Alopecia areata

Age from 2 years onwards
Have I got the right guidance?
This guidance covers the management of children and adults presenting with alopecia areata.
This guidance does not cover in detail the management of alopecia totalis or alopecia universalis.
There is separate PRODIGY guidance on Fungal (dermatophyte) skin infections and Seborrhoeic dermatitis.
The target audience for this guidance comprises healthcare professionals working within the NHS in England, who are providing first-contact or primary health care. This guidance is intended for use by generalist practitioners, rather than by practitioners with a Special Interest in Dermatology. Patient information leaflets (PILs) are intended to be printed and given to people with this condition. The Shared decision making section is designed to provide a focus for discussion during the consultation about the treatment options.

Changes
Last revised in May 2006
October-December 2005 - written. Validated in March 2006 and issued in May 2006.
Goals and outcome measures

Goals
• To diagnose alopecia areata correctly
• To ensure affected individuals understand the condition and the management options
Outcome measures
• Extent of hair regrowth

Background information
What is it?
• Alopecia areata is a chronic inflammatory condition which affects the hair follicles (and which can also affect the nails). It leads to partial hair loss that most commonly involves the scalp, eyebrows, eyelashes, or beard.
• Hair loss can be categorized by extent or pattern [Madani and Shapiro, 2000]:
o Patchy, limited hair loss is the most common presentation [Madani and Shapiro, 2000].
o Over 50% hair loss is generally considered as 'extensive' [Bolduc and Shapiro, 2001].
o Diffuse hair loss occurs occasionally but this is usually caused by other conditions.
o Alopecia totalis is total loss of scalp hair.
o Alopecia universalis is total loss of body hair.
1
• Nail changes are estimated to affect 10-30% of people with alopecia areata, and may be present before, during, or after an episode of hair loss associated with alopecia areata [Papadopoulos et al, 2000; MacDonald Hull et al, 2003].
• Alopecia areata is non-scarring and the destruction of hair follicles is not permanent.
• The exact cause is unknown but the general consensus is that alopecia areata is a manifestation of a T-cell immune-mediated response in genetically predisposed individuals.
• A positive family history is found in up to 25% people with alopecia areata [Mitchell and Krull, 1984; Madani and Shapiro, 2000; BAD, 2004].
• Alopecia areata has been found to be associated with atopy and autoimmune diseases such as pernicious anaemia, thyroid disease (myxoedema), and vitiligo [Mitchell and Krull, 1984; Messenger, 2004].
• Environmental factors, including viral infection and stress, have also been suggested as possible causes but there is only anecdotal evidence to support these claims [Messenger, 2004].

How common is it?
• Alopecia areata is a relatively common condition and it has been estimated that it affects 0.15% of the UK population [Dobbins et al, 2003]. Other national and international estimates of the incidence of alopecia areata vary between 0.05% and 2% [Seiter et al, 2001; BAD, 2004; Messenger, 2004].
• The exact incidence and prevalence are unknown because people with mild disease and people with non-scalp involvement might never go to their doctor [Mitchell and Krull, 1984; Drake et al, 1992].
• Alopecia areata accounts for 2% of new dermatology outpatient clinic appointments in the UK and US [Fiedler and Alaiti, 1996; Madani and Shapiro, 2000; Dobbins et al, 2003].
• Alopecia areata can present at any age but children and adolescents are most commonly affected, with 60% of people developing their first patch before 20 years of age and the peak incidence occurring between 15 and 29 years of age [Madani and Shapiro, 2000; Bolduc and Shapiro, 2001]. People under the age of 16 years account for 20% of cases of alopecia areata [Sharma and Muralidhar, 1998].
• Alopecia areata affects both sexes equally and it is not known to show any racial preponderance [Dobbins et al, 2003; MacDonald Hull et al, 2003].

How do I know my patient has it?
History
• Typically, someone presenting with alopecia areata will report:
o An abrupt onset of patchy hair loss affecting any hair-bearing area (most commonly the scalp, eyebrows, eyelashes, or beard).
o Single or multiple patches of hair loss.
• In the area of hair loss some people will have experienced associated itching, burning, or tenderness.
• Factors which can help to confirm a diagnosis of alopecia areata include:
o Age of the patient
o Previous episodes of hair loss
o Family history
o Presence of atopy/autoimmune disease
• Factors which might suggest an alternative diagnosis include:
o Medical history (including any illness or infection within the past 6 months)
o Drug history
o Hair care routine
2
o Diet
Examination
• Signs of alopecia areata (which might not always be present) [MacDonald Hull et al, 2003] include:
o Round, well-circumscribed, bald, and smooth patches on the scalp or within facial hair.
o Normal-coloured or slightly red skin without scarring (follicular markings are still present).
o Exclamation hairs (short broken hairs which taper proximally) might be seen around the the margin of the patches during active disease [Bertolino, 2000].
o Nail changes may occur - pitting, onycholysis (loosening), splitting, beau lines (transverse grooves), koilonychia (concave outer surface), or leukonychia (white patches under the nails) [Drake et al, 1992].
o Scaling may be present but its presence should raise the possibility of an alternative diagnosis (skin scrapings should be taken to exclude a fungal infection such as tinea capitis).
• To identify if there is active hair shedding, the 'pull test' can be performed at the periphery of a lesion. This involves grasping about 60 hairs between the finger and thumb and tugging gently but firmly. This test is positive (confirming active shedding) when 2-10 hairs are obtained [Shapiro and Madani, 1999; Madani and Shapiro, 2000; University of Texas at Austin, 2004].

Investigations
• Investigations are unnecessary in the majority of cases of alopecia areata [MacDonald Hull et al, 2003].
• Routine screening for possible associated autoimmune disease is not justified. However, if clinical signs or symptoms are suggestive of other autoimmune disorders, then further investigations may be appropriate (e.g. diffuse hair loss may be caused by hypothyroidism).
• If the diagnosis is in doubt, investigations that can be performed in either primary or secondary care include:
o Skin scrapings and fungal culture
o Systemic lupus erythematosus and syphilis serology
• Skin biopsies might be carried out in secondary care.

What else might it be?
• The most common differential diagnoses for patchy alopecia areata are tinea capitis and trichotillomania.
o Tinea capitis - a contagious fungal scalp infection mostly found in children (aged 4-14 years), who present with patchy hair loss and often complain of itch and scaling [University of Texas at Austin, 2004]. On examination, patches are irregular with erythema, scaling, and broken hairs, but they do not have the exclamation hairs or nail changes characteristic of alopecia areata. A kerion (a painful, boggy, and inflamed nodule) may be present on the head.
o Trichotillomania - a psychiatric condition which can be associated with obsessive-compulsive disorder, in which people pull their own hair out but often deny it [University of Texas at Austin, 2004]. In children it is more common in boys, but in adolescence it is more common in girls. Hair loss is asymmetrical and has an unusual shape, with broken hairs across the bald patch which are not easily removed. Single or multiple areas can be affected, including eyebrows and eyelashes. There is minimal or no inflammation.
• Other possible causes to consider include:
3
o Androgenetic alopecia - there is a typical pattern of balding but shedding is not prominent and the pull test is negative.
o Scarring alopecia in its early stages [MacDonald Hull et al, 2003].
o Traction alopecia - hair loss secondary to hair styling techniques (e.g. tight braids, pony tails).
o Secondary syphilis - a moth-eaten, patchy hair loss is characteristic and appears 2-8 months after the primary syphilitic chancre-type lesions. Serology testing confirms the diagnosis.
o Systemic lupus erythematosus.
• Alopecia areata occasionally presents as diffuse hair loss. Many conditions can cause this but the main differential diagnoses are:
o Telogen effluvium - the most common form of diffuse alopecia. Generalized hair loss over the whole scalp occurs about 3 months after a significant event, such as physical or psychological stress [University of Texas at Austin, 2004]. Bitemporal recession is a common sign in women. Hair loss lasts for 3-6 months and then the hair regrows.
o Anagen effluvium (drug-induced) may mimic diffuse alopecia areata [MacDonald Hull et al, 2003].
o Female androgenic alopecia is the most common cause of diffuse hair loss in women.

Complications
• People with alopecia areata may suffer considerable psychological distress [MacDonald Hull et al, 2003], which can affect socializing and employment.
Prognosis
• Alopecia areata is an unpredictable disease with variable progression, and hair recovery may be complete, partial, or non-existent.
• The following stages of disease progression may be experienced:
o A single patch of hair loss which regrows in a few months, although hair loss may recur and most people have more than one episode of alopecia areata.
o Following the initial lesion, further patches can develop in the next 3-6 weeks; patches may become confluent if there is diffuse loss of other hair.
o There can be patches of regrowth at the same time as new patches are developing.
o When hair regrows it is initially fine and depigmented (white) before it returns to its original colour. Note: if regrowth of hair remains white it is important to consider vitiligo.
• In people with less than 40% or mild hair loss, if they receive no treatment, regrowth can be expected within in 1 year in up to 80% of people, as the condition is usually self-limiting [Bolduc and Shapiro, 2001; MacDonald Hull et al, 2003]. Therefore, the smaller the area of hair loss, the better the prognosis.
• Overall, 34-50% of people with alopecia areata recover in 1 year; almost all people with the condition experience more than one episode; and 14-25% progress to alopecia totalis or alopecia universalis [Ikeda, 1965; MacDonald Hull et al, 2003].
• A poor prognosis is associated with:
o Atopy
o Childhood-onset alopecia areata
o Chronic and extensive alopecia areata
o Down's syndrome
o Eyelash and/or eyebrow hair loss
o Family history of alopecia areata
o Ophiasis (alopecia areata of the scalp margin)
o Nail changes
4
o Presence of other autoimmune disease

Management issues
Overview of management
• Exclude tinea capitis (especially in children) and trichotillomania.
• Establish whether hair loss is extensive or non-extensive (i.e. greater than or less than 50%) - we only recommend management options for hair loss on the scalp or face.
• Explain that alopecia areata is difficult to treat successfully and that hair loss is unpredictable, although in many cases the condition is self-limiting.
• In children and adolescents up to 16 years of age, unless the primary care professional is confident in managing this population, PRODIGY recommends that specialist advice should be sought before starting topical treatment.
• Consider referral for counselling and support, especially in people where visible hair loss is causing psychological distress.
• Consider primary care options, but referral to a dermatologist for consideration of secondary care options (e.g. intralesional corticosteroids, topical immunotherapy) may be more appropriate.
• In people with non-extensive alopecia areata (less than 50% hair loss), management options include:
o Watchful waiting with provision of reassurance (as spontaneous remission can occur after 3 months).
o Referral to dermatology for the consideration of intralesional corticosteroids.
o Topical corticosteroid or topical minoxidil in primary care if the person:
􀂃 Is waiting for referral
􀂃 Declines referral and only wants treatment in the primary care setting
• In people with extensive alopecia areata (more than 50% hair loss), alopecia totalis and alopecia universalis, management options include:
o Early referral to dermatology (topical immunotherapy is an effective treatment, but many dermatologists will not provide immunotherapy unless the risk/benefit assessment is favourable).
o Use of a topical corticosteroid or topical minoxidil in primary care while waiting for referral (although evidence of their effectiveness is limited in extensive hair loss).
o Watchful waiting, though spontaneous remission after 3 months is less likely than in people with non-extensive alopecia areata.
• Wigs may be a desirable option for some people (especially women). Advice on the different types
5
of wigs available should be provided, but wigs can only be prescribed in secondary care.
• We are unable to make any recommendations on the use of alternative and complementary therapies (e.g. aromatherapy, massage, or relaxation) as there is insufficent published evidence of their use in people with alopecia areata.

What assessment do I need to make in somone with alopecia areata?
• An assessment should be made that includes the following:
o Age of the person
o Pattern and extent of the hair loss
o Rate of hair loss and duration of symptoms
o Previous episodes of hair loss and any treatment used
o The person's ideas, concerns, and expectations about the condition
o Psychological issues (e.g. any associated depression)
• Examination should include:
o Hair assessment - patch location and extent
o Pull test (to identify if there is active hair shredding and if further hair loss is likely)
• Estimating hair loss is useful to guide management [Olsen et al, 1999] and this can be done using several different methods, such as:
o Dividing the scalp into quarters
o Using a visual scale as an aid
• To identify if there is active hair shedding, the pull test can be performed at the periphery of a lesion. This involves grasping about 60 hairs between the finger and thumb and tugging gently but firmly. The test is positive (confirming active shedding) when 2-10 hairs are pulled out and this suggests that more hair loss can be expected [Shapiro and Madani, 1999; Madani and Shapiro, 2000; University of Texas at Austin, 2004].

What information should I give my patient with alopecia areata?
• Alopecia areata is an unpredictable condition, there is no satisfactory treatment, and it is difficult to treat successfully.
• Give reassurance, as non-extensive alopecia areata is often self-limiting and therefore a viable option is to 'watch and wait'. Extensive alopecia areata is less likely to be self-limiting than non-extensive alopecia areata.
• Hair regrowth may not be seen for at least 3 months, so if natural improvement is going to occur, it will often take time.
• Alopecia areata will have no effect on general health but can cause psychological distress.
• Drug treatment aims to induce hair growth, not cure it.
• If treatment is the preferred option, discuss the benefits and risks of each available option with the person.
• Topical treatments: if experimenting with the use of a topical preparation, try a corticosteroid for at least 3 months or minoxidil for 6 months. Note: it may take at least 3 months for hair to show any signs of regrowth, irrespective of whether the treatment has been effective or not.
• Intralesional corticosteroids are the most effective treatment for non-extensive hair loss but administration may be painful (they are not usually used in children as they are not well tolerated). Note: corticosteroids may be injected using a Dermo-Jet needle-less injector to minimize pain.
• Topical immunotherapy is the most effective treatment for extensive hair loss. However, it requires commitment in order to comply with the treatment episode and many dermatologists will not provide immunotherapy unless the risk/benefit assessment is favourable. 6
• When hair regrows it is initially fine and depigmented (white) before it returns to its original colour - inform people that hair can be dyed if it is slow to pigment.
• On sunny days, sunblock or a hat should be used to protect bald patches.
Counselling
• Alopecia areata can be a very distressing condition and has a number of psychological implications for people, especially children. They should have adequate counselling to explain the nature of the disease, its likely course, and the high rate of spontaneous remission.
o Some people may benefit from referral for counselling and support if hair loss is causing psychological distress.
o Affected individuals or parents of affected children often want a specialist opinion and this wish should be respected, even if the specialist has no more to offer in terms of treatment.
• All treatment options should be explained, along with their adverse effect profile. People need to be aware that alopecia areata itself will not damage their general health but that treatments may be toxic and potentially time-consuming.
• Support groups are available (for more information, see the Patient Information Leaflet).
How should I manage an episode of alopecia areata?
• Alopecia areata is difficult to treat successfully and recommended treatments aim to induce hair growth rather than cure the underlying cause [Madani and Shapiro, 2000].
• The following need to be taken into consideration when managing alopecia areata:
o Age - in children and adolescents up to 16 years of age, unless the primary care professional is confident in managing this population, PRODIGY recommends that specialist advice should be sought before starting a topical corticosteroid.
􀂃 Note: with children, secondary care use of intralesional corticosteroids is limited due to potential pain around injection sites, and the use of topical immunotherapy is controversial.
o Extent of hair loss - treatment selection will depend on whether there is extensive alopecia areata (more than 50% hair loss) or non-extensive alopecia areata (less than 50% hair loss).
o Patient preference for treatment method.

