clinical practice. Cutis 1989; 43: 222-8. 6. Van Scott EJ, Yu RJ. Control of keratinization with L-hydroxy acid and related compounds. Arch Dermatol 1974; 110: 586-90. Topical and Intralesional Corticosteroids 1. Abell E. Treatment of psoriatic nail dystrophy. Br J Dermatol 1972; 86: 79-82. 2. 3. 4. 5. 6. 7. du Vivier A, Stoughton RB. Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol 1975; 111: 581-3. Katz HI, Hien HT, Prawer SE, et al. Superpotent topical steroid treatment of psoriasis vulgaris: clinical efficacy and adrenal function. J Am Acad Dermatol 1987; 16: 804-11. Lee SS. Topical steroids (review). Int J Dermatol 1981; 20: 632-41. Nilsson JE, Gip LJ. Systemic effects of local treatment with high doses of corticosteroids in psoriatics. Acta Derm Venereol (Stockh) 1979; 59: 245-8. Tan PL, Barnett GL, Flowers FP, et al. Current topical corticosteroid preparations. J Am Acad Dermatol 1986; 14: 79-93. Vickers CFH. Topical corticosteroids. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, eds. Dermatology in general medicine. 3rd Edition, New York: Mcgraw-Hill, 1987: 2540-5. SYSTEMIC THERAPY Methotrexate 1. Ashton RE, Millward - Sadler GH, White JE. Complications in methotrexate treatment of psoriasis with particular reference to liver fibrosis. J Invest Dermatol 1982; 79: 229-32. 2. Dahl MGC. Methotrexate and the liver. Br J Dermatol 1969; 81: 465-7. 3. Hanno R, Gruber GG, Owen LG, et al. Methotrexate in psoriasis. J Am Acad Dermatol 1980; 2: 171-4. 4. Jolivet J, Cowan KH, Curt GA, et al. The pharmacology and clinical use of methotrexate. N Eng J Med 1983; 309: 1094104. 5. Reese LT, Grisham JW, Aach RD, et al. Effects of methotrexate on the liver in psoriasis. J Invest Dermatol 1974; 62: 597-602. 6. Roenigk HH, Auerbach R, Maibach HI, et al. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19: 145-56. 7. Weinstein GD. Methotrexate. Ann Intern Med 1977; 86: 199-204. 8. Zachariae H, Kragballe K, Sogaard H. Methotrexate - induced liver psoriasis. Br J Dermatol 180; 102: 407-12. Retinoids 1. Ellis CN, Hermann RC, Gorsulowsky DC, et al. Etretinate therapy reduces inpatient treatment of psoriasis. J Am Acad Dermatol 1987; 17: 787-91. 2. Ellis CN, Swanson NA, Grekin RC, et al. Etretinate therapy causes increase in lipid levels in patients with psoriasis. Arch Dermatol 1982; 118: 559-62. 3. Ellis CN, Voorhees JJ. Etretinate therapy. J Am Acad Dermatol 1987; 16: 267-91. 4. Goldfarb MT, Ellis CN, Gupta AK, et al. Acitretin improves psoriasis in a dose-dependent fashion. J Am Acad Dermatol 1988; 18: 655-62. 5. Goldfarb MT, Ellis CN, Voorhees JJ. Short-term and long term considerations in the management of psoriasis with retinoids. Dermatologica 1987; 175: 100-6. 6. Kaplan RP, Russell DH, Lowe NJ. Etretinate therapy for psoriasis: clinical responses, remission times, epidermal DNA and polyamine responses. J Am Acad Dermatol 1983; 8: 95-102. 7. Lowe NJ, Lazarus V, Matt L. Systemic retinoid therapy for psoriasis. J Am Acad Dermatol 1988; 19: 186-91. 8. Roenigk HH, Gibstine C, Glazer S, et al. Serial liver biopsies in psoriatic patients receiving long-term etretinate. Br J Dermatol 1985; 112: 77-81. 9. Silveman AK, Ellis CN, Voorhees JJ. Hypervitaminosis A syndrome: a paradigm of retinoid side effects. J Am Acad Dermatol 1987; 16: 1027-39. 10. White SI, Marks JM, Shuster S. Etretinate in pustular psoriasis of palms and soles. Br J Dermatol 1985; 113: 581-5. 