When should I consider referral?
• Consider specialist referral in the following situations:
o Diagnostic uncertainty
o Extensive disease, including alopecia totalis and alopecia universalis
o Pregnant or breastfeeding women
o If secondary care treatments are more appropriate
o If topical treatment initiated in primary care is not effective
o If a wig is required
Non-extensive alopecia areata (less than 50% hair loss)
• Many people with non-extensive alopecia areata experience a spontaneous remission, so consider giving no treatment as an option [Madani and Shapiro, 2000]. People should be advised that initial hair regrowth may not be seen for up to 3 months.
• If treatment is preferred: 7
o There is evidence that intralesional corticosteroids (ILCs) are the most effective treatment for non-extensive alopecia areata. For cosmetically unacceptable patches of hair loss, such as eyebrow involvement, ILCs may be the most suitable treatment option.
􀂃 Referral to a dermatologist is required [MacDonald Hull et al, 2003].
􀂃 See What treatments are not recommended for use in primary care? for more information.
o There is limited evidence to support the use of a topical corticosteroid, but it may be worth trying one in:
􀂃 Adults over 16 years of age (who are either waiting for referral or who have declined referral and want treatment in primary care only).
􀂃 Children, after discussion with a dermatologist where appropriate (ILC use is controversial as it is not well tolerated).
o There is limited evidence to support the use of topical minoxidil, but it may be worth trying in:
􀂃 Adults over 16 years of age who decline ILC treatment.
􀂃 Note: many experts do not recommend the use of minoxidil in children and adolescents under 16 years of age.
• Consider the need for counselling and psychological support, especially in people in whom areas of visible hair loss are causing psychological distress.

Topical corticosteroids
• Corticosteroids act as an immunosuppressant and topical preparations are widely used in alopecia areata.
• In primary care, where treatment options are limited in people with alopecia areata, topical corticosteroids may be worth trying (for more information, see Medicines management), although there is little good-quality evidence to support their use [Madani and Shapiro, 2000; Bolduc and Shapiro, 2001]. Of the trials that have been published, the drug or strength of corticosteroid used is often not available in the UK.
• In children and adolescents up to 16 years of age, unless the primary care professional is confident in managing this population, PRODIGY recommends that specialist advice should be sought before starting a topical corticosteroid.
• When treating adults over 16 years of age, the expert advice is to use a potent topical corticosteroid.
• Topical corticosteroids should be used continuously for at least 3 months before regrowth can be expected [Fiedler, 1992; Fiedler and Alaiti, 1996; Papadopoulos et al, 2000; Bolduc and Shapiro, 2001]. Hair loss may flare up despite treatment with a corticosteroid, but hair loss is minimized [Fiedler and Alaiti, 1996].
• When prescribing topical corticosteroids in primary care:
o Do not change any single treatment sooner than 3 months after starting treatment, as regrowth may first become evident at this time.
o Up to 6 months is a reasonable time for a trial of a treatment - if there is no response after 6 months an alternative treatment can be tried [Drake et al, 1992; Bertolino, 2000]. Note: cosmetic regrowth can take up to 1 year.
o A potent corticosteroid can be applied to the scalp because the thick skin reduces the penetration of the corticosteroid and hence its effectiveness. Note: this should still be applied for the minimum time necessary.
o For more information, see Medicines management.
• Some experts recommend combining a topical corticosteroid with topical minoxidil because the topical application of either agent alone might not be effective [Bolduc and Shapiro, 2001]. See What is the evidence for combining topical corticosteroid and topical minoxidil application? 8

Topical minoxidil
• Minoxidil is a peripheral vasodilator, originally used as an antihypertensive drug.
• Topical minoxidil solution is an option in primary care, although treating alopecia areata represents an off-licence use of minoxidil. The majority of experts do not recommend the use of minoxidil in children and adolescents under 16 years of age.
• Topical minoxidil is not available on the NHS - 2% and 5% strengths can be prescribed privately or are available for purchase over the counter with a recommendation from a medical practitioner.
• When prescribing topical minoxidil in primary care:
o If tolerated, it is best not to change the treatment sooner than 3 months after starting treatment as regrowth may first become evident at this time.
o Six months is recommended as a reasonable time for a trial of minoxidil, although there is little good-quality evidence to support its use - if there is no response after 6 months an alternative treatment can be tried [Drake et al, 1992; Bertolino, 2000]. Note: cosmetic regrowth can take up to 1 year.
o Stop minoxidil use if the hair regrows, as the likelihood is that this is a result of the natural history of the condition rather than the treatment. In some people, relapse will occur after discontinuing minoxidil and so further treatment courses and reassessment may be appropriate.
o For more information, see Medicines management.
• It may take 2-3 months for an initial response [Fiedler, 1992] and 1 year for a maximum response. A cosmetic response is maintained with continued total scalp application, although small patches of alopecia areata may redevelop [Fiedler and Alaiti, 1996].
• Some experts recommend combining topical minoxidil with a topical corticosteroid because the application of either alone might not be effective [Bolduc and Shapiro, 2001]. See What is the evidence for combining topical corticosteroid and topical minoxidil application? for more information.
Extensive alopecia areata (more than 50% hair loss), alopecia totalis and alopecia universalis
• Some people with extensive alopecia areata may experience spontaneous remission but, in general, the prognosis is poor [Madani and Shapiro, 2000].
• Early referral to a dermatologist is appropriate (unless the person does not want this). With increasing extent of hair loss, treatment preferences change. There is some evidence that topical immunotherapy (in the secondary care setting) is the most effective option for people with extensive alopecia areata [MacDonald Hull et al, 2003]. However, many dermatologists will not provide immunotherapy unless the risk/benefit assessment is favourable.
• There is no convincing evidence that topical corticosteroids or topical minoxidil are effective in people with extensive hair loss, but they may be considered in:
o People who are waiting for referral
o People who decline referral and only want treatment in primary care
• Consider the need for counselling and psychological support, especially in people where visible areas of hair loss are causing psychological distress.
• Wigs are a common treatment choice in people with alopecia areata. They can either be obtained on the NHS (via secondary care) or bought privately. For more information, see What treatments are not recommended for use in primary care?

How should I manage a relapse of alopecia areata?
• If a treatment has worked before, try that treatment again; similarly, avoid treatments that have not worked previously.
9
• Consider prompt referral, as treatment with intralesional corticosteroids may help prevent progression.
What treatments are not recommended for use in primary care?
• Intralesional corticosteroids (ILCs) - there is evidence that this is the most effective treatment for non-extensive alopecia areata but referral to a dermatologist is required. ILCs are also the preferred treatment when the hair loss is in a cosmetically sensitive area (e.g. eyebrows) [MacDonald Hull et al, 2003].
• Topical immunotherapy - there is some evidence that topical immunotherapy (a secondary care treatment) is the most effective option for people with extensive alopecia areata [MacDonald Hull et al, 2003]. However, many dermatologists will not provide immunotherapy unless the risk/benefit assessment is favourable.
• Other treatment options for alopecia areata that are not recommended for use in primary care but which might be used in secondary care include:
o Topical dithranol
o Topical or systemic PUVA (psoralen plus ultraviolet A light)
o Oral corticosteroids
o Oral ciclosporin
o Oral minoxidil
o Wigs
o Dermatography
• Topical dithranol needs to be applied sufficiently frequently and in a high enough concentration to produce a brisk irritant reaction to be effective. Administration is cumbersome (it is applied at night to the whole scalp if the disease is widespread and left for 20-60 minutes prior to shampooing) and staining of clothes, skin, and fair hair can be a problem. A cosmetic response has been reported in 20-30% of people with non-extensive alopecia areata [Fiedler and Alaiti, 1996; Madani and Shapiro, 2000] and this may take up to 60 weeks to achieve.
• PUVA - this treatment has been suggested as being beneficial in alopecia areata [Fiedler and Alaiti, 1996]. Two to three treatments a week are required and the time to response is 20-40 sessions. A maximum response is generally achieved within 1 year, although variable responses and high relapse rates have been reported [Healy and Rogers, 1993; Madani and Shapiro, 2000]. However, PUVA is an unsatisfactory treatment option because of its adverse effect profile (nausea, pigment changes, risk of skin cancer).
• Oral ciclosporin is effective in extensive alopecia areata but its use is limited due to its adverse effect profile, and relapse occurs after discontinuation of treatment [Fiedler and Alaiti, 1996; Shapiro et al, 1997].
• Oral corticosteroids are not recommended for alopecia areata. Although there is some evidence that they are effective, the risks associated with their use outweigh any benefits. [Olsen et al, 1992; Perriard-Wolfensberger et al, 1993; Sharma and Muralidhar, 1998; Seiter et al, 2001].
• Oral minoxidil is not recommended for people with alopecia areata. Although there is some evidence that it is effective, the safety risks outweigh any benefits [Fiedler and Alaiti, 1996].
• Dermatography (tattooing) can be used to simulate eyebrows. One study with a 4-year follow-up showed that 77% had excellent results and 8% had good results with a cosmetic approach [Bolduc and Shapiro, 2001]. Two to three dermatography sessions lasting 1 hour are usually required.
• Wigs are a common treatment choice in patients with alopecia areata. They can be obtained on the NHS or bought privately.
o Acrylic wigs are cheaper than real hair, costing about £60 to £200, and are easier to look after. They can be itchy and hot and require frequent replacement.
10
o Real-hair wigs are a better fit and are more socially acceptable, but are they are considerably more expensive than acrylic wigs. They last for 3-4 years but require more maintenance.
o NHS wigs can only be prescribed in secondary care. People who are categorized under certain NHS exemptions may be entitled to two subsidized wigs a year, but people will only qualify for a human-hair wig on prescription if they are allergic to acrylic or have a skin condition requiring the use of human-hair wigs [MacDonald Hull et al, 2003].

Complementary and other treatments
• Many other treatment modalities (e.g. aromatherapy, acupuncture and massage, and relaxation) have been used for alopecia areata but there is insufficient evidence on their efficacy for us to make any recommendations.
• For more information, see What is the evidence for complementary therapies and other treatments in alopecia areata?

Medicines management
Corticosteroids
Which topical corticosteroids and formulations are recommended for alopecia areata?
• Which formulation of corticosteroid?
o Topical gels, lotions, and scalp applications are formulated for use on hair-bearing areas such as the scalp, and expert opinion considers that these formulations are more user-friendly (easier to use, easier to wash out, and may cause less irritation).
o However, some dermatologists may prefer a different formulation (e.g. an ointment may be preferred where a more occlusive effect is required), and if a specific formulation is preferred by an individual patient, then it is important to take this into consideration too.
• In children and adolescents up to 16 years of age, PRODIGY recommends that specialist advice should be sought before starting a topical corticosteroid, unless the primary care professional is confident in managing alopecia areata in this population.
o Many dermatologists are happy to advise a short-term trial (2-3 months) of a topical corticosteroid of high potency in children.
• In adults, a potent topical corticosteroid is recommended (in line with expert opinion) and prescriptions for the following are included:
o Betamethasone dipropionate 0.05% lotion
o Betamethasone valerate 0.1% lotion
o Betamethasone valerate 0.1% scalp application
o Betamethasone valerate 0.12% foam
o Fluocinolone acetonide 0.025% gel
o Hydrocortisone butyrate 0.1% lotion
o Hydrocortisone butyrate 0.1% scalp application
o Mometasone furoate 0.1% scalp application
• Note: the alcohol content of these products varies and if someone reacts to one product, then it might be worth trying another preparation.

How should topical corticosteroroids be applied?
• In people with non-extensive alopecia areata, expert advice is to apply topical corticosteroids to the affected area only, rather than to the whole scalp.
11
• Scalp - a potent corticosteroid can be used because the thick skin reduces the penetration of the corticosteroid and hence its effectiveness. Topical corticosteroids should still be applied sparingly however. Any fingertips and hands that have been in contact with the corticosteroid should be washed.
• Beard area - a moderately potent corticosteroid may be the most appropriate to use here because of the increased risk of skin atrophy.
• Eyebrows and eyelids - referral to secondary care is required for management. Topical corticosteroids should not be applied to these areas in primary care unless advised by a specialist.
• When applying topical corticosteroids to an area of alopecia areata, the surrounding hair should be dry.
• How much topical corticosteroid should be applied? As a practical guide, the quantity of solid-formulation topical corticosteroid to apply is often expressed in terms of fingertip units (FTUs) [MeReC, 1999]. Note: this is of no relevance to the use of scalp applications or topical lotions.
o One FTU is roughly equivalent to the amount of cream or gel that can be squeezed from a tube with a standard nozzle onto an adult index finger from the tip of the finger to the first crease.
o FTUs should be used together with body charts that show the number of FTUs required to cover each area of a child's or adult's body.
o As a rough guide, one FTU of topical corticosteroid is sufficient to treat a skin area about twice the size of the flat of the hand with the fingers together.
• When treating alopecia areata affecting the scalp, occlusion (e.g. a shower cap) can be used at night, and is recommended by some experts.
• Stop corticosteroid use if the hair regrows, as the likelihood is that this is due to the natural history of the condition.
• If there is no response after 3 months, reassess the management options.
What are the key contraindications and adverse effects of topical corticoteroids?
• Topical corticosteroids should be avoided in pregnant or breastfeeding women.
• Topical corticosteroids can exacerbate some conditions and so they are contraindicated [BNF 50, 2005] in people with areas of alopecia areata that are also affected by:
o Untreated bacterial, fungal, or viral skin lesions
o Acne
o Perioral dermatitis
o Plaque psoriasis
• If signs of hypersensitivity appear, application should be stopped immediately.
• Adverse effects of topical corticosteroids can be divided into localized effects (e.g. skin atrophy, exacerbation of skin infection, and acne at the site of application) and systemic adverse effects (e.g. hypophyseal-pituitary-adrenal [HPA] suppression).
o Reversible hypertrichosis on the face and neck may develop in young children [Fiedler and Alaiti, 1996].
• The risk of adverse effects is related to the potency of the topical corticosteroid, duration of use, and area of application (e.g. thin skin on the face) [BNF 50, 2005]. Adverse effects are most likely with potent or very potent topical corticosteroids when used in large quantities for prolonged periods.
• People should be advised that alcohol-based formulations are flammable, and that they must be allowed to dry naturally. People should not use a hairdryer and must keep away from open fires, flames, and cigarettes while the lotion is on.
• All people using topical corticosteroids in the medium to long term should be monitored for adverse effects, and children using long-term topical corticosteroids should have their growth curve monitored [Fiedler, 1992].
12
Minoxidil
What is the availability of minoxidil?
• Topical minoxidil 2% and minoxidil 5% solutions have to be prescribed privately for alopecia areata as they can neither be prescribed on the NHS nor purchased over the counter (for alopecia areata).
• Over-the-counter topical minoxidil solution is only licensed for alopecia androgenetica, and therefore cannot be sold for alopecia areata, which is an off-licence use of the drug.
How should minoxidil be applied?
• Most experts do not recommend the use of minoxidil in children and adolescents under 16 years of age.
• In people with non-extensive alopecia areata, expert advice is to apply topical minoxidil to the affected area only.
• A dose of 1 ml minoxidil solution should be applied to the patch(es) of hair loss twice a day - the hair and scalp should be thoroughly dry prior to its application [ABPI Medicines Compendium, 2005a; ABPI Medicines Compendium, 2005b].
o For the night-time application, the solution should be applied more than 1 hour before bedtime to avoid spreading the solution onto the pillow (and therefore the face).
o Any fingertips and hands that have been in contact with minoxidil should be washed to avoid the development of mild hypertrichosis (unwanted non-scalp hair, including facial hair growth in women).
• Minoxidil may be applied via different applicator mechanisms (but people should avoid breathing in any mist) [ABPI Medicines Compendium, 2005a; ABPI Medicines Compendium, 2005b]:
o Pump-spray applicator - useful for large areas, six sprays represent a 1-ml dose
o Extended spray-tip applicator - useful for small areas, six sprays represent a 1-ml dose
o Rub-on applicator
• Stop minoxidil if the hair regrows, as the likelihood is that this is due to the natural history of the condition. In some people, relapse will occur after discontinuing minoxidil and so further treatment courses and reassessments may be appropriate.
• If there is no response after 6 months, then reassess the management options.

What are the key contraindications and adverse effects of topical minoxidil?
• Topical minoxidil is contraindicated in:
o People with treated or untreated hypertension
o Pregnant or breastfeeding women
o People with any scalp abnormality (including psoriasis and sunburn)
o People with a shaved scalp
• People with cardiovascular disease need careful consideration before topical minoxidil is used. Note: minoxidil is a peripheral vasodilator and the oral form is used as an antihypertensive drug.
• If chest pain or vasodilatory adverse effects develop, the person should be advised to stop using minoxidil and seek medical advice.
• Topical minoxidil is generally safe and easy to use, and it is well tolerated because systemic adverse effects are unlikely. Results from trials show that adverse effects are five times more commonly reported in women than in men.
• Topical minoxidil contains alcohol, which may cause eye irritation and burning. Note: bathe affected eye(s) with large amounts of cool tap water if affected in this way.
13
• Some people experience hair shedding when minoxidil treatment is started, and changes in hair colour and/or texture have also been reported.
• Topical minoxidil contains propylene glycol as an excipient which has been known to cause skin irritation and itching.
• Discontinue minoxidil if the following adverse effects persist:
o Hypertrichosis (unwanted non-scalp hair, including facial hair growth in women)
o Local erythema
o Itching
o Dry skin/scalp
o Exacerbation of hair loss
[ABPI Medicines Compendium, 2005a; ABPI Medicines Compendium, 2005b]

Supporting evidence
Few treatments have been subject to randomized controlled trials and there are even fewer data available on long-term outcomes [MacDonald Hull et al, 2003; Messenger, 2004].
What is the evidence for topical corticosteroids in alopecia areata?
• There are few good-quality trial data (small sample sizes, high withdrawal rates) to support the use of topical corticosteroids in alopecia areata and trials have not been conducted using corticosteroids of mild potency [Madani and Shapiro, 2000; Bolduc and Shapiro, 2001]. Most experts believe that it is unlikely that a topical corticosteroid will prevent a patch of alopecia areata from extending.
• A two-part trial investigated the effect of fluocinolone acetonide 0.2% cream (Synalar HP®) versus placebo (vehicle component), each applied twice a day to half of the scalp, in 28 people with alopecia areata and alopecia totalis [Pascher et al, 1970]. The first part of the trial was a single-blind paired comparison in 15 people. This was followed by a second part, a double-blind study comparing the same agents in 13 people. With the two studies combined, the participants applied the topical preparations for at least 6 months.
o A satisfactory to excellent hair regrowth response was obtained in 17/28 people with fluocinolone.
o Of the 17 people who responded to fluocinolone, 12 retained regrowth satisfactorily for at least 3 months.
o Relapses occurred in 11/17 people, either during the trial or within 3 months of the end of the trial.
o Note: fluocinolone acetonide strengths available in the UK vary from 0.0025% to 0.025%, whereas fluocinolone acetonide 0.2% was used in this trial.
• A randomized controlled trial (RCT) (n = 70) investigated the effect of twice-daily application of topical desoximetasone cream (not available in the UK) for 12 weeks. There was a trend towards more hair regrowth in people using the topical corticosteroid but the rate of hair growth was not statistically significant compared with placebo [Charuwichitratana et al, 2000].
• Topical corticosteroids are considered by some to be largely ineffective in alopecia totalis (AT) and alopecia universalis (AU) [MacDonald Hull et al, 2003]. However, in a recent controlled trial, 28 people (19 with AT and 9 with AT/AU, none of whom had responded to topical immunotherapy) applied 2.5 g clobetasol propionate 0.05% ointment to one side of the scalp every night for 6 months (under occlusion with a plastic film), leaving the other side untreated and therefore acting as a control [Tosti et al, 2003].
o Initially, eight people (29%) were treated successfully but three relapsed and were not able to maintain hair regrowth.
14
o Although only 18% of the participants therefore benefited from this very potent topical corticosteroid in the long term, the people in this trial had long-standing AT/AU with no previous treatment success.
• A small RCT (n = 61) compared betamethasone valerate (0.1%) foam with betamethasone dipropionate (0.05%) lotion, applied to the affected areas twice daily for 12 weeks [Mancuso et al, 2003]. Betamethasone valerate foam was consistently found to be better in terms of a hair regrowth score at 20 weeks' follow-up.
• The benefit of twice-daily application of betamethasone dipropionate 0.05% (the cream formulation rather than the lotion) has been reported by some experts [Fiedler and Alaiti, 1996] to be equivalent to the benefit reported with fluocinolone acetonide 0.2% cream [Pascher et al, 1970].

What is the evidence for topical minoxidil in alopecia areata?
• The effectiveness of minoxidil is considered to correlate with the extent of initial hair loss, although the evidence for minoxidil is variable. Most experts also believe that it is unlikely that topical minoxidil will prevent a patch from extending.
• A double-blind controlled trial compared placebo with topical 3% minoxidil solution in 30 people (age range 7-63 years) with extensive alopecia affecting 25-100% of the scalp [Price, 1987a; Price, 1987b]. After 12 weeks those in the placebo group were changed to minoxidil. Both placebo and intervention groups were treated for 64 weeks.
o After 12 weeks the minoxidil group showed some hair regrowth but this was not statistically significant.
o At the end of the trial, people with 100% scalp involvement (n = 9) showed no hair regrowth or only slight hair regrowth (one person was lost to follow-up), but of the 20 people with 25-99% hair loss, 13/20 had cosmetically acceptable or incomplete hair regrowth; 7/20 did not have acceptable regrowth.
o Minoxidil was found to be ineffective in people with 100% hair loss, or in people who had had alopecia areata for more than 10 years. In other people with hair loss, however, there was a 1 in 2 chance of cosmetically acceptable hair regrowth, although maintenance treatment is likely to be needed as hair loss began again 4 weeks after minoxidil was discontinued. Furthermore, five of the nine people who initially had cosmetically acceptable hair regrowth had further hair loss in the second year of treatment.
o A further comparison of 3% minoxidil and 5% minoxidil found that 5% minoxidil resulted in a greater number of responders and a faster response, but after 1 year of treatment the number of people with cosmetically acceptable results was similar in the two groups [Price, 1987b].
• A 1% minoxidil preparation (not available in the UK) was found to show benefit when compared with placebo in one double-blind study in people with patchy alopecia [Shi, 1986]. Further controlled trials comparing 1% minoxidil and 3% minoxidil have not confirmed these results however [Vestey and Savin, 1986; Price, 1987a; Ranchoff et al, 1989]. In a study comparing 1% minoxidil and 5% minoxidil the regrowth was more frequent in those using the 5% preparation but few people had cosmetically acceptable results nevertheless [Fiedler-Weiss, 1987].
• Minoxidil 5% solution appears to be more effective than weaker solutions, but the 5% solution may just have a quicker onset of action and there might be little real difference in the number of people who achieve a cosmetically acceptable response overall.
What is the evidence for combining topical corticosteroid and topical minoxidil application?
There is some evidence that combination therapies are better than monotherapy [Madani and Shapiro, 2000]. It is thought that the efficacy of topical minoxidil can be enhanced by combining it with a topical
15
corticosteroid applied twice daily, or dithranol [Papadopoulos et al, 2000] and several combination strategies have been tried with variable results.
• A double-blind trial evaluated the use of topical minoxidil plus topical corticosteroid - twice-daily applications to the entire scalp of 5% minoxidil, followed 30 minutes later by 0.05% betamethasone (Diprosone®) [Fiedler, 1992].
o The percentages of people with severe, chronic, treatment-resistant alopecia areata who had fair to good regrowth at 16 weeks were:
􀂃 56% of people receiving combination therapy
􀂃 27% of people treated with topical minoxidil alone
􀂃 22% of people given topical corticosteroid alone
􀂃 13% of people given placebo
o A cosmetic response was seen in:
􀂃 16% of people with 100% scalp loss
􀂃 16% of people with 75-99% hair loss
􀂃 48% of people with 25-74% hair loss
􀂃 63% of people with 0-24% hair loss
• An open-label study of severe, treatment-resistant alopecia areata investigated the combination of 5% minoxidil twice daily plus dithranol (0.5% Dithrocream®) at night. Hair regrowth was seen in 78% of the study participants at 12 weeks, but by 24 weeks only 11% of people had cosmetically acceptable hair regrowth [Fiedler et al, 1990]. The initial response was found to be good but maintenance and cosmetic responses were poor, and the study was terminated early. Adverse effects were limited to irritant reactions.
What is the evidence for intralesional corticosteroids in alopecia areata?
• Intralesional corticosteroids (ILCs) are most suitable for non-extensive patches of hair loss that are cosmetically unacceptable on the scalp, beard, or eyebrows. ILCs stimulate hair regrowth at the site of injection [MacDonald Hull et al, 2003].
• In one trial comparing ILCs of different solubility, triamcinolone hexacetonide (more soluble) was compared with triamcinolone acetonide (less soluble) [Porter and Burton, 1971]. In the triamcinolone hexacetonide group (n = 11) tufts of hair grew in 33 out of 34 sites and in the triamcinolone acetonide group (n = 17) hair grew in 16 out of 25 sites. The effect was seen within 2-4 weeks, was temporary, and was found to last for about 9 months. The trial was neither randomized nor controlled and no statistical analysis was performed because of the small numbers. They concluded that triamcinolone acetonide might be less effective than triamcinolone hexacetonide.
• A study of 66 people with alopecia areata who were all treated with intralesional triamcinolone acetonide using a Porto-Jet (needle-less) injector found that 47/66 people (71%) showed regrowth of hair at 12 weeks after three injections, compared with 1/15 (7%) of the people injected with isotonic saline (i.e. the control treatment) [Abell and Munro, 1973]. Fourteen people (21%) had a relapse after the corticosteroid injections were stopped. The study was neither randomized nor double blind and was unable to confirm whether hair regrowth was due to the corticosteroid or to the natural history. ILCs were more useful in people with alopecia areata than in 18 additional people with alopecia totalis who were also treated.
• Other research has found that monthly injections of triamcinolone acetonide produced a better response in people with fewer than five patches less than 3 cm in diameter, compared with people who had more extensive alopecia areata [Kubeyinje, 1994]. Cosmetic regrowth was achieved in 35 of the 45 people with fewer than five patches (78%). The study had a small number of participants (n = 62), no controls, and there was no randomization.
16
• Adverse effects include atrophy (which resolves when injections are discontinued), acne (which can be treated with topical acne treatments), and dose-related intermenstrual bleeding. If used near the eye there is a risk of cataracts and glaucoma [MacDonald Hull et al, 2003].
• Overall, ILCs are reported as being inappropriate or ineffective in people with rapidly progressive alopecia or extensive disease [Fiedler and Alaiti, 1996; MacDonald Hull et al, 2003].

What is the evidence for topical immunotherapy in alopecia areata?
• Topical immunotherapy is reported to be the most effective treatment for extensive alopecia areata [Madani and Shapiro, 2000] although it remains an unlicensed treatment and there have been few double-blind, randomized studies [MacDonald Hull et al, 2003].
• Topical immunotherapy involves the induction of an allergic contact dermatitis by topical application of a potent contact allergen, the most widely used being diphencyprone (DPCP). Initial regrowth is not expected for 12 weeks [Madani and Shapiro, 2000; Bolduc and Shapiro, 2001].
• A review of published studies of contact immunotherapy in people with alopecia areata concluded that 50-60% of people were reported as having achieved a cosmetically acceptable result over a period of about 6 months, although the range of response rates was very wide (9-87%) [Rokhsar et al, 1998]. Available data on long-term follow-up indicates a significant relapse rate.
• A large retrospective case series of 148 Canadian people with alopecia areata with more than 25% hair loss reported clinically significant improvement in 30% of people after 6 months, which increased to 78% after 32 months [Wiseman et al, 2001]. A cosmetically acceptable end point was achieved in 17% of people with alopecia totalis/universalis, in 60% of people with 75-99% hair loss, in 88% of people with 50-74% hair loss, and in 100% of people with 25-49% hair loss. Poor prognostic factors were early age of onset and extensive baseline hair loss. Three months was needed for significant hair regrowth and relapse was seen in 62% of people.
• Multiple treatments are needed but if no response is seen in 24 weeks treatment is discontinued [Madani and Shapiro, 2000.] Alternatively, the treatment can be tapered off gradually once cosmetically acceptable growth is achieved. Maintenance treatments are often required [Bolduc and Shapiro, 2001].

What is the evidence for complementary therapies and other treatments in alopecia areata?
• Although many alternative and complementary therapies have been used in alopecia areata, our literature search found only three randomized controlled trials.
• Aromatherapy with essential oils (thyme, rosemary, lavender, and cedarwood) massaged daily was compared with carrier oil in 86 people with alopecia areata and they were followed up after 3 months and 7 months [Hay et al, 1998]. Independently assessed photographic evidence was collected throughout the trial and any degree of improvement was measured using a six-point scale and computerized analysis of affected areas. Nineteen people in the active treatment group (n = 43) showed improvement, compared with six people in the control group (n = 41), which was a highly significant difference. However, the study had several limitations:
o It was not clear how long the treatment was given for.
o Thirteen people dropped out of the control group, reducing the impact of the apparent benefit achieved with aromatherapy.
o Some people had other types of treatment before the study was discontinued but no more details were provided.
o It is assumed that the treatment and intervention groups had similar baseline profiles in terms of extent and pattern of alopecia areata but details were not provided.
o Note: manufacturers of aromatherapy products are not bound by statutory monitoring or good manufacturing requirements and there is no formal recognized standardization of active ingredients in aromatherapy products.
17
• Onion juice is thought to act by causing an irritant contact dermatitis. In a single-blind, placebo-controlled study of 62 people with non-extensive alopecia areata, onion juice (n = 45) was compared with tap water (n = 17) [Sharquie and Al Obaidi, 2002]. After 8 weeks, 20 out of 23 people who were applying onion juice (86%) had statistically significant hair regrowth, but 22 of the original 45 people in this group defaulted from the study. Onion juice was shown to be more effective than placebo but its usefulness is likely to be limited by the offensive smell and by non-compliance.
• Imipramine (75 mg daily) was compared with placebo in a double-blind, placebo-controlled trial that lasted 6 months [Perini et al, 1994]. Thirteen people with alopecia areata were enrolled in the study, seven receiving a serotonin reuptake inhibitor and six the placebo. After 3 months there was a significant improvement in the active treatment group - five of the seven people had hair regrowth, although only one person had cosmetically acceptable hair regrowth. There was no regrowth in the people in the placebo group. The study was limited by its small numbers and by the fact that all the study participants had experienced a stressful life event in the 6 months prior to the study; in addition, three participants had psychiatric conditions.

Scenario - Alopecia areata
Management recommendations
Which therapy?
• Exclude differential diagnoses - the most common are tinea capitis (especially in children) and trichotillomania.
• In children and adolescents up to 16 years of age, unless the primary care professional is confident in managing alopecia areata in this population, specialist advice should be sought before starting a topical corticosteroid.
• Establish whether hair loss on the scalp or face is extensive or non-extensive (i.e. greater than 50% or less than 50%).
• For non-extensive alopecia areata (less than 50% hair loss), management options include:
o Watchful waiting, with provision of reassurance (as spontaneous remission can occur after 3 months).
o Referral to dermatology for consideration of intralesional corticosteroids.
o Topical high-potency corticosteroid or topical minoxidil if the person is over 16 years of age and
􀂃 Is waiting for referral
􀂃 Declines referral, wanting treatment in primary care only
• With extensive alopecia areata (more than 50% hair loss), options include:
o Early referral to dermatology (topical immunotherapy is an effective treatment but a risk/benefit assessment has to be made prior to its use). Note: people with alopecia totalis and alopecia universalis should be routinely referred unless they decline this option.
o Topical corticosteroid or topical minoxidil may be used while awaiting referral (although evidence of their effectiveness is limited in extensive hair loss).
o Watchful waiting is an option but spontaneous remission after 3 months is less likely than in people with non-extensive alopecia areata.
• The pattern of hair loss and cosmetic appearance will influence the decision to refer (to dermatology and/or psychological services):
o If there is 20% patchy hair loss that is easily disguised by remaining hair and if it is not causing psychological distress, it could be managed by watchful waiting.
o If there is 20% patchy hair loss in visible areas that is not easily disguised and which is causing psychological distress, this would be more appropriately managed with intralesional corticosteroids (requiring referral) or topical treatment in primary care.
• People with asthma, eczema, or broken skin conditions: a water-based product is preferred.
18
• A minimum of a 3-month trial of a topical treatment is recommended and if there is no response after 6 months it would be reasonable to try an alternative treatment.
Practical prescribing points
For further information please see the Medicines Compendium (www.medicines.org.uk) or the British National Formulary (www.bnf.org).