11. Wolska H, Jablonska S, Bounameaux Y. Etretinate in severe psoriasis. J Am Acad Dermatol 1983; 9: 883-9. Salazopyrine/Sulphasalazine 1. Farr M et al. Sulphasalazine in psoriatic arthritis: double-blind placebo controlled study. Br J Rheumatol 1993; 29: 46-9 2. Fraser SM et al. Sulphasalazine in the management of psoriatic arthritis. Br J Rheumatol 1993; 32: 923-25. 3. Stroehmann L et al. Therapy of seronegative oligoarthritis with salazopyrine. Z Rheumatol 1987; 46: 79-82 4. Gupta AK et al. Sulfasalazine: A potential psoriasis therapy? J Am Acad Dermatol 1989; 20: 797-800. 5. Gupta AK et al. Sulfasalazine improves psoriasis: a double-blind analysia. J Am Acad Dermatol 1990; 126: 487-93. 6. Watkinson G. Sulfasalazine: a review of 40 years' experience. Drugs 1986; 32-1-11. Hydroxyurea 1. Boyd AS et al. Hydroxyurea therapy. J Am Acad Dermatol 1991; 25: 518-24. 2. Layton AM et al. Hydroxyurea in the management of therapy resistance psoriasis. Br J Dermatol 1989; 121: 647-53. 3. Leavell UW, Mersack IP, Smith C. Survey of the treatment of psoriasis with hydroxyurea. Arch Dermatol 1973; 107: 467. 4. McDonald CJ. Chemotherapy of psoriasis. Int J Dermatol 1975; 14: 563-74. 5. Moschella SL. Chemotherapy of psoriasis; ten years of experience. Int J Dermatol 1976; 15: 373-8. 6. Moschella SL, Greenwald MA. Psoriasis with hydroxyurea: an eighteen-month study of sixty patients. Arch Dermatol 1973; 107: 363-8. 7. Roe LD, Wilson JW, Hydroxyurea therapy. Arch Dermatol 1973; 108: 426-7. 8. Rosten M. Hydroxyurea: a new antimetabolite in the treatment of psoriasis. Br J Dermatol 1971; 85: 177-81. Cyclosporin 1. Marks JM. Cyclosporin A - treatment for severe psoriasis. Br J Dermatol 1986; 115: 745-746. 2. Ellis CN et al. Cyclosporin improved psoriasis in a double-blind study. JAMA 1986; 256: 3110-16. 3. Koo J. Cyclosporin in Dermatology - fears and opportunities. Arch Dermatol 1995; 131: 842-3. 4. Mihatsch MJ & Wolff K. Consensus Conference on Cyclosporin A for psoriasis: February 1994. Br J Dermatol 1992; 126: 621-23. 5. 6. 7. 8. 9. 10. Laburte C et al. Efficacy and safety of oral Cyclosporin A for long term treatment of chronic severe psoriasis. Br J Dermatol 1994; 130: 366-75. Gilbert SC et al. Cyclosporin therapy for psoriasis: serum creatinine measurements are an unreliable predictor of decreased renal function. J Am Acad Dermatol 1989; 21: 470-4. Zachariae H et al. Morphologic renal changes during Cyclosporin treatment of psoriasis. J Am Acad Dermatol 1992; 26: 415-9. Powles AV et al. Renal function and biopsy findings after 5 years' treatment with low dose Cyclosporin for psoriasis. Br J Dermatol 1993; 128: 159-165. Korstanje M et al. Sustained renal function loss in psoriasis patients after withdrawal of low-dose Cyclosporin therapy. Br J Dermatol 1992; 127: 501-4. Young EW, Ellis CN, Messana JM et al. A prospective study of renal structure and function in patients treated with Cyclosporin. Kidney Int. 1994 46(4): 1216-22. Systemic Corticosteroids 1. Fergusson AG, Dewar WA. Observations on steroid therapy in psoriasis. Br J Dermatol 1957; 69: 57-60. 2. Goodwin P. The effect of corticosteroids on cell turnover in the psoriatic patient: a review. Br J Dermatol 1976; 94: 95100. 3. Mikhail GR, Livingood CS, Mellinger RC, et al. Effect of long-acting parenteral corticosteroids on adrenal function. Arch Dermatol 1969; 100: 263-8. 