Topical corticosteroids
• Advise that topical corticosteroids should be used sparingly. In people with non-extensive alopecia areata they should only be applied to the affected areas.
• Give specific advice regarding the quantity of solid-formulation corticosteroid to apply. Where larger areas require treatment, explain and demonstrate the use of the fingertip unit (FTU).
• For an adult, one FTU of topical corticosteroid is sufficient to treat a skin area about twice the size of the area of the flat of the hand with the fingers closed.
• For a child aged from 1 year to 4 years, apply a third of the adult amount.
• Children using long-term topical corticosteroids should have their growth curve monitored.
• Any fingertips and hands that have been in contact with the corticosteroid should be washed.

Topical minoxidil
• Advise people with non-extensive alopecia areata to apply treatment to the affected areas only.
• Any fingertips and hands that have been in contact with minoxidil should be washed to avoid the development of unwanted non-scalp hair, including facial hair growth in women.
• Different modes of applicator are provided to aid topical use, the choice depending on the size of the area(s) affected.

Should I refer or investigate?
Refer?
• Consider specialist referral in the following situations:
o Diagnostic uncertainty
o Extensive disease, including alopecia totalis and alopecia universalis
o Pregnant or breastfeeding women
o If secondary care treatments are more appropriate
o If topical treatment initiated in primary care is not effective
o If a wig is required
Investigate?
• Investigations are unnecessary in the majority of people with alopecia areata [MacDonald Hull et al, 2003].
• Routine screening of possible associated autoimmune disease is not justified except if someone has e.g. diffuse hair loss, which may be caused by many other conditions including anaemia, herpes zoster, hypothyroidism, menopause, and psoriasis.
• If the diagnosis is in doubt, investigations that may be performed in either primary or secondary care include:
o Skin scrapings and fungal culture
o Systemic lupus erythematosus and syphilis serology 19
• Biopsies (e.g. incisional) may also be taken (in secondary care only).

Follow-up advice
• People with non-extensive alopecia areata who are managed in primary care should all be reviewed after about 3 months.
• If the condition becomes more extensive, if there are psychological issues that need to be addressed, or if ongoing support is required, then more regular review may be necessary.
• With topical corticosteroids:
o Stop the corticosteroid if the hair regrows, as the likelihood is that this is due to the natural history of the condition.
o If there is no response after 3 months, consider either a further 3-month trial or switching to an alternative topical preparation. If neither option is desirable, refer to a dermatologist.
o Anyone on medium- to long-term corticosteroids should be monitored for adverse effects, and children using long-term topical corticosteroids need to have their growth curve monitored.
• With topical minoxidil:
o If there is no response after 6 months, reassess the management options.
o Stop the minoxidil if the hair regrows, as the likelihood is that this is due to the natural history of the condition. In some people, relapse will occur after discontinuing minoxidil and so further treatment courses and reassessments may be appropriate.

Drug rationale
Drugs not included
• Many potential treatments for alopecia areata are usually only used in secondary care and are therefore not included: see What treatments are not recommended for use in primary care?
• Topical corticosteroid formulations other than gels, lotions, and scalp applications are not included as they may be less user-friendly for people with alopecia areata (e.g. ointments are greasy). Dermatologists recommend a variety of formulations and some may be preferred in different circumstances (e.g. an ointment may be preferred where a more occlusive effect is required [BNF 50, 2005]), and if a specific formulation is preferred by an individual patient, it is important to take this into consideration too.
• Mildly potent topical corticosteroids are not included for use on the scalp in adults as expert opinion recommends the use of potent topical corticosteroids in people with alopecia areata.
• Very potent topical corticosteroids are not included as they are reserved for use under specialist supervision in people with alopecia areata that has proved resistant to potent topical corticosteroids.
Drugs included
• Topical corticosteroid gels, lotions, and scalp applications are included as expert opinion considers that these formulations are more user-friendly than other formulations available (easier to use, easier to wash out, and may cause less irritation), and that they might be better tolerated. Some dermatologists may recommend the use of other formulations in different circumstances, and individual preferences should always be taken into consideration.
• In children and adolescents up to 16 years of age, PRODIGY recommends that specialist advice should be sought before starting a topical corticosteroid, unless the primary care professional is confident in managing alopecia areata in this population.
20
• In adults, a potent topical corticosteroid is recommended (in line with expert opinion) and the following prescriptions are available (as a gel, lotion, or scalp application) on the NHS in England and are included:
o Betamethasone dipropionate 0.05% lotion
o Betamethasone valerate 0.1% lotion
o Betamethasone valerate 0.1% scalp application
o Betamethasone valerate 0.12% foam
o Fluocinolone acetonide 0.025% gel
o Hydrocortisone butyrate 0.1% lotion
o Hydrocortisone butyrate 0.1% scalp application
o Mometasone furoate 0.1% scalp application
• Note: the alcohol content of these products varies and if someone reacts to one product, then it may be worth trying another preparation.
• Topical minoxidil 2% and minoxidil 5% solutions are included as there is some limited evidence to support their use. A private prescription is required as minoxidil solution is not available for use on the NHS, and this might represent significant financial expense for people with alopecia areata.

Patient engagement
Shared decision making
• Alopecia areata is a common form of hair loss. In many cases small bald patches occur. In some cases total baldness occurs.
• Not treating this condition is a common option as there is a good chance that hair will regrow after 3 months or so. The more extensive the bald patches, the less likely it is that the hair will regrow.
• For alopecia areata where less than 50% of the scalp is affected, treatment options include:
o Referral to a skin specialist to consider steroid injections. This is probably the most effective treatment, but does not work in all cases.
o A topical steroid preparation or topical minoxidil. Hair regrowth only occurs in some cases with these treatments. You can also use one of these while you are waiting to see a specialist.
• For more extensive alopecia areata, treatment options include:
o Referral to a skin specialist to consider topical immunotherapy. This is probably the most effective treatment, but does not work in all cases.
o A topical steroid preparation or topical minoxidil. Hair regrowth only occurs in some cases with these treatments. You can also use one of these while you are waiting to see a specialist.
• For any topical treatment, a minimum 3-month trial is recommended. If there is no hair regrowth after 6 months, then it would be reasonable to try an alternative treatment.
• Wigs or hair extensions are an option.
© Crown Copyright 2006
21

Psoriasis Guideline 2006

Introduction
This guidance for the management of patients with psoriasis is based on a document first produced as a multi-author BAD document in 1996. Since this time the BAD has been developing full evidence based guidelines in many areas that overlap with psoriasis. In addition to azathioprine and biologicals, full guidelines are being prepared for PUVA, acitretin, ciclosporin and methotrexate therapy. In the interim, it was felt sensible to update the existing document so this can still be useful without being out of date or misleading.
The document is principally aimed at dermatologists, but will be helpful to general practitioners and other health professionals, including nurses. It may be necessary or even desirable to depart from the suggested course in the interests of specific patients and special circumstances. Just as adherence to guidelines may not constitute defence against a claim of negligence, so deviation from the advice in this document should not be necessarily deemed negligent.
Purchasers or commissioners of dermatology services reading this document should pay particular attention to the provision of day care facilities for the outpatient treatment of patients with psoriasis, the provision of inpatient beds for the treatment of patients with severe or intractable psoriasis, and to the provision of the various forms of ultraviolet therapy.
Good quality information for patients helps with decision making, compliance and effective therapy. All important aspects of psoriasis and the relevant treatments are covered in patient information leaflets on this website.

Clinical Features
The diagnosis of psoriasis is clinical, and laboratory investigations are rarely helpful. There are several forms of psoriasis, and an affected individual may move from one type to another. The extent of involvement can range from small areas to almost total coverage. Psoriasis can change from stable plaques to an unstable form, typified by eruptive inflammatory lesions that are easily irritated by topical treatment.
Drugs thought to precipitate or worsen psoriasis include alcohol, lithium, chloroquine and possibly, sometimes beta-adrenoreceptor blocking drugs and ACE inhibitors. Components involved in the assessment of severity should include: the patient's disability, which can be measured by tools such as the Dermatology Life Quality index (DLQI) the need for treatment, together with an objective assessment of the extent and severity of the disease, assessed by PASI score or body surface area affected. Management should take the patient's views into account. It is helpful to record the patient's view of the most upsetting aspect of their psoriasis.
Management strategies can then be directed appropriately within therapeutic limitations based on the risk:benefit ratio.

Quality of Life
Psoriasis may profoundly affect all aspects of patients' social and personal lives as well as their work. The impact of psoriasis on a patient is not directly related to the overall area affected or to other parameters of disease activity such as redness or thickness of plaques, but more to the site distribution and the attitudes of the patient. It is important to be able to measure handicap caused by psoriasis for use in clinical trials, for audit, to aid clinical decision taking. Questionnaire methods of assessment that can be used to measure quality of life include the DLQI (Dermatology Life Quality Index or Children’s Dermatology Life Quality Index)
These have been validated and used to assess the effect of systemic therapy and of inpatient therapy. They have been used to compare the impact of psoriasis with that of other skin diseases. A DLQI of 10 or more correlates well with severe disease requiring admission, phototherapy or second line therapy and an improvement in DLQI of 5 or more points is considered a worthwhile criterion for response.

Recommendations for initial treatment and when to refer
(joint BAD/PCDS guideline)
• Psoriasis affects 1-2% of the population of the United Kingdom; there is often a positive family history. Most cases are mild
• The degree of psychological and social disability that accompanies psoriasis is commonly underestimated by the medical profession and this can result in suboptimal care
• There is no cure for psoriasis, although there are effective suppressive treatments aimed at inducing a remission or making the amount of psoriasis tolerable to the patient
• For the majority of patients, psoriasis follows a chronic course, interspersed with periods of remission. Relapses are difficult to predict
• The physician should make the patient aware of the possible therapeutic options, including the simplest available therapies and the option that treatment may not be necessary
• The patient's perception of his or her disability will often dictate the need for treatment
• To be able to advise the patient on suitable therapies, the physician needs to know the sites, extent and severity of the psoriasis
• Treatment may depend on the patient's age, sex, occupation, personality, general health, understanding and resources
• Most patients with mild or moderate plaque psoriasis can be treated in primary care using topical therapies
• If the decision is made to refer (see referral) treatment should usually be initiated while awaiting a clinic appointment
• Most patients with uncomplicated psoriasis will only require referral in the instance of treatment failure
Clinical features
• The diagnosis of psoriasis is clinical, and laboratory investigations are unhelpful
• There are several forms of psoriasis, and the type affecting an individual may change over time. The sites and extent of involvement can range from trivial to almost total coverage
• Psoriasis can change from stable plaques to an unstable form, typified by eruptive inflammatory lesions that are easily irritated by topical treatment
• Drugs thought to precipitate or worsen psoriasis include beta-adrenoceptor blocking drugs and NSAIDs. Oral administration of lithium, chloroquine or mepacrine may be associated with severe deterioration of psoriasis. Alcohol may worsen psoriasis and may interfere with treatment in various ways
• Assessment of severity should include the patient's own perception of disability, the need for treatment, and an objective assessment of the extent and severity of the disease
• The total area of involvement is a factor in assessing severity, but is difficult to estimate accurately
• Management should take the patient's views into account. It is helpful to record the patient's views of the most upsetting aspect of his or her psoriasis. Management strategies can then be directed appropriately within therapeutic limitations based on the risk:benefit ratio

Initial presentation
• Basic information about psoriasis and its management should be provided
• To help patients come to terms with what is, for many, a lifelong condition, great efforts should be made to improve communication during consultations and to educate patients
• Patients should have a plan of management, including the therapeutic options for the treatment of their psoriasis at each site involved, and verbal and written information on the probable benefits, and possible side-effects, of each therapy, enabling them to make an informed decision about the treatment
• Ideally, practical demonstrations of the application of treatment should be offered by appropriately trained members of a primary healthcare team
• Points to discuss at initial presentation:
• Explanation of psoriasis, including reassurance that it is neither infectious nor malignant
• Treatment options (including no active treatment)
• The probable benefit the patient can expect from treatment
• Techniques of application of any topical treatment (especially important with dithranol and scalp preparations)
• An introduction to patient support groups may be helpful, e.g. The Psoriasis Association (7 Milton Street, Northampton NN2 7JG Tel - 01604 711129) and the Psoriatic Arthropathy Alliance (PO Box 111, St Albans, Herts AL2 3JQ Tel - 0870 770 3212)

Treatment of chronic plaque psoriasis
• Emollients should be used to soften scaling and reduce any irritation
• For localised plaque psoriasis, e.g. On the elbows or knees, one or more of the following topical preparations can be tried. The sequence of choice will vary according to the extent and pattern of psoriasis, and patient preference:
• A tar-based cream, or a tar/corticosteroid mixture (most are relatively mild; stronger tar preparations tend to be messy)
• A moderate potency topical corticosteroid (e.g. 0.05% clobetasone butyrate); stronger agents can be used on palms and soles or on the scalp
• Use of topical steroids may lead to rebound exacerbation when treatment is discontinued
• A vitamin D analogue (e.g. Calcipotriol, calcitriol or tacalcitol - the latter two tend to be less irritant and are more suitable for face or flexures, but should still be used with caution)
• Calcipotriol with betamethasone dipropionate as a combination product (note that long term data regarding relapse rates is not yet established)
• A vitamin A analogue (tazarotene)
• A dithranol preparation, usually used as a short-contact treatment (these are effective but more difficult to use, especially if there are many small lesions)
• For more widespread plaque psoriasis, e.g. On the trunk or the limbs, the same treatments may be appropriate. However, dithranol is often impracticable to apply to multiple small lesions and will irritate flexures. Topical corticosteroids may be inappropriate for use in widespread psoriasis, particularly more potent agents if used on a long-term basis. Application of treatment by appropriately trained nurses may overcome these problems in some cases
• For scalp psoriasis a tar-based shampoo should be tried first; this can be combined with the use of either a 2-5% salicylic acid preparation, a coconut oil/tar/salicylic acid combination ointment, a potent topical corticosteroid preparation (e.g. 0.1% betamethasone valerate), calcipotriol scalp application, or more than one of these
• It is important to use a keratolytic agent (e.g. 5% salicylic acid in emulsifying ointment) first when there is significant scaling, or other treatments will fail. Keratolytic creams should be applied for a few hours or overnight. A different treatment for day- and night-time is a useful approach
• In palm and sole psoriasis, as for the scalp, both hyperkeratosis and inflammation are usually present and may require separate treatments. Hyperkeratosis usually needs to be treated with a keratolytic agent. Topical steroids (usually potent, due to the thick skin at this site), tars and vitamin D analogues may all be useful
• In general, milder agents are used for flexures. These include low potency topical steroids, mild tar preparations, and tacalcitol or calcitriol (not calcipotriol, this is usually irritant in flexures)
• In facial psoriasis, use mild agents: emollients, mild corticosteroids, calcitriol, tacalcitol, mild tars

Referral
• Those patients with extensive disease who need secondary care treatments such as systemic treatment or phototherapy will normally be under the supervision of a consultant
dermatologist because of the potential adverse effects of these approaches
• The dermatologist will also be involved in the care of difficult cases where the site or unresponsiveness of the rash are important factors
Indications for consultant referral:
• Diagnostic uncertainty
• Request for further counselling and/or education including demonstration of topical treatment
• Failure of appropriately used topical treatment for a reasonable time (e.g. 2-3 months)
• Extensive disease, if unresponsive to initial therapy or difficult to self-manage
• Need for increasing amounts or potencies of topical corticosteroids
• Involvement of sites which are difficult to treat, e.g. Face, palms and soles, genitalia, if unresponsive to initial therapy
• Need for systemic therapy, phototherapy (e.g. guttate psoriasis), day treatment or inpatient admission
• Generalised erythrodermic or generalised pustular psoriasis (emergency referral is indicated); acute unstable psoriasis (urgent referral may be justified)
• Adverse reactions to topical treatment
• Occupational disability or excessive time off work or school

Content of the referral letter:
• The reason for referral and what is hoped to be gained from the consultation
• The consultant should try to address these issues in reply
• The patient's present therapy, if any, its duration, and quantity being used
• Information on previous therapy, including responses or side-effects
• A treatment could be mistakenly recorded as ineffective when the real problem was under-treatment or incorrect use of the prescribed treatment, or discontinued as unsuitable when transient side-effects could have been overcome had more advice been given
• Any relevant background information, including the patient's general health and current medication
• The patient's home circumstances; important because the patients ability to apply topical therapies at affected sites may be compromised, affecting treatment choice

Topical therapy
Topical Coal Tar
Coal tar has been used to treat psoriasis over many years. Although often considered to be safe, there have been doubts about its safety since the 1940's, and recent evidence has provided further evidence on this. There are several commercially available creams, which contain between 0.4% and 2% crude coal tar, and also shampoos, which have a coal tar content of up to 2.5%. Crude extracts of coal tar can be made up in white or yellow soft paraffin, or emulsifying ointment. Coal tar solution is already diluted, so the true concentration of tar in commercial tar products is lower than stated and not equivalent to crude coal tar.

Efficacy
Coal tar is an effective treatment for inducing remission in psoriasis. Coal tar preparations of between 1 and 5% in white or yellow soft paraffin are as effective as higher concentrations. The use of higher concentrations, which has been traditionally advocated, has no evidence-based foundation and is best avoided, especially as it restricts outpatient use.

Safety, side-effects and patient acceptability
Coal tar preparations smell. The crude extract preparations smell more and are messier to use. Recently there has been renewal of concern about the potential carcinogenicity of coal tar products. Occupational exposure to coal tar is associated with an increased risk of skin cancer, and some studies have shown that skin cancers
are more common in patients with psoriasis, although not all studies were controlled for the confounding effects of smoking and alcohol consumption, and many squamous cell carcinomas are accounted for by the effects of photochemotherapy, which may mask other effects. Experimental studies have shown that the use of coal tar shampoos results in the absorbtion of appreciable amounts of polycyclic aromatic hydrocarbons (PAH), substances identified as being carcinogenic. In view of this, the Dutch delegation to the European Commission has suggested limiting the concentration of benzo[a]pyrene (one of the carcinogens known to be in coal tar) in commercially available coal tar products. In Germany, cosmetic manufacturers have voluntarily agreed to ban coal tar from their shampoos.
Despite the above,there is at present, no firm epidemiological evidence that topical tar products cause cutaneous or internal cancer. The extent of percutaneous absorption of tar derivatives in tar-treated patients with psoriasis is currently unknown. It is considered reasonable , therefore, for topical tar containing products remain available.

Synergy with other treatments
Tar treatments act synergistically with ultraviolet B radiation in the traditional Goeckerman regimen. This can be a very effective method of clearing mild psoriasis. In addition, there are reports suggesting that tar and topical steroids have a synergistic effect, and some dermatologists adopt a regimen of a moderately potent topical steroid by day, with tar by night, for ease of patient use. A modified Goeckerman regime using narrow band UVB as the adjunct achieved PASI 75 (75% improvement or more in PASI score) in 95% of cases.

References
Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Cancer 1994; 73: 2759-64
Van Schooten FJ, Moonen EJC, Rhijnsburger E, et al. Dermal uptake of polycyclic aromatic hydrocarbons after hairwash with coal-tar shampoo. Lancet 1995; 344: 1505-6
Zackheim HS. Should coal tar products carry cancer warnings? Cutis. 2004 May;73(5):333-4.
Lee E, Koo J. Modern modified 'ultra' Goeckerman therapy: a PASI assessment of a very effective therapy for psoriasis resistant to both
prebiologic and biologic therapies. J Dermatolog Treat. 2005 Apr;16(2):102-7.

Topical Dithranol
Dithranol has been used for over 50 years in the treatment of stable plaque psoriasis and remains an effective, inexpensive and extensively used topical remedy, without long term local, systemic or teratogenic effects.

Efficacy
Treatment is designed to limit dithranol application to the affected skin by applying dithranol (0.1-2%) in a non-smudging zinc oxide (Lassar's) paste. This is applied to each plaque by a trained nurse or tutored patient and, after covering with powder and Stockinette to reduce smearing, left on for up to 24 hours. Treatment is frequently combined with UVB phototherapy and a tar bath (the Ingram regimen). Patients with plaque psoriasis respond after approximately 20 days of treatment, and relapse at a rate of 10% per month.
Because of the difficulty in its application, this type of dithranol treatment is normally carried out under hospital supervision. Cream or ointment based preparations may smudge onto and, hence, burn, surrounding unaffected skin when used as overnight applications. Application of high concentrations of dithranol (1-10%) for 15-30 minutes daily (short contact therapy), followed by wash-off, allows sufficient dithranol to remain fixed to the plaques for a clinical effect to be obtained without the need for special dressings, as there is less risk of smudging of dithranol onto peri-lesional skin. Skin irritancy may still occur when dithranol is smeared on normal skin during wash-off.
Patients require a careful explanation or, ideally, a demonstration of the technique. Preparations such as dithrocream are available in multiple concentrations. Normally treatment is started at a lower concentration with each course of treatment and gradually increased within the patient’s tolerance, reducing the strength if there is burning and increasing it where possible. Response can be gauged by palpating the plaque. Once lesions are palpably flat dithranol should be discontinued.

Safety, side-effects and patient acceptability
The immediate unwanted effects of skin staining and irritancy, however, limit its use. Brown dithranol staining of treated skin (temporary) and fabrics or bathroom fittings (permanent), is common to all dithranol treatment techniques, and reduces patient acceptability. Skin irritancy is also a problem. Involved psoriatic skin is more resistant to irritancy than the clinically normal peri-lesional skin

Synergy with other treatments
The addition of UVB phototherapy prolongs remission. Comparison of the Ingram and short contact dithranol therapies shows a similar outcome. Dithranol must only be used under expert guidance on the face and flexures, because of the risk of skin or eye irritancy.

Topical Vitamin D Analogues
Three vitamin D analogues are available in the UK for topical treatment of psoriasis, namely calcipotriol, calcitriol and tacalcitol.

Calcipotriol
Calcipotriol is available in ointment and cream formulations containing calcipotriol at the concentration of 50 microg/g, and as a scalp lotion (50 microg/ml). Treatment may be used once or twice daily. Improvement usually becomes apparent within 2 weeks, and continues for at least 8 weeks, at which point some patients are clear but the majority reach a plateau. In the latter case, the improvement can often be maintained by continuing treatment. Calcipotriol is safe, provided that the manufacturer's recommendations are followed and the maximum dose 100g/week for adults, 75g for children over 12 and 50g for children of 6-12 years is not exceeded. Use in children under 6 is not recommended. Calcipotriol is more convenient to use than tar or dithranol and does not produce the side effects of topical corticosteroids However, self limiting, irritant reactions are common.. Calcipotriol has become one of the first-line treatments for psoriasis vulgaris.

Efficacy
Calcipotriol is an effective treatment for mild to moderate chronic plaque psoriasis, more so than calcitriol, tacalcitol, coal tar, and short contact dithranol. Only potent topical corticosteroids seem to have comparable efficacy at eight weeks. Although calcipotriol causes more skin irritation than topical corticosteroids this has to be
balanced against the potential long term effects of corticosteroids. Skin irritation rarely led to withdrawal of calcipotriol treatment.
Use in pregnancy: Although calcipotriol is not believed to be teratogenic, there is little experience of its use in pregnancy.

Safety and side effects
Calcipotriol is irritant and may give rise to redness, soreness or pruritus in around 20% of patients during 6 weeks of treatment. Such reactions are particularly common when the face is inadvertently contaminated with medication. This is self-limiting but occasionally necessitates a break in treatment. This irritancy largely precludes the use of calcipotriol on the face. Flexures are also vulnerable. The maximum recommended rate of usage is 100g of ointment weekly. This should not be exceeded, as there is a risk of vitamin D intoxication.
When doses below 100g weekly have been used, no evidence of any effect has been observed. However, at 100g weekly a small increase in urine calcium excretion is detectable. When the dose rate is increased to 200g or 300g weekly, both urine and serum calcium levels rise, and serum parathyroid hormone is depressed. There are now a number of reports of individual patients in whom hypercalcaemia has developed when the maximum recommended dose rate has been exceeded. Absorption of the vitamin D analogue may be higher in erythrodermic psoriasis, and hypercalcaemia has been reported in such a case when 200g of ointment were applied in 7 days. In another erythrodermic patient, hypercalcaemia developed when using 100g of ointment weekly, and recurred when the treatment was reintroduced at a lower dose rate. There have been four reports of probable sensitisation to calcipotriol. Experience has not lead to concern over the risk of psoriasis rebounding after topical calcipotriol, in a manner similar to that said to occur with topical corticosteroids.

Patient acceptability
Calcipotriol is an improvement on previously existing topical treatments for psoriasis, except for those patients who use emollients alone. Compared to dithranol, it is less irritant, less messy and more convenient. Patients' opinions regarding the acceptability of these treatments have been directly compared in a large trial: calcipotriol
was considered more acceptable. It is less messy than tar, and is free from the odour of tar, which some patients dislike. Calcipotriol is free from the side effects of topical corticosteroids, which are a source of concern to patients. Calcipotriol is often irritant. Although this is a disadvantage, it is only occasionally necessary for treatment to be discontinued as a result.

Synergy with other treatments
Published data suggest that there is a useful additive effect when calcipotriol is used in conjunction with PUVA, cyclosporin, and UVB. It would appear possible that the use of calcipotriol may allow a useful dose sparing effect with UVB phototherapy or PUVA, and systemic treatments, and thus reduce their toxicity, but more research is required to address this question.

References
Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol. 2002 Mar;146(3):351-64.

Calcitriol
This ointment contains vitamin D in the form of 1:25 dihydroxy-cholecalciferol, at the concentration of 3 microg/g. Advantages of calcitriol are that it is less irritant than calcipotriol and may, therefore, be suitable for use on the face and flexures. Duration of remission is greater than with potent topical steroids. The rate of application should not exceed 30g ointment per day and it should not be applied to more than 35% of the body surface daily. More published data are currently needed, before clear guidelines can be issued to establish the precise role of this product. It is a clean non-smelly preparation which is well tolerated and more effective than short contact dithranol therapy.

Use in pregnancy and children
Calcitriol has not been licensed in children and not adequately assessed in pregnancy. There is some evidence in animals of
developmental toxicity at doses, which caused maternal toxicity, and calcium levels should be monitored in situations where it has been used in restricted amounts out of necessity. It also passes into breast milk and should be avoided in breastfeeding.

Tacalcitol
Tacalcitol 4 microg/g is also less irritant but less effective than calcipotriol. It is suitable for use on the face and flexures and the amount applied should not exceed 10g/day. It has not been licensed for use in children and although no toxicity has been found there is insufficient data to support its use in pregnancy and lactation.

Calcipotriol/betamethasone dipropionate
A novel ointment comprising betamethasone 0.05% (as dipropionate), calcipotriol 50 micrograms/g has greater efficacy than either constituent used alone. However, the cost of treatment is also greater and the restrictions that apply to potent topical steroids in psoriasis (see below) apply.
It is normally used in the initial treatment of stable plaque psoriasis where calcipotriol has failed. Patients should be instructed to apply once daily to a maximum of 30% of body surface for a maximum of 4 consecutive weeks; max 15 g daily, max 100 g weekly. After this period repeated treatment with Dovobet can be initiated under medical supervision. A frequent compromise is to use the combined product for 4 weeks alternating with 4 week periods of Calcipotriol. Over the 52 weeks this alternating combination optimised response with the least side effects. It is not recommended for children and adolescents under 18 years and is unsuitable for use on the face or flexures.
Potent topical corticosteroids should be avoided or given only under specialist supervision in psoriasis because, although they may suppress the psoriasis in the short term, relapse or vigorous rebound occurs on withdrawal (sometimes precipitating severe pustular psoriasis). Topical use of potent corticosteroids on widespread psoriasis can lead to systemic as well as to local side-effects

Tazarotene
Tazarotene (0.05% and 0.1%) gel is a topical retinoid which is effective in psoriasis. It is clean and odourless and should be appled once daily for 12 weeks. Irritation is common but it is minimised by adjusting the strength of the treatment and by applying tazarotene sparingly to the plaques, avoiding normal skin. It is suitable for the treatment of moderate plaque psoriasis affecting up to 10% of skin area. Patients should be instructed to wash their hands immediately after use, avoid contact with eyes, face, skin folds, hair-covered areas of the scalp, and eczematous areas. They should also avoid excessive exposure to UV light (including sunlight, solariums, PUVA or UVB treatment) and should avoid applying emollients or cosmetics to the treated area within 1 hour of application

Use in pregnancy and children
As a retinoid this preparation is potentially teratogenic and should strictly be avoided in pregnancy. Women of child-bearing age must ensure adequate contraceptive protection. It is not recommended for use in breastfeeding mothers or children/adolescents under the age of 18.

Side-effects:
Side effects include local irritation (more common with higher concentration and may require discontinuation), pruritus, burning, erythema, desquamation, non-specific rash, contact dermatitis, and worsening of psoriasis; rarely stinging and inflamed, dry or painful skin

Topical Corticosteroids
Topical Corticosteroids are effective, cosmetically acceptable and safe if used carefully under supervision.

Efficacy
A wide selection of products is available ranging from very mild (e.g. 1 per cent hydrocortisone) to highly potent (e.g. 0.05 per cent clobetesol propionate) enabling accurate titration of the potency of the preparation prescribed against the patient's needs. The potency of the cream or ointment used depends not only on the inherent activity of the steroid molecule itself and its concentration, but also on the excipient in the vehicle used in the formulation. Topical corticosteroids are best used on limited areas of psoriasis. More
resistant areas such as the hands, feet and scalp can initially be treated by potent corticosteroids from the onset. There is no evidence that twice daily application of topical steroids is more effective than once daily application. The strength of the steroid should be adjusted commensurate with clinical improvement. In especially resistant psoriasis of the limbs, hands or feet, occlusive treatment in which the treatment area is covered by a thin polythene film will greatly enhance effectiveness (and also local and systemic toxicity). This measure should only be continued for a few days at a time. Flexural areas are usually self occluded and therefore require only mild potency topical steroid treatment, as does the face and neck.

Safety, side-effects and tolerance
Corticosteroid resistance (tolerance) may develop and the use of corticosteroids may be accompanied by local side effects especially if occlusive therapy has been used. These include thinning of the skin and telangiectasia (usually reversible) and irreversible steroid striae. Other side effects include rapid relapse time and transformation to unstable or pustular psoriasis. In extreme cases systemic toxicity including pituitary adrenal suppression and the clinical features of Cushing's syndrome may be caused by extensive percutaneous absorption. These risks are related not only to the potency of the preparation used but also to the total daily amount applied. If appropriate guidelines are followed (below) the use of a British National Formulary mild steroid on the face and flexural areas, and a moderate or, in exceptional circumstances and for a short period a high potency corticosteroid elsewhere is acceptable.
Rarely glaucoma may occur from the use of topical steroids on the eyelids and periorbital area. Systemic toxicity is also more likely to occur in infants and small children because of the large surface area relative to mass. Tolerance may occur in response to continued use of any topical steroid and is related to duration of use rather than potency. Its mechanism is unknown. Use of alternative non-steroid topical treatment usually results in recovery of responsiveness to the corticosteroid. Contact allergy is occasionally a complication of topical corticosteroid treatment and can be confirmed by appropriate patch testing. Newer steroids including mometasone, prednicarbate and fluticasone propionate are more rapidly inactivated or metabolised following percutaneous absorption although retaining local efficacy and local potential for adverse effects. No unsupervised repeat prescriptions should be made: patients should be reviewed every 3 months
• No more than 100 g of a moderately potent or higher potency preparation should be applied per month
• Attempts should be made to rotate topical corticosteroids with alternative non-corticosteroid preparations
• Use of very potent or potent preparations should be under dermatological supervision. The fingertip unit is a measure which helps patients to know how much ointment or cream to apply.
• No topical corticosteroid should be used regularly for more than four weeks without critical review.
• Potent corticosteroids should not be used regularly for more than 7 days.