4. Storrs FJ. Use and abuse of systemic corticosteroid therapy. J Am Acad Dermatol 1979; 1: 95-105. Antimicrobials 1. Rosenberg EW, Noah PW, Zanolli MD, et al. Use of rifampicin with penicillin and erythromycin in the treatment of psoriasis. J Am Acad Dermatol 1986; 14: 701-4. 2. Rosenberg EW, Skinner RB, Noah PW. Antimicrobial treatment of psoriasis. In Roenigk HH, Maibach HI, eds. Psoriasis. 2nd Edition – revised and expanded. New York: Marcel Dekker, 1991; 815-22. 3. Tefler NR, Chalmers RJG, Whale K, et al. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol 1992; 128: 39-42. 4. Whyte HS, Baughman RD. Acute guttate psoriasis and streptococcal infection. Arch Dermatol 1964; 89: 350-6. PHYSICAL THERAPY UVB Phototherapy 1. Adrian RM, Parrish JA, Momtaz TK, et al. Outpatient phototherapy for psoriasis. Arch Dermatol 1981; 117: 623-6. 2. Diffey BL, Farr PM. An appraisal of ultraviolet lamps used for the phototherapy of psoriasis Br J Dermatol 1987; 117: 49-56. 3. Levine MJ, Parrish JA. Outpatient phototherapy of psoriasis. Arch Dermatol 1980; 116: 552-4. 4. Parrish JA. Photobiologic principles of phototherapy and photochemotherapy of psoriasis. Pharmacol Ther 1981; 15: 439-46. 5. Parrish JA. Ultraviolet phototherapy of psoriasis. Pharmacol Ther 1981; 15: 313-20. 6. Stern RS, Armstrong RB, Anderson TF, et al. Effect of continued ultraviolet B phototherapy on the duration of remission of psoriasis: a randomised study. J Am Acad Dermatol 1986; 15: 546-52. Photochemotherapy (PUVA) 1. Farber EM, Abel EA, Cox AJ. Long-term risks of psoralen and UV-A therapy for psoriasis. Arch Dermatol 1983; 119: 426-31. 2. Lowe NJ, Weingarten D, Bourget T, et al. PUVA therapy for psoriasis: comparison of oral and bath-water delivery of 8methoxypsoralen. J Am Acad Dermatol 1986; 14: 754-60. 3. McEvoy MT, Stern RS. Psoralens and related compounds in the treatment of psoriasis. Pharmacol Ther 1987; 34: 75-97. 4. Melksi J, Tanenbaum L, Parrish JA, et al. Oral methoxsalen photochemotherapy for treatment of psoriasis; a cooperative clinical trial. J Invest Dermatol 1977; 68: 328-35. 5. Morison WL. PUVA combination therapy. Photodermatology 1985; 2: 229-36. 6. Parrish JA, Fitzpatrick TB, Tanembaum L, et al. Photochemotherapy of psoriasis with oral methoxsalen and long-wave ultraviolet light. N Eng J Med 1974; 291: 1207-11. 7. Parrish JA, Levine MJ, Fitzpatrick TB. Oral Methoxsalen photochemotherapy of psoriasis and mycosis fungoides. Int J Dermatol 1980; 19: 379-86. 8. Stern RS, Thibodeau LA, Kleinerman RA, et al. Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N Eng J Med 1979; 300: 809-13. Combination Treatment 1. Tanew A et al. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomised, doubleblind comparison study. J Am Acad Dermatol 1991; 125: 682-4. 2. Meigel W. Acetretin and PUVA or UVB. In Retinoids: 10 Years On. Saurat JH (ed): Basel, Karger 1991, 214-27. 3. Saurat JH et al. Randomised double-blind multicenter study comparing Acitretin-PUVA, Etretinate-PUVA and PlaceboPUVA in the treatment of severe psoriasis. Dermatologica 1988; 177: 218-24. 4. Parker S et al. A randomised double-blind comparison of PUVA-Etretinate and PUVA-Placebo in the treatment of chronic plaque psoriasis. Br J Dermatol 1984; 110: 215-20. 5. Lowe NJ et al. Acitretin plus UVB therapy for psoriasis. A Am Acad Dermatol 1991; 24: 591-4. 6. Ruzicka T et al. Efficiency of acitretin in combination with UVB in the treatment of severe psoriasis. Arch Dermatol 1990; 126: 482-6. 7. Iest J et al. 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