Synergy with other treatments
A topical corticosteroid can be used as a monotherapy or in conjunction with other topical agents including tar or dithranol. Some patients who fail to respond to one topical agent may respond to another and it is worthwhile rotating different classes of topical agents before abandoning topical treatment altogether.

Specific Sites
Chronic Plaque Psoriasis
Depending on patients' wishes, appropriate management includes the option of no active treatment. If active treatment is required, most patients can be adequately managed with topical agents of proven efficacy including the use of a simple emollient, dithranol, corticosteroids and vitamin D analogues. Each patient must be individually assessed. Large individual psoriatic plaques can be treated with dithranol, tar or vitamin D analogues. Smaller and more numerous lesions are more difficult to treat with dithranol, but vitamin D analogues, mild tar preparations and corticosteroid are still appropriate. The effect of topical treatments can usually be enhanced by UVB phototherapy.
Care is needed when a patient's psoriasis is in an inflammatory, eruptive or unstable phase. In these circumstances, the skin may show general, non-specific irritancy to topical agents, and treatment
should be confined to emollients or low concentrations of tar, corticosteroids or dithranol.

Guttate Psoriasis
In most cases, guttate (exanthematous papulosquamous) psoriasis is a self-limiting condition. Many patients who have one attack of guttate psoriasis have no further relapses. The general principles for treatment outlined above are applicable to guttate psoriasis. Erupting guttate psoriasis is commonly less tolerant of topical therapy, and therefore calcipotriol, mild or moderately potent corticosteroids, or low concentrations of tar and dithranol should be used. UVB phototherapy may be helpful. A proportion of patients with acute guttate psoriasis have evidence of recent streptococcal infection, which can be confirmed by culture examination of a throat swab and by determination of the serum antistreptolysin O titre. Evidence does not support a therapeutic benefit from antibiotic therapy. However, repeated attacks of guttate psoriasis after well documented episodes of tonsillitis represent an indication for tonsillectomy.

Localised Pustular Psoriasis of Palms and Soles
Pustular psoriasis of the palms and soles is a relatively rare form of chronic psoriasis typified by multiple sterile pustules. Treatment is unsatisfactory but calcipotriol or a potent topical corticosteroid may help. Topical coal tar and dithranol may also be of some benefit and some success can be achieved with the systemic agent acitretin or with photochemotherapy (8 methoxypsoralen-UVA phototherapy; PUVA). In disabling palmoplantar psoriasis systemic therapy may be required with acitretin or methotrexate.

Generalised Pustular and Erythrodermic psoriasis
For the small group of patients with these forms of psoriasis, initial management usually consists of admission to hospital and the use of systemic agents.

Psoriasis of the Scalp
This form of plaque psoriasis can be difficult to manage especially in a domiciliary setting. Thick scale should be softened, by olive, coconut or arachis oil, ideally applied under occlusion (e.g. using a plastic shower cap or cling film), then removed using a detergent shampoo. This can be followed by applications of a coal tar, dithranol, or a topical steroid or vitamin D analogue preparation.
Topical salicylic acid preparations, e.g. 2% salicylic acid in a cream base such as Unguentum M, or coconut oil ointment (e.g. Cocois scalp ointment), can be used to remove thick scale from the scalp.

Phototherapy
Both therapies require good metering and equipment monitoring by trained staff. All patients should be aware of the adverse effects and chronic risks, and a detailed record of an individual's treatment should be kept.

UVB Phototherapy
Broad band ultraviolet radiation in the waveband 290-320 nm (UVB), or narrow band UVB 311nm are an effective treatment of guttate or plaque psoriasis resistant to topical therapy. It is initiated by experienced dermatologistsand is administered under supervision of trained dermatology nursing staff or physiotherapists. Patient compliance is usually good, with the treatment viewed as an escape from the problems of topical agents. Restrictions in use for individual patients often relate to time off work and travel costs.
Within the UK, a range of equipment is in use. The older broad-band UVB fluorescent sources are considered less effective, in time to clear and length of remission period Narrow-band (311nm) phototherapy emits light close to the peak therapeutic wavelengths for psoriasis and has a greater efficacy than broad-band fluorescent tubes. Further guidelines on dosimetry and monitoring are available on this site (BAD guidelines)

Safety, side-effects and patient acceptability
Current human use suggests that TL-01 has a similar long-term risk to the older broad-band tubes and a reduced risk when compared to PUVA
Those patients who have a history of previous skin malignancy, systemic lupus erythematosus or xeroderma pigmentosum, should be excluded from treatment. UVB phototherapy has advantages over PUVA in that it can be used in children, during pregnancy, and does not require photoprotective spectacle use post-treatment. The principal unwanted effects of UVB phototherapy are acute skin burn, which can be avoided by careful dosimetry, and, when used over a long period, a presumed dose-related increase in the risk of developing cutaneous malignancy.

Efficacy
Although UVB phototherapy has been extensively studied, dosage regimens vary, and it seems that different skin type populations require different treatment approaches. The starting dose of UVB can be judged by estimation of the minimal erythema dose (MED). This approach is not essential, and a low dose fixed increment regimen is an acceptable alternative. A suggested approach is to start at 70% of the MED value. Subsequent doses can be increased by 40% of the immediately preceding dose, if there is no erythema, and 20% if there is a slight erythema, or held at the same exposure, if there is a marked response to the previous treatment. With such a regimen, treatments are generally given no more frequently than every two days. It is usual for a course of UVB phototherapy to take between 10 and 30 treatments to achieve clearance

Synergy with other treatments
Combination with other anti-psoriasis treatments such as tars, topical calcipotriol, and oral retinoids have been shown to be effective, increasing the rate of clearance with reduced total UVB exposure to clearance. However, most patients enjoy the freedom from topical therapies and their accompanying adverse effects, so adjunctive treatment is often reserved for resistant cases.

Photochemotherapy (PUVA)

Administration of oral or topical psoralens, followed by irradiation with long wave ultraviolet (320 to 400nm) (UVA), is an established, effective, widely used form of treatment (Psoralens + UVA = PUVA), although it is unlicensed in the UK. While it does have acute adverse effects (i.e. skin burning, nausea and pain) and chronic consequences (i.e. skin ageing, pigmentation and carcinogenicity), it continues to be used for more difficult to clear psoriasis resistant to topical preparations and UVB. Examples of different regimens for the administration of PUVA are listed in the British Photodermatology Group Guidelines for PUVA. Other detailed information sources are available.

Efficacy
Two main PUVA regimens are used. The first involves the use of the minimal phototoxic dose (MPD) to determine the first treatment dose of a course. Such an approach would be similar to that used for UVB phototherapy with, perhaps, 70% of the MPD, followed by successive
doses increased by 40% increments, if there is no erythema, or 20% if the erythema response was slight. As the phototoxic effect is maximal at 48 to 72 hours, treatment is usually given twice weekly. Another approach has a fixed starting dose, which will vary with skin type, followed by fixed or percentage increments as above. No adequate studies have been published to state clearly which approach is best for a particular patient populations. It is common practice for 8-methoxypsoralen (crystalline 8-MOP) to be taken orally 2 hours prior to UVA irradiation. To achieve consistent and optimal absorption of psoralens throughout a course of PUVA, the drug should be taken with a light meal.

Safety, side-effects and patient acceptability
As there is a theoretical risk of cataract formation, patients are advised to wear eye protection for 24 hours from the time of psoralen ingestion. Further advice on eye protection can be found elsewhere on this site (BAD guidelines). If nausea occurs with 8-MOP, 5-methoxypsoralen or bath PUVA using 8-MOP or trimethoxypsoralen (TMP), can be considered. Some centres use the bath approach as the routine, preferring the confidence of knowing the drug to be at the target site, coupled with the possibility that TMP and PUVA may be less carcinogenic than oral forms.
As the risk of developing cutaneous malignancy is related to the number of treatments or the cumulative dose of UVA, PUVA-sparing measures, or alternative treatments, can be used to restrict the total amount of UVA administered. In a follow-up report on the large North American cohort group, it is suggested that patients may be at long term risk of developing squamous cell carcinoma after as little as 120 treatments of PUVA. Those who have had more than 300 treatments have 83 times the risk of developing squamous cell carcinomas which can be multiple and metastasising. Some patients are particularly susceptible, due to other risk factors (e.g. exposure to concomitant methotrexate, ionising radiation or arsenic). This suggests that long-term follow up of high dose PUVA patients is important. Although maintenance PUVA therapy is not recommended, and has been associated with the development of squamous cell carcinoma, informed patients may choose to continue with this approach if no safer alternative treatment exists. Some evidence suggests that Melanoma incidence may increased many years after PUVA therapy, although the North American study was not consistent with the experience in Northern Europe.

Synergy with other treatments
As with UVB, adjunctive therapy using vitamin D analogue preparations, and retinoids, have been shown to be effective and are worth considering if PUVA monotherapy is inadequate.

Operation of phototherapy services
• A senior clinician, usually a consultant, with adequate training and a continuing interest in phototherapy and/or photochemotherapy should supervise the service
• An individual patient's course of therapy should be supervised by an adequately trained person (e.g. a doctor, nurse or physiotherapist)
• All phototherapy equipment should be adequately maintained and regularly calibrated by adequately trained personnel
• Accurate records of the dosage and number of treatments, for each patient, must be maintained
• Neither UVB nor PUVA should be used as permanent maintenance therapy unless alternative topical therapies have proved ineffective

References
Diffey, B.L. Factors affecting the choice of a ceiling on the number of exposures with TL01 ultraviolet B phototherapy. British Journal of Dermatology 149 (2), 428-430.
Guidelines for dosimetry and calibration in ultraviolet radiation therapy: a report of a British Photodermatology Group workshop www.bad.org.uk/guidelines
Weischer M, Blum A, Eberhard F, Rocken M, Berneburg M.No evidence for increased skin cancer risk in psoriasis patients treated with broadband or narrowband UVB phototherapy: a first retrospective study.Acta Derm Venereol. 2004;84(5):370-4.
British Photodermatology Group. British Photodermatology Group Guidelines for PUVA. Br Med J 1994; 130: 246-55.
Lindelof B, Sigurgeirsson B, Tegner E, Larko O, Johannesson A, Berne B, Ljunggren B, Andersson T, Molin L, Nylander-Lundqvist E,
Emtestam L. PUVA and cancer risk: the Swedish follow-up study Br J Dermatol. 1999 Jul;141(1):108-12
Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study.N Engl J Med. 1997 Apr 10;336(15):1041-5.

Systemic therapies for psoriasis
For an excellent evidence based review of systemic therapy see Griffiths CE, Clark CM, Chalmers RJ, Li Wan Po A, Williams HC. A systematic review of treatments for severe psoriasis. Health Technol Assess. 2000;4(40):1-125

Indications for Systemic Therapy
• Failure of adequate trial of topical therapy
• Repeated hospital admissions for topical therapy
• Extensive chronic plaque psoriasis in the elderly or infirm
• Generalised pustular or erythrodermic psoriasis
• Severe psoriatic arthropathy
• Patients considered for systemic therapy will usually conform to the rule of tens whereby the body surface area affected is greater than 10%, or the PASI score is greater than 10 or the DLQI is greater than 10.

Methotrexate
Methotrexate is an effective antipsoriatic agent. It is especially useful in acute, generalised, pustular psoriasis, psoriatic erythroderma, psoriatic arthritis, and for extensive chronic plaque psoriasis in patients who are inadequately controlled by topical therapy alone. In comparison with other systemic therapies for psoriasis, it is inexpensive and of comparable efficacy. It can be used either as a short term option, to gain control of unstable psoriasis such as pustular psoriasis or erythroderma before returning to the other
modes of treatment, or, more often, as long term maintenance treatment. The most important potential side effect is acute marrow suppression, which is the cause of most of the rare deaths attributable to methotrexate therapy of psoriasis. Long term treatment carries with it a risk of hepatic fibrosis and cirrhosis, which is related to the dosage regimen employed, and is increased by exposure to other hepatic toxins, in particular alcohol. The correlation between the cumulative lifetime dose of methotrexate and the risk of development of hepatic fibrosis or cirrhosis is not clear-cut.

Safety, side-effects and patient acceptability

Haematological or renal abnormality: Methotrexate should be avoided in patients with significant haematological abnormalities including severe anaemia, leucopenia or thrombocytopenia. Methotrexate should also be avoided, in all but exceptional circumstances, in patients with significant renal impairment. Because methotrexate is eliminated largely via the kidneys, toxic levels may build up rapidly in patients with renal impairment, and even low doses of the drug may then produce acute myelosuppression. This is particularly liable to occur in the elderly when concomitant drug administration or illness, such as fever or diarrhoea, may result in the sudden deterioration of renal function. Elderly patients especially, should be warned to omit methotrexate doses whenever they are at risk of acute dehydration (e.g. from acute fever, vomiting or diarrhoea).

Drug Interactions: Certain drugs may increase the toxicity of methotrexate by increased antifolate effect (e.g. sulphonamindes, trimethoprim and phenytoin), or by decreasing renal elimination (e.g. aspirin, NSAIDs, probenecid and cyclosporin). As life-threatening myelosuppression may result from interactions between methotrexate, and such drugs, great care must be taken to ensure that all medical attendants are made aware when a patient is receiving methotrexate and patients should be advised to check with their pharmacist on the safety of any new drug prescription they receive.

Liver disease and alcohol: Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. Any patient suspected of alcohol abuse is usually unsuitable for methotrexate, although many dermatologists allow patients receiving methotrexate to continue taking small amounts of alcohol (e.g. 4-6 units weekly).

Fertility: Because methotrexate is both abortifacient and teratogenic it is strictly contraindicated in pregnancy. Adequate contraceptive measures must be taken by women of child-bearing potential during methotrexate therapy, and for at least three months after stopping the drug. Although methotrexate is not mutagenic, and normal children have been born when the father was taking methotrexate at the time of conception the drug may affect spermatogenesis. Men should therefore be advised to avoid fathering children during therapy and for three months after. Discontinue methotrexate and refer immediately if a patient or partner discovers they are pregnant while taking methotrexate
Other precautions: Other important contraindications to the use of methotrexate in psoriasis include active peptic ulceration, active infectious disease, such as tuberculosis or immunodeficiency states, and patient unreliability.

Prescribing methotrexate
Initiation of therapy: The risks and benefits of therapy should be clearly explained to the patient, both verbally and in writing. In addition to the patient information leaflet on this web-site the BAD have produced a hand held patient information leaflet that complies with the National Patient Safety Agency directives for safe use of this of therapy and a hand held patient record to facilitate patient monitoring. These will be available in early 2006. A clear record of the history (including previous therapy), and the extent of psoriasis, should be made. Adequate contraceptive measures must be commenced where appropriate. A full blood count and tests of renal and hepatic function (see below) should be performed. If there are no contradictions, then therapy may be commenced. The dose of methotrexate must be individually assessed for each patient. Most serious problems and the rare deaths associated with methotrexate usage in psoriasis arise because of an absolute or relative overdosage.
Methotrexate is usually given orally but may be administered by the intramuscular or intravenous route. Recently the subcutaneous route has become more practical with the advent of the biological therapies. Details of the subcutaneous route to maximise bio-availability and improve tolerance and safety are to be found on http://www.rcn.org.uk/publications/pdf/administering-methotrexate.pdf It should be given as a single weekly dose. For oral dosing the BAD recommend all patients be prescribed the 2.5mg tablets to avoid
confusion and overdosing on the 10mg tablet formulation. Unambiguous instructions, including which day of the week the tablets are to be taken, should be given to the patient and specified on the prescription. The rationale proposed for giving methotrexate in three divided doses once weekly is obsolete as this schedule is more open to error and may be associated with a greater risk of hepatic fibrosis.
A small test dose, usually 5mg, should be given in order to detect those patients who may be unduly sensitive to the drug. If the full blood count is stable, at seven days, then methotrexate may be continued. Subsequent doses may be gradually increased, usually by 2.5-5 mg steps, according to clinical response and any accompanying toxicity. The aim of therapy should not be to induce complete clearance of psoriasis but to achieve sufficient control that it may be more readily managed with topical therapy. Most patients are adequately controlled on doses of 7.5-15mg weekly and few patients require more than 20mg. The maximum weekly dose should not exceed 30mg. Lower doses are required in the elderly and those with renal impairment.
Monitoring therapy: Initially, patients should be assessed weekly by examination and laboratory measurement of the full blood count, plasma urea, electrolytes and creatinine, and liver enzyme tests. The interval between visits may be gradually increased until therapy has been stabilised, after which continuing assessments should be performed every two to three months. The exact time intervals will vary according to circumstance. Mechanisms should be in place to ensure that further supplies of the drug are dispensed only if appropriate monitoring has been carried out, and that blood test results are reviewed promptly after each visit so that any necessary action, such as dosage reduction, can be taken without delay. In any individual the dose of methotrexate required to maintain adequate control of psoriasis will vary from time to time, and should be adjusted accordingly.
Although liver biopsy is the gold standard measure for hepatic fibrosis due to methotrexate it carries significant risks and the need for this intervention can be considerably reduced by monitoring the serological markers of fibrosis, particularly the aminoterminal peptide of type III procollagen (PIIINP). Patients whose PIIINP levels are consistently normal are very unlikely to have significant liver damage, and liver biopsies may be restricted to the small minority in whom PIIINP levels are repeatedly elevated. PIIINP assay should be performed three monthly and liver biopsy should then be considered
for patients in whom it is persistently abnormal (i.e. greater than 4.2ng/ml for the Orion assay).
Where possible, serum should be collected for PIIINP measurement prior to starting methotrexate. It should subsequently be measured every 2-3 months during continued treatment.

Indications for Considering Liver Biopsy:
• Elevation of pre treatment PIIINP above 8.0 mcg/l
• Elevation of PIINP above normal range (1.7-4.2mcg/l) in at least three samples over a 12 month period.
• Elevation of PIINP above 8.0mcg/l in two consecutive samples.

Indications for considering withdrawal of methotrexate:
• Elevation of PIIINP above 10 mcg/l in at least three samples in one 12 month period.
The decision whether to perform liver biopsy, withdraw or continue treatment despite raised PIIINP levels must also take into account other factors such as disease severity, patient age and the ease with which alternative therapies may be used in place of methotrexate.

As alcohol abuse greatly increases the risks of liver damage in patients receiving methotrexate, they should be reminded regularly of the need to restrict or avoid alcohol intake. Liver damage cannot be reliably detected by standard liver enzyme tests. The risk of serious liver damage in carefully monitored patients receiving once weekly low dose methotrexate is small and the cost and morbidity of repeated liver biopsy may be difficult to justify when compared with the low yield of significant liver pathology. It is, thus, reasonable to recommend that liver biopsy need no longer be performed routinely. If there are concerns about pre-existing liver damage, it may be appropriate to obtain a liver biopsy as a baseline soon after successful methotrexate therapy has been established. The best practice for liver biopsy is for this to be done, by radiologists, under ultrasound control.
Management of problems: Nausea is the commonest side effect reported by patients and may affect up to a quarter of all patients treated. It usually appears within 12 hours of methotrexate ingestion and may last up to three days. It is usually mild, but in some patients, it is sufficiently severe enough to necessitate withdrawal of therapy. No measures are guaranteed to relieve symptoms. The subcutaneous administration has helped reduce problems with gastrointestinal intolerance.
Folic acid, supplementation has been found to be helpful in preventing folate deficiency, reducing myelotoxicity and improving tolerance of methotrexate. It is broadly recognised that folate supplementation should be initiated with methotrexate therapy although practice varies regarding the dose. Commonly it is taken on the 6 days of the week when methotrexate is not taken. The minimum dosage recommended is 5mg taken once weekly.
Although liver enzyme tests are an unreliable indicator of liver fibrosis, an acute rise in liver enzymes may indicate hepatic inflammation. If aspartate or alanine aminotransferase levels rise to greater than three times the upper limit of normal methotrexate would normally be discontinued.
The decision to discontinue methotrexate depends not only on PIIINP and/or the results of liver biopsy, but also on the ease with which an individual patient's psoriasis may be managed by other means. Severe fibrosis and cirrhosis are considered contraindications to further methotrexate therapy. Nevertheless some dermatologists have continued treatment in patients with documented cirrhosis without encountering significant deterioration of liver disease. In patients with hepatic inflammation or mild to moderate fibrosis without cirrhosis, continuation of methotrexate therapy is probably still safe, as long as alcohol is strictly avoided and patients are closely monitored. If PIIINP remains elevated, then a further liver biopsy should be considered, after twelve months to two years of continued therapy.
A rise in the mean corpuscular volume (MCV) is common in patients receiving long term methotrexate, and usually indicates relative folate deficiency. If the MCV rises above the upper limit of normal, folate deficiency is likely and supplementation may be inadequate. If this occurs, it is important to exclude other causes of macrocytosis, in particular vitamin B12 deficiency. If the MCV rises above 106 fl, despite folate replacement, then further methotrexate therapy is probably contraindicated. It is important to note that folate therapy does not reduce the therapeutic effect of methotrexate.

Managing overdosage
Absolute or relative overdosage of methotrexate can result in acute toxicity, manifested clinically by myelosuppression, mucosal ulceration and, rarely, cutaneous necrolysis. The metabolic effects of methotrexate can be bypassed by the administration of folinic acid, which should be readily available to any dermatologist prescribing methotrexate. As soon as overdose is suspected, serum should be collected for measurement of methotrexate levels and folinic acid should be administered intravenously.
In suspected cases of Methotrexate overdose or severe haematological toxicity consider treatment with Folinic acid. The initial dose should be at least 20 mg, given intravenously. Subsequent doses of 15 mg (which may be taken orally) should be given at 6 hourly intervals until the haematological abnormalities are improved (usually not more than 2-8 doses). If serum methotrexate is measured, a dose of 20mg usually is sufficient for a methotrexate concentration of 0.5 micromoles/l or less.
Adequate hydration is essential to ensure maximal renal elimination and, in cases of massive overdose, alkalinisation of the urine with sodium bicarbonate may be required to prevent precipitation of methotrexate in the renal tubules. In patients with poor drug excretion or delayed drug absorption, methotrexate levels can remain dangerously elevated for several days after an overdose and folinic acid should be continued until it is certain that all methotrexate has been excreted. If plasma methotrexate levels are unavailable folinic acid should be continued until the blood count has returned to normal and the mucosae have healed. Early treatment may be life-saving. Every dermatologist using methotrexate should know how to manage overdosage.

Synergy with other treatments
Most forms of topical treatment can be continued in a patient on methotrexate. Systemic immunosuppressive drugs and UV radiation are not usually administered concurrently with methotrexate.

References
Maurice PD, Maddox AJ, Green CA, Tatnall F, Schofield JK, Stott DJ. Monitoring patients on methotrexate: hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen. Br J Dermatol. 2005 Mar;152(3):451-8.
Chalmers RJ, Kirby B, Smith A, Burrows P, Little R, Horan M, Hextall JM, Smith CH, Klaber M, Rogers S.Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis. Br J Dermatol. 2005 Mar;152(3):444-50
Zachariae H, Heickendorff L, Sogaard H. The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up. Br J Dermatol. 2001 Jan;144(1):100-3
Boffa MJ. Methotrexate for psoriasis: current European practice. A postal survey. J Eur Acad Dermatol Venereol. 2005 Mar;19(2):196-202
Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol. 2005 Oct;53(4):652-9

Oral Retinoids
The oral retinoid of choice in the treatment of psoriasis is acitretin. This is the carboxylic acid metabolite of etretinate, the first oral retinoid drug to be used for this disease. Acitretin is readily absorbed and widely distributed after oral administration.

Efficacy
Acitretin has been shown to be an effective agent when given alone for psoriasis, Goldfarb et al found a 66% clearance after 24 weeks, and Berbis et al found an 80% or greater clearance in a 12 week study. Acitretin is effective as a monotherapy, and can be expected to produce about 70% clearance in approximately 8 weeks.
Long term treatment with acitretin may be required as retinoids are only suppressive. Anecdotal evidence suggests that the therapeutic effect is maintained and treatment resistance does not occur.

Synergy with other treatments
Combination with PUVA treatment was found superior to PUVA combined with placebo, with regard to clearance time (47.8 versus 65.4 days), the number of exposures (13.7 compared to 19.9), and the number of patients remitting completely (94% compared to 65% at 10 weeks). The major advantage of combining acitretin with PUVA is the reduction in the dose of UVA, and some reduction in the daily dose of acitretin, to achieve clearance. On this basis, it may be expected that there will be a reduction in the long term side effects of both forms of treatment.

Safety, side-effects and patient acceptability
Acitretin therapy is associated with a large number of side effects and toxicity reactions.
Mucocutaneous and other minor adverse reactions: Acitretin causes mucocutaneous side effects in virtually all patients to whom it is administered in therapeutic doses. Drying and cracking of the lips, referred to incorrectly as cheilitis, may be expected in all after 2 - 4 weeks. For the majority of patients, this is a minor inconvenience that can be improved symptomatically by the use of a bland greasy application, such as white soft paraffin.
Dryness of the nasal, buccal and conjunctival mucosae occurs in a relatively small proportion. An increased rate of loss of scalp hair occurs in 20 - 30% patients, but is only severe enough to be noticeable and cause distress in a few women. Peeling of the skin of the palms and soles, and the development of areas of dermatitis, occurs in 5-50% of patients. Skin stickiness, skin and nail fragility, and itchiness are also seen in a minority of patients. Paronychia, and the development of curly hair, are other infrequent side effects. Musculoskeletal side effects, with arthralgia and myalgia, are uncommon.
As with all retinoid drugs, there is a high risk of teratogenicity if acitretin is administered during the first 3 months of pregnancy. As acitretin can be reverse metabolised to etretinate which has a long half life, pregnancy should be avoided for a period of 2 years after stopping acitretin. Numerous congenital malformations may occur, including Fallot's tetralogy, other cardiac defects, microcephaly, spina bifida and limb defects. Great care must be undertaken to ensure that all fertile women who are described acitretin understand the risk, that they are not pregnant from the start, and that they comply with secure contraceptive measures.
Elevation of liver enzymes is common, occurring in 20 - 30% patients. It is mostly of a minor degree, may be transient, and is generally of little significance. Hepatitis is rare, and maybe of the hypersensitivity, direct toxic, or cholestatic types. Modest elevation of plasma lipid levels occurs in up to 25% of patients, with increases in low density lipoproteins and decreases in high density lipoproteins. In individuals taking acitretin for psoriasis in the longer term, there is a risk of accelerated atherosclerosis if hyperlipidaemia persists. Those with elevated levels of lipids, should be given dietetic advice and, if necessary, lipid lowering agents prescribed.
Retinoid drugs possess the potential for bone toxicity, but it is uncertain to what degree that risk exists in those taking acitretin at the recommended dosage for periods of a few months to up to 2 years. Ossification of ligaments and tendons, bony spurs, and diffuse skeletal hyperostosis, has been reported in 86% of patients taking acitretin for 1 - 3 years at a dose of 10 - 75mgs per day, but adequate determination of the existence of these defects prior to therapy was not made. Premature epiphyseal fusion, and other bone abnormalities such as ossification of interosseous membranes, is rare.

References
Goldfarb MT, Ellis CN, Gupta AK, et al. Acitretin improves psoriasis in a dose dependent fashion. J Am Acad Dermatol.1988;18:655-62.
Berbis P, Geiger JM, Vaisse C, et al. Benefit of progressively increasing doses during the initial treatment with acitretin in psoriasis. Dermatologica.1989; 178: 88-92
Saurat JH, Geiger JM, Amblard P, et al. Randomised double-blind multicenter study comparing acitretin PUVA, etretinate PUVA and placebo PUVA in the treatment of severe psoriasis. Dermatologica. 1988;177:218-24.
Kilcoyne RF. Effects of retinoids in bone. J Am Acad Dermatol. 1988;19: 212-16.

Ciclosporin
Ciclosporin is a highly effective and rapidly acting systemic treatment for psoriasis. This drug was first discovered in 1970, and was developed as an immunosuppressant for use in organ transplantation. The first controlled trial in psoriasis was published in
1986, and a license was granted in the U.K. for the treatment of severe psoriasis in 1992.
The main side effects are renal impairment and hypertension, both of which are largely reversible provided that guidelines regarding monitoring and dosage are followed. In other situations such as transplantation, the incidence of lymphoma is increased in patients receiving long-term ciclosporin. However, these individuals are much more intensively immunosuppressed than those taking ciclosporin for treatment of psoriasis.

Dosage regimens
For treatment of psoriasis the dose should not normally exceed 5 mg/kg/day and this is usually divided into two daily doses. Ciclosporin may be employed either as a maintenance treatment, using long term continuous therapy, or as a short course of treatment for 4 to 12 weeks, to induce remission, which might then be repeated later following relapse. Less severe cases are best treated with intermittent therapy which causes less toxicity and side effects. Patients with the more active disease require maintenance therapy and long-term continuous ciclosporin therapy may be appropriate in a subgroup of patients; however, duration of treatment should normally be kept below 2 years whenever possible. Treatment needs to be tailored to individual patients and when long-term continuous ciclosporin therapy is necessary, annual evaluation of glomerular filtration rate may be useful to accurately monitor renal function.
The starting dose ranges from 2.5 to 5 mg/kg/day. If improvement is not apparent after 2 weeks the dose can be increased by 0.5 to 1 mg/kg/day at fortnightly intervals provided that the maximum dose rate of 5 mg/kg/day is not exceeded. Once adequate improvement has occurred either the drug can be stopped in less severe cases or the dose can be reduced in steps of 0.5 to 1 mg/kg day, at fortnightly intervals to determine the lowest dose at which adequate control of the psoriasis can be maintained. The maintenance dose required may vary over time with disease activity. The aim of maintenance treatment should not be to maintain the patient completely clear of psoriasis, but rather to keep the disease activity at a level tolerable for the patient.

Efficacy
The efficacy of ciclosporin has been demonstrated in double-blind, placebo controlled trials. The effect of the ciclosporin can be maintained by long-term treatment.
Response to cyclosporin has been reported for all the clinical variants and manifestations of psoriasis including erythrodermic psoriasis, generalised pustular psoriasis, palmoplantar pustulosis and acrodermatitis continua of Hallopeau.
Although ciclosporin is currently licensed for treatment of severe psoriasis, it has also been suggested that treatment of more moderate forms of chronic plaque psoriasis may be appropriate.

Safety and side effects
The most frequent problem requiring withdrawal of cyclosporin is renal impairment, which is related to dose and duration of treatment. Even short courses of treatment at the dose of 5 mg/kg/day may produce a measurable effect on renal function. This appears to be largely reversible provided that the recommended dose rate of 5 mg/kg/day is not exceeded and that the dose is reduced, and treatment stopped if required, to prevent the serum creatinine rising to more than 130% of baseline. After prolonged treatment nephrotoxicity will not be completely reversible. However, renal impairment does not become progressive after treatment is discontinued. Hyperkalaemia is a manifestation of renal impairment, which is occasionally problematic. Serum potassium should therefore be monitored in conjunction with the serum creatinine .
Treatment with ciclosporin results in an increase in blood pressure. Significant hypertension may develop at any time during treatment and this is probably a dose dependent effect. Hypertension resulting from ciclosporin therapy can either be treated or the dose of ciclosporin can be reduced. Nifedipine is the drug of first choice if it is considered necessary to treat hypertension. It should be noted that other calcium antagonists are known to increase the plasma level of ciclosporin.
An increase in serum bilirubin is often observed during cyclosporin treatment. Isolated increases in serum bilirubin do not usually require cyclosporin dose adjustment. Other side effects include myalgia, arthralgia, gastrointestinal disorders (nausea, abdominal pain and diarrhoea), gingival hyperplasia, headache, hypertrichosis, paraesthesiae and tremor. Nausea is most frequently encountered after the first few doses and usually resolves. Gum hypertrophy may
respond to improved dental hygiene or a reduction in dose. Hypertrichosis is often seen to some degree and may be a particular problem in female patients with dark hair. Ciclosporin can raise serum cholesterol and triglyceride levels and urate levels, and may also mildly impair glucose tolerance.
Infections, including herpes simplex, have not been a prominent problem during treatment of psoriasis. However, ciclosporin can be hazardous in patients who have suffered from hepatitis B or C.
The risk of malignancy developing as a result of long term immunosuppression is significantly increased. Although there is no doubt that the risk of diverse malignancies, including cutaneous tumours and lymphomas, is increased in transplant patients, this group undergo immunosuppression of a different order of magnitude to dermatological patients. Cutaneous malignancy may be a particular hazard because patients with psoriasis will often have received therapeutic ultraviolet irradiation. Squamous cell carcinomas have been reported in these circumstances.

Contraindications
These include patients with renal disease; hypertension; hyperlipidaemia; impaired glucose tolerance; active chronic infection or evidence of previous infection with hepatitis B or C; history of malignancy. Ciclosporin is not known to be teratogenic. Although its use cannot be recommended in pregnancy, it would seem preferable to using cytotoxic drugs, retinoids and perhaps PUVA. In the elderly, the usefulness of ciclosporin tends to be restricted by a lower renal reserve.

Drug interactions
Potassium-sparing diuretics may exacerbate ciclosporin-induced hyperkalaemia and should only be initiated with regular monitoring of U&E’s.
St Johns Wort is known to decrease ciclosporin levels. Herbal medicines may have an effect on drug levels. Avoid concomitant use.
Ciclosporin should not be taken within one hour of grapefruit juice as this increases drug absorption
Numerous drugs affect the hepatic metabolism of ciclosporin by inhibiting or inducing cytochrome P450 3A and these may reduce the efficacy or increase the toxicity of cyclosporin. Important examples of drugs inhibiting ciclosporin metabolism are diltiazem, erythromycin,
itraconazole, and verapamil. Drugs, which may induce increased ciclosporin metabolism, include carbamazepine, phenytoin rifampicin and orlistat.
It is best to avoid cyclosporin, if possible, in patients requiring any other nephrotoxic drugs, including non-steroidal anti inflammatory agents (particularly diclofenac: Half dose of diclofenac if given concomitantly). An up to date reference list, such as that found in the British National Formulary, should always be consulted when prescribing concomitant systemic medication.
Ciclosporin can increase the risk of myositis with statins. Simvastatin can be used but not more than 10mg daily.

Monitoring
Before starting ciclosporin, blood pressure should be recorded and examination performed for any evidence of lymphadenopathy, malignancy or infection. Female patients should be encouraged to attend for a cervical smear if this has not been performed within the last three years. Serum creatinine should be measured to establish a baseline. Since this may vary considerably from day to day, it is recommended that two estimations be performed, at intervals of a few days, and the mean should be used as the baseline value. A baseline creatinine clearance is useful. Other useful investigations at baseline are liver function tests, serum electrolytes and urate, fasting blood sugar and lipid levels, and urinalysis.
Blood results should be repeated fortnightly for 8 weeks after achieving a stable dose and then monthly, After a period of six months, if the ciclosporin has been well tolerated, it is possible to extend the review interval to six or eight weeks in some patients.
Serum creatinine and electrolytes should be checked at each visit. Small reductions in glomerular filtration rate (GFR) in the normal kidney are not detected by monitoring serum creatinine. However, in subjects in whom renal function is already impaired, the creatinine rises much more promptly with small changes in the GFR. This investigation is therefore most sensitive in the circumstances where it is most important. Experience in the treatment of psoriasis suggests that changes in renal function are largely reversible after stopping treatment provided that the dose is reduced as required to prevent a sustained rise in serum creatinine of more than 30%. If there is a sustained rise in serum creatinine exceeding 30% above the baseline value the dose should be reduced by 0.5 to 1 mg/kg/day and review intervals should not exceed one month. If the creatinine has risen by more than 50% larger dose reductions may be required, and if the
creatinine fails to return to within 130% of baseline consideration should be given to use of an alternative treatment. Measurement of the GFR using radioisotope excretion studies is not essential.
Blood pressure should also be monitored at each review. Fasting serum lipids should be checked on treatment. It is probably not mandatory to monitor these after the first three months. At intervals of three to six months, complete medical examination is recommended particularly to seek evidence of neoplasia.

Patient acceptability
Ciclosporin is generally well tolerated. The reduction in disease activity is often rapid. The most significant side effects, hypertension and renal impairment, are asymptomatic in the early stages and other side effects are not usually troublesome.

Synergy with other treatments
It is likely that a certain level of dose sparing can be achieved by using topical treatment concomitantly with ciclosporin. Very satisfactory control of psoriasis can be achieved, at least in some patients, using a very low dose of ciclosporin, 2 mg/kg/day. Ciclosporin can be effective with relative dose sparing in combination with methotrexate or hydroxycarbamide. Greater care with monitoring is required if combining therapies.

References
van Joost T. Bos JD. Heule F. Meinardi MM. Lowdose cyclosporin A in severe psoriasis. A doubleblind study. Br J Dermatol 1988; 118: 18390.
Ellis CN, Fradin MS, Messana JM et al. Cyclosporine for plaquetype psoriasis. Results of a multidose, doubleblind trial. N Engl J Med 1991; 324: 27784.
Ho VC. The use of ciclosporin in psoriasis: a clinical review.
Br J Dermatol. 2004 May;150 Suppl 67:1-10.
Griffiths CE, Dubertret L, Ellis CN, Finlay AY, Finzi AF, Ho VC, Johnston A, Katsambas A, Lison AE, Naeyaert JM, Nakagawa H,
Paul C, Vanaclocha F. Ciclosporin in psoriasis clinical practice: an international consensus statement. Br J Dermatol. 2004 May;150 Suppl 67:11-23.
Clark CM, Kirby B, Morris AD, Davison S, Zaki I, Emerson R, Saihan EM, Chalmers RJ, Barker JN, Allen BR, Griffiths CE. Combination treatment with methotrexate and cyclosporin for severe recalcitrant psoriasis. Br J Dermatol. 1999 Aug;141(2):279-82
Paul C, Hornig F. Risk of malignancy associated with cyclosporin use in psoriasis. Dermatology. 1999;198(3):320-1

Hydroxycarbamide (Previously known as Hydroxyurea)
Hydroxycarbamide is a second line modality for the treatment of psoriasis and has been used since 1965. It is usually reserved for cases where other second line agents have failed or are contraindicated. The dose used has generally been 0.5 to 2.0g daily, give orally either as a single dose, or divided into two doses (morning and evening). Although only a single controlled trial has been performed, it is generally considered to be effective. Hydroxycarbamide avoids the hepatotoxicity associated with methotrexate, and the nephrotoxicity associated with ciclosporin, and can therefore often be useful when other drugs are contraindicated, although it should be avoided, if possible, when renal function is markedly impaired. The main hazard is myelosuppression and careful monitoring of the full blood count is therefore required. It is recommended that the initial dose in adults should usually be 1g daily and this can be titrated, according to efficacy and toxicity, up to a maximum of 2g daily. Full blood count, including platelet and differential white cell counts, should be performed at least weekly for the first two months.

Efficacy
The use of hydroxycarbamide in the treatment of psoriasis has been confirmed in a double-blind, placebo controlled crossover trial. Each treatment period was 4 weeks, and the dose of hydroxycarbamide was 0.5g twice daily. Twelve subjects were included and 10 completed the protocol. Subjects and investigators considered that improvement had occurred during active therapy in 9 and 7 out of 10 cases respectively. Only one patient improved by either assessment during placebo treatment. The level of response was not quantified and no statistical analysis was presented.
Moschella and Greenwald reported a study in which 60 patients were treated intermittently with hydroxyurea (hydroxycarbamide), starting at the dose of 500mg twice daily. Patients who failed to respond to the initial dose were treated with 1.5g daily. During the first 6 weeks of treatment, 63% of the patients showed a good or excellent response, including some with erythrodermic and pustular psoriasis; a fair response was seen in another 10%. Patients in whom the drug was effective generally began to show some improvement within 2 to 3 weeks. In the majority of these patients the response was able to be successfully maintained by subsequent courses of treatment.
Layton et al. reported their experience of treating 85 patients, at doses of 0.5 -1.5g daily, over a period of eight years. Sixty percent of these patients cleared completely or nearly completely, and a further 20% showed partial clearance. The response was maintained in 52 by continuous therapy, for a mean of 16 months at the time of reporting. The reported duration of remission following cessation of hydroxycarbamide has varied from 24 hours to several months. Rebound of psoriasis after discontinuation has been occasionally reported.
Hydroxycarbamide has sometimes been helpful in treating generalised pustular psoriasis but results are variable.

Synergy with other treatments
Hydroxycarbamide has been used safely and effectively in combination with ciclosporin, more caution is necessary in combination with other potentially myelosuppressive drugs

Safety, side-effects and patient acceptability
The main concern regarding toxicity of hydroxycarbamide has been over myelosuppression, which may manifest as megaloblastic anaemia, thrombocytopenia or leukopenia. Haematological abnormalities are particularly frequent with this drug. Layton et al reported significant blood changes in 35% of their patients and, in one report, macrocytosis and a reduced red cell count, although not anaemia, were seen in 4 of 5 patients treated. These side effects may develop after several months of treatment. They have generally been reversible after discontinuation of the drug. Since hydroxycarbamide is largely excreted in the urine, extra caution is required if renal function is impaired. It may occasionally cause fever. Cutaneous side effects of hydroxycarbamide include partial alopecia, increased pigmentation, scaling, atrophy, nail changes, erythema of
the face and hands, and a lichenoid eruption. Hydroxycarbamide is a cytotoxic drug with potential for teratogenic effects and is best avoided in women of child-bearing age.

Monitoring
It is recommended that patients should have their full blood count, including platelet count and differential white cell count, checked prior to commencing the drug and, at least, weekly intervals for at least the first six weeks. Subsequently, the intervals between haematological assessments may be gradually extended, provided there is no cause for concern. The maximal interval should not exceed three months. Serum creatinine and liver function tests should also be monitored. It would also seem prudent to examine patients every six months for evidence of malignancy and to advise females to attend, when called, for routine cervical smears.

References
Leavell UW, Yarbro JW. Hydroxyurea. A new treatment for psoriasis. Arch Dermatol 1970; 102: 144- 50.
Moschella SL, Greenwald MA. Psoriasis with hydroxyurea. An 18-month study of 60 patients. Arch Dermatol 1973; 107: 363-8.
Layton AM, Sheehan-Dare RA, Goodfield MJ, Cotterill JA. Hydroxyurea in the management of therapy resistant psoriasis. Br J Dermatol 1989; 121: 647-53.
Lebwohl M, Menter A, Koo J, Feldman SR. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol. 2004 Mar;50(3):416-30

Fumaric acid esters (FAE)
Fumaric acid esters are marketed in Germany and constitute a mixture of dimethylfumarate and calcium, magnesium, and zinc salts of monoethyl hydrogen fumarate. As such it has to be imported and used on a named patient basis in the UK, which renders this a more expensive therapy than ciclosporine or methotrexate. It is presented as 2 strengths initial and high strength which are gradually increased within the patients’ tolerance according to the schedule summarised in the table. Dimethylfumarate (DMF), the main
ingredient of the marketed mixture, is the active compound and is now demonstrated as efficacious in a phase III multicentre trial. Although not yet commercially available this single compound has fewer side effects and will be more readily licensed as a single entity drug.
Fumarates are thought to work by shifting a Th1-type cytokine response to a Th2-type pattern whereby IL-10 inhibits Th1 cytokines IL-2 , IL-12 and IFN gamma and by inhibiting translocation of nuclear factor kappa B (NF-κB).
Patients tolerating the therapy can expect a 75% reduction in PASI in 4 months. However, all studies of the mixture of esters have a high dropout rate due to gastrointestinal complaints diarrhoea, stomach cramps and tenesmus that occur in up to 60% of patients and flushing in 30% of patients, which is worse at the onset of therapy. Headaches may be associated with sudden flushing. The frequency of flushing is greatest at the onset of therapy and decreases with prolonged treatment time. Both adverse events lead to drug withdrawal in about 7% of patients
Laboratory monitoring is required monthly particularly for lymphopenia (less than 20% of white cells) in 75% of patients is usually mild and plateaus. Transient eosinophilia is observed in 14-25% and lymphocytopenia was observed in 76%. Liver enzymes are frequently raised (25% of patients) and reverse on stopping therapy, raised cholesterol (17%), increase in triglycerides (8%), raised serum potassium (15%) and increase in serum creatinine (4%) and although proteinuria (11%) may occur there is no evidence of significant nephrotoxicity as seen with ciclosporin. There are no reports of severe long-term toxicity or development of cancer or a higher susceptibility for bacterial infections, thus making FAE a safe regimen, compared to other agents

A reduction in FAE dose is required in the following situations: decrease in leucocyte count to below 3.0 × 109/L; decrease in lymphocytes to below 0.5 × 109/L; persistent eosinophilia ≥ 25%; rise in serum creatinine 30% above baseline; development of proteinuria. If the abnormal parameter improves, treatment with FAEs can be continued at a reduced dose. In case of a persistent abnormality or a further deterioration, FAEs must be withdrawn.

References
J.J. Hoefnagel, H.B. Thio, R. Willemze, J.N. Bouwes Bavinck
Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. British Journal of Dermatology Volume 149, Issue 2, Page 363-369, Aug 2003
Mrowietz, Christophers, Altmeyer For The German Fumaric Acid Ester Consensus Conference Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. British Journal of Dermatology
Volume 141, Issue 3, Page 424-429, Sep 1999

Mycophenolate mofetil
Myconphenolate mofetil is an anti-metabolite immunosuppressive developed for organ transplantation. No randomised trials have been performed in psoriasis but several reports indicate a beneficial effect. PASI decreased within 3 weeks by 40–70% in seven of 11 patients, and by 25–39% in three of 11. It appears less efficacious than ciclosporin but can be combined with low dose ciclosporin.
Usually myconphenolate is commenced at a lower dose of 250-500mg twice daily and gradually increased to 1g twice daily. In transplantation higher doses are associated with increased toxicity but no further efficacy. Response in psoriasis does not appear to be a result of pharmacokinetic effects. Once response is observed the dose can often be reduced.
Initial monitoring is with weekly FBC for one month then fortnightly for two months and monthly thereafter. Women of childbearing potential receiving myconphenolate mofetil should be advised to use effective contraception prior to, during and for six weeks following discontinuation of therapy. Patients discovered or planning to become pregnant should be referred to the specialist at the earliest opportunity. Breastfeeding: women treated with myconphenolate mofetil should not breastfeed.
Myconphenolate interacts with cholestyramine and antacids (reduced absorption). 50% of patients experience gastrointestinal upset, nausea, cramps, diarrhoea. Rarely perforation or haemorrhage or pancreatitis occur. Bone marrow suppression is an important adverse effect with leukopenia in 5% of patients

References
E. Daudén, C. Sánchez-Peinado, D. Ruiz-Genao, M. García-F-Villalta, M.J. Onate, A. García-Díez. Plasma trough levels of myconphenolic acid do not correlate with efficacy and safety of mycophenolate mofetil in psoriasis. British Journal of Dermatology. Volume 150, Issue 1, Page 132-135, Jan 2004
C.C. Geilen, M. Arnold, C.E. Orfanos Myconphenolate mofetil as a systemic antipsoriatic agent: positive experience in 11 patients. British Journal of Dermatology
Volume 144, Issue 3, Page 583-586, Mar 2001

Azathioprine
See separate BAD guidelines on azathioprine therapy on this site

Biological interventions
See separate BAD guidelines on biological therapies including infliximab, etanercept and efalizumab on this site